Table 1.
Genotype and phenotype of common multisystemic mitochondrial “syndromes” presenting with mitochondrial myopathy.
| Disease | mtDNA variation | nDNA genes | Inheritance | Age of onset | Key clinical symptoms | Distinctive features | Prognosis |
|---|---|---|---|---|---|---|---|
| Chronic Progressive External Ophthalmoplegia (CPEO) | MT-TL1 m.3243A>G or large-scale deletion of mtDNA | POLG (95%), C10orf2, RRM2B, SLC25A4, POLG2, DGUOK, SPG7 | Autosomal dominant, autosomal recessive, mitochondrial maternal inheritance | 20–40s | Ptosis, ophthalmo-plegia, hearing loss, mild muscle weakness, dysphagia, cataracts | Pigmentary retinopathy (“salt and pepper” pigmentation) | Slowly progressive |
| Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like episodes (MELAS) | MT-TL1 m.3243A>G (80%), m.3271T>C, MT-TQ, MT-TH, MT-TK, MT-TS1, MT-ND1, MT-ND5, MT-ND6, MT-TS2 | Mitochondrial maternal inheritance | Childhood to 40s | Stroke-like episodes, hemiparesis, seizures, hearing loss, muscle weakness, vision, renal impairment, mitochondrial diabetes | Lactic acidosis; strokes that do not conform to vascular territories | Prognosis depends on level of organ involvement | |
| Kearn-Sayre syndrome (KSS) | Large-scale deletions of mtDNA | Usually sporadic | Childhood, <20y | Progressive external ophthalmoplegia, pigmentary retinopathy, cardiac conduction block, cerebellar ataxia, deafness, short stature | CSF protein >100mg/dL Severe combined defects of mitochondrial complexes especially cytochrome C oxidase |
Progressive disorder, prognosis depends on level of organ involvement | |
| Myoclonus Epilepsy with Ragged Red Fibers (MERRF) | MT-TK m.8344A>G (80%), m.8356T>C, m,8363G>A, m.8361G>A | Sporadic or mitochondrial maternal inheritance | Childhood, <30y | Myoclonus, epilepsy, ataxia, myopathy, optic atrophy, deafness, peripheral neuropathy, cardiomyopathy with WPW syndrome | Myoclonus | Prognosis depends on level of organ involvement | |
| Primary Coenzyme Q10 Deficiency [21] |
COQ2, COQ7, COQ8A, COQ8B COQ9 |
Autosomal recessive | Infantile, childhood to adult onset | Predominant myopathy associated with encephalopathy, ataxia and retinopathy | Late onset disease shows better response to high dose CoQ10 supplementation | ||
| TK2 Deficiency | TK2 | Autosomal recessive | Infantile, Childhood and adult onset | Muscle weakness, hypotonia, bulbar dysarthria and dysphagia | Elevated creatine kinase (5-10x upper limit of normal), Severe reduction in mtDNA content in affected tissues and organs |
Poor | |
| Reversible Infantile Respiratory Chain Deficiency myopathy (RIRCD) [22] | mt-tRNAGlu m.14674T>C (homoplasmic) |
Associated with nDNA genes interacting with mt-tRNA Glu e.g. EARS2, TRMU | Infancy | Profound muscle weakness, hypotonia, feeding difficulties, Reversble transaminitis during periods of severe metabolic crises | Muscle biopsy in neonatal period shows numerous RRF and COX negative fibres, accumulation of lipids and glycogen which later resolve | Spontaneous improvement by 1 year, mostly asymptomatic by 2–3 years old |