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

Mov Disord. 2022 Dec;37(12):2440-2446. doi: 10.1002/mds.29225. Epub 2022 Sep 14.


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.

Keywords: SPAST; cerebral palsy; childhood-onset movement disorders; hereditary spastic paraplegia; neurogenetics.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Cross-Sectional Studies
  • Humans
  • Muscle Spasticity
  • Mutation
  • Phenotype
  • Spastic Paraplegia, Hereditary* / diagnosis
  • Spastic Paraplegia, Hereditary* / genetics
  • Spastin / genetics
  • Young Adult


  • SPAST protein, human
  • Spastin