Differential diagnosis of selected phenotypes commonly associated with mitochondrial disease
| Phenotype | Mitochondrial cause | Limited differential diagnosis |
| Dystonia | Leigh syndrome, deafness-dystonia syndrome, other mitochondrial encephalomyopathies | Biotinidase 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 encephalopathy | Alpers-Huttenlocher syndrome, many other mitochondrial disorders | Many genetic epileptic encephalopathies, including Dravet syndrome and KCNQ2 mutations, Pyridoxine dependent epilepsies (Antiquitin deficiency, PNPO deficiency), viral encephalitis |
| Progressive myoclonic epilepsy | MERRF | Ramsay Hunt syndrome, Unverricht-Lundborg disease, Lafora body disease, sialidosis, PRICKLE1 mutations |
| Leukoencephalpathy | Complex I deficiency, Complex II deficiency, SURF1 deficiency (rarely), disorders of mitochondrial translation and Fe-S cluster assembly | Vanishing 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 biosynthesis | Spinocerebellar ataxias, CAPOS syndrome |
| Demyelination | MNGIE | ADEM, multiple sclerosis |
| Peripheral neuropathy | Mutations in POLG, MPV17, KARS and SURF1; part of multisystem disease in many mitochondrial disorders, for example, MNGIE | Other non-mitochondrial genetic causes of Charcot-Marie-Tooth syndromes, riboflavin transporter deficiency, toxic neuropathies, critical illness |
| Ptosis and ophthalmoplegia | PEO, KSS, MNGIE, MELAS | Some congenital myopathies, pseudo upgaze impairment in OPMD, horizontal gaze palsy and scoliosis (ROBO3 mutation) |
| Optic neuropathy | LHON, ADOA, Leigh syndrome | Toxic optic neuropathy (eg, methanol, cyanide, tobacco) |
| Hypertrophic cardiomyopathy with lactic acidosis | Complex I deficiency, TMEM70 mutations, Sengers syndrome (AGK deficiency), disorders of mitochondrial translation | Viral infection |
| Dilated cardiomyopathy with lactic acidosis | Barth syndrome, disorders of mitochondrial phospholipid remodelling, other mitochondrial cardiomyopathies | Viral infection |
| Exocrine pancreatic insufficiency | Pearson syndrome | Cystic fibrosis |
| Diabetes and deafness | MIDD, other mtDNA mutations | Type II diabetes mellitus with incidental non-syndromic deafness |
| Sideroblastic anaemia | Pearson syndrome, MLASA, TRNT1 deficiency, PUS1 or YARS2 mutations | Blackfan-Diamond syndrome, Schwachman-Diamond syndrome, X linked sideroblastic anaemia |
| B cell immune deficiency | TRNT1 deficiency | Primary immunodeficiency disorder |
| Liver failure | Mitochondrial DNA (mtDNA) depletion syndromes, | NBAS, LARS and IARS deficiencies, viral infection, lysosomal storage disorders, other syndromic genetic conditions |
| Renal tubulopathy/failure | Pearson and Kearns-Sayre syndromes, RMND1-related disease | Gitelman syndrome, Fanconi Bickel (SLC2A2 mutations) syndrome, other syndromic genetic conditions |
| Myopathy | Part of multisystem disease in many mitochondrial disorders, especially mtDNA depletion syndromes | Congenital muscular dystrophies, myositis, many other disorders |
| Rhabdomyolysis | Mitochondrial myopathies (eg, MTCO1, MTCO2, MTCO3 and MTCYB mutations) | LPIN1 mutations, fatty acid oxidation defects (VLCAD, LCHAD), TANGO deficiency, glycolytic defects, toxic, postexercise |
| Low copper | Cytochrome oxidase deficiency | Menkes, SLC33A1 mutations |
| Complex multisystem disorders | Many mitochondrial disorders, particularly in childhood | Congenital 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.