Chen_2024_J.Neurol_272_78

BACKGROUND: PNPLA8 is a gene that causes an autosomal recessive mitochondrial disease characterised by microcephaly and intractable epilepsy in infants and cerebellar ataxia and limb weakness in adults. Herein, we report the clinical, muscle pathology, and brain imaging features of an adult patient with new variants of PNPLA8. METHODS: A 27-year-old Chinese woman presented with abnormal gait at age 11, remained amenorrhoeic with an infantile uterus at age 17, and presented with head and limb tremors at age 21. The results of brain magnetic resonance imaging suggested mild cerebellar atrophy. Whole-exome sequencing was performed, and mitochondrial and spinal cerebellar ataxia genes were screened. In addition, a biceps muscle biopsy was performed. Furthermore, a comprehensive literature search was conducted, and all patients with detailed clinical and genetic data up to October 2024 were included in the analysis. RESULTS: The patient's genetic screening revealed compound heterozygous variants c.1777T > G (p.Tyr593Asp) and c.1515-1516delTT (p.Tyr506Serfs*27) of PNPLA8 inherited from her parents. Her muscle biopsy showed mild myopathic changes on light microscopy and mitochondrial inclusions on electron microscopy. A total of 25 patients from 21 families were reviewed. CONCLUSION: Age of onset is a very important factor in terms of patient clinical phenotype and prognosis of PNPLA8-related disorders. It has been observed that adult females with PNPLA8 variants may present with primary ovarian dysfunction. The presence of mitochondrial inclusion bodies may serve as a pathological hallmark, extending the existing spectrum of the clinical phenotypes and pathogenic variants of PNPLA8.