Leigh syndrome: One disorder, more than 75 monogenic causes

Abstract

Leigh syndrome is the most common pediatric presentation of mitochondrial disease. This neurodegenerative disorder is genetically heterogeneous, and to date pathogenic mutations in >75 genes have been identified, encoded by 2 genomes (mitochondrial and nuclear). More than one-third of these disease genes have been characterized in the past 5 years alone, reflecting the significant advances made in understanding its etiological basis. We review the diverse biochemical and genetic etiology of Leigh syndrome and associated clinical, neuroradiological, and metabolic features that can provide clues for diagnosis. We discuss the emergence of genotype-phenotype correlations, insights gleaned into the molecular basis of disease, and available therapeutic options.

Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome

“…They had progressive clinical courses with brain MRI and/or neuropathology analysis showing lesions in the basal ganglia, brainstem, and/or midbrain that were diagnostic of the progressive neurodegenerative disorder Leigh syndrome ( Figure S1 for subject 4 MRI). 19 Similar but milder clinical courses typical of Leigh or Leigh-like syndrome have been seen in subjects 2a, 2b, 3a, and 3b, with all still alive at ages ranging from 2 to 17 years. The subject with Leigh-like syndrome had neuroradiological imaging that did not fulfil stringent diagnostic criteria for Leigh syndrome.…”

“…Our study expands the known genetic causes of Leigh(-like) syndrome to now include mutations in a gene that encodes a small mitoribosomal protein. 19 While Leigh-like lesions were observed in an adult subject with mutations in MRPL44 and a clinical presentation characterized by hypertrophic cardiomyopathy, hemiplegic migraine, and exerciseinduced muscle pain, 16 our study broadens the clinical heterogeneity of human disorders of the mitoribosome to also include infantile-onset Leigh(-like) syndrome. To date, pathogenic mutations in $10% of all genes encoding mitoribosomal proteins have been described to cause disease.…”

“…The subject with Leigh-like syndrome had neuroradiological imaging that did not fulfil stringent diagnostic criteria for Leigh syndrome. 19 The three older subjects have developed dystonic and/or choreoathetoid movements, with wheelchair dependence. Four of the subjects had OXPHOS enzymology performed in skeletal muscle, liver, and/or skin fibroblast cell lines, which showed deficiency of one or more OXPHOS complexes (Tables 1 and S2).…”

Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD)

“…Causative variants have been identified in up to 75 genes involved in energy metabolism, encoded by either the nuclear or mitochondrial genomes, including each of the five OXPHOS complexes, electron carrier coenzyme Q10 (CoQ10) and components of the pyruvate dehydrogenase complex (Lake et al 2015). Mitochondrial DNA (mtDNA) mutations underlie approximately 10-20% of LS cases (Rahman et al 1996;Sofou et al 2014).…”

Leigh map: A novel computational diagnostic resource for mitochondrial disease

“…With these challenges in mind, we present the Leigh Map, a novel computational gene‐to‐phenotype network to be used as a diagnostic resource for mitochondrial disease, using Leigh syndrome (Mendelian Inheritance in Man 256000), the most genetically heterogeneous and most frequent phenotype of pediatric mitochondrial disease,3, 4 as a prototype. Leigh syndrome is a progressive neurodegenerative disorder defined neuropathologically by spongiform basal ganglia and brainstem lesions 4, 5.…”