Biallelic variants in XPNPEP3 are associated with a rare mitochondrial syndrome characterized by nephronophthisis leading to kidney failure, essential tremor, hearing loss, seizures, and intellectual disability. Only 2 publications on this condition are available. We report a man with a complex ataxia syndrome, hearing loss, and kidney failure associated with a new biallelic variant in XPNPEP3.

Clinical evaluation, neuroimaging studies, a kidney biopsy, and whole genome sequencing (WGS) were applied. Since the phenotype was compatible with a mitochondrial disease, a muscle biopsy with morphological and mitochondrial biochemical investigations was performed.

Axial ataxia, cerebellar atrophy, hearing loss, myopathy, ptosis, supranuclear palsy, and kidney failure because of nephronophthisis were the prominent features in this case. WGS revealed the novel biallelic variant c.766C>T (p.Gln256*) in XPNPEP3. A muscle biopsy revealed COX negative fibers, a few ragged red fibers, and ultrastructural mitochondrial changes. Enzyme activity in respiratory chain complex IV was reduced in muscle and fibroblasts.

This is the first report of a slowly progressive cerebellar ataxia associated with a novel biallelic variant in XPNPEP3. Abnormalities typical for mitochondrial disease and the slow progression of kidney disease are also striking. Our report expands the spectrum of XPNPEP3-related diseases.

XPNPEP3的双等位基因变异与一种罕见的线粒体综合征相关，其特征是肾痨导致肾衰竭、原发性震颤、听力损失、癫痫发作和智力障碍。仅有 2 篇有关此情况的出版物可供查阅。我们报告了一名患有复杂共济失调综合征、听力损失和肾衰竭的男性，这些症状与XPNPEP3中的新双等位基因变异有关。

应用了临床评估、神经影像学研究、肾活检和全基因组测序（WGS）。由于该表型与线粒体疾病相一致，因此进行了肌肉活检以及形态学和线粒体生化研究。

轴性共济失调、小脑萎缩、听力丧失、肌病、上睑下垂、核上性麻痹以及肾结核引起的肾功能衰竭是本例的突出特征。WGS 揭示了XPNPEP3中新的双等位变体 c.766C>T (p.Gln256*) 。肌肉活检显示 COX 阴性纤维、一些参差不齐的红色纤维和线粒体超微结构变化。肌肉和成纤维细胞中呼吸链复合物 IV 的酶活性降低。

这是第一篇关于与XPNPEP3中的新型双等位基因变异相关的缓慢进行性小脑共济失调的报告。线粒体疾病的典型异常和肾脏疾病的缓慢进展也令人震惊。我们的报告扩大了XPNPEP3相关疾病的范围。