We established genetic diagnoses in 13 of 60 previously unsolved cases using confirmatory experiments, including cDNA complementation to show that mutations in NUBPL and FOXRED1 can cause complex I deficiency.
Mutation screening of the ND5 gene is advised for routine diagnostics of patients with OXPHOS disease, especially for those with MELAS- and Leigh-like syndrome with a complex I deficiency.
This is one of the mildest known clinical presentations of complex I deficiency secondary to mutations in NDUFS1, expanding the clinical spectrum and natural history of this disorder.
In this study, we investigated the pathogenicity of a homozygous Asp446Asn mutation in the NDUFS2 gene of a patient with a mitochondrial respiratory chain complex I deficiency.
Our study further emphasizes that NDUFS6 sequence should be analyzed in patients presenting with lethal neonatal lactic acidemia due to isolated complex I deficiency.
The authors' objective is to report two heterozygous missense mutations in the NDUFAF1 gene as a cause of fatal infantile HCM in a patient with isolated complex I deficiency.
We provide functional evidence to support the pathogenicity of these TMEM126B variants, including evidence of founder effects for both variants, and establish defects within this gene as a cause of complex I deficiency in association with either pure myopathy in adulthood or, in one individual, a severe multisystem presentation (chronic renal failure and cardiomyopathy) in infancy.
Cycle sequencing of amplified NDUFS8 cDNA of 20 patients with isolated enzymatic complex I deficiency revealed two compound heterozygous transitions in a patient with neuropathologically proven Leigh syndrome.
Only a few patients were reported with proven NDUFS6 pathogenic variants and all presented with severe neonatal lactic acidemia and complex I deficiency, leading to death in the first days of life.
Since the likeliest target of mitochondrial mutation is Complex I, deficiency of which causes MnSOD-inhibitable lethality, we propose that rising mtDNA mutations with age will cause an increase in superoxide-mediated cell death.
Our report highlights that the long-term prognosis related to the p.Trp22ArgNDUFB3 mutation can be good, even for some patients presenting in acute metabolic crisis with evidence of an isolated Complex I deficiency in muscle.
Our data identify novel mechanisms underlying the cellular pathogenesis of RC dysfunction, including the combined induction of proteotoxic stress, the ER stress response and autophagy. mTORC1 inhibition with rapamycin partially ameliorated renal disease in B6.Pdss2(kd/kd) mice with complexes I-III/II-III deficiencies, improved viability and mitochondrial physiology in gas-1(fc21) nematodes with complex I deficiency, and rescued viability across a variety of RC-inhibited human cells.
Early-onset cataracts, spastic paraparesis, and ataxia caused by a novel mitochondrial tRNAGlu (MT-TE) gene mutation causing severe complex I deficiency: a clinical, molecular, and neuropathologic study.