Related Experiment Video

Updated: Aug 28, 2025

A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia
05:51

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Published on: June 15, 2011

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

Alisa Mo1, Afshin Saffari1, Melanie Kellner2,3

  • 1Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Movement Disorders : Official Journal of the Movement Disorder Society
|September 14, 2022
PubMed

Insights

De novo variants in the SPAST gene cause a severe form of hereditary spastic paraplegia (HSP) in children, distinct from typical familial HSP. This condition presents with early-onset motor and speech delays, spasticity, and other neurological issues.

Area of Science:

  • Genetics
  • Neurology
  • Pediatrics

Background:

  • Hereditary spastic paraplegia (HSP) caused by SPAST (SPG4) variants usually presents as a pure HSP phenotype.
  • The genetic basis and clinical manifestations of sporadic HSP cases, particularly in children, require further elucidation.

Purpose of the Study:

  • To characterize the genotypic and phenotypic spectrum of hereditary spastic paraplegia (HSP) in children with de novo SPAST variants.
  • To differentiate the clinical presentation of de novo HSP-SPAST from classic familial forms.

Main Methods:

  • Systematic cross-sectional analysis of clinical and molecular data.
  • Genotyping of 40 pediatric patients with heterozygous pathogenic de novo variants in the SPAST gene.

Main Results:

  • Nineteen unique de novo SPAST variants were identified in 40 patients, with p.Arg499His being the most recurrent.
  • Symptom onset occurred in early childhood (median 11 months) with motor and speech delays, followed by progressive spasticity, dystonia, neurogenic bladder, gastrointestinal dysmotility, and epilepsy.
  • Patients exhibited a mean Spastic Paraplegia Rating Scale score of 32.8 ± 9.7.

Conclusions:

  • De novo SPAST variants result in a severe, complex form of HSP distinct from familial pure HSP-SPAST.
  • This condition should be considered in the differential diagnosis of cerebral palsy in children.
  • Awareness of this syndrome is crucial for accurate diagnosis and management.
Abstract

Keywords:
SPASTcerebral palsychildhood-onset movement disordershereditary spastic paraplegianeurogenetics

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