PT  - JOURNAL ARTICLE
AU  - Rossi, Salvatore
AU  - Rubegni, Anna
AU  - Riso, Vittorio
AU  - Barghigiani, Melissa
AU  - Bassi, Maria Teresa
AU  - Battini, Roberta
AU  - Bertini, Enrico
AU  - Cereda, Cristina
AU  - Cioffi, Ettore
AU  - Criscuolo, Chiara
AU  - Dal Fabbro, Beatrice
AU  - Dato, Clemente
AU  - D'Angelo, Maria Grazia
AU  - Di Muzio, Antonio
AU  - Diamanti, Luca
AU  - Dotti, Maria Teresa
AU  - Filla, Alessandro
AU  - Gioiosa, Valeria
AU  - Liguori, Rocco
AU  - Martinuzzi, Andrea
AU  - Massa, Roberto
AU  - Mignarri, Andrea
AU  - Moroni, Rossana
AU  - Musumeci, Olimpia
AU  - Nicita, Francesco
AU  - Orologio, Ilaria
AU  - Orsi, Laura
AU  - Pegoraro, Elena
AU  - Petrucci, Antonio
AU  - Plumari, Massimo
AU  - Ricca, Ivana
AU  - Rizzo, Giovanni
AU  - Romano, Silvia
AU  - Rumore, Roberto
AU  - Sampaolo, Simone
AU  - Scarlato, Marina
AU  - Seri, Marco
AU  - Stefan, Cristina
AU  - Straccia, Giulia
AU  - Tessa, Alessandra
AU  - Travaglini, Lorena
AU  - Trovato, Rosanna
AU  - Ulgheri, Lucia
AU  - Vazza, Giovanni
AU  - Orlacchio, Antonio
AU  - Silvestri, Gabriella
AU  - Santorelli, Filippo Maria
AU  - Melone, Mariarosa Anna Beatrice
AU  - Casali, Carlo
TI  - Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4
AID  - 10.1212/NXG.0000000000000664
DP  - 2022 Apr 01
TA  - Neurology Genetics
PG  - e664
VI  - 8
IP  - 2
4099  - http://ng.neurology.org/content/8/2/e664.short
4100  - http://ng.neurology.org/content/8/2/e664.full
SO  - Neurol Genet2022 Apr 01; 8
AB  - Background and Objectives Hereditary 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.Methods A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed.Results A 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).Discussion The 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.AAA=ATPases Associated with diverse cellular Activities; AAE=age at the last available examination; AAO=age at onset; AD=autosomal dominant; DD=disease duration; HSP=hereditary spastic paraplegia; MEP=motor evoked potential; SPG=spastic paraplegia gene; SPG4=SPG type 4; SPRS=Spastic Paraplegia Rating Scale; SSEP=somatosensory evoked potential; TCC=thin corpus callosum; UL=upper limb