Natural disease course and genotype‐phenotype correlations in Complex I deficiency caused by nuclear gene defects: what we learned from 130 cases

Abstract

Mitochondrial complex I is the largest multi-protein enzyme complex of the oxidative phosphorylation system. Seven subunits of this complex are encoded by the mitochondrial and the remainder by the nuclear genome. We review the natural disease course and signs and symptoms of 130 patients (four new cases and 126 from literature) with mutations in nuclear genes encoding structural complex I proteins or those involved in its assembly. Complex I deficiency caused by a nuclear gene defect is usually a non-dysmorphic syndrome, characterized by severe multi-system organ involvement and a poor prognosis. Age at presentation may vary, but is generally within the first year of life. The most prevalent symptoms include hypotonia, nystagmus, respiratory abnormalities, pyramidal signs, dystonia, psychomotor retardation or regression, failure to thrive, and feeding problems. Characteristic symptoms include brainstem involvement, optic atrophy and Leigh syndrome on MRI, either or not in combination with internal organ involvement and lactic acidemia. Virtually all children ultimately develop Leigh syndrome or leukoencephalopathy. Twenty-five percent of the patients died before the age of six months, more than half before the age of two and 75 % before the age of ten years. Some patients showed recovery of certain skills or are still alive in their thirties . No clinical, biochemical, or genetic parameters indicating longer survival were found. No clear genotype-phenotype correlations were observed, however defects in some genes seem to be associated with a better or poorer prognosis, cardiomyopathy, Leigh syndrome or brainstem lesions.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-012-9492-z) contains supplementary material, which is available to authorized users.

Acute stimulation of glucose influx upon mitoenergetic dysfunction requires LKB1, AMPK, Sirt2 and mTOR–RAPTOR

“…Each OXPHOS complex comprises multiple subunits and requires the assistance of proteinaceous assembly factors to catalyze its biogenesis (Acin-Perez and Enriquez, 2014;Nouws et al, 2012). Mutations in structural subunits or assembly chaperones induce mitochondrial disease in humans (Koene et al, 2012;Loeffen et al, 2000;van den Heuvel and Smeitink, 2001). Inherited complex-I deficiencies are the most common OXPHOS disorders (Bénit et al, 2009), whereas myopathy has been linked to an off-target effect of statins on complex III (Schirris et al, 2015).…”

Cellular and animal models for mitochondrial complex I deficiency: A focus on the NDUFS4 subunit

“…This suggests that the cellular aberrations in the fibroblast model correlate with the clinical phenotype. Conversely, analysis of a cohort of 130 patients with CI deficiency (14 of which displayed an Ndufs4 mutation) revealed no correlation between the AOO/ AOD of the patients and residual CI activity in the patient fibroblasts (15). This suggests that sole analysis of residual CI activity is not predictive of disease prognosis in CI deficient patients.…”

“…Since then, several other recessive Ndufs4 mutations have been identified resulting in CI deficiency (OMIM 252010): a single base deletion at position 289/290 in exon 3, a C316T transition in the same exon, a G44A nonsense mutation in exon 1, and a nonsense mutation (IVS1nt -1) in intron 1 of the NDUFS4 gene, all of which result in the absence of the NDUFS4 protein. In total, 14 NDUFS4 patients have currently been described in the literature (14,15). Clinically, these patients develop Leigh(-like) syndrome (LS) (6,15,16).…”

“…In total, 14 NDUFS4 patients have currently been described in the literature (14,15). Clinically, these patients develop Leigh(-like) syndrome (LS) (6,15,16). LS is a multisystemic progressive neurodegenerative disorder of infancy.…”

“…CI activity in fibroblasts from identified NDUFS4 patients analyzed so far ranges from 15% up to 75% enzyme activity of the lowest control value (15,22). During recent years, our group has focused on determining the cellular consequences of mutations in nDNA-encoded CI subunits, including NDUFS4 (2,6,25).…”