Abstract
Abstract Leigh syndrome is a devastating neurodegenerative disease, typically manifesting in infancy or early childhood. Hallmarks of the disease are symmetrical lesions in the basal ganglia or brain stem on MRI, and a clinical course with rapid deterioration of cognitive and motor functions. It is genetically heterogeneous, causative mutations have been disclosed in mitochondrial DNA and nuclear genes involved in the process of energy production in the mitochondria .We investigated the whole mitochondrial DNA in three Brazilian patients with LS, based on their clinical and biochemical data, with the aim to identify the disease-causing mutations. In two of the patients, with complex I deficiency, a novel heteroplasmic variant m.4142G>T (p.R279L) in MT-ND1 and a recurrent homoplasmic mutation m.10197G>A (p.A47T) in MT-ND3 were identified. In the remaining patient, with complex IV deficiency, a de novo heteroplasmic variant in MT-CO1 m.6547T>C (p.L215P) was found. The molecular investigation in mitochondrial diseases have shifted their focus from mitochondrial DNA to nuclear DNA, however, mtDNA protein-coding genes are one of the important genetic causes of mitochondrial disorders for Leigh syndrome. This study expands the molecular and clinical spectrum associated with this disease.
Highlights
Leigh syndrome (LS) or subacute necrotising encephalopathy (OMIM #256000) is a progressive neurodegenerative disorder, typically manifesting in infancy or early childhood
The variant was absent in the patient’s sibling (Fig. 3C). This heteroplasmic variant was not present in the human mitochondrial genome databases and was not detected in about 500 mitochondrial DNA (mtDNA) genomes previously sequenced by our group
mitochondrially encoded complex I genes (MT-ND) genes are relevant mutation hot spots in pediatric patients with complex I deficiency accompanied by variable severity of mitochondrial encephalopathy as described in two of these patients
Summary
Leigh syndrome (LS) or subacute necrotising encephalopathy (OMIM #256000) is a progressive neurodegenerative disorder, typically manifesting in infancy or early childhood. Since its first description by Denis Archibald Leigh in 1951,[1] it has evolved from a postmortem diagnosis, strictly defined by histopathological observations, to a clinical entity characterized by neurodegenerative symptoms, typical characteristic magnetic resonance imaging (MRI) lesions and heterogenic genetic causes of deficient mitochondrial energy metabolism. Hallmarks of the disease are symmetrical lesions in the basal ganglia or brain stem on MRI, and a clinical course with rapid deterioration of cognitive and motor functions.[1,2]. The severe neurological symptoms are caused by a range of different biochemical and molecular defects interfering with cellular energy production in affected brain regions.[3] Non-specific biochemical
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