Table 3 Clinical syndromes, inheritance pattern and phenotypic features of mitochondrial diseases

From: Mitochondrial diseases

Syndrome Genetics Clinical features Refs
Childhood-onset mitochondrial diseases
Leigh syndrome >75 genes in nDNA and mtDNA Acute periods of neurodevelopmental regression followed by partial recovery, hypotonia, dystonia, hypopnoea, dysphagia, epilepsy, failure to thrive, encephalopathy, and basal ganglia and brainstem lesions 8,53,54
Alpers–Huttenlocher syndrome (AHS) nDNA (POLG-related) Intractable epilepsy, psychomotor regression and liver disease; might also include the clinical features of MCHS and MEMSA 5557
Childhood myocerebrohepatopathy spectrum (MCHS) Neuropathy, ataxia, hypotonia, myoclonus (spontaneous muscle contractions), choreoathetosis (the occurrence of involuntary jerky, writhing movements of muscles or muscle groups) and Parkinsonism, in addition to renal tubulopathy
Ataxia neuropathy spectrum (ANS; previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO)) Sensory axonal neuropathy with variable sensory and cerebellar ataxia
Myoclonic epilepsy myopathy sensory ataxia (MEMSA; previously referred to as spinocerebellar ataxia with epilepsy (SCAE)) Epilepsy, PEO, seizures, dysarthria, dementia, spasticity and myopathy
Sengers syndrome nDNA (AGK mutations) Congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance and lactic acidosis. Patients can present with or without mtDNA depletion in muscle 45,66
MEGDEL syndrome (also known as 3-methylglutaconic aciduria with deafness, encephalopathy and Leigh-like syndrome) nDNA (SERAC1 mutations) Sensorineural hearing loss, encephalopathy, failure to thrive, hypotonia, psychomotor delay, dystonia, spasticity, hypoglycaemia, hepatopathy and lactic acidosis 65
Pearson syndrome Single, large-scale mtDNA deletion or rearrangements of mtDNA (often sporadic) Sideroblastic anaemia of childhood associated with exocrine and/or endocrine pancreatic dysfunction, pancytopaenia and renal tubulopathy 61,62
Congenital lactic acidosis (CLA) nDNA, de novo mtDNA point mutations or inherited mtDNA point mutations Childhood onset, often fatal, progressive neuromuscular weakness, accumulation of lactate in the blood (acidosis), urine and/or CSF 63
Adult-onset mitochondrial diseases
Leber hereditary optic neuropathy (LHON) Mutations in mtDNA, for example, m.11778G>A (MT-ND4), m.14484T>C (MT-ND6) and m.3460G>A (MT-ND1) Subacute painless bilateral visual loss. Might also include dystonia, cardiac pre-excitation syndromes and LHON associated with multiple sclerosis-like symptoms (Harding syndrome) 69,194
Kearns–Sayre syndrome (KSS) Single, large-scale mtDNA deletion (often sporadic) PEO, pigmentary retinopathy (progressive vision impairment due to degeneration of the rod photoreceptors), CSF protein levels of >1 g per l, cerebellar ataxia, cardiac conduction abnormalities (age of onset <20 years), myopathy, diabetes mellitus, deafness, bulbar weakness and dementia 73,74
Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome Mutations in mtDNA, such as m.3243A>G in MT-TL1, and 23 other pathogenetic variants in MT-TL1 and in other mtDNA genes (for example, MT-TF, MT-TV and MT-TQ) Stroke-like episodes. Can also include deafness, diabetes mellitus, pigmented retinopathy, cardiomyopathy, cerebellar ataxia, seizures, encephalopathy, lactic acidosis and mitochondrial myopathy 31,75,76
Myoclonic epilepsy with ragged red fibres (MERRF) Mutations in mtDNA, such as m.8344A>G in MT-TK, and other pathogenetic variants in MT-TF, MT-TL1, MT-TI and MT-TP Progressive myoclonic epilepsy, ataxia, weakness. Can also include pigmented retinopathy, sensorineural hearing loss, lactic acidosis, lipomata, spasticity and cardiac conduction defects (Wolff–Parkinson–White syndrome) 78,79
Neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP) Mutations in mtDNA, such as MT-ATP6 m.8993T>G, which is the most common variant, and m.8993T>C, a less severe variant Early childhood onset, can remain quiescent or stable into adulthood, sensorimotor neuropathy, ataxia and pigmentary retinopathy. Can also include seizures, learning disability, dementia, proximal neurogenic muscle weakness, basal ganglia abnormalities, sensorineural hearing loss, short stature, CPEO, cardiac conduction defects, obstructive sleep apnoea and neuropsychiatric disorders8. These syndromes form a clinical continuum with Leigh syndrome 8083
Chronic progressive external opthalmoplegia (CPEO)84 TYMP, which encodes thymidine phosphorylase Gastrointestinal dysmotility, muscle weakness and atrophy, neuropathy, retinopathy, hearing loss, leukoencephalopathy and depleted TYMP activity 93
POLG1, which encodes α-DNA polymerase subunit γ1 Ataxia, peripheral sensory neuronopathy, Parkinsonism, premature ovarian failure, psychiatric symptoms, MELAS syndrome and epilepsy 195
POLG2, which encodes DNA polymerase subunit γ2 Ptosis and proximal myopathy, dystrophy, cerebellar ataxia and gastrointestinal symptoms 196
MPV17, which encodes protein MPV17 Distal limb weakness, neuropathy, exercise intolerance, diabetes mellitus, ptosis, hearing loss, gastrointestinal dysmotility, depression and Parkinsonism 197
DGUOK, which encodes deoxyguanosine kinase Exercise intolerance, limb girdle weakness, muscle cramps and occasional dysphagia 198
TK2, which encodes thymidine kinase 2 Ptosis, scapular winging, facial and proximal muscle weakness and wasting, dysphagia and respiratory deficiency 199
RRM2B, which encodes ribonucleotide-diphosphate reductase subunit M2B Hearing loss, bulbar dysfunction, renal disease and gastrointestinal disturbance 200
C10orf2, which encodes Twinkle protein Isolated PEO with or without mild proximal myopathy and exercise intolerance, fatigue, hearing loss, Parkinsonism psychiatric symptoms and cardiac involvement 201
SLC25A4, which encodes ADP/ATP translocase 1 Indolent or mild PEO with or without ptosis, facial weakness, mild hearing loss, psychiatric symptoms and neuropathy 202
SPG7, which encodes paraplegin Ataxia, optic atrophy, myopathy, spastic paraparesis and cerebellar atrophy 203
AFG3L2, which encodes AFG3-like protein 2 Ataxia, spastic paraparesis, myopathy and cerebellar atrophy 204
OPA1, which encodes dynamin-like 120 kDa protein Optic atrophy, early-onset visual loss, ataxia and deafness, spasticity, axonal neuropathy, diabetes mellitus, epilepsy and dementia 85,87
C20orf7, which encodes mitochondrial genome maintenance exonuclease 1 Proximal muscle weakness, generalized muscle wasting, respiratory deficiency, chronic renal failure, cardiac arrhythmias and depression 24
DNA2, which encodes DNA replication ATP-dependent helicase/nuclease DNA2 Progressive myopathy 205
RNASEH1, which encodes ribonuclease H1 Myopathy, dysphagia and spinocerebellar signs 206
DNM2, which encodes dynamin 2 Facial and proximal weakness, axonal neuropathy and cardiomyopathy 207
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) syndrome TYMP, RRM2B and POLG Gastrointestinal dysmotility, muscle weakness and atrophy, PEO, neuropathy, retinopathy, hearing loss, leukoencephalopathy* and depleted TYMP activity* 93,122124
  1. CSF, cerebrospinal fluid; mtDNA, mitochondrial DNA; nDNA, nuclear DNA; PEO, progressive external ophthalmoplegia.
  2. *Not affected in RRM2B and POLG variants.