We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.

我们将双等位基因致病HPDL变异报告为渐进的、儿科发作的痉挛性运动障碍的原因，该疾病具有不同的临床表现。单外显子基因HPDL编码一种功能未知的蛋白质，其序列与 4-羟基苯基丙酮酸双加氧酶相似。对 13 个家族的外显子组测序研究揭示了受这种临床异质性常染色体隐性神经系统疾病影响的 17 个个体中的每一个的双等位基因HPDL变异。HPDL 水平在来自受影响更严重个体的成纤维细胞系中显着降低，表明已确定的HPDL变异导致 HPDL 蛋白丢失。临床表现范围从严重的新生儿神经发育迟缓和类似线粒体脑病的神经影像学结果到青少年发病的较轻表现，孤立的遗传性痉挛性截瘫。在疾病过程中，所有受影响的个体都出现了主要是下肢的痉挛。我们通过生物信息学和细胞研究证明 HPDL 具有线粒体定位信号，因此定位于线粒体，表明在线粒体代谢中具有推定的作用。综上所述，这些遗传、生物信息学和功能研究表明 HPDL 是一种线粒体蛋白，其缺失会导致临床上不同形式的儿童痉挛性运动障碍。