Department of Neurology, Kepler University Hospital, Krankenhausstr. 9, 4020, Linz, Austria.
Department of Human Genetics, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.
J Neurol. 2022 Dec;269(12):6476-6482. doi: 10.1007/s00415-022-11313-6. Epub 2022 Aug 10.
The term hereditary spastic paraplegia comprises an ever-expanding array of neurological disorders with distinct aetiologies. Spastic paraplegia gene 39 is one of the many genetically defined types with features of other organs and neurological systems in addition to paraspasticity. We describe a large kindred with a novel clinical phenotype as, in addition to spastic paraplegia, affected subjects suffered from a prominent cerebellar oculomotor dysfunction with two hitherto undescribed mutations of PNPLA6.
Three of five genetically tested family members of a large kindred were affected by spastic gait and a unique and prominent cerebellar oculomotor dysfunction. Further clinical, imaging, laboratory and videonystagmographic data were analyzed. Genetic analysis was done using next-generation sequencing.
The most salient clinical feature, in addition to paraspasticity, in three of five subjects was cerebellar oculomotor dysfunction with an upbeating nystagmus provoked by downward gaze. Genetic analysis revealed two hitherto unknown sequence variants in the PNPLA6 gene, a splice-site variant c.1635 + 3G > T and a missense variant c.3401A > T, p.(Asp1134Val). In addition to cerebellar oculomotor dysfunction, compound-heterozygous siblings presented with paraspasticity and a moderate hypogonadotropic hypogonadism in the female. A paternal uncle being homozygous for the splice-site variant of PNPLA6 presented with increased lower limb reflexes and an unstable gait. Treatment with 4-aminopyridine, a potassium channel blocker, lead to meaningful improvement of clinical symptoms.
The unique and prominent cerebellar ocular motor disorder in our family broadens the spectrum of clinical phenotypes associated with variations in the PNLA6 gene. The finding of paraspasticity with cerebellar oculomotor dysfunction alongside inconspicuous brainstem imaging may raise suspicion of complex HSP with PNPLA6 mutations.
遗传性痉挛性截瘫是一组不断扩展的神经系统疾病，具有不同的病因。痉挛性截瘫基因 39 是许多具有基因定义的类型之一，除了痉挛性外，还具有其他器官和神经系统的特征。我们描述了一个具有新型临床表型的大家族，除了痉挛性截瘫外，受影响的患者还患有明显的小脑眼球运动功能障碍，这与 PNPLA6 的两个迄今尚未描述的突变有关。
一个大家族的五名遗传测试的家庭成员中有三名受影响，表现为痉挛性步态和独特而明显的小脑眼球运动功能障碍。进一步分析了临床、影像学、实验室和视频眼动图数据。使用下一代测序进行基因分析。
除了痉挛性外，在五名受试者中的三名中，最显著的临床特征是小脑眼球运动功能障碍，伴有向下注视时出现的上扬性眼球震颤。基因分析显示，PNPLA6 基因中有两个迄今未知的序列变异，一个剪接位点变异 c.1635 + 3G > T 和一个错义变异 c.3401A > T，p.（Asp1134Val）。除了小脑眼球运动功能障碍外，复合杂合子兄弟姐妹还表现出痉挛性和女性中度促性腺激素低下性性腺功能减退症。携带 PNPLA6 剪接位点变异的父系叔叔表现出下肢反射亢进和不稳定步态。用钾通道阻滞剂 4-氨基吡啶治疗可显著改善临床症状。
我们家族中独特而显著的小脑眼球运动障碍拓宽了与 PNLA6 基因突变相关的临床表型谱。发现痉挛性截瘫伴有小脑眼球运动功能障碍和不明显的脑干影像学可能会怀疑存在具有 PNPLA6 突变的复杂 HSP。
