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

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 crosssectional 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 AE 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.

A Young Woman With Hypertonia, Severe Scoliosis, and Encephalopathy

“…Early-onset SPG4 presents as complex HSP, with symptoms of motor and speech delays, progressive ascending spasms, dystonia, epilepsy, and autonomic dysmotility (neurogenic bladder, gastrointestinal dyskinesia). 2,3 This patient exhibited developmental abnormalities of movement and speech without signs of upper motor neuron lesions, and genetic testing did not reveal any HSP genes.…”

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

“…Interestingly, despite a severe phenotype, normal imaging has usually been described. 1,3,4 In our patient, magnetic resonance imaging initially suggested a metabolic disorder and, later, brain iron accumulation, posing an additional challenge. The WESbased multigene panel was crucial for diagnosis, after three decades of investigation.…”

“…Joana Dam asio, MD, 1,2,3 * Clara Barbot, MD, PhD, 2 Rui Felgueiras, MD, 1 Ana Filipa Brand ão, MSc, 3 José Barros, MD, PhD, 1,4 Jorge Oliveira, MSc, PhD, 2,3 and Jorge Sequeiros, MD, PhD…”

A novel missense mutation in SPAST causes hereditary spastic paraplegia in male members of a family: A case report

“…approximately 75% of HSP-SPaST cases are inherited, and the remaining 25% of cases involve de novo mutations; patients with SPG4 mainly receive symptomatic treatment because no cure is available (17). Therefore, genetic counseling is essential for affected families.…”