Mitochondrial DNA depletion syndrome 20 (MTDPS20) is a rare disorder caused by variants in the LIG3 gene, which encodes a DNA ligase essential for mitochondrial DNA repair and replication. Defects in LIG3 impair mitochondrial replication, leading to reduced mitochondrial DNA copy numbers and mitochondrial dysfunction. Since its description in 2021, fewer than 20 cases have been reported, with features including gastrointestinal dysmotility, leukoencephalopathy, muscle weakness, neurogenic bladder, and cognitive decline. A more severe phenotype, including progressive myopathy, fatal muscle degeneration, decreased cytochrome c oxidase (COX) activity, and lipid accumulation in muscle fibers, was also reported. Here, we report a case of MTDPS20 with biallelic LIG3 variants that presented with immunodeficiency as part of the clinical phenotype for the first time.
The patient was a 23-month-old female with a history of developmental delay, infantile spasms, sensorineural hearing loss, bilateral cataracts, optic nerve hypoplasia, failure to thrive, gastroesophageal reflux, gastrointestinal dysmotility, anhidrosis, and progressive encephalopathy. On examination, she had severe hypotonia with no head control, microcephaly, and choreiform movements. Immune findings included hypogammaglobulinemia requiring subcutaneous immunoglobulin therapy, while endocrine features included central hypothyroidism and type 1 diabetes mellitus. Muscle biopsy demonstrated COX-negative muscle fibers with lipid accumulation. Neuroimaging demonstrated mildly delayed myelination and volume loss. The patient died at age 4 due to respiratory distress.
Comprehensive genetic testing, including exome sequencing, RNA sequencing, genome sequencing, and metabolomics, was uninformative. Reanalysis of genome sequencing data identified biallelic LIG3 variants: a missense mutation (c.1209-2A>G) and a 93-bp insertion, each inherited from unaffected parents. Functional validation via western blot and Sanger sequencing confirmed the pathogenic nature of these variants.
This case includes the first report of immune dysfunction in MTDPS20, characterized by hypogammaglobulinemia and type 1 diabetes mellitus, suggesting involvement of immune dysregulation. These findings, alongside typical manifestations such as gastrointestinal dysmotility, leukoencephalopathy, and COX-negative fibers, expand the recognized phenotype of MTDPS20 to include immunodeficiency.
Immunodeficiency is identified as a feature of MTDPS20 in this case, expanding the clinical spectrum of the disorder. Further research is needed to investigate the underlying mechanisms and implications for diagnosis and management.
