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Novel Biallelic LIG3 mutations causing lethal phenotype of mtDNA depletion syndrome 20; a case solved by multi-omics research re-analysis

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Genomic Medicine
  • Secondary Categories:
    • Genomic Medicine
Introduction
Mitochondrial DNA depletion syndrome 20 (MTDPS20) is a rare disorder caused by mutations in the LIG3 gene, which encodes a mitochondrial DNA ligase essential for the repair and replication of mitochondrial DNA. Defects in LIG3 impair mitochondrial replication, leading to reduced mitochondrial DNA copy numbers and severe mitochondrial dysfunction. MTDPS20 was first described in 2021, based on seven patients presenting with poor feeding, growth failure, leukoencephalopathy, seizures, and macular degeneration (Bonora et al., 2021). A follow-up study identified two additional patients with a more severe phenotype, including progressive myopathy, fatal muscle degeneration, decreased cytochrome c oxidase (COX) activity, and lipid accumulation in muscle fibers (Invernizzi et al., 2021). Common manifestations of MTDPS20 include gastrointestinal dysmotility, stroke-like episodes, neurogenic bladder, cerebellar atrophy, cognitive decline, and muscle weakness/atrophy. Here, we present a case of bi-allelic LIG3 variants causing MTDPS20 with a complex clinical phenotype leading to childhood demise.

Case Presentation
The patient was a 23-month-old female with a history of congenital hypotonia, developmental delay, failure to thrive (FTT), nystagmus, bilateral cataracts, congenital alacrima, gastroesophageal reflux (GER), gastrointestinal dysmotility, oropharyngeal dysphagia, ankyloglossia, anhidrosis, high pain tolerance, silent aspiration, microcephaly, progressive encephalopathy, hyperlipidemia, central hypothyroidism, Type 1 diabetes mellitus, hypogammaglobulinemia, metabolic acidosis, and mild to moderate sensorineural hearing loss. There were concerns for oculogyric crises and abnormal movements, though seizures were excluded. Neuroimaging showed mildly delayed myelination and mild volume loss. Muscle biopsy revealed COX-negative fibers with lipid accumulation, and decreased complex IV activity was noted. Optic nerve hypoplasia was also observed. The patient ultimately passed away at age 4 due to respiratory distress. Family history was unremarkable, and consanguinity was denied.

Diagnostic Workup
Comprehensive genetic testing, including whole exome sequencing, whole genome sequencing, RNA sequencing on blood and fibroblasts, and metabolic analyses (e.g., CDG testing, MPS screening, untargeted metabolomics, and lipidomics), was initially uninformative. However, research whole genome reanalysis revealed bi-allelic variants in LIG3: a missense mutation (c.1209-2A>G) and a 93bp insertion, each inherited from an unaffected parent. Functional validation via Western blot and Sanger sequencing confirmed the pathogenic nature of these variants, which have been previously described in the literature.

Discussion
The clinical and molecular findings, including gastrointestinal dysmotility, leukoencephalopathy, muscle weakness, neurogenic bladder, cognitive decline, and learning disabilities, strongly support the diagnosis of MTDPS20. Pathological features such as lipid droplets in muscle fibers, COX-negative fibers, and decreased complex IV activity further corroborated the genetic findings. Unique features in this case, including endocrine dysfunction (central hypothyroidism and Type 1 diabetes mellitus), and immune deficiency (hypogammaglobulinemia) may represent an expansion of the currently described MTDPS20 phenotype.

Conclusion
Although fewer than 20 cases have been reported worldwide, the expanding clinical spectrum suggests that more cases may emerge, offering further insights into the disorder. This underscores the need for continued research into the pathophysiology of mitochondrial diseases and the development of targeted therapeutic interventions.

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