Table 1 Clinical, biochemical and molecular genetic characteristics of our patient cohort with isolated Complex I deficiency.
Patient | Gender | Adult/Paediatric | Clinical Presentation | Gene | Genetic Defect | Residual Complex I activity | Mutation Load |
|---|---|---|---|---|---|---|---|
Nuclear-encoded Complex I structural subunits | |||||||
P1a | F | Paediatric | IUGR and oligohydramnios, FTT, mild hypertrophic cardiomyopathy | NDUFB3 | Homozygous c.64 T > C, p.(Trp22Arg) | 33% | n.a. |
P2b | F | Paediatric | IUGR. Acute life-threatening event, age 20 days, required intubation. Hypertrophic cardiomyopathy | NDUFB3 | Homozygous c.64 T > C, p.(Trp22Arg) | 32% | n.a. |
P3c | F | Paediatric | Oligohydramnios. IUGR. Poor feeding at birth. MRI brain and echocardiogram normal. Age-appropriate skills. Family history of previous neonatal death | NDUFB3 | Homozygous c.64 T > C, p.(Trp22Arg) | 35% | n.a. |
P4 | F | Paediatric | Leigh syndrome | NDUFS4 | Compound heterozygous c.99-1 G > A + c.416_417delinsC, p.(Glu139Alafs*50) | 39% | n.a. |
P5 | F | Paediatric | Consanguineous, first cousin parents; Leigh-like syndrome; elevated lactates | NDUFS4 | Homozygous exon 3 and 4 deletion | 37% | n.a. |
P6 | M | Paediatric | Infantile-onset mitochondrial disease; marked lactic acidosis | NDUFS6 | Homozygous c.316_319delGAAA, p.(Glu106Glnfs*41) | 5% | n.a. |
P7 | F | Paediatric | Leigh syndrome | NDUFS2 | Homozygous c.998 G > A, p.(Arg333Gln) | 42% | n.a. |
P8 | F | Paediatric | Leigh-like syndrome; elevated serum lactates | NDUFS3 | Homozygous c.642_644delTGA, p.(Asp214del) | 26% | n.a. |
Nuclear-encoded Complex I assembly factors | |||||||
P9 | F | Paediatric | Leigh-like syndrome; elevated lactates | NDUFAF6 | Compound heterozygous c.805 C > T, p.(His269Tyr) and c.581-7 A > G, p.(Leu193_Gly194insValIle) | 26% | n.a. |
P10 | F | Paediatric | Lethal infantile mitochondrial disease presentation; presented day 1 with persistent lactic acidosis; died at 9 weeks | NDUFAF6 | Homozygous c.659 C > A, p.(Thr220Lys) | 45% | n.a. |
P11 | F | Paediatric | Presented at 8 months; developmental regression, rotatory nystagmus bilaterally; elevated blood and CSF lactate; extensive basal ganglia and brainstem changes on MRI | NDUFAF5 | Compound heterozygous c.826 C > T, p.(Arg276*) and c.848 C > T, p.(Ala283Val) | 44% | n.a. |
P12 | M | Paediatric | Myoclonic seizures, developmental delay | FOXRED1 | Compound heterozygous c.612_615dup, p.(Ala206Serfs*15) and c.1261 G > A, p.(Val421Met) | 31% | n.a. |
P13 | M | Paediatric | Hypertrophic cardiomyopathy at birth; severe metabolic acidosis (18–30 mmol/L); died at 2 days of age | ACAD9 | Compound heterozygous c.868 G > A, p.(Gly290Arg) and c.976 G > C, p.(Ala326Pro) | 13% | n.a. |
P14 | M | Adult | Exercise intolerance, muscle cramps, elevated serum lactate | ACAD9 | Compound heterozygous c.1150 G > A, p.(Val384Met) and c.1168 G > A, p.(Ala390Thr) | 13% | n.a. |
P15d | M | Adult | Exercise intolerance, unable to perform sustained aerobic exercise; normal strength; normal ECG and echocardiogram; normal resting lactate, normal CK | TMEM126B | Homozygous c.635 G > T, p.(Gly212Val) | 36% | n.a. |
Mitochondrial DNA-encoded Complex I structural subunits | |||||||
P16e | F | Adult | Exercise intolerance, persistent lactic acidaemia | MTND1 | m.3356 T > C, p.(Met17Thr) | 3% | 92% |
P17 | M | Paediatric | Leigh syndrome | MTND3 | m.10158 T > C, p.(Ser34Pro) | 44% | 90% |
P18 | M | Paediatric | Leigh syndrome | MTND3 | m.10197 G > A, p.(Ala47Thr) | n.d. | 93% |
P19 | M | Paediatric | Leigh syndrome | MTND5 | m.13514 A > G, p.(Asp393Gly) | 27% | 66% |
P20f | F | Paediatric | Chronic renal failure, myopathy and persistent lactic acidosis | MTND5 | m.12425delA, p.(Asn30Thrfs*7) | 16% | 85% |
P21 | F | Paediatric | Bilateral ptosis, ophthalmoplegia, pyramidal tract signs, elevated blood and CSF lactates | MTND5 | m.13094 T > C, p.(Val253Ala) | 59% | 58% |
P22 | M | Adult | Mitochondrial myopathy, elevated lactates | MTND5 | m.13513 G > A, p.(Asp393Asn) | 39% | 60% |
P23 | M | Paediatric | Leigh syndrome | MTND5 | m.13513 G > A, p.(Asp393Asn) | 38% | 77% |
P24 | F | Adult | Elevated CK, muscle pain and fatigue, myopathy | MTND5 | m.13513 G > A, p.(Asp393Asn) | 100% | 45% |
P25 | M | Paediatric | Failure to strive, myopathy, increased brainstem signal on MRI, lactic acidosis | MTND5 | m.13513 G > A, p.(Asp393Asn) | 100% | 63% |
