Variants in the PNPLA6 gene are known to cause 4 distinct phenotypes. One known phenotype is Hereditary Spastic Paraplegia type 39 (HSP 39), a rare neurodegenerative condition characterized by variable onset of lower limb spasticity, weakness and ataxia. Little is known about complications of HSP 39 in adulthood. Here, we report a family of three siblings who presented with bilateral lower limb spasticity in childhood, consistent with HSP, with confirmed bi-allellic PNPLA6 mutations. Two siblings developed parkinsonian features in middle age, a novel finding in this sibship. The proband had a positive dopamine transporter scan, indicating degeneration in dopaminergic neurons, and dopa-responsive extrapyramidal symptoms. Testing for known genetic causes of Parkinsonism was negative. The PNPLA6 gene encodes neuropathy target esterase, an enzyme involved in lipid metabolism that is critical to the stability of cell membranes. We hypothesize that the development of Parkinsonism in these patients may be related to the PNPLA6 mutations, as lipid dysregulation has been implicated in the pathogenesis of Parkinson disease.

已知PNPLA6基因中的变异会导致 4 种不同的表型。一种已知的表型是遗传性痉挛性截瘫 39 型 (HSP 39)，这是一种罕见的神经退行性疾病，其特征是下肢痉挛、虚弱和共济失调的不同发作。对成年期 HSP 39 的并发症知之甚少。在这里，我们报告了一个由三个兄弟姐妹组成的家庭，他们在儿童时期出现双侧下肢痉挛，符合 HSP，并证实为双等位基因PNPLA6突变。两个兄弟姐妹在中年时出现了帕金森症，这是这个兄弟姐妹中的一个新发现。先证者多巴胺转运体扫描呈阳性，表明多巴胺能神经元退化，以及多巴反应性锥体外系症状。对已知的帕金森症遗传原因的检测结果为阴性。PNPLA6基因编码神经病变靶酯酶，这是一种参与脂质代谢的酶，对细胞膜的稳定性至关重要。我们假设这些患者中帕金森病的发展可能与PNPLA6突变有关，因为脂质失调与帕金森病的发病机制有关。