Mitochondrial cytopathies can have kidney involvement in up to half of cases. Their diagnosis is challenging due to phenotypic variability, lack of noninvasive tests to assess mitochondrial dysfunction, and genetic heterogeneity. We report on a young adult male with hypertrophic cardiomyopathy (HCM) and chronic kidney disease (CKD) with subnephrotic proteinuria who presented to the emergency department with kidney failure and hypervolemia requiring dialysis. A kidney biopsy showed focal segmental and global glomerulosclerosis, extensive foot process effacement, and abnormal mitochondria in podocytes and tubular epithelial cells; the genetic workup identified a rare FASTKD2 exon 2 variant, c.29G>C p.(Ser10Thr), in homozygosity; and functional mitochondrial assays in cultured skin fibroblasts showed reduction in FASTKD2 protein expression and moderate combined impairment in mitochondrial respiratory chain (MRC) assembly and function. This is the first report of a FASTKD2-associated cardiorenal mitochondrial cytopathy, characterized by young adult-onset proteinuric CKD and dilated HCM, in the absence of the severe neurologic manifestations described in patients with biallelic FASTKD2 variants. We hypothesize that the increased production of reactive oxygen species associated with moderate MRC impairment could result in a smoldering podocytopathy with progressive proteinuric CKD, without overt tubulopathy or encephalomyopathy—which might be, instead, pathogenically related to adenosine triphosphate deficiency.

中文翻译：

---

导致成人常染色体隐性遗传线粒体足细胞病的罕见 FASTKD2 变异的纯合性


线粒体细胞病在多达一半的病例中可累及肾脏。由于表型变异性、缺乏评估线粒体功能障碍的无创测试以及遗传异质性，他们的诊断具有挑战性。我们报告了一名患有肥厚型心肌病 （HCM） 和慢性肾脏病 （CKD） 伴肾病蛋白尿的年轻成年男性，他因肾衰竭和高血容量需要透析而到急诊科就诊。肾活检显示局灶节段和整体肾小球硬化、广泛的足突消失以及足细胞和肾小管上皮细胞线粒体异常;遗传学检查在纯合性中发现了一种罕见的 FASTKD2 外显子 2 变异，c.29G>C p.（Ser10Thr）;培养的皮肤成纤维细胞中的功能性线粒体测定显示 FASTKD2 蛋白表达降低，线粒体呼吸链 （MRC） 组装和功能出现中度联合损伤。这是 FASTKD2 相关心肾线粒体细胞病的首次报道，其特征是年轻成人起病的蛋白尿 CKD 和 HCM 扩张，而没有双等位基因 FASTKD2 变异患者描述的严重神经系统表现。我们假设与中度 MRC 损伤相关的活性氧产生增加可能导致闷烧性足细胞病伴进行性蛋白尿 CKD，而没有明显的肾小管病或脑肌病——相反，这可能与三磷酸腺苷缺乏症的致病性有关。