Elsevier

Pediatric Neurology

Volume 36, Issue 1, January 2007, Pages 54-57
Pediatric Neurology

Case report
Early-Onset Ophthalmoplegia in Leigh-Like Syndrome Due to NDUFV1 Mutations

https://doi.org/10.1016/j.pediatrneurol.2006.08.007Get rights and content

Mitochondrial disorders can be linked to mutations in both mitochondrial and nuclear deoxyribonucleic acid, corresponding to various clinical phenotypes. Mutations in nuclear genes, including NDUFV1, have been associated with severe encephalomyopathies in infants, but genotype-phenotype correlations have remained elusive. This report details the complete clinical, biochemical, and molecular data of a 7-year-old male who presented at the age of 7 months with progressive ophthalmoplegia and later developed cerebellar ataxia, spasticity, and dystonia. Complex I deficiency was demonstrated in muscle, and two pathogenic missense mutations were present in the NDUFV1 gene. Ketogenic diet has seemingly improved the oculomotor palsy but has been unable to correct other neurologic symptoms. Considering other cases from the literature, this report broadens our understanding of genotype-phenotype correlations for NDUFV1 mutations and illustrates a potential and partial efficacy of ketogenic diet in complex I deficient patients.

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.

Section snippets

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.

References (15)

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