Case reportEarly-Onset Ophthalmoplegia in Leigh-Like Syndrome Due to NDUFV1 Mutations
Introduction
Mitochondrial disorders share a common fundamental defect in cellular energy metabolism, but are clinically and genetically heterogeneous. Complex I deficiency notably, which is the most common biochemical defect among mitochondrial disorders in infancy and childhood, is associated with a wide spectrum of clinical phenotypes, including Leigh syndrome, and can be caused by mutations in both mitochondrial and nuclear deoxyribonucleic acid (DNA) [1], [2]. Complex I (nicotinamide adenine dinucleotide:ubiquinone oxidoreductase) is a multiprotein complex resulting from the assembly of seven mitochondrial-encoded and at least 39 nuclear-encoded subunits including NDUFV1 [3]. In recent years, mutations have been described in at least 10 nuclear-encoded subunits of complex I and account for the majority of complex I deficient cases in infancy and childhood [2], [4], [5]. Despite significant advances in molecular understanding of mitochondrial disorders, therapeutic options have remained poorly effective. The ketogenic diet—as a high-fat diet—has been proposed in complex I deficiency to bypass the defective step: electrons originating from the fatty acid oxidation will enter the respiratory chain directly before complex III and thus activate an alternative pathway for oxidative phosphorylation [6], [7]. This report describes a child presenting a Leigh-like syndrome with early-onset external ophthalmoplegia, caused by complex I deficiency and mutations in the NDUFV1 gene. In this case, the ophthalmologic symptoms have been strikingly improved by the ketogenic diet. Genotype-phenotype correlations for NDUFV1 mutations are discussed, as well as the use of the ketogenic diet for complex I deficient patients.
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Case Report
The patient is a male, born at term from healthy, nonconsanguineous and Caucasian parents, after an uneventful pregnancy (birth weight 2600 gm, length 45 cm, head circumference 33 cm, Apgar score 10 at 1 and 5 minutes). He presented at the age of 7 months with progressive external ophthalmoplegia causing divergent strabismus and bilateral ptosis (early ophthalmologic findings have been reported separately [8]). The ptosis was not responsive to neostigmine. At the age of 9 months, global
Discussion
Mitochondrial disorders can be classified by clinical, biochemical or, more recently, genetic approaches [3], [4]. Despite clinical overlap among syndromes and genetic heterogeneity, there is a better correlation between the clinical syndromes and the underlying genetic defect than with the biochemical analysis [10]. Most previous studies have focused on mtDNA abnormalities and have thoroughly investigated the link between the genetic defect in mtDNA and some clinically well-defined syndromes.
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The ketogenic diet as a therapeutic intervention strategy in mitochondrial disease
2021, International Journal of Biochemistry and Cell BiologyLeigh syndrome: Resolving the clinical and genetic heterogeneity paves the way for treatment options
2016, Molecular Genetics and MetabolismCitation Excerpt :The first mutation affecting complex I was described in 1998 in NDUFS8 [79]. In the following years, mutations have been described in the mtDNA encoded subunits MT-ND1 [98], MT-ND2 [152], MT-ND3 [91], MT-ND4 [65], MT-ND5 [143] and MT-ND6 [62] and in thirteen nuclear encoded subunits, including 6/7 core subunits, namely, NDUFA2 [54], NDUFA4 [116], NDUFA9 [157], NDUFA10 [55], NDUFA12 [108], NDUFS1 [11], NDUFS2 [151], NDUFS3 [13], NDUFS4 [17], NDUFS7 [148], NDUFS8 [79] and NDUFV1 [71]. In addition, mutations leading to Leigh syndrome have been described in four assembly factors, NDUFAF2 [102], NDUFAF5 [45], NDUFAF6 [109] and FOXRED1 [19].
Exome sequencing identifies complex I NDUFV2 mutations as a novel cause of Leigh syndrome
2015, European Journal of Paediatric NeurologyCitation Excerpt :It comprises 45 subunits, of which 38 are encoded by the nuclear genome and seven encoded by the mitochondrial genome. Molecular nuclear mutations causing complex I deficiency have been identified in 19 of the subunits.1–53 As many as 17 proteins required for assembly of the complex have been identified, with causative molecular mutations identified in ten of these.54–85