Table 1.
Clinical, genetic, and biochemical characteristics of individuals with disease-associated MT-CYB variants.
| No. of patient phenotype |
Sex/age at onset | Variant | Heteroplasmy/transmission | Clinical features | Brain MRI/MRS | Lactate/ metabolite |
Muscle histology/ RC enzyme activity |
Course/ outcome |
Reference |
|---|---|---|---|---|---|---|---|---|---|
| 1. MM | M/10y | m.15615G > A (p. G290D) | 80% (Mu), 0% (B)/ De novo |
EI, EIM | U/U | 4.8↑ (B)/N | RRF (COX+)/CIII↓ (Mu) | Stable/Alive (29y) | (Dumoulin et al., 1996; Mousson et al., 1995) |
| 2. MM | F/25y | m.15762G > A (p. G339E) | 85% (Mu), 0% (B)/ De novo |
EI, MW | U/U | N/U | N/CIII↓ (Mu) | Stable/Alive (38y) | (Andreu et al., 1998) |
| 3. MM | M/12y | m.15059G > A (p. G105*) | 63% (Mu), 0% (B)/ De novo |
EI, MW, EIM, MU | U/U | 3.9↑ (B)/U | RRF (COX+)/CIII↓ (Mu) | Stable/Alive (27y) | (Andreu et al., 1999) |
| 4. MCM | F/5y | m.15243G > A (p. G166E) | 90% (Ht), 100% (F)/ De novo |
HCM, MA, HF, LFT↑ | N/U | 5 ↑ (B)/N | U/CIII↓ (Ht) | Progression/ Dead (9y) | (Valnot et al., 1999) |
| 5. MELAS/JP | M/6y | m.14787_14790del (p. I14fs*50) | 95% (Mu), 60% (B, F, H, OM)/De novo | EI, IM, Myo, EP, SE, WPW, Psych, Cortical blindness, Akinetic rigid syndrome | Cortical lesions, Cerebral and cerebellar atrophy/U | 2.9↑ (B), 9.8↑ (CSF)/U | Rare RRF/CIII↓ (Mu) | Progression/ Alive (20y) | (De Coo et al., 1999) |
| 6. MM | M/30y | m.15498_15521del (p. G251_L258del) | 50% (Mu), 0% (B, F)/U | EI, MW, EIM, MU | U/U | N/U | RRF (COX+)/CIII↓ (Mu) | Stable/Alive (43y) | (Andreu et al., 1999) |
| 7. MM | F/Child | m.14846G > A (p. G34S) | 85% (Mu), 0% (B, F)/U | EI, MW, EIM | U/U | ↑ (B)/U | RRF (COX+)/CIII↓ (Mu) | Stable/Alive (52y) | |
| 8. MM | F/Child | m.15168G > A (p. W141*) | 70% (Mu), 0% (B)/U | EI, EIM, WPW | U/U | ↑ (B)/U | RRF (COX+)/CIII↓ (Mu) | Stable/Alive (38y) | |
| 9. MM | M/Child | m.15084G > A (p. W113*) | 87% (Mu), 0% (B)/U | EI, EIM | U/U | ↑ (B)/U | RRF (COX+)/CIII↓ (Mu) | Stable/Alive (32y) | |
| 10. MM | M/Child | m.15723G > A (p. W326*) | 70% (Mu)/U | EI, MW, EIM | U/U | ↑ (B)/U | RRF (COX+)/CIII↓ (Mu) | Stable/Alive (51y) | |
| 11. MCM | F/3w | m.15498G > A (p. G251D) | 90% (L), 82% (K)/ De novo |
Histiocytoid CM, CA, FTT, ATN, Tachypnea, Hepatic steatosis | U/U | U/U | N/CIII↓ (Ht) | Progression/ Dead (1 m) | (Andreu et al., 2000; Papadimitriou et al., 1984) |
| 12. NSMD | F/9y | m.15242G > A (p. G166*) | 87% (Mu), 0.7% (B), 4.6% (H), 5% (Ov)/ De novo |
EI, MA, EP, Psych, Myo, Diplopia, Stroke, Encephalopathy | U/Pcr↓ | ↑ (B)/U | RRF (COX+)/CIII↓ (Mu) | Progression/ Alive (34y) | (Keightley et al., 2000) |
| 13. NSMD | F/6y | m.15579A > G (p. Y278C) | 88% (Mu), 15% (B)/ De novo |
EI, MW, CogI, FTT, HA, EP, RP, Cataract, Deafness | N/U | 8↑ (B), 8.8↑ (CSF)/U | RRF (COX+)/CIII↓ (Mu) | Progression/ Alive (19y) | (Wibrand et al., 2001) |
| 14. MM | U/Child | m.15150G > A (p. W135*) | 60% (Mu), 0% (B, F)/U | EI, MW | U/U | U/U | U/CIII↓ (Mu) | U/U | (Legros et al., 2001) |
| 15. MM | U/Child | m.15197 T > C (p. S151P) | 80% (Mu), 0% (B, F)/U | EI, MW | U/U | U/U | U/CIII↓ (Mu) | U/U | |
| 16. NSMD | M/7 m | m.14849 T > C (p. S35P) | 69% (Mu), 6% (B), 12% (F)/De novo | DD, CogI, RM, SS, EI, VI, RP, RI, HT, MA, WPW, HCM, Ataxia, Hypotonia | SOD, Cerebellar hypoplasia/U | 31↑ (B)/U | N/CIII↓ (Mu) | Progression/ Alive (25y) | (Schuelke et al., 2002) |
| 17. MM | F/10y | m.15800C > T (p. Q352*) | 45% (Mu), 0% (B, F, H, OM)/De novo | EI, EIM, MW | U/U | 6.5↑ (B)/U | RRF (COX+), Lipid↑/CI, CIII↓ (Mu) | Stable/Alive (24y) | (Lamantea et al., 2002) |
| 18. MM | F/Child | m.15761G > A (p. G339*) | 73% (Mu), 0% (B), <1% (Ur)/De novo | EI, EIM, MW | U/U | 6.2↑ (B)/U | RRF (COX+)/CIII↓ (Mu) | Stable/Alive (19y) | (Mancuso et al., 2003) |
| 19. MM | F/30y | m.15170G > A (p. G142*) | 99% (Mu), 0% (B, F)/U | EI, EIM, MW | U/U | 7.2↑ (B)/U | RRF (COX+)/CI, CIII↓ (Mu) | Stable/Alive (40y) | (Bruno et al., 2003) |
| 20. NSMD | F/Teen | m.15699G > C (p. R318P) | 88% (Mu), 13% (B), 42% (F), 16% (Ur)/ De novo |
HA, EI, EIM, MW, TIA, SNHL | BGS, CWM lesions/U | 3.1↑ (B), 3.9↑ (CSF)/U | RRF (COX+)/CI, CIII↓ (Mu) | Progression/ Alive (38y) | (Blakely et al., 2005) |
| 21. NSMD | M/Birth | m.15635 T > C (p. S297P) | 100% (Mu, B, F, L)/ De novo |
RD, MA, LF, HCM, MOF, Hypotonia | U/U | 23↑ (B)/U | U/CIII↓ (Liver) | Progression/ Dead (1d) | (Fragaki et al., 2009) |
| 22. MM | M/7y | m.14849 T > C (p. S35P) | 85% (Mu)/U | EI, EIM, Facial MW, PE | N/U | 3.5↑ (B)/U | RRF (COX+), RBF/CII, CIII↓ (Mu) | Stable/Alive (18y) | (Massie et al., 2010) |
| 23. MELAS | F/10y | m.14864 T > C (p. C40R) | 39% (Mu), 32% (B), 14% (H), 57% (Ur)/ De novo |
HA, SLE, EP, SE, CogI, GD, VI, EI, MW, PN, IM, SS | Temporo-occipital cortical lesions/Lac↑ | 3.3↑ (B)/U | Subsarcolemmal staining↑/CI, CIII↓ (Mu) | Stable/Alive (15y) | (Emmanuele et al., 2013) |
| 24. MELAS | F/13y | m.15092G > A (p. G116S) | 97% (Mu), 45% (B), 87% (Ur)/De novo | HA, SLE, EP, EPC, CogI, VI, PN, Dysphagia | Multifocal cortical lesions/U | ↑ (B, CSF)/U | N/CIII↓ (Mu) | Progression/ Alive (21y) | (Mancuso et al., 2014) |
| 25. NSMD | F/Child | m.15649_15666del (p. I302_P307del) | 60% (Mu), 7% (B), 65% (F), 36% (Ur)/De novo | EI, MW, GD, RP, VI, OP, PN, DCM, SNHL, Cataract, Hypotonia, Dysphagia, Gastroparesis | Global brain atrophy, CWM lesions/Lac↑, Pcr↓ | 2.3↑ (B)/U | RRF (COX+)/CI, CIII, CIV↓ (Cybrid cell) | Progression/ Alive (41y) | (Carossa et al., 2014) |
| 26. NSMD | M/7y | m.15319_15327del (p. L192_T194del) | 90% (Mu), 0% (B, L), Low heteroplasmy (F)/U | EI, MA, KH, CK↑, LFT↑, Weight loss | N/Lac↑ | 11↑ (B), 3.1↑ (CSF)/TC↓ (B), LCAC↑ (F) | RRF/CIII↓ (Mu) | Improvement/Alive (15y) | (Mori et al., 2015) |
| 27. NSMD | F/Infant | m.15385_15405del (p. H215_F221del) | 72% (Mu), 0% (B)/U | MA, CogI, MW, IM, RP, Blind, Cataract, Spastic tetraparesis, Glaucoma | MCP lesions, Cerebral and cerebellar atrophy/U | 2.6↑ (B)/U | RRF/CI, CI + CIII, CII + CIII↓ (Mu) | Progression/ Dead (45y) | (Chaussenot et al., 2018) |
| 28. MM | U/8y | m.15579A > G (p. Y278C) | 95% (Mu), Low heteroplasmy (B, OM)/De novo | EI, EIM | U/U | 2.4–6↑ (B)/MCAC, LCAC↑ (B) | RRF (COX+)/CIII↓ (Mu) | Stable/Alive (25y) | (Kaphan et al., 2018) |
| 29. MM | M/11y | m.15045G > A (p. R100Q) | 100% (Mu), 0% (B, Ur)/U | EI, EIM, PN, Deafness | U/U | 2.4–6↑ (B)/ All-chain AC↑ (B) | RRF (COX+)/CIII↓ (Mu) | Stable/Alive (66y) | |
| 30. NSMD | F/1.5y | m.15108 T > G (p. L121R) | 30% (Mu), 45% (B), 60% (Ur)/U | DD, EI, MW, GD, ON, FTT, CogI, AHS, Scoliosis, Ptosis, Hypotonia | N/U | 3↑ (B)/N | RRF (COX+)/CI, CIII, CIV↓ (Mu) | Progression/ Alive (9y) | (Barcia et al., 2020) |
| 31. MCM | M/U | m.14757 T > C (p. M4T) | U/U | DCM | U/U | U/U | N/CIII↓ (Mu) | U/Alive (40y) | (Zarrouk et al., 2021) |
| 32. LHON | M/19y | m.15309 T > C (p. I188T) | 65% (B)/Maternal | ON, Fluctuating VI | N/U | U/U | U/U | Improvement/Alive (27y) | (Petrovic Pajic et al., 2025) |
| 33. LS | M/8 m | m.15635 T > C (p. S297P) | 95.0% (Mu), 45.9% (B), 92.6% (Ur)/Maternal | DD, CogI, GD, SNHL, ON, EI, RP, PE, HCM, Dystonia, Dysphagia | BG lesions, Cerebellar atrophy/U | 2.8↑ (B)/U | N/CIII↓ (Mu) | Progression/ Alive (45y) | (Tropeano et al., 2025) |
| 34. MM | F/8y | m.15045G > A (p. R100Q) | 95.5% (Mu), 22.5% (B), 70.5% (Ur)/De novo | EI, CogI, FTT, SS | N/U | 4.8–6.4↑ (B)/ MCAC, LCAC↑ (B) | RRF (COX+)/CIII↓ (Mu) | Stable/Alive (13y) | This study |
For plasma/CSF lactate, the unit is mmol/L. The reference range for normality was adopted as reported in the respective source literature. For cases without available exact age at onset, categorical age descriptors reported in the original publications (Birth, Infant, Child, and Teen) were used. NSMD, non-syndromic mitochondrial disease; MM, mitochondrial myopathy; MCM, mitochondrial cardiomyopathy; MELAS, mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes; LHON, Leber hereditary optic neuropathy; JP, juvenile Parkinsonism; M, male; F, female; w, weeks; m, months; y, years; B, blood; Mu, muscle; F, fibroblasts; Ur, urine; H, hair; OM, oral mucosa; L, liver; K, kidney; Ov, ovary; Ht, heart; CSF, cerebrospinal fluid; +, positive/abnormal finding; −, negative/normal finding; U, unknown/not determined; N, normal; ↑, increased; ↓, decreased; HA, headache; GD, gait disturbance; DD, developmental delay; CogI, cognitive impairment; SLE, stroke-like episodes; TIA, transient ischemic attack; IM, involuntary movement; Myo, myoclonus; EP, epilepsy; EPC, epilepsia partialis continua; SE, status epilepticus; PN, peripheral neuropathy; EI, exercise intolerance; EIM, exercise-induced myalgia; MW, muscle weakness; MU, myoglobinuria; RM, rhabdomyolysis; RP, retinitis pigmentosa; VI, visual impairment; ON, optic neuropathy; OP, ophthalmoplegia; SNHL, sensorineural hearing loss; SS, short stature; FTT, failure to thrive; CM, cardiomyopathy; HCM, hypertrophic cardiomyopathy; DCM, dilated cardiomyopathy; WPW, Wolff-Parkinson-White syndrome; CA, cardiac arrest; HF, heart failure; RD, respiratory distress; AHS, alveolar hypoventilation syndrome; LFT, liver function test; LF, liver failure; RI, renal impairment; ATN, acute tubular necrosis; MA, metabolic acidosis; MOF, multiple organ failure; HT, hypothyroidism; KH, ketotic hypoglycemia; CK, creatine phosphokinase; PE, psychotic episode; Psych, psychiatric symptoms; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy; SOD, septo-optic dysplasia; BG, basal ganglia; BGS, basal ganglia calcification; CWM, cerebral white matter; MCP, middle cerebellar peduncle; PCr, phosphocreatine; Lac, lactate peak; TC, total carnitine; AC, acylcarnitine; MCAC, medium-chain acylcarnitine; LCAC, long-chain acylcarnitine; RRF, ragged-red fiber; COX, cytochrome c oxidase; RC, respiratory chain; CI, complex I; CII, complex II; CIII, complex III; CIV, complex IV.