Expanding the phenotype of DNAJC30-associated Leigh syndrome

Clin Genet. 2022 Nov;102(5):438-443. doi: 10.1111/cge.14196. Epub 2022 Jul 29.

Abstract

Leigh syndrome (LS) is a progressive neurodegenerative disease, characterized by extensive clinical, biochemical, and genetic heterogeneity. Recently, biallelic variants in DNAJC30 gene, encoding a protein crucial for the repair of mitochondrial complex I subunits, have been associated with Leber hereditary optic neuropathy and LS. It was suggested that clinical heterogeneity of DNAJC30-associated mitochondrial disease may be attributed to digenic inheritance. We describe three Polish patients, a 9-year-old boy, and female and male siblings, aged 17 and 11 years, with clinical and biochemical manifestations of LS. Exome sequencing (ES) identified a homozygous pathogenic variant in DNAJC30 c.152A>G, p.(Tyr51Cys) in the 9-year-old boy. In the siblings, ES identified two DNAJC30 variants: c.152A>G, p.(Tyr51Cys) and c.130_131del, p.(Ser44ValfsTer8) in a compound heterozygous state. In addition, both siblings carried a novel heterozygous c.484G>T, p.(Val162Leu) variant in NDUFS8 gene. This report provides further evidence for the association of DNAJC30 variants with LS. DNAJC30-associated LS is characterized by variable age at onset, movement disorder phenotype and normal or moderately elevated blood lactate level. Identification of a candidate heterozygous variant in NDUFS8 supports the hypothesis of digenic inheritance. Importantly, DNAJC30 pathogenic variants should be suspected in patients with LS irrespective of optic nerve involvement.

Keywords: DNAJC30; Leigh syndrome; basal ganglia; dystonia; dystonic gait; mitochondrial disease; neurodegenerative disease; optic neuropathy; spasticity.

Publication types

  • Case Reports

MeSH terms

  • Female
  • Humans
  • Lactates
  • Leigh Disease* / genetics
  • Leigh Disease* / pathology
  • Male
  • Mitochondrial Diseases* / genetics
  • Mutation
  • Neurodegenerative Diseases*
  • Phenotype

Substances

  • Lactates