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 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 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：

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罕见 FASTKD2 变异的纯合性导致成人发病的常染色体隐性线粒体足细胞病


多达一半的线粒体细胞病可累及肾脏。由于表型变异、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。我们报道了一名患有肥厚性心肌病 (HCM) 和慢性肾脏病 (CKD) 并伴有肾病性蛋白尿的年轻成年男性，他因肾功能衰竭和血容量过多而需要透析而到急诊科就诊。肾活检显示局灶性节段性和整体性肾小球硬化、广泛的足突消失以及足细胞和肾小管上皮细胞中的线粒体异常；基因检查发现了一个罕见的外显子 2 变异，c.29G>C p.(Ser10Thr)，具有纯合性；培养的皮肤成纤维细胞的功能性线粒体检测显示 FASTKD2 蛋白表达减少，线粒体呼吸链 (MRC) 组装和功能出现中度综合损伤。这是 FASTKD2 相关心肾线粒体细胞病的第一份报告，其特征是年轻成人发病的蛋白尿 CKD 和扩张性 HCM，但不存在双等位基因变异患者中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冒烟性足细胞病伴进行性蛋白尿性 CKD，而没有明显的肾小管病或脑肌病，而这可能与三磷酸腺苷缺乏症在致病上有关。