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2004-9-26 0:31:00

线粒体紊乱的病理生理学研究综述

佚名

MITOCHONDRIAL DISORDERS

Biochemical Pathways
Fatty acid oxidation
Oxidative phosphorylation

Mitochondria
General features
Mitochondrial DNA (mtDNA)
General Features
Mutations
Nuclear encoded proteins
General Features
Mutations

Mitochondrial disorders
Biochemical classification
Clinical syndromes
Evaluation
Clinical Signs
Laboratory
General mechanisms
Mutation types
Mitochondrial
Nuclear encoded proteins
Functional defects
Pathology
Histology
Ultrastructure

Mitochondria: General³³

Origin of mitochondria

Primordial eukaryotic cells lacked ability to use oxygen metabolically
- Colonized by aerobic bacteria
- Intracellular aerobic bacteria
  - Added oxidative metabolism to cells
  - Evolved into mitochondria
Time: 10⁷ years ago

Structural features of mitochondria: 4 compartments

Outer membrane
Inner membrane: Composed predominantly of cardiolipin
Intermembrane space: Between outer & inner membranes
Matrix: Region inside inner membrane

Mitochondrial DNA (mtDNA)

Only organelle other than nucleus with own DNA
Different structure than nuclear DNA

Functions of mitochondria

Pyruvate oxidation: Disorders
Krebs cycle
Metaboloism: Amino acids; Fatty acids; Steroids
Generation of energy as adenosine triphosphate (ATP): Via
- Electron-transport chain
- Oxidative-phosphorylation system (Respiratory chain)
- Location: Inner mitochondrial membrane

Mitochondrial DNA (mtDNA): General features

Differences from Nuclear DNA
External link: General features
Inheritance
mtDNA variation
Mutations
Pathogenic mechanisms
Structure
Transcription & translation

Structure
- Double-stranded, circular molecule: Except for D-loop which is triple stranded (Contains extra 7S DNA)
- 16,569 nucleotide pairs
- Copies
  - 2 to 10 in each mitochondrion
  - Polyplasmy: > 1,000 in each cell
- Strands
  - Heavy (H) strand
    - Rich in guanines
    - 28 genes
  - Light (L) strand
    - Rich in cytosines
    - 9 genes: ND6; 8 tRNAs
Functions: mtDNA encodes for 37 genes
- Peptides
  - Encodes 13 of mitochondrial peptide subunits
  - All 13 peptides are in mitochondrial respiratory-chain complex (OXPHOS)
  - Remaining > 67 OXPHOS subunits are nuclear encoded
- rRNAs: 2
- tRNAs: 22; Located between every 2 rRNA or Protein coding genes
- Non coding region: Triple stranded (D) displacement-loop
  - Produced from additional synthesis of a piece of mitochondrial DNA, 7s DNA
  - Contains promoter region
    - Origins of replication for H and L strand replication
    - Contains elements for initiation of leading strand replication
- Other mitochondrial proteins encoded by nuclear DNA
- Mitochondrial genes: External link
Inheritance of mtDNA
- Maternal
  - Usual pattern
  - Sperm mtDNA is actively degraded
- Paternal
  - Transmission of mtDNA in skeletal muscle (but not in other tissues) reported³⁴: ND2 mutation
Transcription & translation of mtDNA
- Promoters: Controlled by nucleus
  - 3 Promoters
    - H1: H-strand; Produces complete symmetric transcription of heavy strand of mtDNA
    - L: L-strand; Produces complete symmetric transcription of light strand of mtDNA
    - H2: Synthesis of 2 rRNAs; Acts with factor, mTERF
  - Promoters started by: Mitochondrial RNA polymerase + Specificity factor (mtTFA)
  - Promoter location: D-loop; Only non-coding region of mtDNA
    - 7% of mtDNA length
    - Contains cis elements involved in mtDNA replication & transcription
- Transcripts: Large
  - Produced by H1- & L-strand
  - Subsequently cleaved into individual genes
Mitochondrial DNA variation
- Normal: Homoplasmy; All copies of mtDNA are identical within coding region
- Heteroplasmy: Single cells contain different mtDNA populations
  - Occurs with some mtDNA mutations
  - Due to presence of multiple mitochondria in one cell, each containing several mtDNA copies
  - Produces tissue variation
  - Post-mitotic tissues
    - Usually contain highest levels of mutated mtDNA
    - Neurons; Skeletal & Cardiac muscle; Endocrine tissue
    - Mutations in mtDNA
      - % vs normal in mtDNA can vary widely among tissues in an individual
      - Mutational loads may change over time
      - Tissues are differentially sensitive to levels of mtDNA mutations: ? Related to oxidative energy requirements
  - Pathogenic heteroplasmic mutations: Severity of related symptoms
    - Increase with higher proportion of mutated mtDNA
    - Relation to severity not necessarily linear
- Frequency of mtDNA-related disorders: 6 to 17 per 100,000 population
Differences from nuclear DNA
- No introns
- Small intergenic spacing: Coding sequences of most genes are contiguous or separated by 1 or 2 bases
- Codon sequences
  - Different start, stop & arginine, tryptophan, isoleucine
  - Some mitochondrial genes lack termination codon: Insertion of UAA at the transcriptional level instead
- Replication of mtDNA
  - Rapid rate
  - Lacks proofreading
  - Mutation rate 10 to 100x > than nuclear DNA
- Mitochondria lack an adequate DNA-repair mechanism
- Mode of inheritance: mtDNA inherited maternally
mtDNA Replication: Asynchronic & asymmetric mechanism
- DNA synthesis
  - Starts in origin of replication of heavy strand (O_H)
  - Procedes unidirectionally: To origin of replication of light strand (O_L)
    - 2/3 of way around genome
    - Between cluster of 5 tRNA genes
  - When O_L is single stranded mtDNA synthesis starts in opposite direction
- Other factors in mtDNA replication
  - Primer for H-strand replication: Small RNA synthesized from L-strand promoter
  - Transition between mtDNA replication & transcription: Produced by ribonucleoprotein, RNase MRP
  - Polymerase for mtDNA replication: DNA polymerase γ (pol γ)
  - Mitochondrial single-stranded binding protein (mtSSB)
- All factors involved in maintenance, replication & expression of mtDNA: Nuclear encoded
External links

Mitochondrial disorders: General pathogenic mechanisms⁷

Mitochondrial disorders: Mutation types
- Mitochondrial DNA (mtDNA) mutations: General features
  - Mutation effects
    - Often cause deficient function in respiratory-chain
    - Abnormal Oxidative-phosphorylation enzymes
  - Threshold effect
    - % of mutant mtDNAs must be above a threshold to produce clinical manifestations
    - % of mutant mtDNAs needed to cause cell dysfunction varies according to tissue oxidative requirements
    - Disease signs especially manifest in
      - Tissues with a high energy expenditure: Dependent on oxidative metabolism
      - Specific tissues: Brain, Heart & Muscle
    - Mitotic segregation
      - % of mutant mtDNAs in daughter cells can shift at cell division
      - Produces rapid changes of genotype that may lead to crossing of threshold
    - Skewed heteroplasmy
      - mtDNA mutation surpasses pathogenic threshold in 1 tissue
      - Examples: A3243G may produce only cardiomyopathy; Myopathy with early respiratory involvement
  - Inheritance
    - During fertilization mtDNA is derived only from the oocyte
    - Maternal inheritance: mtDNA mutations transmitted only from mother
    - Mutations transmitted to all offspring, Male & Female
    - Increased Mutant mtDNA in the mothers' blood ® Increased Frequency of affected offspring
    - Risks of having affected offspring differ between different mtDNA mutations
      - Same level of maternal mutation load ® Increased frequency of affected offspring for
        A3243G MELAS mutation compared to A8344G MERRF mutation
- Mutations in nuclear DNA coding for mitochondrial components
  - Some identified mutations cause defects in oxidative-phosphorylation
- Defects of intergenomic communication
  - Probably nuclear DNA mutations
  - Alter control of replication & expression of mitochondrial genome leading to
    - Multiple mtDNA deletions
    - Reduced amounts of mtDNA
- Mutation distribution
  - Homoplasmic: Similar distribution of mtDNA mutation in all tissues
  - Heteroplasmic: Variable distribution of mtDNA mutation in different cells or tissues
Mitochondrial gene disorders: Effects on protein synthesis
- Disorders of general protein synthesis
  - Mutations: Single deletions & point mutations in rRNA or tRNA genes
  - Clinical features
    - Typical: Multisystem disorders
    - Other: Myopathy
  - Laboratory: Lactic acidosis
  - Muscle: Mitochondrial proliferation; COX negative ragged red fibers
- Mutations in Protein-coding genes
  - Clinical syndromes: LHON; NARP/MILS; Exercise intolerance
  - Inheritance: Maternal or Sporadic
  - Mitochondrial proliferation: Absent in LHON & NARP; Present with Complex III deficiency

Mitochondrial disorders: Biochemical & Genetic abnormalities of mitochondrial function

Mitochondrial substrate transport
ATP/ADP translocator deficiency
ATPase deficiency
Carnitine-acylcarnitine translocase deficiency
Carnitine deficiency
Primary deficiency
Secondary deficiency
Carnitine palmitoyl transferase
Protein import defects
Solute carriers

Substrate utilization
Pyruvate disorders
β-oxidation defects (Fatty acid)
Ketone synthesis
HMG-CoA lyase
HMG-CoA synthase

Citric acid (TCA) cycle
Aconitase deficiency
Lipoamide dehydrogenase
Fumarase deficiency

Oxidation-Phosphorylation coupling
ATP Synthase
Luft's disease

Respiratory chain
Composition
I. NADH-CoQ Reductase
II. Succinate-CoQ Reductase
III. CoQ-Cytochrome C Reductase
IV. Cytochrome oxidase
V. ATP Synthase
Coenzyme Q₁₀
mtDNA mutations
Intergenomic communication
Multiple mtDNA deletions
mtDNA depletion
Nuclear gene defects
Tissue-specific
Generalized
Succinic dehydrogenase

Nuclear gene defects

TCA cycle

Mitochondrial disorders: mtDNA mutations

mtDNA: General disease features
- Lactic acidosis
- Mitochondrial proliferation in muscle
  - Massive
  - Produces ragged-red fibers
    - Mutant mtDNAs accumulate preferentially in ragged-red fibers
    - Ragged-red fibers are typically negative for cytochrome c oxidase activity
- Genetics
  - Relatively few mutations in rRNA genes: All confined to 12s RNA
  - Heteroplasmy: Pathogenic threshold of mtDNA mutations
    - Phenotype changes when threshold in a previously unaffected tissue is surpassed
    - Threshold for disease is lower in tissues highly dependent on oxidative metabolism
      - Brain, Heart, Skeletal muscle, Retina, Renal tubules, Endocrine glands
Point mutations in mtDNA
- Many different point mutations identified in mtDNA
  - Most in tRNA genes
    - Hot spots: mtRNA^{Leu [UUR]} ; mtRNA^Ile
  - Skeletal muscle restricted mtDNA point mutations
    - Associated with 652 base pair duplication in D-loop (control region) of mtDNA⁴³
  - External links
    - Missense mutations
    - rRNA or tRNA mutations
- Clinical: Point mutations associated with wide variety of syndromes
- Gene types with point mutations
  - Genes needed for mitochondrial protein synthesis
    - Usually tRNA genes
    - Mutations generally impair mitochondrial protein synthesis
    - Mutations produce defects in all respiratory chain complexes except Complex II (Nuclear encoded)
  - Genes encoding proteins
    - Respiratory chain subunits
    - Mutations produce defects in single respiratory chain complex
- Example of tRNA mtDNA gene mutation: A-to-G mutation at nucleotide 3243 (A3243G)
  - Most frequent mtDNA mutation
    - > 16/100,000 in the adult population (Finland)
  - Varied clinical presentations
    - Leigh syndrome
    - MELAS
    - Oligosymptomatic
      - Systemic: Diabetes, Short stature, Pigmentary retinopathy
      - Neural: Migraine, Hearing loss, Cognitive decline,
        Occipital infarction (Young patients)
  - Higher levels of mutated mtDNA: More severe disease
    - Leigh > MELAS > Oligosymptomatic
- Example of mutation in protein encoding mtDNA gene: Nucleotide 8993 in gene for ATPase6, T-to-G & T-to-C
  - General correlations
    - 8993C clinically milder than 8993G
    - Mutant loads: Similar in Different fetal and adult tissues; No age-related variation
    - Greater Median % mutant load with Increased Severity of symptoms.
    - Threshold effect: Severe symptoms Increased when mutant load reaches
      - 60% to 70% for 8993G mutation
      - 80% to 90% for 8993C mutation
    - Disturbs H⁺-translocating, membrane spanning F₀ region of ATPase complex
  - Syndrome correlations
    - NARP with intermediate levels of mutated mtDNA
    - Maternally inherited Leigh's Syndrome with high (> 95%) levels of mutated mtDNA
Deletions and duplications of mtDNA occur.
- Features
  - Single deletions are usually
    - Large
    - Involving both tRNA and Protein encoding mitochondrial genes
  - 50% of patients with single deletion share common mutation
- Clinical associations
  - Single large deletions are associated with Kearns-Sayre, Ocular Myopathy (sporadic) and Pearson's syndrome.
  - MNGIE & Leigh syndrome also have mtDNA deletions.
  - Multiple different mtDNA deletions occur in individuals with Autosomal dominant PEO, Inclusion body myositis, & Normal aging.
  - Tissue dysfunction
    - Correlates better with number of deleted mtDNA molecules
    - Less correlation with location or size of deletion in mtDNA
  - Inheritance
    - Deletions: Usually sporadic
    - Duplications: May be maternally inherited
- mtDNA changes
  - DNA break points differ in disorders with single or multiple DNA deletions.
  - Patients with mtDNA deletion also often have mtDNA duplication
    - Duplication corresponds mtDNA in deleted region
Quantitative loss of entire mtDNA molecules occurs in some syndromes.
- mtDNA regulation
  - Nuclear transcription factor (NRF-1) : Interacts with several nuclear genes encoding mitochondrially-destined proteins
  - Levels of mitochondrial DNA can be regulated by one of these proteins, mitochondrial transcription factor (mtTFA) .
- Disorders
  - Inherited mitochondrial deletion disorders: Usually autosomal recessive
  - Toxins may also cause mtDNA depletion: AZT

Specific disorders with mtDNA mutations

mtDNA Point mutations
Cardiomyopathy
Leber's optic neuropathy
Leigh's syndrome
MELAS
MERRF
NARP/MILS

Single deletion or duplication
Ataxia, Leukodystrophy
Diabetes: Maternal inheritance
Kearns-Sayre
Pearson's
PEO: Sporadic

Multiple deletions
Aging
Myositis
Inclusion body
COX- muscle fibers
MNGIE
PEO
Wolfram

Depletion of mtDNA
Infantile myopathy
Fatal
"Later-onset"
AZT treatment

Several types of mtDNA defect
Deafness
Diabetes
External ophthalmoplegia (PEO)
Sporadic
Maternal
Dominant
Recessive
Leigh's
Myopathy
Rhabdomyolysis
Sensory neuropathy
Systemic disorders

Intense SDH staining
of a muscle fiber with
mitochondrial proliferation

Nuclear encoded mitochondrial proteins

General features
- Synthesized in cytoplasm
- Imported into mitochondria
- Respiratory chain molecules targeted to inner mitochondrial membrane
- 67 nuclear encoded proteins in respiratory chain
- ~ 1,000 mitochondrial peptides not involved in the respiratory chain
Nuclear mutations causing Mitochondrial disorders
- Inheritance: Dominant or Recessive
- Respiratory chain elements: Structural
  - Mutations found only in complexes I & II: ? Complex III-V mutations lethal
  - Clinical associations of mutations
    - Severe neurologic disorders of childhood: Leigh’s syndrome; Leukodystrophy
    - Neoplasms: Paraganglioma; Pheochromocytoma
- Ancillary proteins of respiratory chain
  - May cause defects in Complexes III & IV: Ancillary proteins needed for assembly or insertion of cofactors
  - Disorders may be tissue specific
    - SURF1: Brain (Leigh’s syndrome)
    - SCO2 & COX15: Infantile cardiomyopathy & brain disease
    - COX10: Kidney disease
    - SCO1: Liver disorders
- Defects in intergenomic signalling: Mutations affect mtDNA quantitatively or qualitatively
  - Quantitative: mtDNA depletion syndromes
  - Qualitative
    - Multiple mtDNA deletion syndromes
    - Syndromes: Ophthalmoplegia +...; MNGIE
- Other mitochondrial defects
  - Mitochondrial membrane structure: Barth syndrome
  - Mitochondrial protein importation: Deafness-Dystonia syndrome
  - Mitochondrial motility: Optic neuropathy
  - Neurodegenerative disorders: Friedreich ataxia; Spastic paraparesis (7; 13); Wilson's
- Non-human changes: Mutations often found in highly conserved subunits also found in simpler complex I in yeast
- Mitochondrial disorders with nuclear mutations
  - Myopathies
  - Encephalopathies
    - Leigh: SURF-1; NDUFS7; NDUFS8; NDUFV1; SDHA; Pyruvate carboxylase; PDHC
    - Infantile
    - Wilson's disease : ATP7B
    - COX10
    - Deafness-Dystonia syndrome: DDP protein
  - Other systemic disorders
    - Cardiomyopathies: SCO2
    - DIDMOAD
    - Friedreich ataxia
    - HHH syndrome
    - Optic neuropathy
    - Paraganglioma
    - Sideroblastic anemia & Ataxia
    - Spastic paraparesis: 7; 13
    - Stuve-Wiedemann syndrome
    - Triosephosphate isomerase
  - Mitochondrial disorders due to mutations in non-mitochondrial proteins
    - MNGIE: Thymidine phosphorylase
    - Huntington's disease: Huntingtin
- Nuclear genes affecting multiple mitochondrial enzymes
  - Lon proteases
  - Import proteins
    - Deafness-Dystonia syndrome: DDP protein
    - Infantile encephalopathy: Chromosome 2p14-p13
  - mtDNA Depletion syndromes

General clinical features of mitochondrial disorders

Onset
- Infancy: Infantile with COX- Fibers; Encephalopathy; Leigh's
- Childhood
- Adult: CNS; PEO
CNS
- Ataxia: MELAS, MERRF; NARP; Deafness; Leukodystrophy; Leigh's; HAM; Friedreich ataxia
- Seizures: MELAS; MERRF; MILS
- Movement disorders
  - Myoclonus: MERRF; HAM
  - Dystonia: MELAS; Leber's; Deafness-Dystonia
- Spinal
- Migraine: MELAS; Myopathy
- Cognitive disorders
  - Striatal necrosis: ATPase 6 (Leigh's) mutation
  - Retardation: Leigh's, Maternal (MILS)
  - Psychomotor regression: MELAS; Kearns-Sayre; Infantile encephalopathies
  - Dementia: MELAS; MERRF; Kearns-Sayre; PEO 3; Cytochrome b; ND3
  - Episodic encephalopathy: MELAS; MERRF; Myopathy; Infantile; Leigh's
- Septo-optic dysplasia
Myopathy
- Weakness
- Rhabdomyolysis: Recessive syndromes
- Fatigue: Associated with high serum lactate at rest in PEO
Polyneuropathy
- Mitochondrial DNA: NARP; MNGIE; MERRF; Myopathy + Diabetes
- Autosomal: HADHA; CMT 2A (MFN2); Friedreich ataxia; SCO2 (Motor); POLG1; Sensory ataxic; Alpers-Huttenlocher
Autonomic: MNGIE; Wolfram
Ophthalmologic
- Ophthalmoplegia & Ptosis: Kearns-Sayre; External ophthalmoplegia (PEO); MELAS (Rare); MNGIE
- Visual loss
  - Cortical: MELAS
  - Pigmentary retinopathy: Kearns-Sayre; NARP; MNGIE; Leigh's; MELAS
  - Optic neuropathy: Leber's; OA1, Dominant; NARP; Leigh's
Hearing loss: Kearns-Sayre; Other
Systemic
- Short stature: MELAS; MERRF; Kearns-Sayre
- Diabetes
- Heart
  - Conduction block: Kearns-Sayre
  - Cardiomyopathy
- Gastrointestinal
  - Pseudoobstruction: MELAS; Cartilage-Hair hypoplasia
  - Hepatic failure, infantile: SCO1
Neoplasms
- Paraganglionoma: SDH subunits B, C, D
- Leiomyomatosis: Fumarate hydratase
- Renal cell cancer: Fumarate hydratase
- B-cell lymphoma: BCL2 overexpression

Laboratory evaluation of mitochondrial disorders

Lactate & Pyruvate
- Source
  - Arterial better than venous
  - CSF may be abnormal when blood normal
- Usually elevated in children
- Lactate/Pyruvate ratio
  - High (> 50:1): Suggests metabolic block in respiratory chain
  - Normal: Metabolic block is upstream, e.g. Pyruvate dehydrogenase complex
- High lactate at rest in PEO
  - Rare with pure CPEO
  - Common (80%) with A3243G and A8344G mutations
  - Suggests fatigue is likely
- Normal values do not exclude mitochondrial disorders
  - Examples: NARP; MILS
Serum CK
- Usually: Normal or Mildly elevated
- High: Chronic progressive external ophthalmoplegia (CPEO) & Ptosis; Limb weakness
- Very high: Mitochondrial DNA depletion
Muscle biopsy: Distinctive features
- Stains
  - Succinate Dehydrogenase (SDH)
    - Most sensitive & specific stain for mitochondrial proliferation in muscle fibers.
  - Trichrome stains: Much less specific & sensitive for mitochondrial proliferation than SDH.
  - Cytochrome Oxidase (COX) stain identifies additional patients with mitochondrial disorders
    - Absent or reduced staining of muscle fibers
    - No mitochondrial proliferation
- Increased SDH staining of muscle fibers
  - Specific confirmation of mitochondrial dysfunction & proliferation
  - Muscle fibers: Mitochondrial proliferation
  - Strongly SDH reactive blood vessels: MELAS
  - SDH positive (Ragged red) muscle fibers with prominent lipid accumulation: Coenzyme Q₁₀ deficiency
- COX stain changes
  - Scattered COX- fibers ± Ragged red fibers: Suggests
    - mtDNA mutation affecting mitochondrial protein synthesis
    - Mutations in COX I, COX II, or COX III genes
    - Heteroplasmic mutation
  - Muscle fibers with both COX-positive & Increased SDH staining : Suggests specific mutations
    - MELAS: Many SDH+ fibers are COX+
    - Mutations in mtDNA protein encoding genes, except COX genes
      - Cytochrome b: All SDH+ fibers are COX+
      - ND genes
    - See: Pathology
  - COX reduction: Diffuse, severe, Sparing Spindles & Smooth muscles of vessels
    - Fatal or benign infantile myopathy
    - Homoplasmic mutation
  - COX reduction: Diffuse, moderate, including Spindles & Smooth muscles of vessels
    - Leigh syndrome with COX deficiency
  - Ragged red COX- fibers with reduced immunocytochemical detection of cytochrome oxidase II
    - Suggests mutations affecting mitochondrial protein synthesis generally
  - Reduced mtDNA-encoded COX subunits I and II in COX-deficient muscle fibres: mtDNA mutations
  - Reduction of all COX subunits in all muscle fibers: ? Nuclear mutations
- Inflammation: Inclusion body myositis; PM/COX-
- Electron microscopy: Not specific; Not helpful in differential diagnosis
- Also see: Mitochondrial pathology
Neuroradiology
- Bilateral signal intensities in putamen, globus pallidus, & caudate: Leigh's
- Strokelike lesions in posterior cerebral hemisphere: MELAS
- Diffuse signal change in central white matter: Kearns-Sayre
- Basal ganglia calcifications: Kearns-Sayre; MELAS
Biochemistry
- Muscle preferable to cultured fibroblasts
- Fresh muscle preferable to frozen
- Combined partial defects of respiratory enzymes containing mtDNA-encoded subunits: Suggests mtDNA mutations
- Can be normal in mtDNA defects
Molecular genetics: Mutation screening
- Positive result: Confirms diagnosis
- Screen for most common mutations associated with syndrome
  - e.g. MELAS A3243G then T3271C
- Blood DNA: Adequate for
  - Point mutations in tRNA genes: MELAS; MERRF
  - Some mutations in structural genes: NARP; Lebers
  - Single large mtDNA deletions with systemic disorders: Kearns-Sayre; Pearson
- Muscle DNA: Required for
  - Multiple deletions
  - Single mtDNA deletions in PEO & other localized disorders
  - MELAS point mutation in oligo- or asymptomatic relatives
  - Some point mutations in structural genes
Treatment
- Aerobic training
  - Exercise tolerance: Increased
  - Serum lactate: Reduced
- ? Dichloroacetate: MELAS

MITOCHONDRIAL DISORDERS: CLINICAL SYNDROMES

Adult onset
Alexander disease: NDUFV1; 11q13
Alzheimer/Parkinsonism
Amino Acid disorders: Nuclear mutations
Ataxias
Barth: Tafazzins; Xp28
Cardiomyopathy
Carnitine disorders
Cartilage-Hair hypoplasia
CNS
Infantile & Childhood onset
Syndromes
Congenital muscular dystrophy: Nuclear mutation
Cramps
Deafness
Maternal (mtDNA): Point mutations
Syndromic (HAM; MELAS; MERRF): tRNA
Non-syndromic & amino-glycoside induced: 12s rRNA
Nuclear mutations
DIDMOAD: WFS1; 4p16
Deafness-Dystonia: DDP protein; Xq22
Diabetes
Dystonia
Encephalopathies
Fatigue & Exercise intolerance
Friedreich ataxia: Frataxin; 9q13
Functional defects
Gastrointestinal
HAM: mtDNA tRNA Ser
Huntington's chorea
Infantile CNS: mtDNA & Nuclear mutations
Kearns-Sayre: Single mtDNA deletion
Leber's optic neuropathy: mtDNA NADH-Dehydrogenase +
Leigh's syndrome: mtDNA & Nuclear mutations
Leukodystrophy
Longevity
Maple syrup urine disease
MELAS: mtDNA tRNA Leu + other
Menkes: ATPase 7a; Xq12
MERRF: mtDNA tRNA Lys & Ser
MNGIE: Thymidine phosphorylase; 22q13
Multiple symmetric lipomatosis: mtDNA tRNA Lys & Nuclear
Myalgias
Myoglobinuria

Myopathy syndromes
Infantile myopathies
Fatal: mtDNA depletion
"Later-onset": mtDNA depletion
Inflammatory myopathy
Inclusion body myositis: Mpl mtDNA deletions
mtDNA depletion: "Later-onset"
PM + COX- muscle fibers: Mpl mtDNA deletions
NARP/MILS: mt ATPase6
Neoplasms
Neuropathy syndromes
CMT 2A (MFN2)
Sensory neuropathy: Recessive; Sporadic
Occipital horn syndrome: ATPase 7a; Xq12
Ophthalmoplegia, External (PEO)
Dominant: Multiple mtDNA deletions
Maternal: mtDNA point mutations
Recessive: mtDNA depletion; Multiple mtDNA deletions
Sporadic: Single mtDNA deletion
? Immune (HyperThyroid)
Optic atrophy
Paraganglioma
PGL1: SDH Subunit D; 11q23
PGL3: SDH Subunit C; 1q21
PGL + Pheochromocytoma: SDH Subunit B; 1p36
Parkinson's
Pearson's: mtDNA deletion
Rhabdomyolysis: mtDNA
Selenium deficiency
Spastic paraparesis
SPG7: Paraplegin; 16q24
SPG13: HSPD1; 2q24
HHH: Ornithine transporter; 13q14
Spinal muscular atrophy: TK2; 16q22
Stuve-Wiedemann syndrome: 1p34
Sudden infant death (SIDS): mtDNA tRNA Leu
Systemic disorders
Toxic
AZT (Zidovudine)
Copper
Germanium
Valproate: Precipitates seizures in MELAS
Wilson's disease: ATPase 7B; 13q14
Wolfram
WFS1; 4p16
WFS2; 4q22

Classifications of Mitochondrial Disorders
Biochemical
Clinical
Genetic: mtDNA; Nuclear

NARP

(Neuropathy; Ataxia; Retinitis Pigmentosa)

Clinical features
- Sensory neuropathy
- Cerebellar ataxia
- Retinitis pigmentosa
- CNS
  - Dementia
  - Seizures
  - Developmental delay
- Proximal weakness
- Serum lactate: Normal
Inheritance: Maternal
ATPase 6 (Complex V)
- mtDNA point mutations: nt-8993
- Same mutation in maternally inherited Leigh's syndrome & some Kearns-Sayre
- % of abnormal mtDNA: Correlates with clinical severity
  - 70% to 80%: Associated with NARP syndromes
  - > 90%; Leigh's syndromes (MILS) & more clinical severity
- Other mutations in same gene (nt-8851 & nt-9176)
  - Striatonigral degeneration, infantile, mitochondrial
    - Also see: Familial bilateral striatal necrosis, autosomal recessive (19q13)
Pathology: No ragged red fibers

MELAS

(Mitochondrial Encephalomyopathy; Lactic Acidosis; Stroke)

Inheritance
- Maternal
- Occasional sporadic & non-inherited mutation (tRNA Leu)
- Clinical heterogeneity
  - Rare to find more than 1 fully expressed MELAS in same family
  - Maternal relatives often oligo- or asymptomatic
mtDNA point mutations
- Heteroplasmic: Mutant mtDNA proportion ~ 56% to 95%
- Genes
  - tRNA Leu (common)
    - A3243G mutation: 80% of MELAS syndromes
    - Other MELAS mutation loci: T3271C has later age of onset; 3291
    - Other syndromes with tRNA Leu mutations
      - Riboflavin sensitive myopathy (T3250C)
      - Isolated cardiomyopathy (A3243G; A3260G)
      - Diabetes (A3243G; C3256T)
      - Sudden infant death (SIDS)
      - MERRF-like with diabetes, optic neuropathy & retinopathy (C3256T)
      - Fatigue
      - Rhabdomyolysis (A3243G)
  - tRNA Leu 2 (MTTL2; CUN) : Also cardiomyopathy, PEO, sideroblastic anemia
  - Cytochrome c Oxidase (Subunit 3 of Complex IV) : COX reduced; Few SDH + fibers
  - tRNA Val (G1642A) : Also Leigh syndrome
  - tRNA Ser : MERRF/MELAS overlap
  - tRNA Phe (G583A) : Also myoglobinuria
  - tRNA Lys (T8316C) : MERRF with other mutations
  - tRNA His (T12417G)
  - tRNA Gln (A4332G) : Atypical MELAS syndrome with deafness
  - MTND5 (Complex I): MELAS + Leigh syndromes
  - MTND6 (Complex I): LHON is most common phenotype; Occasional early onset MELAS
  - Cytochrome b (Complex III): Myopathy is most common phenotype; Occasional MELAS
- Genetic counseling: A3423G mutation
  - % of affected offspring: Increased with higher mutant load in maternal blood
  - Mutant load 1% to 19%: 20% chance of affected offspring
  - Mutant load > 20%: 50% chance of affected offspring
  - Full expression of phenotype in multiple family members: Rare
  - Partial expression in multiple family members: Common
Clinical Syndrome
- Onset
  - Mean = 10 years; Range = 2 to 40
  - Migraine-like attacks: Headache & Vomiting
  - Hearing loss
  - Occasional seizures
- Encephalopathy: Often episodic
  - Generalized
    - Headache & vomiting (90%)
    - Loss of consciousness (85%)
    - Seizures (85%): May be precipitated by Valproate
    - Dementia or mental retardation (50%-60%)
  - Focal events ("Strokes")
    - Onset
      - Typical: < 15 years
      - Usual: < 40 years
      - Some up to 63 years
    - Distribution: Do not conform to single vascular territories
    - Cortical visual defect
      - Often 1st focal manifestation
      - Occipital blindness or hemianopia
    - Hemiplegia
    - Associated with
      - Neuronal hyperexcitability: Focal epileptiform discharges in acute period
      - Basal ganglia calcifications
    - MRI
      - T1-weighted hyperintense cortical signal
      - Compatible with cortical laminar necrosis & cytotoxic edema
      - Distribution: Do not conform to single vascular territories
      - Reduced diffusion
  - Hearing loss (25%)
- Systemic features
  - Pigmentary retinopathy (10% to 40%): More common in symptomatic relatives
  - Cardiomyopathy (15%)
  - Short stature
  - Diabetes: May occur as isolated syndrome
- Myopathy
  - Exercise intolerance
  - Weakness: Proximal; Symmetric
- Mean life span with full clinical syndrome ~ 2 to 4 decades
  - Causes of death: Cardiopulmonary failure; Status epilepticus; Pulmonary disease
Laboratory
- Lactic acidosis: Blood & CSF
- EMG: Mormal or Myopathic
- MRI: Strokes
  - Multifocal, mainly cortical lesions
  - Lesions not confined to vascular territories
- Biochemistry
  - Respiratory chain dysfunction
  - Reduced activity of Complexes I & IV
- Pathology⁶
  - Muscle
    - Ragged red fibers (RRF): COX +; SDH +
      - Few RRF in cytochrome c mutation
    - Mitochondrial proliferation in blood vessels
  - CNS
    - Abnormal cellular metabolism
    - Mitochondrial capillary angiopathy: CNS ± Heart
    - ± Changes in larger vessels: ? Endothelial pathology
    - Regional changes
      - Basal ganglia calcification: 26%
      - Cerebral: Focal necrosis; Cortical atrophy; White matter gliosis
      - Cerebellum: Cortical atrophy; White matter gliosis;
        Purkinje dendrite cactus formations with increased mitochondria (60%)
    - Possible mechanisms of damage
      - Ischemia 2° mitichondrial angiopathy
      - Cytopathy 2° mitochondrial dysfunction
Possible treatments⁴⁴
- Dichloroacetate: Headache, Abdominal pain, Weakness, Stroke-like episodes
- L-arginine (0.5 g/kg): For acute stroke-like episodes

MERRF

(Myoclonic Epilepsy; Ragged Red Fibers)

Inheritance: Maternal
mtDNA point mutations: Heteroplasmic
- tRNA Lys : A8344G (Frequent); T8356C; G8363A; G8361A
  - Syndromes: MERRF or MERRF/MELAS overlap
- tRNA Ser
  - Syndromes: MERRF/MELAS overlap; Epilepsia Partialis Continua; HAM
- tRNA Leu
Onset: Late adolescence - Early adult
Clinical syndrome: Also see HAM syndrome
- CNS
  - Myoclonus (60%)
  - Epilepsy (45%)
  - Cerebellar dysfunction: Ataxia
  - Dementia
  - Optic atrophy (20%)
- Polyneuropathy (20%)
  - Distal sensory loss (large fiber modalities)
- Hearing loss (40%)
- Myopathy
- Short stature (10%)
- Lipomata (10%)
Genetic counseling: G8344A mutation
- Mutant load < 35% in maternal blood: Transmission risk < 5%
- Prognosis: Related to mutant load in blood
Laboratory
- Lactic acidosis: Variable
- Pathology of muscle
  - Ragged red fibers: COX -
Other mitochondrial tRNA Lys syndromes
- Cardiomyopathy (G8363A)
- PEO with myoclonus (G8342A)
- Deafness & Diabetes (A8296G)
- Multiple Symmetric Lipomatosis (A8344G)
- Leigh syndrome (A8344G)
- MELAS
- MNGIE (G8313A)

MNGIE¹⁰

Also see: Neuro-Gastro-intestinal variants

(Myopathy and external ophthalmoplegia; Neuropathy; Gastro-Intestinal; Encephalopathy)
l Thymidine phosphorylase

; Chromosome 22q13.32-qter; Recessive

Thymidine phosphorylase genetics: MNGIE
- Types
  - Missense mutations most common
  - Occasional insertions, deletions or splice acceptor change in intron
  - Location
    - > 12 Different mutations identified
    - More than 1 family with A3371C, G1419A
    - More in Exons 4 & 7
- Loss of function of thymidine phosphorylase: Measured in leukocytes
  - MNGIE patients: All have absent, or nearly complete loss of, TP function
  - Carriers: ~ 35% of normal activity; Range 15% to 60%
Thymidine phosphorylase protein (Endothelial cell growth factor, platelet derived)
- Catalyzes phosphorolysis of thymidine to thymine & deoxyribose 1-phosphate
- Plays role in homeostasis of cellular nucleotide pools
- ? Has angiogenic effects
Clinical features: Homogeneous
- Onset
  - Age: Usually < 20 years (75%); Range 5 mo to 43 years
  - Signs: Gastric dysmotility (45%); Extraocular (26%)
- Visceral neuropathy (100%)
  - Diarrhea
  - Obstipation
  - Episodic intestinal pseudo-obstruction & Gastroparesis
    - Nausea
    - Vomiting
    - Weight loss
    - Malabsorption
  - Borborygmi 96%
  - Early satiety
  - Diverticulae: In duodenum & jejunum
- Ocular
  - External ophthalmoplegia (100%)
  - Ptosis (100%)
  - Retinal degeneration (6% to 25%)
- Musculoskeletal
  - Thin body habitus & Cachexia: Weight loss (100%)
  - Short stature (70%)
- Neuropathy (87%)
  - Sensory predominant: Distal loss; Pain
  - Weakness
    - Distal: Early
    - Proximal with disease progression
    - Symmetric
  - Areflexia (45%)
  - Axonal loss
  - Demyelinating features: Some patients³⁸
    - Conduction velocity: Reduced (<80% of lower limit of normal)
    - Conduction block & temporal dispersion in some patients
  - Course
    - Progression over months
    - Spontaneous fluctuations may occur
- CNS
  - Hearing loss (60%)
  - Cognition: Normal intelligence; No dementia
  - Leukoencephalopathy (100%): Increased T2 signal on brain MRI
- Disease course: Early death, Mean 38 years, Range 18 to 53 years
Lab
- Serum
  - Lactic acidosis (64%)
  - Plasma thymidine levels: Increased 20-fold
  - Plasma deoxyuridine levels: Increased
- Abnormal EKG (18% to 35%)
- CSF: High protein (89%)
- EMG
  - Neurogenic only: 61%
  - Neurogenic + Myogenic: 39%
- Muscle pathology
  - Mitochondrial changes in muscle fibers
    - Mitochondrial proliferation
    - COX - fibers (90%)
    - SDH + fibers (60%)
    - Oxidative enzyme levels: May be normal
    - Eye muscles: Myopathic changes
  - Neurogenic changes
- mtDNA³⁵
  - Multiple deletions without duplications (62%)
    - Microdeletions occur at
      - Imperfectly homologous breakpoints (Similar but not identical mtDNA sequences)
      - Perfect direct sequence repeats
    - Five major species of mtDNA deletions
    - Hot-spot for mtDNA rearrangements
      - Nicotinamide adenine dinucleotide dehydrogenase 5 (ND5) gene
      - Occurs in 4 of 5 species of deletions
    - Deletions in tissue: Most prominent in skeletal muscle; Not present in intestine
  - Somatic point mutations: High frequency of 5’-ATT to 5’-GTT
  - mtDNA abnormalities may be produced by
    - Increased intracellular Thymidine & Deoxyuridine that may cause
    - Imbalances of mitochondrial nucleotide pools
    - Homologous recombination
  - mtDNA depletion: Variable
    - 6% to 20 % of normal total mtDNA, especially in liver
    - ? Secondary to mtDNA point mutations & multiple deletions
- Biochemistry: Thymidine phosphorylase activity < 5% of normal in leukocytes
MNGIE variant: MNGIM syndrome without encephalopathy³⁶
- Genetics: No thymidine phosphorylase or dNT-2 mutations
- Onset: 2nd decade
- Clinical
  - Gastrointestinal malabsorption
    - Diarrhea
    - Borborygmia,
    - Abdominal pain
    - GI pseudo-obstruction
    - Weight loss
    - Parenteral nutrition eventually needed
  - Eye
    - Ophthalmoplegia
    - Ptosis: Mild
  - Weakness
    - Diffuse
    - Associated with cachexia
  - Polyneuropathy
    - Pain
    - Gait disorder: Sensory ataxia
    - Axonal loss: Sensory > Motor
  - CNS: Normal
  - Disease course: Death in 4th decade
- Laboratory
  - Serum CK: Normal
  - Serum Lactate: Normal
  - Plasma thymidine: Normal
  - CSF protein: High
  - MRI: Normal brain
- Muscle
  - COX negative muscle fibers: 5%
  - Raged red fibers: Occasional
  - Complex I–IV activities: 24% of normal
MNGIE variant: POLG mutation
MNGIE variant: Neurogastrointestinal syndrome
l mtRNA Trp ; Sporadic
- Mutation
  - G5532A
  - Heteroplasmic
  - Present in all tissues: Highest in muscle (92%)
  - Low levels of mutation (7% to 9%) found in patient's unaffected mother & brother
- Clinical
  - Onset
    - Age: 1 year
    - Early: Recurrent vomiting; Failure to thrive
  - Later features
    - Leg discomfort
    - Eye: Ptosis, Ophthalmoplegia, Pigmentary retinopathy, Constricted visual fields, Blindness
    - Ear: Sensorineural deafness
    - Muscle: Wasting
    - CNS: Cognitive regression, Seizures
    - GU: Incontinence
    - GI: Feeding difficulties; Constipation; Diarrhea; Colitis
    - Skeletal: Short stature
- Muscle
  - SDH positive fibers: COX-negative & -positive
  - Complexes I & IV: Reduced activity (< 20% of normal)
  - COX- fibers have highest levels of mutation
- Laboratory
  - Lactate: High in Blood & CSF
  - MRI of brain: General atrophy; Periventricular white matter changes

LHON ³⁰

(Leber's; Hereditary; Optic; Neuropathy)

Genetic-Clinical correlations: Maternal Inheritance
- Recurrence risks: Brother 30%; Sister 8%; Nephew 46%; Niece 10%; Male cousin 31%; Female cousin 6%
- 40% of patients with commonest mutation (G11778A) have negative family history
- Large families with maternal inheritance: G11778 & T14484C mutations
Genetics: Many different mtDNA point mutations
- Each mutation has a characteristic clinical manifestation in terms of degree of severity
- Manifestations of severity include
  - Penetrance
  - Dependence on a secondary mtDNA mutation for clinical expression
  - Tendency to recover from episodes of visual loss (4% to 40%)
  - Extraocular neural involvement
- Mutations
  - General
    - 3 Mutations account for 96% of cases
      - All in Complex I genes
      - Mutations: G11778A (69%), G3460A (13%), T14484C (14%)
    - Mutation pattern
      - Most patient's mutations are homoplasmic
      - Some patients in each family may be heteroplasmic
  - NADH-Dehydrogenase Subunit 4 (MTND4) : Complex I
    - Mutation: G11778A
      - Missense: R340H
      - Most common LHON mutation
      - Mutation load in an individual's blood: Correlations
        
        Higher mutation load: Frequency of blindness in males greater
        Frequency of clinically affected sons: Related to mutant mtDNA in mother's blood
        
        Mothers with < 80% less likely than Mothers with 100%
        
        Changes in mutation load from one generation to the next
        
        Largely determined by random genetic drift
      - Clinical features
        
        Most severe syndrome
        No light perception
        Visual recovery in 4% after 36 months
        May have associated adult-onset ataxia syndrome
  - NADH-Dehydrogenase Subunit 1 (MTND1) : Complex I
    - Mutation: G3460A
      - Missense: A52T
      - Moderate severity
      - Recovery in 22%
  - NADH-Dehydrogenase Subunit 6 (MTND6) : Complex I
    - Mutation: T14484C
      - Missense: M64V
      - Best prognosis
      - Recovery in 37% at 16 months
    - Mutation: A14495G¹¹
      - Heteroplasmic
      - Onset: 17 to 30 years
      - Improvement in visual acuity after event in some patients
    - Other mutations causing LHON ± Dystonia
      - G14459A/A72V; C14482G/M64I; C14498T/Y59C; C14568T/G36S; T14596A/I26M
      - Hotspot in hydrophobic cleft
  - Other mutations
    - NADH dehydrogenase (Subunits 1 , 2 , 4 , 5 , or 6 ); Complex I
    - Cytochrome c Oxidase (Subunits 1 or 3 ); Complex IV
    - Cytochrome b; Complex III
    - ATP Synthase; Complex V
Clinical features: General
- Male predominance
  - No relation to any X-linked genes
- Onset
  - Midlife: Mean 30 years; Range 1 to 70
  - Visual loss
- Visual loss
  - Clinical features
    - Painless
    - Visual loss pattern
      - Central or Ceco-central
      - May extend to periphery
    - Severity: May deteriorate to 20/200 or less
    - Progression: Mean 4 months; Range 1 to 24 months
    - Interval between eyes affected: ~ 2 months
    - Tendency to recover depends on mutation
    - Pupillary reactions: May be relatively spared for degree of visual loss
  - Ocular pathology
    - Early
      - Disc microangiopathy
      - Pseudo disc edema
      - Vascular tortuosity
    - Late: Optic atrophy
- Other features: Some families
  - Cardiac conduction defects: Pre-excitation syndromes
  - Spastic dystonia: Complex I, Subunit ND4 (MTND4)
  - Dystonia: NADH-Dehydrogenase Subunit 6 (MTND6, Complex I)
  - Other CNS: Multiple sclerosis-like disorder; Encephalopathy
Laboratory
- Muscle pathology: No ragged red fibers
- MRI: Optic nerve may enhance on T2 weighted images

Kearns-Sayre Syndrome

Family history
- Sporadic: Most patients
- Familial cases: Rare; Mother to offspring³⁷
Genetics
- mtDNA mutation types
  - Single large mtDNA deletion (2 to 8 kb)
    - Most common mutation type (80%)
    - Identical deletions in Pearson syndrome & PEO
    - Common deletions
      - Most common: 4977 base pairs from 8488 to 13460; 13 base pair repeat at mutation break point
      - Thai patients: 3558 bp deletion; 10204 to 13761, or 10208 to 13765
    - Most deletions preserve
      - Promoters of transcription of heavy & light strands
      - 12S & 16S ribosomal RNA genes
      - Origin of heavy strand replication
    - Change in number of deletions over time
      - Increased in muscle
      - Reduced in rapidly turning over cells (hematopoetic)
  - Large scale tandem duplication
  - Also patients with NARP/T8993G mutation
- Heteroplasmic distribution of mutations
Clinical features
- General
  - Characteristic signs: PEO; Pigmentary degeneration of retina; Heart block; Mitochondrial myopathy
  - Partial expression of signs common
- Onset: < 20 years; Later onset patients may have only PEO
- Ocular
  - External Ophthalmoplegia
    - Progressive
    - Limitation, or absence, of movement in all fields of gaze
  - Ptosis
  - Retinal Pigmentary Degeneration (Retinitis pigmentosa): Peripheral retina > Central
- Dysphagia: 50% of adults symptomatic
  - Regurgitation of liquids
  - Problems with solids also
  - Weight loss
  - Most commonly associated with cricopharyngeal achalasia¹⁷
  - Treatment: ? Cricopharyngeal myotomy
- Myopathy
  - Weakness (90%): Proximal > Distal; Symmetric
  - Occasional fatigue or pain on exertion
  - Course: Slowly progressive
- Polyneuropathy (10%): Sensory-Motor
- CNS
  - Respiratory drive: Reduced
  - Hearing loss (95%)
  - Ataxia (90%)
  - Dementia, or impaired intellect (85%)
  - Upper motor neuron: Spasticity; Increased Tendon reflexes
  - Stroke (8%)
- Systemic features
  - Cardiac: Conduction Block; Sudden death
  - Endocrinopathies: Glucose Intolerance (15%); Hypothyroidism; Hypoparathyroidism (6%)
  - Skeletal: Short stature
- Laboratory
  - Muscle pathology
    - Ragged red fibers (98%): COX + and COX -
    - Variation in muscle fiber size
  - Lactic acidosis (80%)
  - Head CT: Basal ganglia calcifications (5%)
  - CSF Protein: High
- Prognosis: Death common in 3rd or 4th decade
Related disorders
- Pearson's Syndrome
  - Sideroblastic anemia: Pancytopenic crises
  - Pancreatic insufficiency: Insulin-dependent diabetes; Malabsorption
  - Infancy: Low birth weight; Death; Metabolic & lactic acidosis
  - May precede development of Kearns-Sayre syndrome if survival past infancy
- 2-Oxoadipic aciduria & 2-Aminoadipic aciduria
  - Onset: 2 years
  - Organic acidemia
    - Episodes of ketosis & acidosis
    - Progressive to coma
    - Resolution of clinical & metabolic features
    - Kearns-Sayre syndrome may develop later in childhood

PEO + (Progressive External Ophthalmoplegia)

Sporadic
Mitochondrial DNA changes
Single mtDNA deletion, or
Multiple mtDNA deletions
Kearns-Sayre: Single large mtDNA deletion
PEO + Proximal myopathy
Sensory ataxic neuropathy
? Immune (HyperThyroid)

Dominant
Mitochondrial DNA changes
Multiple mtDNA deletions
Twinkle: 10q23
ANT1: 4q35
POLG: 15q25
Hypogonadism

Recessive
Mitochondrial DNA changes
mtDNA depletion, or
Multiple mtDNA deletions
MNGIE: Thymidine phosphorylase; 22q13
POLG: 15q25
PEO + Cardiomyopathy
PEO + Myopathy & Parkinsonism
Sensory neuropathy

Also see: Congenital ophthalmoplegia

Maternal
Mitochondrial DNA changes
mtDNA point mutations
May be sporadic
tRNA^Leu(UUR)
MELAS
PEO
tRNA^Leu(CUN)
tRNA^Asn
tRNA^Gln: PEO-plus
tRNA^Ala: PEO-plus
tRNA^Tyr: PEO-plus
tRNA^Lys: PEO-plus
tRNA^Ile

Ophthalmoplegia: General Features

Gaze limited in all directions
Eye movement speed: slow
Bilateral
Associated with ptosis
Course: Slowly progressive

Sporadic PEO

More severe ophthalmoplegia
- Kearns-Sayre: Single large mtDNA deletion
- PEO + Proximal myopathy
Sensory ataxic neuropathy⁸
- Onset
  - Age: 10 to 31 years
  - Gait unsteadiness
- Clinical features
  - Polyneuropathy
    - Sensory loss: Joint position; Vibration; Mildly reduced pain & temperature
    - Gait disorder: Sensory ataxia; Romberg +
    - Motor: Normal in most; Late distal weakness
    - Tendon reflexes: Absent
  - Cranial nerve disorders
    - External ophthalmoplegia: Onset after neuropathy
    - Ptosis
    - Dysarthria
    - Facial weakness: Mild
  - Myopathy: Mild proximal weakness
  - Cerebellar: Normal
  - Progression: Slow over decades
- Laboratory
  - Electrophysiology
    - Sensory NCV: Axonal loss (Reduced or absent SNAP amplitude, Legs > Arms
    - Motor NCV: Normal, or Low CMAP amplitude in legs
    - EMG: Distal denervation; Proximal normal or myopathy
  - Serum CK: Mildly elevated
  - Serum lactate: Normal or Mildly elevated
  - Muscle biopsy
    - Myopathic changes: Mild
    - Ragged red muscle fibers 50%
  - Nerve biopsy: Loss of large & Small axons
  - Mitochondrial DNA: Multiple deletions
- Also see: Sensory neuropathy, Recessive
tRNA^Gln : PEO
- Genetic
  - Case reported is sporadic
  - Mutation
    - 1 base-pair insertion, 4366A
    - Heteroplasmic
    - Most in skeletal muscle; Some in fibroblasts
- Clinical
  - Onset: 5 years; Weakness; Ptosis
  - Cranial nerves
    - Facial weakness
    - Dysphonia; Dysphagia
    - Ptosis: Bilateral; Symmetric; Severe
    - Ophthalomoplegia
  - Weakness: Mild; Extremity
  - Tendon reflexes: Reduced
  - No signs of cardiac, cerebellar, or retinal disorders
- Laboratory
  - NCV: Normal
  - EMG: Myopathic
  - Muscle pathology
    - Ragged red fibers
    - Many COX- muscle fibers (89%)
    - Impairment in mitochondrial protein synthesis
    - Mutated DNA: Skeletal muscle (87%); EOM (61%)
tRNA^Ala ¹⁶: PEO
- Genetics: T5628C mutation
- Onset
  - 6th decade
  - Ptosis
- Clinical
  - Family history: Negative
  - Eye movements: Decreased in horizontal direction
  - Weakness: Proximal; Symmetric; Mild
  - Dysphagia
- Laboratory
  - Muscle
    - Many COX negative muscle fibers ± Mitochondrial proliferation
    - Biochemistry: Partial defect of Complex I
  - EMG: Myopathic
  - Serum CK: Normal
tRNA^Leu(UUR) : PEO
- Genetics: T3273C mutation
  - One of 13 reported mutations in tRNA^Leu(UUR) gene
  - Other tRNA^Leu(UUR) mutations causing PEO+: A3243G; A3251G; C3256T
  - Other tRNA^Leu(UUR) mutations in anticodon stem
    - A3260G: Myopathy & Cardiomyopathy; MELAS
    - T3271C: MELAS
- Onset
  - 5th decade
  - Ptosis
- Clinical
  - Family history: Migraines
  - Eye movements: Decreased L > R
  - Exercise intolerance
  - Short stature
- Laboratory
  - Muscle
    - Many COX negative, ragged red muscle fibers
    - Biochemistry: Partial defects of Complex I & IV
    - Mutant mtDNA: RRF with 99%; Normal fibers 88%
  - Lactate: Normal
  - Serum CK: Mildly elevated
tRNA^Tyr ²⁰: PEO
- Genetics: T5885del mutation
- Onset
  - 4th decade
  - Ptosis
  - Exercise intolerance: Muscle pain
- Clinical
  - Family history: Negative
  - Eye movements: Ophthalmoplegia
  - Exercise intolerance: Muscle pain
- Laboratory
  - Muscle
    - Myopathy: Varied fiber size; Increased connective tissue
    - Many COX negative muscle fibers with increased SDh staining
    - Biochemistry: Partial defect of Complex I & IV
    - Mutation load: COX+ fibers 20%; COX- fibers 79%
  - EMG: Myopathic
  - Serum lactate: Abnormal increase after exercise
  - Serum CK: Normal

Maternal PEO

mtDNA Point mutations
- t-RNA Leu : See MELAS
  - Myopathy
  - Psychiatric disorder
  - Sudden death
- mt-RNA Asn
  - Ophthalmoplegia only
- Other mtRNA
  - tRNA^Gln
  - tRNA^Ala
  - tRNA^Lys: PEO + Myoclonus

PEO: Autosomal Dominant

Autosomal Dominant PEO: Clinical features

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Ophthalmoplegia

Triple furrowed tongue

Mitochondrial DNA breakage syndromes: Autosomal dominant PEO
- PEO 1
  l Twinkle (C10ORF2) ; Chromosome 10q23.3-q24.3; Dominant
  - Genetics
    - Gene mutations
      - Missense most common: Homozygotes (Ala359Thr) more severe than heterozygotes
      - Severe CNS phenotype with polyneuropathy: 39 bp duplication
      - Location: Cluster in region of protein involved in subunit interactions
      - Frequency: 15% of Italian PEO with multiple mtDNA deletions
    - Muscle: Multiple mtDNA deletions
      - May occur in similar patterns in diferent patients
      - No strong correlation between deletion load & clinical severity
  - Twinkle protein
    - Structural similarity to phage T7 gene 4 primase/helicase
    - Colocalizes with mtDNA in mitochondrial nucleoids (units of mtDNA segregation)
      - Not dependent on DNA binding
    - Mutations have no effect on Twinkle localization or multimerization
    - Function: DNA helicase, adenine nucleotide dependent
    - Mutation actions
      - ? Alter subunit interactions: ? Dominant negative action
      - ? Gain of function: Alter nucleotide metabolism
      - No effect on Twinkle localization or multimerization
  - Epidemiology: Multiple families with different ethnic origins
  - Clinical features
    - Onset: Average = early 20's to early 30's; Variable within families
    - Eye (100%): Bilateral ptosis; PEO
    - Myopathy
      - Weakness: Proximal
      - Cramps
      - Respiratory failure: Occasional
    - Occasional psychiatric disorders: Depression; Avoidant personality traits
    - Cataracts
    - Occasional: Bulbar weakness; Muscle pain; Ataxia; Polyneuropathy
  - Laboratory
    - Muscle Pathology: Ragged red fibers; COX- fibers
    - Mutant mtDNA: Brain > Muscle & Heart
    - Ketoacidosis: Occasional
- PEO 2
  - Disorder mistakenly localized to Chromosome 3p
  - See PEO 3
- PEO 2/PEO 3
  l Adenine nucleotide translocator 1; (ANT1; SLC25A4) ; Chromosome 4q35; Dominant
  - Genetics mutations
    - Mutation type: Missense
      - Familial patients: Ala114Pro; Leu98Pro
      - Sporadic patient: Val289Met
    - Mutation effects
      - Structural: Alter α-helix of protein
      - Alters oxidative metabolism
      - mtDNA mutations
    - Other disease association: FSH dystrophy
      - Gene location: Near FSH locus on 4q35
      - Over-expression of ANT1 in FSH dystrophy muscle
  - SLC25A4 protein
    - Class: Mitochondrial solute carrier
    - Adenine nucleotide translocator (ANT1)
    - Most abundant protein in inner mitochondrial membrane
  - Epidemiology: Italian & Greek families
  - Onset: 20 to 35 years
  - Clinical
    - Ocular: Ophthalmoplegia & Ptosis
    - Severity: Milder than 10q linked PEO
    - Weakness: Variable
      - Some patients: No fatigue or generalized muscle weakness
      - Occasional: Dysphagia, Dysphonia, Face, Proximal & Respiratory
    - Cataracts: After 40 years
    - Other changes in some patients
      - Sensorineural hypoacusia
      - Goiter
      - Dementia
      - Bipolar affective disorder²⁸
  - Laboratory
    - Serum: High lactic acid
    - Muscle mtDNA: Multiple deletions
    - Respiratory-chain enzymes with mtDNA-encoded subunits: Mild deficiency of some
- PEO²⁵
  l Polymerase, DNA, Gamma (POLG1) ; Chromosome 15q25; Dominant or Recessive
  - Genetics
    - Dominant mutations
      - Tyr955Cys: Most common mutation
      - Other: G923D; R943H; Arg953Cys; A957S; Asn468Asp; Ala1105Thr; S1176L
      - Some dominant mutations (G923D; A957S) may have
        
        Low penetrance
        Severe phenotype & more mtDNA mutations if homozygous
    - Recessive mutations
      - Homozygous: Ala467Thr; Leu304Arg; Arg3Pro; G848S
      - Compound heterozygote T251I & R309L
    - Other mutations
      - Absence of ten-repeat polyglutamine tract encoded by CAG repeat: Associated with male infertility
  - POLG protein
    - Catalytic subunit of mitochondrial DNA polymerase
    - Function
      - Required for mitochondrial DNA replication and repair
      - C-terminal domain: DNA polymerase responsible for mtDNA replication
      - N-terminal exonuclease (exo) domain: Increases the fidelity of mtDNA replication
    - Location: Diffusely in mitochondria
  - Epidemiology
    - Common (45%) cause of familial PEO with multiple mitochondrial DNA deletions
  - Clinical features: PEO syndrome
    - Onset: 16 to 39 years
    - Ophthalmoplegia, Progressive external
    - Muscle
      - Weakness: Proximal
      - Exercise intolerance
    - Neuropathy
      - Sensory loss: Vibration
      - Tendon reflexes: Often absent
    - Endocrine
      - Poorly formed 2° sex characteristics: Breasts; Pubic hair
      - Early menopause: < 35 years
      - Testicular atrophy
    - Parkinsonism⁴⁵
      - Increased association with POLG pol-domain mutations
      - Onset: After PEO
      - Oset: 4th to 8th decade
      - PET scan: Dopaminergic neuron loss
      - Levodopa responsive
    - Severe disease
      - Proximal weakness & wasting: May be severe
      - Cranial nerves: Dysphagia; Dysphonia; Facial diplegia
      - Abnormal gait: Due to spinal ataxia or distal weakness
      - Depression,
      - Extrapyramidal syndrome: Also seen in recessive syndrome
  - Clinical features: Sporadic mitochondrial myopathy syndromes with multiple mtDNA deletions
    - Onset: 20 to 62 years
    - PEO: All patients
    - Myopathy: Most patients
    - Dysphagia: 2 patients
    - Neuropathy: Sensory-Motor; 1 patient
    - MNGIE-like syndrome
  - Clinical syndrome: Hereditary sensory neuropathy, Recessive
    - Mutations in exo-domain
    - Ataxic neuropathy
    - No Parkinsonism
  - Pathology
    - Muscle
      - Ragged red fibers
      - COX- & SDH + fibers: Numerous
      - Multiple mtDNA deletions
    - Normal mtDNA copy number in affected tissues
  - Laboratory
    - Serum CK: Mildly high
    - Serum Lactate: Mildly elevated
    - EMG
      - Denervation: Distal
      - Myopathy: Proximal
Dominant PEO: Other
- PEO + Hypogonadism
  l Autosomal Dominant
  - Epidemiology: Sweedish family
  - Clinical
    - Hypogonadism: Delayed sexual maturation, 1° Amenorrhea, Early menopause; Testicular atrophy
    - Cataracts
    - CNS: Cerebellar ataxia; Tremor; Parkinsonism; Depression Mental retardation
    - Polyneuropathy
      - Vibratory loss: Distal; Symmetric
      - Tendon reflexes: Reduced
    - Muscle
      - PEO
      - Bulbar: Dysarthria; Dysphonia
      - Proximal weakness
      - Rhabdomyolysis precipitated by alcohol: 1 patient
    - Hypoacusis
    - Pes cavus
  - Laboratory
    - EMG: Myopathic
    - Muscle biopsy
      - Ragged-red fibers
      - Cytochrome c oxidase negative muscle fibers
      - Multiple mtDNA deletions

PEO: Autosomal Recessive

PEO + Cardiomyopathy
l Autosomal Recessive
- Onset: 1st decade
- PEO
- Cardiomyopathy: Dilated
- Proximal weakness
- Fatal in 2nd decade
- Pathology: Multiple mtDNA deletions; Ragged red fibers
PEO + Myopathy & Parkinsonism²²
l Autosomal Recessive
- Epidemiology: Libyan Sephardic Jewish family
- Onset
  - 30 to 74 years
  - Ptosis or Extrapyramidal signs
- Clinical
  - Extrapyramidal: Akinesia; Rigidity; Rest tremor
  - Eyes: Ptosis; Ophthalmoplegia
  - Myopathy: Proximal & Facial weakness: Occasional distal leg weakenss
  - Hearing loss (50%)
- Laboratory
  - Muscle
    - Mitochondrial proliferaion: SDH +, COX - muscle fibers
    - Biochemistry: Reduced complex III + Varied other complexes
    - Multiple mtDNA deletions
PEO: POLG mutations
Hereditary sensory neuropathy¹
l Polymerase, DNA, Gamma (POLG1) ; Chromosome 15q25; Recessive
- Nosology: SANDO (Sensory Ataxic Neuropathy Dysarthria Ophthalmoparesis)
- Genetics
  - Belgian families: Compound heterozygotes with A467T mutation
- Onset: 16 to 30 years
- Clinical
  - Neuropathy: 1st manifestation
    - Sensory loss
      - Large & Small fiber: Vibration; JP; Temperature
      - Sensory ataxia: Ataxic gait; Pseudoathetosis
      - Small fiber modality loss may be earliest feature
    - Strength: Variable
      - Normal, Distal weakness or Diffuse weakness
    - Gait: Unsteady
    - Tendon reflexes: Absent
  - Later signs
    - PEO: Ptosis; Ophthalmoplegia
    - Other cranial nerves: Dysarthria; Facial weakness
    - Myoclonic epilepsy
  - Course
    - Progressive
    - Death: As early as 4th decade; Due to epileptic status in some patients
- Laboratory
  - Electrophysiology: Axonal loss
  - Lactate: High in CSF & serum in some patients
  - Serum CK: Normal or Mildly elevated
  - CNS
    - Degeneration of spinocerebellar & dorsal column tracts
    - Thalamic lesions in some patients
  - Muscle Pathology
    - Ragged red fibers: COX + and COX -
    - May be Normal
  - Nerve pathology
    - Loss of myelinated & unmyelinated axons
    - Axonal regeneration
- Also see
  - Ataxic sensory neuropathy, Sporadic
  - PEO, Recessive

Myopathy, Myoglobinuria & Fatigue: Mitochondrial Disorders

Autosomal Dominant
Autosomal Recessive
Maternal
Sporadic

Myoglobinuria

Mitochondrial disorders: Sporadic Myopathy & Fatigue syndromes

Myopathy with large mtDNA mutations
- Kearns-Sayre: Single large mtDNA deletion
- Large scale tandem mtDNA duplication
Myopathy with point mutations in tRNA genes: No eye signs
- tRNA^{Leu (UUR)} (A3243G): Myoglobinuria; Multiple other presentations (MELAS)
- tRNA^{Leu (UUR)} (T3250C): Riboflavin responsive myopathy/ SIDS
- tRNA^{Leu (UUR)} (A3302G): Myopathy
- tRNA^Pro (G15990A): Myopathy, childhood
- tRNA^Phe (T618C): Myopathy
- tRNA^Met (U4409C): Myopathy (Dystrophic); Growth retardation; Exercise intolerance
- tRNA^{Ser (UCN)} (A7480G): Myopathy; Deafness; Dementia; Ataxia
Myopathy with point mutations in tRNA genes: Eye signs present
- tRNA^{Leu (CUN)} (A12320G): Myopathy; Ptosis
- tRNA^Gln: PEO
- tRNA^Ala: PEO
- tRNA^Tyr
Exercise intolerance
- Myopathy, Exercise intolerance, Encephalopathy, Lactic acidemia
  l Cytochrome c Oxidase, Subunit III (Complex IV)
- Exercise intolerance, Proximal weakness ± Myoglobinuria
  l Cytochrome b (MTCYB; Complex III)
- Exercise intolerance ± Mild weakness: Several mitochondrial genes identified
- Coenzyme Q₁₀ deficiency
Multiple mtDNA deletions
- Inflammatory myopathies
  - Inclusion Body Myositis
  - Polymyositis with COX- muscle fibers
- Myopathy with aging
Other
- Selenium deficiency
- PEO

Specific sporadic mitochondrial myopathy syndromes

Myopathy, Exercise intolerance, Encephalopathy, Lactic acidemia
l Cytochrome c Oxidase, Subunit III (Complex IV)
- Mutations
  - G9952A point mutation at 3' end of gene
    - Stop codon
    - Heteroplasmic
    - Sporadic: Not maternally inherited
  - Deletion
  - Also see: Maternally inherited myopathies, MELAS-like disorder
- Onset: Adult ~ 20 years
- Clinical
  - Muscle
    - Weakness: Proximal
    - Myalgia & Fatigue
    - Myoglobinuria: With deletion mutation
  - CNS syndromes
    - Encephalopathy: Recurrent; Migraine
    - Spastic paraparesis, Mental retardation & Ophthalmoplegia
- Lab
  - Serum CK: High
  - Serum lactate: High
- Biochemistry: Isolated COX deficiency
- Pathology
  - Cytochrome c oxidase (COX) activity: Reduced in 90% of muscle fibers
  - Few SDH positive fibers
Myoglobinuria & Exercise intolerance
l Cytochrome c Oxidase, Subunit I (Complex IV)
- Genetics
  - Mutation: G5920A
    - Nonsense
    - Heteroplasmic: Especially abundant in COX negative muscle fibers
    - Sporadic: Not maternally inherited
  - Also see: Maternally inherited myopathies
- Onset
  - Childhood
  - Exercise intolerance
- Clinical
  - Myoglobinuria: Recurrent
  - Exercise intolerance: Fatigue
  - Strength between episodes: Normal
- Lab at rest
  - Serum CK: Normal
  - Serum lactate: Normal
  - EMG: Normal
  - Exercise testing: Low oxygen use by muscle
  - Biochemistry: COX deficiency; Mild defects in complex I & III
  - Muscle Pathology
    - Cytochrome c oxidase (COX) immunostaining
      - Reduced for mitochondrial encoded COX I & COX II
      - Normal for nuclear encoded COX IV & VIc
    - SDH positive fibers: COX reduced
    - Many muscle fibers with reduced COX staining
- Other Cytochrome c Oxidase, Subunit I clinical syndromes
  - Acquired sideroblastic anemia
  - Deafness, Ataxia, Blindness
  - Motor neuron disease
Exercise intolerance, Proximal weakness ± Myoglobinuria
l Cytochrome b (MTCYB; Complex III)
- Genetics: Sporadic syndromes; Also see Familial myalgias
  - Muscle specific mutations in mtDNA
  - Mutation types: Most point; G to A
    - Nonsense: G15059A; G15084A; G15168A; G15723A; G15762A
    - Missense: G14846A
    - Deletion: 24-bp; Nucleotides 15498 to 15521
    - ? Frequency of mutations in this gene related to oxidative damage
- Clinical
  - Onset: Childhood
  - Exercise intolerance
    - Progressive with age
    - Sensation of cramps, myalgias or fatigue
    - Precipitants: Normal daily activities; Chewing
  - Weakness
    - Proximal limb: Mild
    - Face: Occasional
    - EOM: Normal
  - Myoglobinuria: Some patients (28%)
  - CNS: Septo-optic dysplasia; Retardation; Encephalopathy & Seizures
- Laboratory
  - Serum lactate: High
  - Serum CK: Normal at rest
  - EMG: Mildly myopathic
  - Muscle biochemistry: Deficient Complex III activity
  - Muscle morphology
    - Ragged red fibers (5% to 22%); All SDH + & COX +
    - Some mutations: Reduced Complex III staining in some muscle fibers
- Specific syndromes with Cytochrome b (MTCYB) mutations
  - Encephalopathy & Seizures
    - Mutation: G15242A
    - Treatment: Menadione + Ascorbate
  - Septo-optic dysplasia²¹
    - Mutation: T14849C; Heteroplasmic
    - Clinical
      - Mental retardation
      - Motor: Delayed walking; Exercise intolerance
      - Eye: Retinitis pigmentosa; Optic atrophy
      - Cardiomyopathy: Hypertrophic; Wolff-Parkinson-White
    - Laboratory
      - Lactic acidosis
      - MRI: Septo-optic dysplasia; Cerebellar hypoplasia
  - Familial myalgia syndrome⁵
    l Cytochrome b (MTCYB; Complex III)
    - Mutation: Missense T15747C; Homoplasmic
    - Myalgias
    - Muscle pathology: Lipid storage
    - Also see: Sporadic exercise intolerance
  - Exercise intolerance: A14846G
  - LHON
  - Colon cancer
  - Cardiomyopathy
Exercise intolerance ± Mild weakness⁹
- Mutations in several mitochondrial genes identified
  l mtRNA Trp : T5543C
  l Cytochrome b (Complex III) : A14846G
  l ND1 (Complex I) : Inversion of 7 nucleotides; Preserves reading frame
  l ND2 (Complex I) : 2 bp deletion; Mutations also cause LHON
  l ND4 (Complex I) : G11832
- Genetics
  - Distribution of mutations
    - Usual: Heteroplasmic
    - ND2 mutation: Homoplasmic
  - Paternal inheritance identified with ND2 mutation
- Clinical features
  - Onset: Childhood
  - Examination
    - Weakness: Mild; Proximal
    - May be Normal
  - Exercise: Dyspnea; Tachycardia
- Laboratory
  - Serum lactate: High, especially with exercise
  - Biochemistry: Working muscle not able to extract available O₂
  - Muscle: Some ragged red fibers are COX +

Mitochondrial myopathy: Maternal; mtDNA Point Mutations

Cytochrome c Oxidase: Subunit 2
Mitochondrial tRNA mutations

tRNAs
- Leu (UUR) (A3288G): Cramps & Weakness
- Leu 2
- Pro
- Met
- Ser
- Gln
- Glu : With diabetes
- Trp : Encephalomyopathy
Myopathy
- Weakness
  - Distribution: Proximal > Distal; Symmetric; ± PEO
  - May be normal strength with subclinical myopathy on EMG or biopsy
- Exercise intolerance
- Rhabdomyolysis
- Riboflavin sensitive: tRNA Leu mutation (T3250C)
- Serum CK
  - Normal or high
  - Especially increased with tRNA^Met mutation
- Lactate (serum): Increased at rest or after exercise
- Muscle pathology
  - Myopathy
    - Fiber size variability
    - Connective tissue: Especially increased with tRNA^Met (U4409C) mutation
  - Mitochondrial proliferation: Ragged red fibers (GT stain); Dark SDH stain
  - Cytochrome oxidase - (COX-) muscle fibers
    - Frequency: Up to 50%; greater with increased age
    - Mutant DNA more abundant than in normal fibers
  - Electron microscopy
    - Abnormal mitochondrial morphology
    - Paracrystalline inclusions
    - Usually not diagnostically useful with normal light microscopic histochemistry
Associated systemic syndromes
- MELAS
- MERRF
- Encephalopathy
- PEO and sudden death
- Cardiomyopathy
Cytochrome c Oxidase, Subunit II (Complex IV)
- Genetics
  - T7671A mutation
    - 90% of DNA in muscle; 5% in blood
    - Sporadic
    - Myopathy
    - Mechanism
      - Reduced Assembly of COX enzyme
      - Reduced Anchoring of COX II in mitochondrial membrane
  - T7587C
    - Maternal inheritance
    - Myopathy + CNS
  - G8009A: Somatic mutation found in colorectal cancer
- Myopathy
  - Onset: Teens
  - Weakness: Distal or Proximal predominant
  - Fatigue
  - May occur in isolation or with CNS signs
- CNS: Ataxia; Retinopathy; Optic atrophy
- Biochemistry: Mildly increased Lactate in serum or CSF
- Muscle pathology
  - COX deficiency in 97% of muscle fibers: All COX subunits reduced
  - Mitochondrial proliferation: Increased SDH stain
Myopathy, Deafness & CNS disorders⁴¹
l Mitochondrial tRNA^Ser(UCN) (MTTS1) ; Sporadic
- Genetics
  - Mutation: A7480G; Heteroplasmic
  - Other syndromes with tRNA^Ser(UCN) mutations
    - MELAS/MERRF overlap: T7512C; Heteroplasmic
    - Hearing loss, ataxia & myoclonus (HAM): C insertion at position 7466–7472
    - Encephalopathy with cytochrome c oxidase deficiency: 7472insC
    - Myopathy: G7497A
    - Exercise intolerance: G7497A
    - Keratoderma, palmoplantar, with deafness: A7445G
    - Sensorineural hearing loss: Maternal inheritance; T7510C, T7511C & T7445C; Heteroplasmic
- Onset
  - Age: 8 years
  - Gait disorder: Weakness or contractures
- Clinical
  - Weakness: Proximal
  - Fatigue: Exertional
  - Deafness: Sensorineural
  - Ataxia: Limb & Trunk
  - Cognitive impairment
  - Optic atrophy
- Laboratory
  - CT scan: Generalized atrophy
  - EEG: Low voltage
  - EMG: Myopathy; Axonal sensory neuropathy
  - Lactate: High in serum & CSF
  - Muscle biopsy
    - Myopathy: Fiber size variation
    - Mitochondrial pathology: Proliferation; COX- fibers
    - Mitochondrial biochemistry: Complex I & IV reduced
    - May be normal early in disease course
Myopathy, Ptosis & Dysphonia
l Mitochondrial tRNA^Trp (MTTW) ; Sporadic
- Mutation
  - G5521A
  - Heteroplasmic in muscle (98%)
  - Absent in leukocytes
- Clinical
  - Onset: 50 years
  - Eyes: Ptosis; No ophthalmoplegia
  - Myopathy
    - Weakness: Proximal; Mild
    - Fatigue
- Muscle
  - Histochemistry: SDH+, COX- muscle fibers
  - Biochemistry: Cytochrome c oxidase reduction
Myopathy, Diabetes & CNS disorders⁴²
l Mitochondrial tRNA^Glu (MTTE) ; Maternal
- Genetics
  - Mutation: Missense; T14709C
  - Distribution
    - Homoplasmic or Heteroplasmic
    - Most tissues
  - Clinical correlations
    - Symptoms in patients with mutation level > 80%
    - Some homoplasmic patients (blood) are asymptomatic
- Clinical
  - Onset
    - Age: Teens or Adult; Occasional congenital
    - Fatigue
    - Weakness
  - Myopathy
    - Weakness
      - Proximal
      - Orbicularis oculi
      - Late: Respiratory failure
      - Some patients described with FSH phenotype
      - Progression: Slow
    - Fatigue
  - Polyneuropathy: Sensory-Motor; Mild
  - CNS: Some patients
    - Cerebellar: Ataxia; Nystagmus
    - Congenital encephalopathy
  - Diabetes
- Laboratory
  - EMG: Myopathy
  - NCV: Sensory-motor axonal neuropathy
  - Muscle
    - Myopathy: Endomysial fibrosis; Varied fiber size
    - Mitochondrial morphology: Proliferation; COX- muscle fibers
    - Biochemistry: Reduced Complex I & IV activity
  - Cardiac muscle: Focal COX reductions, especially in left ventricle

Mitochondrial Myopathy: Autosomal Recessive disorders

Fatal infantile myopathy with severe mtDNA depletion
Benign "later-onset" myopathy with moderate reduction in mtDNA
Cytochrome c Oxidase I
Congenital muscular dystrophy with mitochondrial structural abnormalities
Glutaricaciduria IIA (MADD)
Hydroxyacyl-CoA Dehydrogenase/3-Ketoacyl-CoA Thiolase/Enoyl-CoA Hydratase
- Alpha subunit (HADHA): Trifunctional protein, alpha subunit
- Beta subunit (HADHB): Trifunctional protein, beta subunit
Succinic Dehydrogenase deficiency: Biochemical defects
- SDH (Complex II) deficiency
- Succinic Dehydrogenase + Aconitase (Chromosome ?)
Multiple mtDNA deletions
Myopathy with lactic acidosis & sideroblastic anemia
mtDNA depletion syndromes
Recurrent myoglobinuria
- Multiple mtDNA deletions
- Cytochrome c Oxidase deficiency, Subunit III: Complex IV
Familial myalgia syndrome : Cytochrome b (MTCYB; Complex III)
Myopathy with abnormal mitochondrial translation

mtDNA Depletion Syndromes

Fatal infantile myopathy with severe mtDNA depletion
- Inheritance: Probably recessive
- Clinical
  - Onset: birth to 14 months
  - Death: 60% < 1 year
  - Clinical: Weakness & hypotonia
  - Family history positive in 50%
  - Lactic acidosis in more severe cases
  - Serum CK: Mildly, or Prominently elevated to > 1,000
  - Some with renal dysfunction
- Muscle
  - Ragged red fibers in 88%
  - Cytochrome oxidase
    - Activity: Very reduced or absent in extrafusil fibers
    - Normal in spindles & arteries
    - Most mitochondrial peptides absent
    - COX VIIa,b selectively reduced
    - Other nuclear-encoded mitochondrial enzymes normal
Mitochondrial DNA depletion myopathy
l Thymidine kinase, mitochondrial (TK2) ; Chromosome 16q22; Recessive
- Mutations
  - Missense: His90Asn; Ile181Asn; Ile22Met; Thr77Met; Asp11Gly
  - Exon 5: Hotspot for mutations
- TK2 protein
  - Location: Mitochondria
  - Tissue expression: Ubiquitous
  - Phosphorylates nucleotides
    - Deoxythymidine, deoxycytidine & deoxyuridine to monophosphate form
    - Phosphate source: ATP
- Epidemiology
  - Geography: Moslem; Ashkenazi Jewish; Hispanic
  - Frequency of TK2 mutation in mtDNA depletion syndromes: 11%
- Onset
  - 8 to 24 months
  - Gait impairment
- Clinical
  - Hypotonia
  - Weakness
    - Proximal > Distal
    - Progressive
      - Severe cases: Complete paralysis by 12 to 36 months
      - Death in childhood
  - Respiratory failure: By 2 to 3 years
  - Normal: EOM; Face; Cognition
  - No involvement of systems other than muscle & nerve
- Laboratory: Myopathy & SMA-like changes
  - Serum CK: High; 900 to 4,000
  - Muscle histology
    - Partial denervation, chronic: Grouped atrophy (SMA-like)
    - Reduced COX staining
    - SDH+, COX- muscle fibers
    - Respiratory chain activities: Markedly reduced
  - Mitochondrial changes in muscle
    - Low activity: Complex I, III, IV, V
    - Normal activity: Complex II
    - mtDNA depletion: 16% to 22% of control levels
  - Plasma lactate: Normal or Elevated
  - EMG
    - Myopathic: Early in course
    - Denervation changes: Develop in occasional patient²⁷
Benign "later-onset" myopathy with moderate reduction in mtDNA
l Recessive vs Sporadic
- Onset < 1 week to 5 years
- Weakness
  - Proximal > Distal; Hypotonia
  - Other: Respiratory failure; ± Dysphagia; ± Ophthalmoplegia
- Neuropathy (40%): Axonal ± Demyelinating; Sensory > Motor; May be subclinical
- CNS: Seizures; Encephalopathy
- MRI: Delayed myelination; Variable other changes
- Course
  - Often non-progressive
  - Survival: < 15 years; Pneumonia; Respiratory failure
  - Occasional spontaneous improvement; Normal by 2 years
- Lactic acidosis (60%)
- Serum CK: High in 60%
- Muscle pathology
  - Ragged red fibers: Early COX-; Later some COX+
  - Cytochrome oxidase
    - Early (1 to 4 months)
      - COX activity 6% to 66%: Diagnostic < 30% of control
      - COX VIIa,b & COX II selectively reduced
    - Reduced in mosaic pattern
    - Late: COX activity returns toward normal
- Fiber size: Variable
- Occasional: Degeneration & regeneration; Inflammation; Lipid droplets in fibers

Other recessive mitochondrial syndromes

Succinic Dehydrogenase deficiency
- Clinical features
  - Fatigue
  - Rhabdomyolysis
- Biochemical defects
  - SDH (Complex II) deficiency
  - Succinic Dehydrogenase + Aconitase
Familial myalgia syndrome
l Cytochrome b (MTCYB; Complex III)
Myopathy with abnormal mitochondrial translation²⁴
l Autosomal
- Epidemiology: Two sporadic patients
- Onset
  - Childhood
  - Motor: Weakness or Fatiguability
- Clinical
  - Weakness
    - Proximal > Distal
    - Fatiguability
    - Course: Slowly progressive
  - Hypotonia
  - Ocular (50%): Ptosis & Ophthalmoplegia
  - Short stature (50%)
- Laboratory
  - Sideroblastic anemia (50%)
- Muscle
  - Mitochondrial proliferation: All muscle fibers
  - COX activity: Severely reduced
  - Biochemistry: Complexes I and IV (5% of control); Complex II+III (41% of control)
  - Immunoblot: Complexes I, III and IV 90% reduced; Nuclear complexes II and V normal
  - Mitochondrial translation defect: Generalized

Mitochondrial Myopathy: Autosomal Dominant

Myopathy with focal depletion of mitochondria
Mitochondrial DNA breakage syndrome: PEO + Myopathy
Mitochondrial myopathy: Lipid type
- Myopathy: Facioscapulohumeral (FSH) distribution
- Cerebellar disorder
- Diabetes
Mitochondrial myopathy with exercise intolerance¹⁹
- Onset
  - First decade
  - Exercise intolerance
  - Leg weakness
- Clinical
  - Weakness
    - Early: Proximal; Legs > Arms
    - 2nd decade: Neck flexor; Shoulder; Distal legs
    - 3rd & 4th decade: Mild face weakness
    - Pulmonary function: Restrictive deficits
    - Progression: Slow
    - Subjective improvement with methylprednisolone treatment
  - EOM: Unaffected
  - CNS: Normal cognition, sensation, cerebellar
  - Systemic: Short stature
- Laboratory
  - Serum CK: 287 to 984
  - Serum lactate: High
  - Serum pyruvate: High
  - EMG: Myopathic
- Muscle pathology
  - Ragged red fibers
  - Biochemistry
    - Cytochrome c oxidase (Complex IV): Reduced
    - Succinate cytochrome c reductase (Complex II & III): Reduced
    - NADH dehydrogenase (Complex I): Normal
Also see: Progressive External Ophthalmoplegia, Dominant

Systemic Mitochondrial Syndromes

Adult onset
Anemia
Ataxia
Cardiac
Deafness
Diabetes
Infantile encephalopathies
Multiple symmetric lipomatosis
Optic atrophy

Infantile encephalopathies: Mitochondrial disorders

Cardiomyopathy: Mitochondrial disorders

Infantile onset syndromes
- Fatal infantile cardiomyopathy
  l tRNA Ile
  - Mutation: A4317G; A4269G
  - Onset: Neonatal
  - Clinical
    - Heart: Dilated & Hypertrophic
    - Other: Some features of MELAS; Short stature; Deafness
    - Death due to cardiac failure: Childhood to 18 years
  - Other tRNA Ile syndcromes
    - Familial hypertrophic cardiomyopathy (A4295G; A4300G)
    - Familial progressive necrotizing encephalopathy (T4290C)
    - Spastic paraparesis; Ataxia; PEO; Retardation (G4284A)
- Cardiomyopathy (hypertrophic)
  l tRNA Lys
  - Mutation: A8296G (Also found in Diabetes)
  - Onset: Neonatal
  - Death in infancy
  - Lab: High serum Lactate & Pyruvate
- Cardiomyopathy (hypertrophic) & Cataracts (Sengers syndrome)
  - Hypotonia
  - Lactic acidosis
  - Death: Neonatal to early adult
  - Biochemistry
    - Complex I deficiency
    - Adenine nucleotide translocator 1 (ANT1): Levels in muscle reduced; No mutations
- Cardiomyopathy (hypertrophic); Brain swelling & Macrocephaly
  - Familial
  - Onset: 1st month
  - Lab: Complex I deficiency; High lactate
  - CNS Pathology: Small vessel proliferation & gliosis
- Cardioencephalomyopathy with cytochrome c oxidase deficiency
  l SCO2 ; Chromosome 22q13; Recessive
  - SCO2
    - COX assembly gene: Enables incorporation of subunits 1 and 2 into holoprotein
    - Complex IV
  - Mutations
    - Types: Missense & Nonsense
    - Many patients heterozygous for E140K mutation: Severe disease
    - Some patients homozygous for E140K mutation: Modreately severe disease
  - Clinical: Heterozygous for E140K mutation; Fatal infantile
    - Onset: Infantile (1st 3 months); Male = Female
    - Motor: Hypotonia; Respiratory failure
    - Cardiomyopathy: Hypertrophic; COX deficiency
    - Encephalopathy
    - Course: Fatal by 6 months
  - Clinical: Homozygous for E140K mutation¹⁸
    - Onset age: 3 to 6 months
    - Motor: Hypotonia; Respiratory insufficiency; Limb spasticity
    - Cardiomyopathy: Hypertrophic
    - Leigh-like syndrome
    - Ocular: Ptosis; Ophthalmoplegia
    - PNS
      - ? Motor neuropathy
      - EMG: Denervation in some patients
    - Encephalopathy: Especially white matter lesions
    - Survival: 8 to > 24 months
    - Residual COX activity: 16% to 51%
  - Laboratory
    - Muscle
      - COX deficiency (Moderate to Severe); SDH normal
        
        More reduction in mitochondrial COX I & II; than nuclear COX IV & Va
        Residual COX activity low: 0% to 18%
      - Atrophic muscle fibers
      - May have denervation pattern similar to SMA
    - CNS: Gliosis
    - Biochemistry
      - Lactic acidosis
      - Increased copper uptake by fibroblasts
- Hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit (HADHB)
  Trifunctional protein deficiency, type 2
  l Chromosome 2p23; Recessive
  - Cardiomyopathy
  - Myopathy
  - Liver dysfunction
  - Encephalopathy
- Cardiomyopathy + Encephalomyopathy¹³
  l NADH-Ubiquinone oxidoreductase Fe-S Protein 2 (NDUFS2) ; Chromosome 1q23; Recessive
  - NDUFS2 Mutations: Missense; Homozygous
  - NDUFS2 protein: Complex I; Extramembranous near membrane domain; ? Role in protein transport
  - Onset
    - Age: Birth to 7 months
    - Hyoptonia or Failure to thrive
  - Clinical
    - Cardiomyopathy: Hypertrophic
    - Hypotonia: Axial
    - Pyramidal signs: Limb hyperreflexia
    - Ocular: Optic atrophy; Nystagmus
    - CNS: Progressive encephalopathy; Sleep apnea
    - Course: Death < 2 to 3 years
  - Laboratory
    - Lactate: High in CSF & Blood
    - Brain CT: Hypodensities in basal ganglia; Generalized atrophy
    - Exchocardiogram: Hypertrophic cardiomyopathy
    - Biochemistry: Selective Complex I deficiency
    - Riboflavin reverses adenosine triphosphate production deficit in fibroblasts
- Infantile histiocytoid Cardiomyopathy
  l Mitochondrial cytochrome b ; Often sporadic
  - Onset: < 2 years
  - Females > Males
  - Clinical
    - Dysrhythmia
    - Cardiac arrest
    - CNS & Eye anomalies
    - Course: Usually fulminant; May simulate sudden infant death syndrome
  - Pathology
    - Pale granular foamy histiocyte-like cells in myocardium
    - Mitochondrial proliferation
Autosomal with PEO
- Dominant: Multiple mtDNA Deletions
- Recessive
X-linked
- Barth syndrome: Allelic with Familial dilated cardiomyopathy 3A
Maternal
- mtDNA Point mutations: tRNAs Leu , Lys , Gly & Ile
  - A3243G (tRNA Leu)
    - Up to 10% of hypertrophic cardiomyopathy
    - Barth-like syndrome: Dilated cardiomyopathy
- Skeletal Muscle Pathology: Ragged red fibers (COX -)
Dilated cardiomyopathy
- Right ventricular dilated cardiomyopathies (ARVD): ? Mitochondrial disorder
- Transfer RNA, mitochondrial, Histidine (tRNA His) : G12192A ± A16318T homoplasmic substitutions
Selenium deficiency

Deafness: Mitochondrial disorders

Autosomal Recessive inheritance, Syndromic
Wolfram (DIDMOAD): WFS1; WFS2
Deafness-Dystonia syndrome
Maternal (mitochondrial) inheritance
Non-syndromic
Syndromic
Sporadic syndromic

Deafness: Maternal & Non-syndromic
- mtDNA Point mutation: 12s rRNA
  - Mutation: A1555G
  - Clinical: Aminoglycoside-induced & non-syndromic deafness
  - May be more severe with associated mutant GJB2 (connexin 26) allele (heterozygous)
Deafness: Maternal ± Syndromic
- Point mutations: Mitochondrial DNA
  - A3243G, mtRNA Leu (MTTL1) : Isolated hearing loss or Syndromic
    - Frequency
      - 7% of patients with matrilinear sensorineural hearing loss
      - Overall: 1%
    - More severe in males
    - Onset: Teens to 5th decade
    - Progression of deafness: Increases with age
    - Syndromic features
      - MELAS: Hearing loss present in many patients
      - Diabetes mellitus
      - Cardiomyopathy
    - A3243G: Mutation features
      - Heteroplasmic
      - Most commonly found in muscle or hair follicles
      - Less common in leukocytes with increasing age
  - MERRF
  - tRNA Ser (MTTS1)
    - A7445G mutation
      - Sensorineural hearing loss: May be homoplasmic
      - Palmoplantar keratoderma
    - 7472 insC (1 base pair insertion) & T7512C
      - Hearing loss; Ataxia; Myoclonus (HAM Syndrome)
      - Neurolgic feature: Epilepsia partialis continua; with high levels of mutation
      - Pathology: COX deficiency; No ragged red fibers
      - Biochemistry: Complex IV deficiency
    - Disease mechanism: ? Mutations produce functional insufficiency of mitochondrial tRNA-Ser
    - Also related to MELAS/MERFF overlap syndrome
  - tRNA Ser (MTTS2) :
    - Sensorineural hearing loss: Progressive
      - Recruitment: Distortion & physical discomfort as a result of loud noise
      - Persistent tinnitus
      - Similar to Usher syndromes, Type III but with maternal (dominant) inheritance
    - Retinitis Pigmentosa
    - Muscle: Mitochondrial proliferation
    - EKG: Right-axis deviation
    - Mutation: C12258A; Same mutation produces Ataxia, Cataract & Diabetes syndrome
  - tRNA Leu: with Diabetes
  - tRNA Lys : with Diabetes or Cardiomyopathy
  - tRNA Gln : Increased risk of sensorineural hearing loss & migraine¹⁴
- Large (> 1 kb) heteroplasmic deletion: Kearns-Sayre ; PEO; Diabetes
- Large (> 1 kb) heteroplasmic partial duplication: Kearns-Sayre; Diabetes; Ataxia; Tubulopathy
- Wolfram syndrome: ? Mitochondrial form
Sporadic syndromic deafness
- Single large mtDNA deletion: with Optic Atrophy, Diabetes
- Cytochrome c oxidase (COX) 1 (Complex IV)
  - Genetics
    - Mitochondrial DNA encoded
    - Mutations: G6930A, Stop codon; G6480A
    - Disrupts assembly of respiratory-chain complex IV
    - Biochemical correlates with the amount of mutant G6930A mtDNA
      - Differs from high threshold effect in mitochondrial tRNA point mutations
    - Other COX 1 mutations found in patients with sideroblastic anemia & Leber's
  - Clinical
    - Onset: 3 years; Cataracts
    - Hearing loss: 7 years; Sensorineural; Progressive
    - Myopathy
    - CNS: Ataxia; Myoclonic epilepsy
    - Ocular: Visual loss; Optic atrophy
  - Muscle biopsy
    - Mitochondrial enzymes: 90% reduction in COX; Normal SDH
    - No ragged red fibers
  - MRI
    - Cerebellar atrophy: Diffuse
    - Basal ganglia: Bilateral small symmetrical nodular hyperintensities
Recessive syndromic deafness
- Wolfram syndrome (DIDMOAD)
  - Major diagnostic features
    - Insulin-dependent diabetes mellitus
    - Optic atrophy: Progressive
  - Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness
  - Subtypes
    - Wolframin (WFS1): Chromosome 4p16
    - WFS2: Chromosome 4q22-24
    - ? Mitochondrial
  l Wolframin (WFS1) ; Chromosome 4p16; Recessive (or Semi-Dominant)
  - WFS1 gene mutations
    - ~24 mutations identified: Nonsense, Missense...
    - Most mutations in exon 8
    - Most patients compound heterozygotes
    - Carrier frequency: 1/350
  - mtDNA
    - Multiple mtDNA deletions common (up to 90%) in affected tissues such as brain
    - Few deletions in muscle or leukocytes
  - Wolframin protein
    - Endoglycosidase H-sensitive glycoprotein
    - Location
      - Subcellular: Transmembrane; Endoplasmic reticulum; Not in mitochondria
      - CNS (Neurons): Hippocampus CA1, Amygdaloid areas, Olfactory tubercle & Allocortex (Superficial layer)
    - Expressed in heart, brain, pancreas, liver, kidney, skeletal muscle
    - Mutations: Loss of function
  - Clinical
    - Prevalence: 1:100,000 to 1:700,000
    - Onset: 95% by age 15
    - CNS: > 60% by 4th decade
      - Deafness
      - Optic atrophy
        
        Onset Mean 15 years, Range 6 weeks to 30 years
        Usually begins after diabetes mellitus
      - Ocular: Occasional patient with Parinaud's
      - Cerebellar: Ataxia; Nystagmus (50%)
      - Myoclonus
      - Cortical
        
        Seizures
        Retardation
        Psychiatric change: Depression; Psychosis; Organic brain syndrome
      - Central respiratory failure: Some patients
    - PNS
      - Autonomic dysfunction: Urinary tract atony
      - Polyneuropathy
    - Systemic
      - Diabetes mellitus
      - Diabetes insipidus (Onset 5 to 10 years)
      - Renal tract change: Distended bladder
    - Heterozygous carriers: Predisposition to
      - Psychiatric disease (?26x)
      - Diabetes
  - Lab
    - Hematology: Anemia; Low WBC; Low Platelets
    - Reduced
      - Vasopressin
      - Erythrocyte thiamine pyrophosphate activity
      - Thiamine pyrophosphokinase activity
  - MRI: Brain atrophy
  - CNS pathology
    - Optic nerve degeneration
    - Neuronal loss: Lateral geniculate; Basis pontis; Paraventricular & Supraoptic nuclei
    - Axonal dystrophy: Swellings; ? Frequency
  l WFS2: Chromosome 4q22-q24 ; Recesssive
  - Epidemiology: Jordanian consanguinous families
  - Typical features
    - Diabetes mellitus
    - Optic atrophy
    - Sensory-neural hearing loss
    - Urinary tract dilatation
  - Distinctive features
    - Diabetes insipidus: Milder or absent
    - ? Peptic ulcer disease
  l ? Mitochondrial form
- Deafness-Dystonia-Dementia syndromes
  l DDP protein ; Chromosome Xq22
  - TIMM8A gene mutations: Missense; Stop; Small deletion
  - DDP protein (Translocase of inner mitochondrial membrane 8 (TIMM8A)
    - Location: Mitochondrial intermembrane space
    - Homology to yeast Tim (Translocase of inner mitochondrial membrane) mitochondrial proteins
    - Function: ? Import of metabolite transporters from Cytoplasm to Mitochondrial inner membrane
    - ? Mutations cause defect in mitochondrial protein import system
  - Clinical: Mohr-Tranebjaerg syndrome; Deafness-dystonia syndrome
    - Sensory-neural hearing loss: Progressive
    - Eye: Myopia; Reduced visual acuity; Constricted visual fields; Retinal change
    - CNS: Dystonia; Mental deficiency; Cortical blindness
  - Clinical: Jensen syndrome
    - Eye: Blindness; Optic atrophy
    - Ear: Sensorineural hearing loss
    - CNS: Dementia; CNS calcifications
    - Muscle: Wasting

Ataxia: Mitochondrial disorders

Leukodystrophy: Sporadic
- Single large mtDNA deletion
MELAS; MERRF; NARP; Deafness; Leigh's; HAM
Friedreich ataxia
Ataxia, Cataract & Diabetes mellitus: tRNA Serine 2 (MTTS2)
- Same mutation produces Progressive sensorineural deafness & retinitis pigmentosa
Coenzyme Q10 deficiency
COX10 (Heme A:farnesyltransferase)
Cytochrome c Oxidase I
Cytochrome c Oxidase II : Ataxia; Distal weakness; Retinopathy & Optic atrophy
Pyruvate dehydrogenase: Episodic ataxia; Leigh syndrome
Sideroblastic anemia & Spinocerebellar ataxia (XLSA/A)
Possible dominant syndromes: CAPOS; Cerebellar ataxia, Deafness & Narcolepsy; SCA7

Diabetes: Mitochondrial disorders

Myopathy: mtDNA Point mutation tRNA Glu: Heteroplasmic or Homoplasmic
tRNA Leu : See MELAS; A3243G mutation
- Frequency: 0.9% in unselected DM; 2% to 5% in inherited
tRNA Lys
Kearns-Sayre
Single large mtDNA deletion
Large scale mtDNA tandem duplication: Maternally transmitted; Deafness
Wolfram syndrome
Friedreich ataxia
Ataxia, Cataract & Diabetes mellitus: tRNA Serine 2 (MTTS2)

Anemia (Sideroblastic)

Myopathy with lactic acidosis & sideroblastic anemia (MLASA)

l Pseudouridine synthase 1 (PUS1)

; Chromosome 12q24.33; Recessive

Epidemiology: Jewish families of Iranian extraction
Genetics
- Mutation: Missense; Arg116Trp
Clinical
- Onset
  - Age: Childhood & Teens
  - Weakness
- Myopathy
  - Weakness: Progressive
  - Exercise intolerance: Fatigue; Nausea & Vomiting
  - Ptosis: Mild; Occasional patient
- Short stature
Laboratory
- Anemia: Sideroblastic; Blood transfusions may be necessary
- Lactic acidosis: At rest
- Muscle
  - Histology: Varied fiber size; No SDH+ or COX- muscle fibers
  - Biochemistry: Reduced mitochondrial oxidative enzyme activities

Multiple symmetric lipomatosis

Optic neuropathy: Mitochondrial disorders

Leber's
Optic atrophy (OPA1)
l OPA1 protein ; Chromosome 3q28-q29; Dominant
- OPA1 protein
  - Cellular location: Mitochondrial
  - Tissue location: Widely expressed; Most abundant in retina; Also brain, testis, heart, skeletal muscle
  - Role: Maintenance of mitochondrial DNA
  - Dynamin-related GTPase
- Clinical: Heterogeneous
  - Onset: 60% < 10 years
  - Visual acuity: Variably reduced
- Pathology: Degeneration of retinal ganglion cells
? OPA4
l Chromosome 18q12.2–q12.3; Dominant

Leigh's Syndrome

Clinical features
Lab features
Types
Mitochondrial
mtDNA deletions
Nuclear mutations

Clinical features

Causes of Leigh-like Syndrome³

Defect Frequency (%)

mtDNA mutation 18

PDHC 10

Complex I 19

COX deficiency 14

Complex II + Other 39
- Onset: 1^st year, or occasionally later
- Hypotonia
- Episodic
  - Vomiting
  - Ataxia
  - Choreoathetosis
  - Hyperventilation
- Encephalopathy: Loss verbal milestones
- Motor: Spasticity; Abnormal breathing rhythm
- Brainstem & Basal ganglia signs
  - Hearing loss
  - Cerebellar: Ataxia; Nystagmus
  - Dystonia
- Ophthalmologic: Visual loss; Ophthalmoparesis
- Peripheral neuropathy
  - Often subclinical: Prevalence by nerve conduction testing: 45%
  - Pathology: Reduced Myelinated & Unmyelinated axons; ? Demyelination
- Clinical signs may become manifest with
  - Stress: Intercurrent infection
  - Carbohydrate intolerance
- Course
  - Progression: Motor & Intellectual regression
  - Death often within 2 years of onset
Lab
- Lactate: High in CSF > blood
- Muscle biopsy
  - Normal histology
  - COX deficiency: All subunits, nuclear & mitochondrial encoded
- CNS pathology
  - Focal, bilaterally symmetric spongiform lesions
  - Location: Especially in thalamus and brain stem
  - MRI: Symmetrical hyperintense lesions on T2
General pathophysiology: Severe deficiency in mitochondrial ATP production

Causes of Leigh-like Syndrome³
Defect	Frequency (%)
mtDNA mutation	18
PDHC	10
Complex I	19
COX deficiency	14
Complex II + Other	39

Leigh syndrome (LS) & Infantile encephalopathies (IE): Genetically defined types

Mitochondrial mutations
MILS (LS): ATPase 6
tRNAs
ND5
COX III
mtDNA deletions (LS)
Nuclear mutations
Complex I
NDUFS8 (LS): 11q13
NDUFS7 (LS): 19p13
NDUFS4 (LS & IE): 5q11
NDUFV1 (LS): 11q13
Complex II
SDHA (LS): 5p15
Complex IV
LRPPRC (LS): 2p16
Surfeit-1 (LS): 9q34
SCO2 (IE): 22q13
Pyruvate metabolism
Pyruvate carboxylase (LS): 11q13
Pyruvate decarboxylase (LS)
Pyruvate dehydrogenase
Pyruvate dehydrogenase E1-α (LS): Xp22
Dihydrolipoyl transacetylase E2 (IE)
Lipoamide dehydrogenase E3 (LS): 7q31
Protein X
Phospho-E phosphatase
Infantile encephalopathies: Other

Leigh syndrome: Maternal (MILS) & other mitochondrial DNA disorders
- mtDNA point mutations
  l ATPase 6 (Complex V)
  - Mutations: Also found in NARP, Leber's, Familial bilateral striatal necrosis
  - Motor: Hypotonia; Developmental delay 50% to 90%
  - Peripheral neuropathy 30%
  - T8993G mutation
    - Onset: 4 to 5 months
    - Frequency: Common
    - Seizures 67%
    - Retinitis pigmentosa or optic atrophy 33%
    - Increased severity
  - T8993C mutation
    - Onset: Median = 4 years; Range = 0.5 to 56 years
    - Frequency: Rare
    - Ataxia 90%
    - Juvenile Leigh's with respiratory failure
  - T9176C mutation: Variable presentation
    - Leigh syndrome
    - Later onset: Bilateral striatal necrosis
  - Severity also dependent on level of mutant DNA (heteroplasmy)
  l Mitochondrial tRNAs
  - Lys (A8344G); Trp ; Val ; Leu ; Ser
  l ND5 (Complex I)
  - Leigh syndrome
    - Mutation: A13084T
    - Combined features of Leigh & MELAS
    - Progressive
  - Mutations also found in
    - Atypical MELAS syndrome
    - MNGIE: Hotspot for mtDNA mutations
  l COX III (Complex IV)
  - Leigh syndrome
    - Onset: 4 years
    - Spastic paraparesis + Ophthalmoplegia
    - Lactic acid: High in serum
    - Muscle: Isolated COX defecit
    - MRI: Leigh-like lesions in putamen
  - Mutations also found in
    - Leber optic atrophy
    - Myopathy with exercise intolerance
    - Rhabdomyolysis
    - Episodic encephalopathy
- mtDNA deletions
Nuclear mutations: Leigh
- Complex IV
  - Cytochrome oxidase deficiency (Complex IV)
    l Surfeit-1 (SURF-1) protein ; Chromosome 9q34; Recessive
    - Genetics: SURF-1 mutations
      - Small rearrangements: All predict loss of function of SURF-1 gene
      - Occur in 75% of typical Leigh syndrome in Caucasians
      - Rarely occur in atypical Leigh syndromes
    - Protein: Located in inner mitochondrial membrane
    - Biochemistry: Reduced COX activity to ~10% of controls in fibroblasts > muscle
    - Clinical: Specific for typical Leigh syndrome
      - Early onset
      - Encephalopathy: Rapidly progressive psychomotor regression
      - Generalized hypotonia
      - Tendon reflexes: Brisk
      - Ataxia: Truncal
      - Oculomotor disorders: Slow saccades; Ophthalmoparesis; Irregular EOM
      - Respiratory: Episodic apnea & Irregular hyperpnea
      - Death: Central ventilatory failure
    - Laboratory
      - Lactate: High
      - MRI: Symmetric lesions; Scattered from basal ganglia to brain stem
  - Cytochrome oxidase deficiency: French-Canadian type ³¹ (Complex IV)
    l LRPPRC ; Chromosome 2p16; Recessive
    - Mutations
      - Type: Missense in most; 1 deletion
      - Commonly homozygous for A354V
    - Leucine-rich pentatricopeptide repeat-containing protein (LRPPRC)
      - mRNA-binding protein
      - Likely involved with mtDNA transcript processing
    - Epidemiology: Quebec families (Saguenay-Lac-Saint-Jean)
    - Clinical
      - Onset: Developmental delay; Hypotonia
      - Facial dysmorphism: Mild
      - Leigh syndrome
      - Mortality: Due to episodes of severe acidosis and coma
    - Laboratory
      - Congenital lactic acidosis
      - Metabolic acidosis: Mild, Chronic, Well-compensated
      - Low COX activity: Especially in Brain & Liver
      - Pathology
        
        CNS: Leigh disease
        Liver: Microvesicular steatosis
- Complex I
  - NADH:ubiquinone oxidoreductase 23-kD subunit (NDUFS8) protein
    l Chromosome 11q13; Recessive
    - Onset: Birth
    - Neural: Hypotonia; Brisk tendon reflexes; Seizures; Drowsiness
    - Cardiomyopathy
    - Laboratory
      - Lactate: Increased in blood & CSF
      - MRI: Hypodensity of white-matter, Putamen & Mesencephalon
      - Muscle biopsy: Few Type I fibers; No ragged red fibers
    - Brain pathology
      - Spongiform changes
      - Capillary proliferation & endothelial swelling
      - Demyelination
      - Gliosis
  - NADH:ubiquinone oxidoreductase Fe-S Protein 7 (NDUFS7)
    l Chromosome 19p13; Recessive
    - Onset: 1st year; Repeated vomiting
    - Neural: Hemiparesis; Hypotonia; Hyperactive tendon reflexes
    - Death: 1st decade
    - Pyruvate & Lactate: Normal in serum urine & CSF
    - MRI: Symmetric lesions in caudate, putamen & dentate
  - NADH-Ubiquinone Oxireductase Flavoprotein 1 (NDUFV1) (Complex 1) deficiency
    l Chromosome 11q13; Recessive
    - Protein: NADH- and FMN-binding site of complex I
    - Clinical
      - Onset: 5 months
      - Repeated vomiting
      - Strabismus
      - Hypotonia
      - Encephalopathy: Myoclonic epilepsy; Psychomotor regression
      - Some patients with Alexander disease
- Complex II: Succinate dehydrogenase, subunit A, Flavoprotein (SDHA; Fp) ²⁹
  l Chromosome 5p15; Recessive or Dominant
  - Genetics
    - Mutations: Missense
  - Epidemiology: 4 patients described
  - Clinical: Variable syndromes
    - Late onset: Dominant
      - Mutation: Arg451Cys
      - Onset: 4th decade
      - Cardiopathy: Hypertrophic
      - Skeletal muscle: Myopathy
      - Cerebellar ataxia
      - Optic neuropathy
    - Leigh syndrome: Recessive
      - Mutations
        
        Commonly in region of amino acids 524-555
        Action: ? Interfere with Fp-Ip molecular interaction
        Cause partial reduction in complex II activity
      - Onset: 9 months with psychomotor delay
      - Truncal ataxia: Delayed walking
      - Lactate: Mild increase in serum & CSF
      - MRI: Necrotic lesions in basal ganglia
  - Biochemistry of early onset disorders
    - Complex II activity
      - Reduced to 50% to 75% of lower limit of normals
      - Other complexes normal
    - Carnitine: High free & total
    - Lactate & Pyruvate: High
    - Krebs cycle intermediates high: Succinate > Fumarate & Malate
    - Ketone: High in urine
- Pyruvate carboxylase deficiency
  l Chromosome 11q13.4-q13.5; Recessive
  - Neonatal type
    - Onset: Neonatal
    - Delayed neurologic development
    - Ataxia
    - Chronic lactic acidemia
      - Normal lactate:pyruvate ratio
  - Less severe phenotype
    - Later infantile onset
    - Increased lactate:pyruvate & acetoacetate to 3-hydroxybutyrate ratios
- Pyruvate dehydrogenase complex (PDHC)
  - Pyruvate dehydrogenase complex: General
    - Structure
      - Nuclear-encoded mitochondrial matrix multienzyme complex
      - Composed of multiple copies of 3 enzymes
        
        E1 (PDHA1)
        
        Heterotetramer of 2 alpha and 2 beta subunits
        E1-alpha subunit contains E1 active site
        
        Dihydrolipoyl transacetylase (DLAT)
        Dihydrolipoyl dehydrogenase (DLD)
    - Function: Link between glycolysis and the tricarboxylic acid (TCA) cycle
    - Action: Catalyzes irreversible conversion of pyruvate into acetyl-CoA
- Pyruvate dehydrogenase E1-α deficiency (Pyruvate decarboxylase deficiency)
  l Pyruvate dehydrogenase E1-α (PDHA1) Chromosome Xp22.2-p22.1; Recessive
  - Onset: Early childhood
  - Clinical
    - Seizures
    - Hyperventilation
    - Cerebellar ataxia: Episodic
    - Chorioathetosis
    - Males: Presentation depends on the functional severity of E1-α mutation
    - Females: Clinical presentation may depend on pattern of X-inactivation in brain
    - Treatment: ? Thiamine
  - Laboratory
    - Lactic acidosis
    - Carbohydrate intolerance
    - Serum pyruvic acid: High
    - Serum alanine: High
    - E1-alpha protein: Low
- E3: Lipoamide (α-ketoglutaric) dehydrogenase deficiency
  l Chromosome 7q31-q32; Recessive
  - Genetics
    - Mutations: Missense or Truncating
    - G229C mutation in Ashkenazi Jews
  - Clinical
    - Onset
      - Infancy to Adulthood
      - More severe with earlier onset
    - Recurrent vomiting & Abdominal pain
    - Hypothermia
    - Motor retardation
    - Myoglobinuria: Occasional
    - Exertional fatigue between episodes
    - Treatment: ? Lipoic acid (Oral); Reduced Branched chain amino acids in diet
  - Laboratory
    - Lactic acidosis
    - High pyruvate, lactate, α-ketoglutarate, Branched-chain amino acids
    - Hypoglycemia: Intermittent
- Pyruvate dehydrogenase phosphatase deficiency
- Pyruvate dehydrogenase E3-binding protein deficiency
  l Pyruvate dehydrogenase complex, component X (PDHX) ; Chromosome 11p13; Recessive
Also see: Infantile encephalopathies

Quantitative errors in mtDNA (mtDNA depletion)

Autosomal Recessive
Acquired mitochondrial disorders: AZT (azidothymidine; Zidovudine) therapy

AZT
- Moderate depletion of mtDNA (70% to 80%)
- Myopathy associated with greater drug dose
- Muscle signs
  - Proximal weakness
  - Myalgia
  - Wasting
- EMG: Myopathic; Spontaneous activity
- Serum CK: High
- Myopathology
  - Necrosis
  - Mitochondrial proliferation: SDH + fibers
  - Numerous COX - muscle fibers
  - Fiber size variability
  - ± Inflammation
- Course: Improves after discontinuation of drug: Usually within 3 to 4 months

Inclusion Body Myositis

Multiple DNA deletions
Different deletions in each affected muscle fiber

Paragangliomas: Non-chromaffin, Hereditary

Succinate dehydrogenase complex, Subunit B, Iron sulfur protein (SDHB)
- Susceptibility to Pheochromocytoma & Paraganglioma
  l SDHB; Chromosome 1p36.1-p35; Dominant or Sporadic
  - Mutations: Germline; Truncating or Missense
  - Syndromes: Hereditary or Sporadic tumors
Succinate dehydrogenase complex, Subunit C, Integral membrane protein (SDHC)
- Protein
  - Large subunit (cybL) of cytochrome b in mitochondrial complex II
  - Integral membrane protein
- Hereditary paraganglioma (PGL3) : Nonchromaffin
  l SDHC; Chromosome 1q21; Dominant
  - Mutation: Point truncation
  - Benign vascularized tumors in the head and neck
  - No maternal imprinting
Succinate dehydrogenase complex, Subunit D, Integral membrane protein (SDHD)
- Protein
  - Small subunit (cybS) of cytochrome b in mitochondrial complex II
  - Integral membrane protein
- Hereditary paraganglioma (PGL1) : Nonchromaffin
  l SDHD; Chromosome 11q23; Dominant
  - Mutations: Point missense & truncation
  - Benign vascularized tumors in the head and neck
  - Tumor inheritance: Paternal, not maternal
    - ? Maternal imprinting of the disease gene
    - Penetrance: Incomplete; Age-dependent
NOTE: Mutations in SDHA cause Leigh like syndromes
External links
- Radiology
- General description

Other Mitochondrial Syndromes & Mutations

Mitochondrial syndromes: Infantile & Childhood Onset

Alpers
ATP12: 17p11
ATPase 7 (Menkes; Occipital horn): Xq12
Cardiomyopathy
COX10: 17p13
Dihydrolipoyl transacetylase E2
Ethylmalonic encephalopathy: ETHE1; 19q13
Fatal multisystemic complex I deficiency: NDUFS4: 5q11
Finnish neonatal metabolic syndrome: 2q33
Fumarate hydratase: 1q42
Glutaricaciduria, Type II
HADHA: 2p23
Hepatocerebral syndrome: mtDNA depletion
HMGCS2 deficiency: 1p13
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH syndrome): SLC25A15; 13q14
Infantile encephalopathy
Multiple mitochondrial dysfunctions: 2p14
Encephalopathy with Complex I deficiency: NDUFS1; 2q33
Leigh's
Lipoamide dehydrogenase deficiency (α-ketoglutaric dehydrogenase): 7q31
Mitochondrial ATPase deficiency
NADH Dehydrogenase (Ubiquinone) Fe-S Protein 4 (NDUFS4): 5q11
Necrotizing encephalopathy
Pantothenate kinase–associated neurodegeneration: PANK2; 20p13
Pyruvate dehydrogenase: Xp22
SCO1: 17p13
Severe neonatal lactic acidosis
Sudden infant death

Fumarase deficiency
l Fumarate hydratase ; Chromosome 1q42.1; Recessive
- Fumarate hydratase protein
  - Conversion of fumarate to malate
- Encephalopathy
  - Clinical
    - Onset: Infancy
    - Hypotonia
    - Microcephaly
    - Delayed development
    - Death < 1 year
  - Laboratory
    - Cerebral atrophy
    - Lactic and pyruvic acidemia
    - Fumaricaciduria
    - Fumarase deficiency: Reduced generally or selectively in skeletal muscle
- Other syndromes
  - Hereditary multiple cutaneous and uterine leiomyomatosis : Dominant or Mosaic
  - Hereditary leiomyomatosis and renal cell cancer : Dominant
Pyruvate dehydrogenase, E1-α Polypeptide 1
l Recessive; Chromosome Xp22.2-p22.1
NADH Dehydrogenase (Ubiquinone) Fe-S Protein 4 (NDUFS4) : Complex I
l Chromosome 5q11; Recessive
- Clinical syndrome: Fatal multisystemic complex I deficiency
  - Onset: Vomiting; Failure to thrive; Hypotonia
  - Other CNS: Psychomotor retardation; Convulsions; Bradypnea; Reduced tendon reflexes
  - Course: Progressive cardiorespiratory; Death in 2nd year
- Laboratory
  - Cerebral MRI: Generalized brain atrophy; Symmetric basal ganglia change
  - Serum lactate: Normal
  - Muscle morphology: Normal
- Also: Leigh syndrome
Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH syndrome)
l Ornithine transporter, Mitochondrial 1 (ORNT1; SLC25A15) ; Recessive; Chromosome 13q14
- ORNT1 protein
  - Transports ornithine across inner mitochondrial membrane
  - From cytosol to mitochondrial matrix
  - Component of urea cycle
- Clinical syndrome
  - General
    - Similar to other urea cycle disorders
    - External link: Urea cycle disorders
  - Onset age: Infancy to 18 years
  - CNS
    - Mental retardation & Learning difficulties
    - Episodic confusion
    - Seizures: Myoclonus epilepsy
    - Buccofaciolingual dyspraxia
  - Spastic paraparesis: Progressive
    - Pyramidal signs
    - Vibration sense: Reduced
  - Weakness & Atrophy
    - Distal legs
    - ? 2° Motor neuron loss
  - GI: Episodic vomiting
  - Ocular: Retinal depigmentation; Chorioretinal thinning
- Lab
  - Hyperornithinemia
  - Hyperammonemia
  - Homocitrullinuria
  - Reduced Ornithine transport into mitochondria
  - Abnormal white matter on cranial MRI
- Treatment
  - Low protein diet
  - Ornithine supplementation
Mitochondrial ATPase deficiency⁴
l ? Autosomal Recessive
- Genetics
  - ? Nuclear DNA mutation: ? gene
  - Several other syndromes with mitochondrial DNA ATPase mutation (ATPase6)
    - Nucleotide 8993 in mitochondrial gene: Leighs (Maternal); NARP
    - T8851C: Bilateral striatal syndrome; Homoplasmic
    - T9176C: Leigh or Sudden death; Heteroplasmic or Homoplasmic
    - T9101C: LHON
- Onset: Congenital
- Systemic: Cardiomegaly; Hepatomegaly
- Lab
  - Serum: Lactic Acidosis
  - Tissue biochemistry
    - Selective reduction in oligomycin sensitive ATPase activity (18 to 33% of normal)
    - Short half-life of ATPase β subunit
    - Reduced Proton leak in inner mitochondrial membrane
- Prognosis: Death at 2 days
Complex V (ATP synthase) deficiency³⁹
l ATP 12 ; Chromosome 17p11.2; Recessive
- Epidemiology: 1 patient from consanguinous family
- ATP12 mutations: W94R homozygous
- ATP12 protein
  - Role in assembly of F1 moiety of ATP synthase
  - Protects F1 subunits from forming non-productive large complexes during assembly of enzyme oligomer
- Clinical
  - Onset: Congenital
  - Skeletal: Dysmorphic features
    - Mouth: Large; Micrognathia
    - Nasal bridge: Prominent
    - Feet: Rocker bottom
    - Contractures: Flexion; Camptodactylia
  - Motor: Hypertonia; Poor suck
  - Hepatomegaly
  - Death: 14 months due to infection
- Laboratory
  - Lactate: High
  - Urine: High lactate, fumarate, methylglutaconic acid, & amino acids
  - Imaging
    - Cortical–subcortical atrophy
    - Corpus callosum: Dysgenesis; Absent anterior genu and rostrum
    - White matter: Hypoplasia
    - Basal ganglia & thalami: Atrophic
  - Complex V
    - Reduced activity
    - More prominent changes in liver than muscle
  - Muscle morphology
    - Lipid: Increased
    - No ragged red fibers
  - Liver: Reduced Complex V immunoreactivity (α, β & δ subunits)
- NOTE: Other patients with similar syndrome & Complex V deficiency without ATP12 mutations
SCO1
l Chromosome 17p13.1; Recessive
- SCO1 protein
  - Location: Inner mitochondrial membrane
  - Tissue distribution: Ubiquitious
  - Role in assembly of Complex IV (Cytochrome oxidase)
    - More in mitochondrial rich tissues: Skeletal muscle; Heart; Liver; Kidney
    - Lower expression in brain
- Clinical
  - Liver: Neonatal hepatic failure; Hepatomegaly
  - Neurologic: Ketoacidotic coma; Hypotonia
  - Course: Recurrent apnea & bradycardia; Death < 2 to 3 months
- Laboratory
  - Metabloic acidosis
  - Hypoglycemia
  - Hyperlactatemia
  - COX deficiency in liver, muscle lymphocytes
  - Muscle pathology: Lipid droplets
Sudden infant death syndrome: Occasional mutations identified in
- Mitochondrial Leucine Transfer RNA 1 (MTTL1) : Also see MELAS
- NADH Dehydrogenase, Subunit 1 (MTND1) (Complex 1): Also see Leber's optic atrophy
- Hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-coa hydratase, beta subunit (HADHB) :
  Trifunctional protein deficiency, type 2
Finnish lethal neonatal metabolic syndrome
l Chromosome 2q33-q37; Recessive
- Genetics: Locus near ATP-Binding cassette B6 (ABCB6)
- Epidemiology: Several Finnish families
- Clinical
  - Growth retardation: Intrauterine
  - Failure to thrive
  - Death: Neonatally or Early infancy
- Laboratory
  - Lactic acidosis: 1st days of life
  - Aminoaciduria: Fanconi-type
  - Iron metabolism disorder: Liver hemosiderosis
Severe neonatal lactic acidosis
Cu⁺⁺ transporting ATPase 7
- Menkes : α polypeptide
  l Chromosome Xq12-q13; Recessive
- Occipital horn syndrome : α polypeptide
  l Chromosome Xq12-q13; Recessive
Infantile encephalopathy with multiple mitochondrial dysfunctions¹²
l Chromosome 2p14-p13; Recessive
- Clinical
  - Onset: 1st month
  - Feeding difficulty
  - Motor: Weakness; Hypotonia; Respiratory failure
  - CNS: Lethargy; Seizures
  - Hepatomegaly
  - Course: Death 1 month to 1 year
- Laboratory
  - Biochemistry: Multiple mitochondrial enzymopathies
  - Metabolic acidosis
  - High blood lactate
  - Glycine: High
  - Pathology: White matter spongiosis
2,4-Dienoyl-CoA reductase deficiency
l Chromosome 8q21.3; Recessive
- Protein
  - Allows β-oxidation of lineolate
- Neonatal hypotonia
- Lab: Disorder of Fatty acid oxidation
  - Hyperlysinemia
  - Hypocarnitinemia
  - 2-trans,4-cis-decadienoylcarnitine in urine & blood
  - Normal organic acids
Hydroxyacyl-CoA Dehydrogenase/3-Ketoacyl-CoA Thiolase/Enoyl-CoA Hydratase, alpha subunit (HADHA)
Trifunctional protein, alpha subunit
l Chromosome 2p23; Recessive
- Trifunctional Protein function
  - Catalyzes 3rd step in long-chain intra-mitochondrial β-oxidation
  - Source of energy in skeletal muscle & heart
- Clinical: Several syndromes
  - Infantile
    - Onset: 1st 2 years
    - Cardiomyopathy
    - Muscle hypotonia
    - Hepatomegaly
    - Retinopathy: Pigmentary
    - Course
      - Recurrent metabolic crises, or Steadily progressive
      - Death < 2 years
      - ? Benefit from dietary management
    - Mother: Acute fatty liver during pregnancy; Associated severe complications
    - Laboratory
      - Hypoketotic Hypoglycemia
      - Lactic acidemia
      - Dicarboxylic aciduria
      - Reduced Carnitine levels
  - Myopathy & Neuropathy
    - Myopathy
      - Onset: 2nd year
      - Episodes: Severe weakness; Precipitated by fever, vomiting, or dehydration
      - Myoglobinuria: Precipitated by infection, fasting, exertion, or cold exposure
      - Weakness: Proximal; Symmetric
    - Polyneuropathy
      - Weakness: Distal; Symmetric
      - Sensory loss
      - Axonal loss: ? 2° Demyeliantion
    - No hepatic or cardiac disorders
    - Treatment
      - Frequent feeding: High-carbohydrate, low-fat diet
      - Uncooked oral cornstarch
      - ? Cod liver oil, High in Docosahexaenoic acid (DHA)
      - ? Prednisone
Dihydrolipoyl transacetylase E2
l Recessive
- Clinical
  - Onset: 2 weeks
  - Encephalopathy
  - Mental retardation
  - Microcephaly
  - Treatment: Carbohydrate restriction; Bicarbonate supplementation
- Laboratory
  - Hyperammonemia
  - Lactic acidosis
3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency
l Chromosome 1pter-p33; Recessive
- Disorder of ketone synthesis
- Clinical
  - Onset: First year
  - Fever
  - Encephalopathy
  - Hepatomegaly
  - Especially severe & common in Saudi Arabia
  - Urine odor resembles cat
  - Treatment: Leucine restriction; Supplementary glucose to prevent hypoglycemia
- Laboratory
  - Metabolic acidosis
  - Hypoglycemia
  - Organic aciduria
  - Sensitivity to dietary leucine
  - Carnitine deficiency
mtDNA depletion: Hepatocerebral syndrome
l Deoxyguanosine kinase (DGUOK) ; Chromosome 2p13; Recessive
- Mutations: Homozygous²⁶
  - Single nucleotide deletion in exon 2
  - Nonsense mutation in exon 3
  - ? Non-coding region mutations
- DGUOK protein
  - Expressed in all tissues
  - Mitochondrial
  - Function: Deoxynucleoside salvage
  - Phosphorylates deoxyguanosine and deoxyadenosine
- Epidemiology: Israeli-Druze & German families
- Onset: Birth to 6 months
- Clinical
  - Hepatic failure: Hepatomegaly
  - Failure to thrive
  - Eyes: Oscillating (Pendular) movements
  - Neurological disorders
    - Muscle hypotonia
    - Hyperreflexia
    - Irritability
  - Death: < 1 year; Hepatic failure
- Laboratory
  - Lactic acidosis
  - Hypoglycemia
  - α-Fetoprotein: High in serum
  - Muscle: May be morphologically normal
  - Mitochondrial changes in muscle
    - Low activity: Complex I, III, IV
    - Normal activity: Complex II
    - mtDNA depletion: 8% to 39% of control levels
    - mtDNA size: Normal
  - Liver: Mosaic pattern of normal and deficient cytochrome-c oxidase in hepatocytes
- Also see
  - Later onset mtDNA depletion myopathy
  - mtDNA depletion syndromes
Childhood encephalopathy with complex I deficiency
l NADH-ubiquinone oxidoreductase Fe-S protein 1 (NDUFS1) ; Chromosome 2q33-q34; Recessive
- Mutations: Point mutations; Small Deletions
- NDUFS1 protein: NADH:ubiquinone oxidoreductase; Subunit of complex I
- Onset: 2 months to 2 years
- Clinical
  - Psychomotor retardation
  - Hypotonia
  - Ocular: Nystagmus; Optic atrophy
  - Ataxia: Episodic; Older onset patients
  - Course: Death < 1 year in early onset patients
- Laboratory
  - CNS: Leukodystrophy
  - Lactate: High in Blood & CSF
Encephalomyopathy with Dominant mtRNA^Trp mutation²³
l mtRNA^Trp (MTTW) ; Mitochondrial DNA; Dominant
- Mutation: C5545T
- Clinical
  - Developmental delay: Severe
  - Hypotonia
  - Ataxia
  - Chorea
  - Seizures
  - Hypertrophic cardiomyopathy
- Laboratory
  - Lactic acidosis
  - Muscle: Reduced COX activity; No ragged red muscle fibers
- Other mtRNA^Trp syndromes
  - Encephalopathy: G5549A
  - Encephalopathy or Leigh syndrome: 1-BP ins, 5537T
  - Myopathy: G5521A
  - Exercise intolerance: T5543C
  - Neurogastrointestinal syndrome: G5532A
Microcephaly, Amish type
l SLC25A19 ; Chromosome 17q25.3; Recessive
- SLC25A19 protein
  - Mitochondrial solute carrier: Mitochondrial deoxynucleotides
- Epidemiology: Old-Order Amish of Lancaster County, Pennsylvania
- Clinical features
  - Congenital microcephaly: Frontal sloping; Small cranial vault
  - CNS: No orientation to light or sound
  - Motor: No fine or gross development; Normal tone
  - Episodic viral illnesses precipitate metabolic acidosis
  - Hepatomegaly: Mild
  - Progression
    - Increasing irritability after 1st 2 or 3 months
    - Death: Mean 24 weeks; Range 0 to 60 weeks
- Laboratory
  - 2-Ketoglutaric aciduria
  - Pathology: Immature brain with no gyral development; Cerebellar vermal hypoplasia, mild
Alpers-Huttenlocher disease³²
l Recessive or Sporadic
- Epidemiology: Mild male prevalence
- Clinical
  - Onset: Childhood; Epilepsia partialis continua
  - Encephalopathy: Episodic; Precipitated by fever
  - Epilepsy: Myoclonic
  - Central visual function: Impaired
  - Sensory loss: Described in 1 patient with juvenile form³²
    - Sensory ataxia
    - Dorsal root ganglion: Loss of neurons
    - Nerve pathology: Loss of myelinated axons
    - Posterior columns: Loss of myelinated axons
  - Liver: Progressive failure; Acute dysfunction precipitated by valproic acid
  - Course: Progressive over years; Episodes of deterioration
- Laboratory
  - Mitochondrial disorder: Abnormal oxidative metabolism
  - Muscle: Occasional COX- muscle fibers; Respiratory enzymes normal
  - CSF: High protein & Lactate
Glutaricaciduria, Type II:
- Type IIA (MADD)
  l Electron transfer flavoprotein, α subunit (ETFA) ; Chromosome ?; Recessive
- Type IIB
  l Electron transfer flavoprotein, β subunit (ETFA) ; Chromosome 19q13.3; Recessive
- Type IIC
  l Electron transfer flavoprotein dehydrogenase (ETFDH) ; Chromosome 4q32-qter; Recessive
- Clinical
  - All have similar neonatal syndromes: See Type IIA
Ethylmalonic encephalopathy
l ETHE1 ; Chromosome 19q13; Recessive
- Nosology
  - EPEMA: Encephalopathy, Petechiae, Ethylmalonic Aciduria
- Genetics: Mutations
  - Most are loss of function: Stop, Frameshift, Deletion or Aberrant splicing
  - Missense mutations: All predict amino acid changes in highly conserved positions
  - Patients often homozygous
- ETHE1 protein
  - Mitochondrial matrix protein (Inner compartment)
  - Function: Mitochondrial homeostasis & energy metabolism
- Clinical
  - Onset: Bimodal
    - Age
      - Neonatal (25%)
      - Infantile (2 to 7 mo)
    - Course
      - Acute: Orthostatic acrocyanosis, petechiae, seizures, hypotonia
      - Chronic: Delayed development; Cognitive dysfunction
  - Skin
    - Petechiae: Recurrent
    - Acrocyanosis: Hands & Feet; Orthostatic
  - CNS
    - Developmental delay & Regression
    - Hypotonia: Axial
    - Seizures
    - Pyramidal signs
    - Extrapyramidal
  - Diarrrhea: Chronic
  - Course
    - May be acute or chronic
    - Death: 1st decade; Often 1st year
- Laboratory
  - MRI (FLAIR): High-intensity signal in deep gray (Caudate & Putamen)
  - Muscle histochemistry: COX staining markedly reduced
  - Fibroblasts: COX activity often normal
  - Lactic acidemia
  - C4 and C5 acylcarnitine species: High in plasma
  - Urine high in
    - Ethylmalonic acid (EMA)
    - C_4–6 acylglycines (Isobutyrylglycine and 2-methylbutyrylglycine)
- Differential diagnosis of high EMA
  - Short-chain acyl-CoA dehydrogenase deficiency
  - Glutaric acidemia type 2 (Ethylmalonic adipic aciduria)
  - Jamaican vomiting sickness
Also see
- Leigh's syndrome(s)
- Cardiomyopathy

Mitochondrial syndromes: Childhood Onset

COX10 (Heme A:farnesyltransferase) : Cytochrome oxidase deficiency
l Chromosome 17p13.1-q11.1; Recessive
- Mutations
  - Missense
  - Asp204Lys
  - Located in 2nd transmembrane segment of protein
  - Other: COX10 may be mutated with HNPP deletion
- Protein
  - Complex IV
  - Function: Required for biogenesis of functional cytochrome c oxidase
  - Location: Mitochondrial inner membrane
- Epidemiology: Family of African ancestry
- Onset
  - 1 to 2 years
  - Ataxia
- Clinical
  - Motor
    - Weakness
    - Hypotonia
    - Pyramidal syndrome
  - Ataxia
  - Ptosis
  - Status epilepticus
- Course: Death by 3 to 5 years
- Laboratory
  - Lactate: Increased in Blood & CSF
  - Increased Urinary amino acids: Suggests proximal renal tubulopathy
  - Biochemistry: Isolated deficiency of cytochrome oxidase (COX)
    - Tissues: Muscle, Lymphocytes, Fibroblasts
    - Selective reduction of Subunit II by Western blot analysis
3-Hydroxy-3-methylglutaryl-CoA synthase 2, mitochondrial deficiency
l HMGCS2 ; Chromosome 1p13-p12; Recessive
- HMGCS2 Protein: Mediates early step in ketogenesis
- Onst: 1st decade
- Encephalopathy or seizures: Episodic
  - After prolonged fasting
  - Associated with hypoglycemia
Acute necrotizing encephalopathy
l Autosomal Dominant
- Epidemiology: Single family
- Genetic: Dominant with incomplete penetrance
- Onset
  - Acute
  - Altered mental status
  - Age: Usually < 4 years; Range 8 months to 6 years
  - Prodrome: Febrile illness (94%); URI (50%)
- Clinical
  - Initial development: Normal
  - Vomiting (30%)
  - CNS
    - Seizures (50%)
    - Tone: Spasticity; Rigidity; Abnormal posturing,
    - Altered mental status: Usually leading to coma
    - Breathing patterns: Abnormal (25%); Hypopnea, Apnea, Cheyne–Stokes
    - Hemiparesis: (12%)
  - Course
    - Death in 20%
    - Relapses
      - Some patients
      - Age: Usually < 6 years; Range 3 to 27 years
      - Time from previous episode: Usually 6 months to 3 years
    - Residual disability: Common
      - Full recovery in 36%
      - More disability after recurrent episodes
      - Types
        
        Weakness
        Seizures
        Gait abnormalities
        Speech disturbance
        Mental retardation
        Mood disorders
    - Difference from Leigh encephalopathy: No chronic course
- Pathology
  - Cerebral edema
  - Hemorrhagic lesions
    - Perivascular
    - Thalamus; Putamen; Brain stem
  - Microgliosis
  - No inflammation
- MRI
  - Symmetric T2-weighted hyperintensities
  - Localization: Cortex; Thalamus; Brainstem
- Muscle biopsy
  - Light microscopy: Normal
  - Ultrastructure: Pleomorphic mitochondria
  - Biochemistry
    - Loose coupling of oxidative phosphorylation: High O₂ consumption when ADP depleted
    - Electron transport chain complexes I to IV & Pyruvate dehydrogenase complex: Normal
Pantothenate kinase–associated neurodegeneration (PKAN; Hallervorden-Spatz syndrome) ⁴⁰
l Pantothenate kinase 2 (PANK2) ; Chromosome 20p13-p12.3; Recessive
- Genetics
  - Early-onset, rapidly progressive disease: Associated with null mutations
  - More mild disease with later age at onset: Missense mutations; Likely to retain partial enzyme function
- Pantothenate kinase (PANK2) protein
  - Regulatory enzyme in biosynthesis of coenzyme A (CoA)
  - CoA roles: Energy metabolism; Fatty acid synthesis & degradation; Neurotransmitter & glutathione metabolism
  - PANK2 subcellular location: Mitochondria
- Typical PKAN phenotype
  - Onset
    - Age: 1st decade; Mean 3 to 4 years
    - Gait abnormality
  - Clinical
    - Extrapyramidal: Dystonia, Dysarthria, Rigidity
    - Corticospinal: Spasticity, Hyperreflexia, Extensor toe signs
    - Ocular
      - Pigmentary retinopathy: Two thirds of childhood cases
      - Optic atrophy
  - Progression
    - Rapid
    - Lose ability to ambulate independently within 10 to 15 years of onset
    - Intermittent periods of rapid, often precipitous, clinical deterioration
  - Variant subgroup
    - Hypoprebetalipoproteinemia, acanthocytosis, retinopathy, and pallidal degeneration (HARP)
- Atypical PKAN
  - Onset
    - Mean 13 to 14 years
    - Neurobehavioral disorders
  - Clinical
    - Behavioral
      - Mood: Depression, Emotional lability
      - Personality changes
      - Cognitive decline
      - Speech disorders
        
        Palilalia & Tachylalia
        Hypophonia
        Difficulty initiating speech
    - Extrapyramidal
      - Dystonia
      - Rigidity
    - Corticospinal: Spasticity
  - Progression
    - Slower than typical form
    - Loss of independent ambulation after 15 to 40 years
    - Intermittent periods of rapid clinical deterioration
- MRI: Globus pallidus on T2-weighted images
  - Central region of hyperintensity
    - Primary tissue insult
    - Produces edema
  - Surrounding hypointensity
    - Region high in iron
    - May be 2° process
  - "Eye-of-the-tiger" sign
- Pathology
  - Deposition of iron
    - Especially globus pallidus & retina
    - Other iron deposition disorders
      - Karak syndrome
      - Neuroferritinopathy
      - Aceruloplasminemia
      - Friedreich ataxia
  - Axonal spheroids: In regions of iron deposition
- Other laboratory features
  - Acanthocytosis
  - Hypoprebetalipoproteinaemia
  - Serum CK: May be high or normal
  - Muscle
    - Scattered fiber necrosis
    - Macrophage activation
    - Mitochondrial: Reduced COX staining

Mitochondrial syndromes: Adult onset CNS

NADH Dehydrogenase, Subunit 1
- Alzheimer's/Parkinsonism
- Leber hereditary optic neuropathy
NADH Dehydrogenase, Subunit 2
- Increased longevity
  - 5178C-A transversion: Increased frequency in Japanese centenarians
- Leber hereditary optic neuropathy
NADH Dehydrogenase, Subunit 3 (ND3)
- Parkinsonism: Protective effect
  - 10398G: Nonconservative amino acid change from threonine to alanine
  - Protective effect in whites; Women > Men
- Migraine & Encephalopathy: Ser45Pro mutation
NADH Dehydrogenase, Subunit 4
- Spastic dystonia
- Leber hereditary optic neuropathy
tRNA Thr & tRNA Pro
- Occasional sporadic Parkinsonism
Cu⁺⁺ transporting ATPase 7B
- Wilson's : β polypeptide
  l Chromosome 13q14.3-q21.1; Recessive
Huntingtin
- Huntington's chorea
  l CAG repeat disorder; Chromosome 4p16.3; Dominant
  - Huntingtin protein: Not mitochondrial
  - Mitochondrial OXPHOS defects
    - Severe deficiencies of complexes II and III & moderate defect of complex IV
    - Aconitase deficiency
  - Locations
    - Caudate > Putamen & Cortex: Similar to neuronal pathology
    - Skeletal muscle
POLG1
- PEO
- Parkinson syndrome
- Sensory neuropathy

Migraine & Encephalopathy
l Complex I, Subunit 3 (ND3)

; Mitochondrial DNA

Genetics
- Mutation: Serine45Pro (T10191C)
- Heteroplasmic: Skeletal muscle 77%; Blood 14%
- Low level of mutation in mother: 3% in blood
Onset
- Age: 24 years
- Migraine
Clinical
- Migraine
- Epilepsy: Progressive myoclonic
- Ataxia
- Eye
  - Optic atrophy: Subacute painless central scotoma
  - EOM: Absent upgaze & Convergence; Reduced downgaze
  - Pupils: Bilateral afferent defects
- Upper motor neuron: Increased tone; Brisk tendon reflexes
- Myoclonic jerks: Occasional
- Peripheral nerve: Neuropathy on electrical studies
- Disease progression: Over 20 years
Laboratory
- MRI: Increased signal in midbrain
- Muscle pathology: Varied fiber size; No ragged red or COX- muscle fibers
- Respiratory enzymes: Reduced Complex I activity

Germanium myopathy

Myopathy: Proximal weakness
Polyneuropathy: Axonal; Autonomic
Systemic
- GI: Nausea & vomiting; Anorexia & weight loss
- Renal failure: Tubular degeneration & Interstitial fibrosis
Myopathology
- Myopathy: Necrosis & regeneration
- Ragged red fibers
- Cytochrome oxidase: Reduced in atrophic fibers
- Lipid: Increased in muscle fibers
- Vacuoles
- Mitochondria with electron dense inclusions

Mitochondrial Solute Carriers (SLC25A family & Others)

Inner mitochondrial membrane

SLC25A family: General
- Transported to inner mitochondrial membrane by carrier proteins
- 6 potential transmembrane domains
- Nuclear encoded
- External links: Saier
  - Carrier proteins
  - Mitochondrial carrier proteins
Types of carriers
- SLC25A1
  - Tricarboxylate transporter (Citrate transport protein (CTP))
- SLC25A3
  - Phosphate carrier
- SLC25A4 (ANT1)
  - Adenine nucleotide translocator
  - Tissue: Skeletal & cardiac muscle
  - Disease: PEO2/PEO3
  - Mouse knockout
    - Exercise intolerance
    - ATP deficiency
    - Skeletal muscle: Ragged-red muscle fibers; Increased Mitochondrial number
    - Cardiac: Hypertrophy with mitochondrial proliferation
    - Serum Lactate: High
- SLC25A5 (ANT2)
  - Catalyzes exchange of ADP & ATP
  - Most abundant mitochondrial protein
  - No related disease
- SLC25A6 (ANT3)
  - Catalyzes exchange of ADP & ATP
  - Tissue: Liver
- SLC25A10
  - Dicarboxylate carrier
  - Transports pyruvate & H⁺ across inner mitochondrial membrane into matrix
  - Exchange for phosphate, sulfate & thiosulfate
  - Supplies substrates for Krebs cycle, gluconeogenesis, urea synthesis & sulfur metabolism.
- SLC25A11
  - Oxoglutarate carrier
- SLC25A12
  - Ca⁺⁺ binding
  - Expression: Heart & Skeletal muscle > Brain & kidney
- SLC25A13
  - Expression: Most abundant in liver
  - Ca⁺⁺ binding
  - Disease: Adult-onset type II citrullinemia (CTLN2)
- SLC25A14
  - Expression: Brain
  - Uncoupling protein: Proton channel
- SLC25A15
  - Ornithine transporter: Across inner mitochondrial membrane
  - Maintains NH₄⁺ ions in non-toxic range
  - Disease: HHH syndrome
- SLC25A16 (Graves Disease Carrier Protein (GDC))
  - ADP/ATP carrier protein
  - Target of IgG autoantibodies in Graves disease
- SLC25A17
  - Peroxisomal membrane protein
- SLC25A19
  - Mitochondrial deoxynucleotide carrier (Deoxynucleotide diphosphates)
  - Disease: Microcephaly, Amish type
  - ADP/ATP carrier protein
  - Target of IgG autoantibodies in Graves disease
- Mitochondrial uncoupling protein (UCP1)
  - Proton channel
  - Inactivation of gene (mouse): Cold-sensitivity; No obesity
  - ? Disorder: Oxidation-phosphorylation uncoupling
- ATPase deficiency: Reduced H⁺ transport
- Carnitine transport
  - Carnitine-acylcarnitine translocase deficiency
  - Carnitine palmitoyltransferase II deficiency

Outer mitochondrial membrane

Voltage dependent anion selective channel proteins
- VDAC1
- VDAC2

Also see: Mitochondrial protein carriers

Return to Neuromuscular Home Page
Return to Neuromuscular Syndromes

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