RT Journal Article
SR Electronic
T1 Clinical-Genetic Features Influencing Disability in Spastic Paraplegia Type 4
JF Neurology Genetics
JO Neurol Genet
FD Lippincott Williams & Wilkins
SP e664
DO 10.1212/NXG.0000000000000664
VO 8
IS 2
A1 Rossi, Salvatore
A1 Rubegni, Anna
A1 Riso, Vittorio
A1 Barghigiani, Melissa
A1 Bassi, Maria Teresa
A1 Battini, Roberta
A1 Bertini, Enrico
A1 Cereda, Cristina
A1 Cioffi, Ettore
A1 Criscuolo, Chiara
A1 Dal Fabbro, Beatrice
A1 Dato, Clemente
A1 D'Angelo, Maria Grazia
A1 Di Muzio, Antonio
A1 Diamanti, Luca
A1 Dotti, Maria Teresa
A1 Filla, Alessandro
A1 Gioiosa, Valeria
A1 Liguori, Rocco
A1 Martinuzzi, Andrea
A1 Massa, Roberto
A1 Mignarri, Andrea
A1 Moroni, Rossana
A1 Musumeci, Olimpia
A1 Nicita, Francesco
A1 Orologio, Ilaria
A1 Orsi, Laura
A1 Pegoraro, Elena
A1 Petrucci, Antonio
A1 Plumari, Massimo
A1 Ricca, Ivana
A1 Rizzo, Giovanni
A1 Romano, Silvia
A1 Rumore, Roberto
A1 Sampaolo, Simone
A1 Scarlato, Marina
A1 Seri, Marco
A1 Stefan, Cristina
A1 Straccia, Giulia
A1 Tessa, Alessandra
A1 Travaglini, Lorena
A1 Trovato, Rosanna
A1 Ulgheri, Lucia
A1 Vazza, Giovanni
A1 Orlacchio, Antonio
A1 Silvestri, Gabriella
A1 Santorelli, Filippo Maria
A1 Melone, Mariarosa Anna Beatrice
A1 Casali, Carlo
YR 2022
UL http://ng.neurology.org/content/8/2/e664.abstract
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