Leigh Syndrome Associated With Mitochondrial Complex I Deficiency Due to a Novel Mutation in the NDUFS1 Gene

Abstract

Background: Mutations in the nuclear-encoded subunits of complex I of the mitochondrial respiratory chain are a recognized cause of Leigh syndrome (LS). Recently, 6 mutations in the NDUFS1 gene were identified in 3 families. Objective: To describe a Spanish family with LS, complex I deficiency in muscle, and a novel mutation in the NDUFS1 gene. Design: Using molecular genetic approaches, we identified the underlying molecular defect in a patient with LS with a complex I defect. Patient: The proband was a child who displayed the clinical features of LS. Results: Muscle biochemistry results showed a complex I defect of the mitochondrial respiratory chain. Sequencing analysis of the mitochondrial DNA-encoded ND genes, the nuclear DNA-encoded NDUFV1, NDUFS1, NDUFS2, NDUFS4, NDUFS6, NDUFS7, NDUFS8, and NDUFAB1 genes, and the complex I assembly factor CIA30 gene revealed a novel homozygous L231V mutation (c.691C→G) in the NDUFS1 gene. The parents were heterozygous carriers of the L231V mutation. Conclusions: Identifying nuclear mutations as a cause of respiratory chain disorders will enhance the possibility of prenatal diagnosis and help us understand how molecular defects can lead to complex I deficiency.

Natural variation and genetic covariance in adult hippocampal neurogenesis

“…Ndufs2 mutations are part of complex I deficiency disorders such as Leigh disease and mitochondrial diseases that include encephalopathies (31). A particular hippocampal function has not yet been reported, but in a rat model of depression, NADH dehydrogenase was up-regulated in the hippocampus (32), and a role for NADH dehydrogenases has been suggested in the context of neurodegenerative disorders (33).…”

Mitochondrial Disease in Childhood: Nuclear Encoded

“…Thirty-nine of these are nuclear-encoded, and at least 13 mutations in these genes have been reported to cause complex I deficiency [25]. The most common neurologic manifestation is Leigh syndrome [26]; other manifestations include cardiomyopathy, hepatopathy, myopathy, encephalomyopathy, tubulopathy, hypotonia, and some forms of Parkinson disease [27,28]. Neuroimaging findings in complex I deficiency includes brainstem lesions with associated basal ganglia lesions, which are hyperintense on T2-weighted images and hypointense on T1-weighted images; leukoencephalopathy; stroke-like lesions; cerebellar hyperintensities [29]; and increased lactate on magnetic resonance spectroscopy.…”

Mitochondrial complex I: Structure, function and pathology

“…Further clinical features are optic atrophy, ophthalmoparesis, hypotonia, ataxia and dystonia (Smeitink et al 2001a). Mutations causing complex I deficiency associated with Leigh syndrome have been found in six nuclear genes encoding complex I subunits: NDUFS1 (Benit et al 2001;Martin et al 2005), NDUFS3 (Benit et al 2004), NDUFS4 (Benit et al 2003b), NDUFS7 (Triepels et al 1999), NDUFS8 (Loeffen et al 1998;Procaccio et al 2004), and NDUFV1 (Benit et al 2001). Mutations in NDUFS4 have also been described for Leigh-like syndrome (Budde et al 2000;Petruzzella et al 2001;Van den Heuvel et al 1998).…”