Mitochondrial DNA Depletion Syndrome 1 ( MTDPS1 )—A Novel Cause of Premature Ovarian Insufficiency

Journal article

Mitochondrial DNA depletion syndrome 1 (MTDPS1) is a rare autosomal recessive disorder caused by mutations in the TYMP gene, leading to mitochondrial failure. Hallmark features include gastrointestinal dysmotility, cachexia, peripheral neuropathy, ocular signs, hearing loss, and leukoencephalopathy. We present a 39‐year‐old woman with premature ovarian insufficiency (POI) as a novel endocrine manifestation of MTDPS1. She had normal pubertal development with menarche at age 10. In her mid‐20s, she developed fatigue, nausea, vomiting, abdominal pain, weight loss, and amenorrhoea at age 29. Investigations revealed POI with elevated FSH levels, a normal karyotype, negative autoimmune markers. Imaging showed a thin endometrium, small ovaries, osteoporosis, severe gastroparesis. An incidental renal angiomyolipoma prompted an MRI of the brain, revealing symmetrical abnormal white matter changes, suggestive of leukodystrophy. Given diagnostic uncertainty and a history of consanguinity she was referred to clinical genetics and underwent whole genome sequencing which identified a novel homozygous variant (c.559C > T; p.(Gln 187*)) in the TYMP gene, confirming MTDPS1. Though POI is not a well‐established feature of MTDPS1, mutations in other genes linked with mitochondrial function are known to be associated with POI and we postulate that this is an endocrine manifestation of MTDPS1. Genetic assessment should be considered in unexplained POI, particularly if associated with other clinical features/consanguinity.

Authors: Matheou, M; Turner, H; Shears, D; Karpe, F

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Clinical Genetics
• Publication date: 2025-10-29
• Acceptance date: 2025-10-23
• DOI: 10.1111/cge.70100
• EISSN: 1399-0004
• ISSN: 0009-9163
• Language: English
• Keywords: TYMP gene mutation; premature ovarian insufficiency; mitochondrial DNA depletion syndrome 1