Table 1

Differential diagnosis of selected phenotypes commonly associated with mitochondrial disease

PhenotypeMitochondrial causeLimited differential diagnosis
DystoniaLeigh syndrome, deafness-dystonia syndrome, other mitochondrial encephalomyopathiesBiotinidase deficiency, thiamine transporter deficiency 2, ADAR mutations (Aicardi- Goutières syndrome 6), organic acidaemias (especially glutaric aciduria type I), NBIA, acute (viral) necrotising encephalopathy, mutations in NUP62, RANBP2 and PDE8B, primary genetic dystonias
Epileptic encephalopathyAlpers-Huttenlocher syndrome, many other mitochondrial disordersMany genetic epileptic encephalopathies, including Dravet syndrome and KCNQ2 mutations, Pyridoxine dependent epilepsies (Antiquitin deficiency, PNPO deficiency), viral encephalitis
Progressive myoclonic epilepsyMERRFRamsay Hunt syndrome, Unverricht-Lundborg disease, Lafora body disease, sialidosis, PRICKLE1 mutations
LeukoencephalpathyComplex I deficiency, Complex II deficiency, SURF1 deficiency (rarely), disorders of mitochondrial translation and Fe-S cluster assemblyVanishing white matter disease, lysosomal storage disorders, Canavan disease, Alexander disease, Pelizaeus-Merzbacher(-like), hypo/dysmyelination
Ataxia ADCK3 mutations, ataxia-neuropathy syndromes, for example, SCAE, MIRAS, MERRF, NARP, disorders of coenzyme Q10 biosynthesisSpinocerebellar ataxias, CAPOS syndrome
DemyelinationMNGIEADEM, multiple sclerosis
Peripheral neuropathyMutations in POLG, MPV17, KARS and SURF1; part of multisystem disease in many mitochondrial disorders, for example, MNGIEOther non-mitochondrial genetic causes of Charcot-Marie-Tooth syndromes, riboflavin transporter deficiency, toxic neuropathies, critical illness
Ptosis and ophthalmoplegiaPEO, KSS, MNGIE, MELASSome congenital myopathies, pseudo upgaze impairment in OPMD, horizontal gaze palsy and scoliosis (ROBO3 mutation)
Optic neuropathyLHON, ADOA, Leigh syndromeToxic optic neuropathy (eg, methanol, cyanide, tobacco)
Hypertrophic cardiomyopathy with lactic acidosisComplex I deficiency, TMEM70 mutations, Sengers syndrome (AGK deficiency), disorders of mitochondrial translationViral infection
Dilated cardiomyopathy with lactic acidosisBarth syndrome, disorders of mitochondrial phospholipid remodelling, other mitochondrial cardiomyopathiesViral infection
Exocrine pancreatic insufficiencyPearson syndromeCystic fibrosis
Diabetes and deafnessMIDD, other mtDNA mutationsType II diabetes mellitus with incidental non-syndromic deafness
Sideroblastic anaemiaPearson syndrome, MLASA, TRNT1 deficiency, PUS1 or YARS2 mutationsBlackfan-Diamond syndrome, Schwachman-Diamond syndrome, X linked sideroblastic anaemia
B cell immune deficiencyTRNT1 deficiencyPrimary immunodeficiency disorder
Liver failureMitochondrial DNA (mtDNA) depletion syndromes,NBAS, LARS and IARS deficiencies, viral infection, lysosomal storage disorders, other syndromic genetic conditions
Renal tubulopathy/failurePearson and Kearns-Sayre syndromes, RMND1-related diseaseGitelman syndrome, Fanconi Bickel (SLC2A2 mutations) syndrome, other syndromic genetic conditions
MyopathyPart of multisystem disease in many mitochondrial disorders, especially mtDNA depletion syndromesCongenital muscular dystrophies, myositis, many other disorders
RhabdomyolysisMitochondrial myopathies (eg, MTCO1, MTCO2, MTCO3 and MTCYB mutations) LPIN1 mutations, fatty acid oxidation defects (VLCAD, LCHAD), TANGO deficiency, glycolytic defects, toxic, postexercise
Low copperCytochrome oxidase deficiencyMenkes, SLC33A1 mutations
Complex multisystem disordersMany mitochondrial disorders, particularly in childhoodCongenital disorders of glycosylation, peroxisomal disorders, lysosomal storage disorders, other syndromic genetic conditions
  • ADEM, acute disseminated encephalomyelitis; ADOA, autosomal dominant optic atrophy; CAPOS, cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss; Fe-S, iron-sulphur; KSS, Kearns-Sayre syndrome; LHON, Leber hereditary optic neuropathy; MERRF, myoclonic epilepsy with ragged red fibres; MIDD, maternally inherited diabetes and deafness; MIRAS, mitochondrial recessive ataxia syndrome; MLASA, myopathy, lactic acidosis, sideroblastic anaemia; MNGIE, mitochondrial neurogastrointestinal encephalomyopathy; NBIA, neurodegeneration with brain iron accumulation; PEO, progressive external ophthalmoplegia; SCAE, spinocerebellar ataxia with epilepsy.