Early‐Onset and Severe Complex Hereditary Spastic Paraplegia Caused by De Novo Variants in SPAST. Issue 12 (14th September 2022)

• Record Type: Journal Article
• Authors: Mo, Alisa; Saffari, Afshin; Kellner, Melanie; Döbler‐Neumann, Marion; Jordan, Catherine; Srivastava, Siddharth; Zhang, Bo; Sahin, Mustafa; Fink, John K.; Smith, Linsley; Posey, Jennifer E.; Alter, Katharine E.; Toro, Camilo; Blackstone, Craig; Soldatos, Ariane G.; Christie, Michelle; Schüle, Rebecca; Ebrahimi‐Fakhari, Darius
• Is Part Of: Movement disorders. Volume 37:Issue 12(2022)
• Page Start: 2440
• Page End: 2446
• Publication Date: 2022-09-14
• Subjects: hereditary spastic paraplegia -- neurogenetics -- childhood‐onset movement disorders -- SPAST -- cerebral palsy; Movement disorders -- Periodicals; 610
• DOI: 10.1002/mds.29225
• Languages: English
• ISSNs: 0885-3185

Abstract

ABSTRACT: Background: Familial hereditary spastic paraplegia (HSP)‐ SPAST (SPG4) typically presents with a pure HSP phenotype. Objective: The aim of this study was to delineate the genotypic and phenotypic spectrum of children with de novo HSP‐ SPAST . Methods: This study used a systematic cross‐sectional analysis of clinical and molecular features. Results: We report the clinical and molecular spectrum of 40 patients with heterozygous pathogenic de novo variants in SPAST (age range: 2.2–27.7 years). We identified 19 unique variants (16/40 carried the same recurrent variant, p.Arg499His). Symptom onset was in early childhood (median: 11.0 months, interquartile range: 6.0 months) with significant motor and speech delay, followed by progressive ascending spasticity, dystonia, neurogenic bladder dysfunction, gastrointestinal dysmotility, and epilepsy. The mean Spastic Paraplegia Rating Scale score was 32.8 ± 9.7 (standard deviation). Conclusions: These results confirm that de novo variants in SPAST lead to a severe and complex form of HSP that differs from classic familial pure HSP‐ SPAST . Clinicians should be aware of this syndrome in the differential diagnosis for cerebral palsy. © 2022 International Parkinson and Movement Disorder Society.