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- Mitochondria

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Table 1 Genetic classification of human mitochondrial disorders

Type of disorder Inheritance pattern
Mitochondrial genetic disorders*
Rearrangements (large scale partial deletions and duplications)
Chronic progressive external ophthalmoplegia (CPEO) S
Kearns-Sayre syndrome S
Diabetes and deafness S
Pearson marrow-pancreas syndrome S
Sporadic tubulopathy S
Point mutations
Protein encoding genes
    
  • LHON (G11778A, T14484C, G3460A)
M
    
  • NARP/Leigh syndrome (T8993G/C)
M
tRNA genes
    
  • MELAS (A3243G, T3271C, A3251G)
M
    
  • MERRF (A8344G, T8356C)
M
    
  • CPEO (A3243G, T4274C)
M
    
  • Myopathy (T14709C, A12320G)
M
    
  • Cardiomyopathy (A3243G, A4269G, A4300G)
M
    
  • Diabetes and deafness (A3243G, C12258A)
M
    
  • Encephalomyopathy (G1606A, T10010C)
M
rRNA genes
    
  • Non-syndromic sensorineural deafness (A7445G)
M
    
  • Aminoglycoside induced non-syndromic deafness (A1555G)
M
Nuclear genetic disorders
Disorders of mtDNA maintenance
Autosomal dominant progressive external ophthalmoplegia (with 2° multiple mtDNA deletions)
    
  • Mutations in adenine nucleotide translocator (ANT1)
AD
    
  • Mutations in DNA polymerase {gamma} (POLG)
AD or AR
    
  • Mutations in Twinkle helicase (C10orf2)
AD
Mitochondrial neuro-gastrointestinal encephalomyopathy (with 2° multiple mtDNA deletions)
    
  • Mutations in thymidine phosphorylase (TP)
AR
Myopathy with mtDNA depletion
    
  • Mutations in thymidine kinase (TK2)
AR
Encephalopathy with liver failure
    
  • Mutations in deoxyguanosine kinase (DGK)
AR
Primary disorders of the respiratory chain
Leigh syndrome
    
  • Complex I deficiency: mutations in complex I subunits (NDUFS2, 4, 7, 8, and NDUFV1)
AR
    
  • Complex II deficiency: mutations in complex II flavoprotein subunit (SDH)
AR
Leukodystrophy and myoclonic epilepsy
    
  • Complex I deficiency: mutations in complex I subunit (NDUFV1)
AR
Cardioencephalomyopathy
    
  • Complex I deficiency: mutations in complex I subunit (NDUFS2)
AR
Optic atrophy and ataxia
    
  • Complex II deficiency: mutations in complex II flavoprotein subunit (SDH)
AD
Disorders of mitochondrial protein import
Dystonia-deafness
    
  • Mutations in deafness-dystonia protein DDP1 (TIMM8A)
XLR
Disorders of assembly of the respiratory chain
Leigh syndrome
    
  • Complex IV deficiency: mutations in COX assembly protein (SURFI)
AR
    
  • Complex IV deficiency: mutations in COX assembly protein (COX10)
AR
Cardioencephalomyopathy
    
  • Complex IV deficiency: mutations in COX assembly protein (SCO2)
AR
Hepatic failure and encephalopathy
    
  • Complex IV deficiency: mutations in COX assembly protein (SCO1)
AR
    
  • Complex IV deficiency: mutations in protein affecting COX mRNA stability (LRPPRC)
AR
Tubulopathy, encephalopathy, and liver failure
    
  • Complex III deficiency: mutations in complex III assembly (BCS1L)
AR
*mtDNA nucleotide positions refer to the L-chain, and are taken from the standard Cambridge reference sequence). AD, autosomal dominant; AR, autosomal recessive; M, maternal; S, sporadic; XLR, X linked recessive.

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Table 2 Clinical syndromes associated with mitochondrial disease

Syndrome Primary features Additional features
Chronic progressive external ophthalmoplegia (CPEO) External ophthalmoplegia and bilateral ptosis Mild proximal myopathy
Infantile myopathy and lactic acidosis (fatal and non-fatal forms) Hypotonia in the first year of life; feeding and respiratory difficulties Fatal form may be associated with a cardiomyopathy and/or the Toni-Fanconi-Debre syndrome
Kearns-Sayre syndrome (KSS) PEO onset before age 20 with pigmentary retinopathy, plus one of the following: CSF protein >1 g/l, cerebellar ataxia, heart block Bilateral deafness; myopathy; dysphagia; diabetes mellitus and hypoparathyroidism; dementia
Leber hereditary optic neuropathy (LHON) Subacute painless bilateral visual failure; male:female approx 4:1; median age of onset 24 years Dystonia; cardiac pre-excitation syndromes
Leigh syndrome (LS) Subacute relapsing encephalopathy with cerebellar and brain stem signs presenting during infancy Basal ganglia lucencies
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) Stroke-like episodes before age 40 years; seizures and/or dementia; ragged-red fibres and/or lactic acidosis Diabetes mellitus; cardiomyopathy (hypertrophic leading to dilated); bilateral deafness; pigmentary retinopathy; cerebellar ataxia
Myoclonic epilepsy with ragged-red fibers (MERRF) Myoclonus; seizures; cerebellar ataxia; myopathy Dementia, optic atrophy; bilateral deafness; peripheral neuropathy; spasticity; multiple lipomata
Neurogenic weakness with ataxia and retinitis pigmentosa (NARP) Late childhood or adult onset peripheral neuropathy with associated ataxia and pigmentary retinopathy Basal ganglia lucencies; abnormal electroretinogram; sensorimotor neuropathy
Pearson syndome Sideroblastic anaemia of childhood; pancytopenia; exocrine pancreatic failure Renal tubular defects
PEO, progressive external ophthalmoplegia.

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Table 3 Animal models of mitochondrial disease (adapted from Larsson and Rustin47)

Type Mouse model Gene (reference) Biochemical abnormality Phenotype
Nuclear gene knockouts Adenosine nucleotide translocase ANT1 (48) Defect of coupled respiration Myopathy and cardiomyopathy
Mitochondrial superoxide dismutase SOD2 (49) Mitochondrial superoxide deficiency Myopathy and cardiomyopathy
Mitochondrial transcription factor A
    Germ line TFAM, germ line (25) Respiratory chain defect Embryonic lethal. Abnormal development with absence of heart and optic disc
    Heart specific TFAM, tissue specific (50) Respiratory chain defect Dilated cardiomyopathy and cardiac conduction block
    Pancreatic ß cell specific TFAM, tissue specific (51) Respiratory chain defect Diabetes
COX assembly protein SURF-1 SURF1 (52) Respiratory chain defect Embryonic lethality
Thymidine phosphorylase TP (53) Reduction in liver TP activity None
Mitochondrial DNA BALB/NZB heteroplasmic NZB/BALB mtDNA (44) None Random drift during transmission. Tissue specific selection of different genotypes
Chloramphenicol resistance CAP-R T2443C mtDNA (54) None Myopathy, cardiomyopathy, perinatal death
{Delta}mtDNA 4.7 kb mtDNA deletion (46)
Spontaneous mutants Defect of nuclear–mitochondrial communication Not known (55) None Deafness

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Table 4 Mitochondria on the world wide web

Information Name URL
Information for patients United Mitochondrial Diseases Foundation (USA) www.umdf.org
Mitolinks (UK) http://www.communigate.co.uk/ne/mitolinks/index.phtml
Leber hereditary optic neuropathy trust (UK) www.leberstrust.btinternet.co.uk
Clinical and molecular information for clinicians and scientists On-line Mendelian Inheritance in Man www.ncbi.nlm.nih.gov
Clinical and genetic information for clinicians and patients Mitomap www.mitomap.org
Geneclinics www.geneclinics.org
Molecular data for scientists Uppsala http://www.genpat.uu.se/mtDB/index.html
Biochemical and molecular data for scientists Mitop mips.gsf.de/proj/medgen/mitop
Mitodat http://www-lecb.ncifcrf.gov/mitoDat/

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Source: Journal of Neurology Neurosurgery and Psychiatry 2003;74:1188-1199. © 2003 BMJ Publishing Group




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