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线粒体紊乱的病理生理学研究综述

信息来源：本站原创　更新时间：2004-9-26 0:31:00

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
 TCA cycleBeta-OxidationFatty acyl-CoA & Carnitine transportATPANTGlycolysisGeneral mitochondrial functionsAcetyl-CoAPyruvate via PDHC to Acetyl-CoAOxidative Phosphorylation


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

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
    • 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 (OH)
      • Procedes unidirectionally: To origin of replication of light strand (OL)
        • 2/3 of way around genome
        • Between cluster of 5 tRNA genes
      • When OL 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: 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
    • 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
      • 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

    Intense SDH staining
    of a muscle fiber with
    mitochondrial proliferation

Nuclear encoded mitochondrial proteins

General clinical features of mitochondrial disorders

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
  • 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
      • 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
      • 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)
      • 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


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
        • 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
        • 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
    • 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
  tRNALeu(UUR)
    MELAS
    PEO
  tRNALeu(CUN)
  tRNAAsn
  tRNAGln: PEO-plus
  tRNAAla: PEO-plus
  tRNATyr: PEO-plus
  tRNALys: PEO-plus
  tRNAIle


Ophthalmoplegia: General Features
  • Gaze limited in all directions
  • Eye movement speed: slow
  • Bilateral
  • Associated with ptosis
  • Course: Slowly progressive
Sporadic PEO
  • More severe ophthalmoplegia
  • 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

  • tRNAGln : PEO
    • Genetic