Neuromuscular

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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 cycle Beta-Oxidation Fatty acyl-CoA & Carnitine transport ATP ANT Glycolysis General mitochondrial functions Acetyl-CoA Pyruvate via PDHC to Acetyl-CoA Oxidative Phosphorylation



Mitochondria: General33

Origin of mitochondria Structural features of mitochondria: 4 compartments Mitochondrial DNA (mtDNA) Mitochondrial Biogenesis: Skeletal muscle Functions of mitochondria

Mitochondrial DNA (mtDNA): General features

Differences from Nuclear DNA
Inheritance
mtDNA variation
Mutations
Pathogenic mechanisms
Structure
Transcription & translation

Mitochondrial disorders: General pathogenic mechanisms7


Mitochondrial disorders: mtDNA mutations

External links: Mitochondrial DNA mutations

Nuclear encoded mitochondrial proteins


General clinical features of mitochondrial disorders

Laboratory evaluation of mitochondrial disorders



MITOCHONDRIAL DISORDERS: CLINICAL SYNDROMES
Adult onset
Alexander disease: GFAP; NDUFV1
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
Eye
  Blindness
    Gyrate atrophy
    Optic atrophy
      Wolfram
        WFS1; 4p16
        WFS2; 4q22
  Ophthalmoplegia, External (PEO)
    Dominant: Multiple mtDNA deletions
    Maternal: mtDNA point mutations
    Recessive: mtDNA depletion; Multiple mtDNA deletions  
    Sporadic: Single mtDNA deletion
    ? Immune (HyperThyroid)
Fatigue & Exercise intolerance
Friedreich ataxia: Frataxin; 9q13
Functional defects
Gastrointestinal
HAM: mtDNA tRNA Ser
Huntington's chorea
Hypoglycemia
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: mtRNA Leu + other
Menkes: ATPase 7a; Xq12
MERRF: mtRNA Lys & Ser
MILS
MNGIE: Thymidine phosphorylase; 22q13
Multiple symmetric lipomatosis: mtRNA 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 2A2: MFN2; 1p36
  CMT 2K: GDA P1; 8q21
  CMT 4A: GDA P1; 8q21
  Sensory neuropathy: Recessive; Sporadic
Occipital horn syndrome: ATPase 7a; Xq12
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
  SPG31: REEP1; 2p12
  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
  Trichloroethylene
  Valproate: Precipitates seizures in MELAS
Wilson's disease: ATPase 7B; 13q14
Classifications of Mitochondrial Disorders
  Biochemical
  Clinical
  Genetic: mtDNA; Nuclear


NARP

(Neuropathy; Ataxia; Retinitis Pigmentosa)
  l ATPase 6 (Complex V)

MELAS

(Mitochondrial Encephalomyopathy; Lactic Acidosis; Stroke)

MERRF 66

(Myoclonic Epilepsy; Ragged Red Fibers)


MNGIE10

Also see: Neuro-Gastro-intestinal variants


(Myopathy and external ophthalmoplegia; Neuropathy; Gastro-Intestinal; Encephalopathy)
  l Thymidine phosphorylase (TP; ECGF1) ; Chromosome 22q13.32-qter; Recessive

LHON 30

(Leber's; Hereditary; Optic; Neuropathy)

Kearns-Sayre Syndrome


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
  POLG2: 17q
  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
Sporadic PEO
Maternal PEO


PEO: Autosomal Dominant

Autosomal Dominant PEO: Clinical features

Ophthalmoplegia

Triple furrowed tongue
  Twinkle: 10q23
  ANT1: 4q35
  POLG: 15q25
  POLG2: 17q
  Hypogonadism