Abstract

The Hereditary Spastic Paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders characterized by length dependent degeneration of the corticospinal tracts. Genetic data related to HSPs are limited from India. We aimed to comprehensively analyse the phenotypic characteristics and genetic basis of a large cohort of HSP from India. Patients with HSP phenotype were evaluated for their clinical features, electrophysiological and radiological abnormalities. Genetic analyses were carried out by clinical exome sequencing (n = 52) and targeted sequencing (n = 5). The cohort comprised of 57 probands (M:F 40:17, age: 3.5–49 years). Based on the phenotype, the cohort could be categorized as ‘pure’ (n = 15, 26.3%) and ‘complicated’ (n = 42, 73.7%) HSP. Brain MRI showed thin corpus callosum (n = 10), periventricular hyperintensities (n = 20), cerebral atrophy (n = 3), cerebellar atrophy (n = 3) and diffuse atrophy (n = 4). Sixty-seven variants representing 40 genes were identified including 47 novel variants. Forty-eight patients (84.2%) had variants in genes previously implicated in HSP and other spastic paraplegia syndromes (SPG genes = 24, non-SPG genes = 24); among these 13 had variations in more than one gene and 12 patients (21.0%) had variations in genes implicated in potentially treatable/modifiable metabolic disorders (MTHFR = 8, MTRR = 1, ARG1 = 2 and ABCD1 = 1). In nine patients, no genetic variants implicated in spastic paraplegia phenotype were identified. Thus, the present study from India highlights the phenotypic complexities and spectrum of genetic variations in patients with HSP including those implicated in metabolically modifiable disorders. It sets a platform for carrying out functional studies to validate the causal role of the novel variants and variants of uncertain significance.

摘要

遗传性痉挛性截瘫 (HSPs) 是一组临床和遗传异质性疾病，其特征是皮质脊髓束的长度依赖性退化。与 HSP 相关的遗传数据在印度是有限的。我们旨在全面分析来自印度的一大群 HSP 的表型特征和遗传基础。评估具有 HSP 表型的患者的临床特征、电生理学和放射学异常。通过临床外显子组测序（ n  = 52）和靶向测序（n  = 5）进行遗传分析。该队列由 57 名先证者组成（男：女 40:17，年龄：3.5-49 岁）。根据表型，队列可分为“纯”（n  = 15, 26.3%）和“复杂”（n  = 42, 73.7%) HSP。脑部 MRI 显示胼胝体薄 ( n  = 10)、脑室周围高信号 ( n  = 20)、脑萎缩 ( n  = 3)、小脑萎缩 ( n  = 3) 和弥漫性萎缩 ( n  = 4)。鉴定了代表 40 个基因的 67 个变体，包括 47 个新变体。48 名患者 (84.2%) 存在先前与 HSP 和其他痉挛性截瘫综合征有关的基因变异（SPG 基因 = 24，非 SPG 基因 = 24）；在这 13 名患者中，12 名患者（21.0%）的基因变异与潜在可治疗/可改变的代谢疾病有关（MTHFR  = 8，MTRR  = 1，ARG1 = 2 和ABCD1  = 1)。在 9 名患者中，未发现与痉挛性截瘫表型有关的遗传变异。因此，来自印度的本研究强调了 HSP 患者的表型复杂性和遗传变异谱，包括与代谢可改变疾病有关的那些。它为进行功能研究以验证新变体和不确定意义的变体的因果作用提供了一个平台。