Version July 2025
| Mitochondrial DNA |
| Pathogenic variants in genes encoding respiratory chain proteins |
| Complex I (ND1 and ND4 cause a pure myopathy; ND5 causes a myopathy with MELAS/LHON/MERRF) |
| Complex III (Cytochrome b causes exercise intolerance/myalgia and rarely causes cardiomyopathy or multisystem disorder) |
| Complex IV (COXI, COXII, COXIII) causes exercise intolerance/myoglobinuria; can also cause severe encephalomyopathy (all three), or MELAS (COXIII only) |
| Pathogenic variants affecting protein synthesis |
| Pathogenic variants in genes for transfer RNA most commonly cause MELAS or MERRF; can also cause isolated myopathy, CPEO, or respiratory muscle weakness |
| Pathogenic variants in genes for ribosomal RNA cause aminoglycoside-related deafness and cardiomyopathy but not skeletal myopathy |
| Large scale deletions/duplications most often cause sporadic CPEO/Kearns-Sayre syndrome; less commonly cause Pearson syndrome |
| Nuclear DNA |
| Pathogenic variants in genes encoding respiratory chain proteins |
| Coenzyme Q10 deficiency can cause isolated myopathy or rapidly fatal encephalomyopathy of infancy with nephrotic syndrome |
| Complex I pathogenic variants (NDUFS1, 2, 3, 4, 6, 7, 8, NDUFV1, 2, NDUFA1, 2, 11) and complex II mutations (SDHA) can cause autosomal recessive Leigh syndrome |
| Complex II pathogenic variants (SDHB, SDHC, SDHD) can cause paraganglioma and sarcoma |
| Complex III pathogenic variants (UQCRB, UQCRQ) can cause lactic acidosis, hypoglycemia, and psychomotor retardation |
| Complex IV pathogenic variants (COX6B1, COX4I2) can cause infantile encephalopathy, anemia, and pancreatic dysfunction |
| Pathogenic variants in nuclear genes encoding proteins required for assembly or function of respiratory chain proteins |
| Complex I pathogenic variants (NDUFAF1, 2, 3, 4, C20orf7, C8orf38, C6orf66) can cause variable disorders including Leigh syndrome and lethal infantile encephalopathy |
| Complex II pathogenic variants (SDHAF1, 2) can cause infantile leukoencephalopathy and paraganglioma |
| Complex III pathogenic variant (BCS1L) can cause GRACILE syndrome |
| Complex IV pathogenic variant (SURF1, COX10, COX15, SCO1, SCO2) can cause Leigh syndrome and infantile cardioencephalomyopathy |
| Complex V pathogenic variants (ATPAF2, ATP5A1, ATP5E, TMEM70) can cause encephalopathy and 3-methylglutaconic aciduria |
| Nuclear gene variants affecting mitochondrial protein synthesis (causing multiple deletions or depletion of mitochondrial DNA) |
| Pathogenic variants in POLG, C10orf2 (encodes twinkle helicase), RRM2B, SLC25A4, POLG2, and DGUOK can cause autosomal dominant or recessive CPEO |
| Pathogenic variants in TK2, SUCLA2, SUCLA2, SUCLG1, RRM2B, and DGUOK can cause congenital encephalomyopathy and muscular dystrophy-like encephalomyopathy; TK2 mutations can also cause a slowly progressive generalized myopathy |
| Nuclear gene variants causing abnormal mitochondrial dynamics (fusion/fission) |
| Pathogenic variants in OPA1 can cause bilateral optic neuropathies and may be accompanied by sensorineural hearing loss; MFN2 mutations can cause an axonal form of Charcot-Marie-Tooth disease |
| Nuclear gene variants affecting mitochondrial proteins implicated in apoptosis |
| Pathogenic variants in AIF1 can cause multiple mtDNA deletions or mtDNA depletion and present with a mitochondrial encephalomyopathy; FASTKD2 may also present with a mitochondrial encephalomyopathy; APOPT1 mutations can cause a leukodystrophy |
| Nuclear gene variants causing abnormalities of the lipid milieu |
| Pathogenic variants in TAZ can cause Barth syndrome, an X-linked mitochondrial myopathy, cardiomyopathy, neutropenia, and short stature |
| Pathogenic variants in SERAC1 can cause MEGDEL |
| Nuclear gene variants affecting mitochondrial metabolic pathways other than the respiratory chain |
| Abnormalities of mitochondrial substrate transport include CPT 1A deficiency, which results mainly in hepatic disease; CPT 2 deficiency most commonly produces a syndrome of recurrent rhabdomyolysis |
| Abnormalities in mitochondrial substrate utilization include trifunctional protein deficiency, which causes neuropathy, myopathy, and recurrent rhabdomyolysis |
| Nuclear gene variants affecting iron-sulfur cluster assembly or homeostasis |
| Pathogenic variants in ISCU are associated with myopathy, exercise intolerance, and recurrent rhabdomyolysis |
