Abstract
BackgroundLeigh Syndrome (LS) is a severe neurodegenerative disorder characterized by bilateral symmetrical necrotic lesions in the basal ganglia and brainstem. Onset is in early infancy and prognosis is poor. Causative mutations have been disclosed in mitochondrial DNA and nuclear genes affecting respiratory chain subunits and assembly factors.Case presentationHere we report the clinical and molecular features of a 15-month-old female LS patient. Direct sequencing of her muscle-derived mtDNA revealed the presence of two apparently homoplasmic variants: the novel m.14792C > G and the already known m.14459G > A resulting in p.His16Asp change in cytochrome b (MT-CYB) and p.Ala72Val substitution in ND6 subunit, respectively. The m.14459G > A was heteroplasmic in the mother's blood-derived DNA.ConclusionsThe m.14459G > A might lead to LS, complicated LS or Leber Optic Hereditary Neuropathy. A comprehensive re-evaluation of previously described 14459G > A-mutated patients does not explain this large clinical heterogeneity.
Highlights
Leigh Syndrome (LS) is a severe neurodegenerative disorder characterized by bilateral symmetrical necrotic lesions in the basal ganglia and brainstem
LS inheritance is complex since patients may present mutations in mitochondrial DNA or in nuclear genes, which predominantly encode for proteins involved in respiratory chain structure and assembly or in coenzyme Q10 biogenesis [2]
Direct sequencing of muscle-derived mitochondrial DNA (mtDNA) revealed the presence of two apparently homoplasmic variants: the novel m.14792C > G and the already known m.14459G > A resulting in p.His16Asp change in cytochrome b (MT-CYB) and p.Ala72Val substitution in ND6 subunit, respectively
Summary
The variant m.14459G > A has been so far reported in six patients affected by Leber’s hereditary optic neuropathy (LHON), in seven probands mainly showing dystonia and in four LS/Leigh-like Syndrome (LLS) patients [4,5,6,7,8,9]. Muscle biopsy did not show striking signs of mitochondrial impairment: in our proband no ragged-red or cytochrome c oxidase-negative fibers were observed. Minor changes such as mild variations in fiber size and accumulation of subsarcolemmal mitochondria have been reported in a few patients [5,7,8]. The pathological manifestation of the m.14459G > A mutation is thought to be highly tissue-specific,
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