Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4

Abstract

Background and ObjectivesHereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability.MethodsA cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed.ResultsA total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormal motor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3).DiscussionThe SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability.

Early‐Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST

“…1F; R adj 2 = 0.27, P < 0.01; r = 0.66, P < 0.0001). The mean SPRS score in our cohort was 32.8 AE 9.7 (SD), which is significantly higher than the average SPRS score of 18.2 AE 12.7 (two-tailed P < 0.001, Welch's t test) in large, likely familial HSP-SPAST cohorts published previously, 17 despite the older age in that cohort (mean age: 32.5 AE 17.4 [SD] years). The SPATAX score similarly increased with age (Fig.…”

New cellular imaging‐based method to distinguish the SPG4 subtype of hereditary spastic paraplegia

“…In addition, dcnc senses MT organization changes induced by spastin inactivation by an ATP‐competitive inhibitor. Thus, to begin evaluating whether the dcnc‐based method can also discriminate SPG4 missense mutations, LCLs were analysed from three patients carrying three different missense mutations in the catalytic domain (Table 1,5). Consistent with the effect of the spastin inhibitor, dcnc was able to discriminate the missense SPG4 ‐carrying LCLs from those of the HDs (Figure S5).…”

“…M1 and M87 have alternative splicing variants, lacking the exon 4 [4]. More than 250 mutations of the SPG4 gene have been reported, which can be subdivided into missense mutations (inactivating mutations clustering mainly in the catalytic domain and other mutations whose functional outcome is largely unknown) and into truncating mutations (frameshift, nonsense and insertions/deletions, commonly associated with a reduced amount of spastin protein as a result of mRNA nonsense‐mediated decay) [5]. Therefore, SPG4 ‐HSP is mostly thought to be mediated by haploinsufficiency and insufficient MT severing activity [1].…”

“…Therefore, SPG4-HSP is mostly thought to be mediated by haploinsufficiency and insufficient MT severing activity [1]. For a given variant, age at onset, clinical severity and course of progression are highly variable and unpredictable, even in the same family [3,[5][6][7]. To predict the probability of fast disease progression, fluid biomarkers are emerging.…”

Movement disorders in hereditary spastic paraplegia (HSP): a systematic review and individual participant data meta-analysis

“…Nevertheless, data from the subset of HSP-nMD patients collectively reported in the articles included in our study were gathered, and this subset of patients was used as a comparison group, assuming these cases are representative of the entire HSP-nMD population. This search strategy has potentially resulted in an under-representation of SPG4 , which is one of the commonest genotypes of HSP in patients with no prominent movement disorder [ 27 ]. Second, handling missing data is quite challenging in an IPD-level meta-analysis due to considerable inconsistencies in reporting symptoms and signs between original reports and the lack of a standardized checklist for data gathering.…”