Childhood-onset hereditary spastic paraplegia and its treatable mimics

Mol Genet Metab. 2022 Dec;137(4):436-444. doi: 10.1016/j.ymgme.2021.06.006. Epub 2021 Jun 24.


Early-onset forms of hereditary spastic paraplegia and inborn errors of metabolism that present with spastic diplegia are among the most common "mimics" of cerebral palsy. Early detection of these heterogenous genetic disorders can inform genetic counseling, anticipatory guidance, and improve outcomes, particularly where specific treatments exist. The diagnosis relies on clinical pattern recognition, biochemical testing, neuroimaging, and increasingly next-generation sequencing-based molecular testing. In this short review, we summarize the clinical and molecular understanding of: 1) childhood-onset and complex forms of hereditary spastic paraplegia (SPG5, SPG7, SPG11, SPG15, SPG35, SPG47, SPG48, SPG50, SPG51, SPG52) and, 2) the most common inborn errors of metabolism that present with phenotypes that resemble hereditary spastic paraplegia.

Keywords: Biotinidase deficiency; Cerebrotendinous xanthomatosis; Hereditary spastic paraplegia; Inborn error of metabolism; Spasticity; Urea cycle disorders.

Publication types

  • Review

MeSH terms

  • Child
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Metabolism, Inborn Errors*
  • Mutation
  • Phenotype
  • Proteins / genetics
  • Retinal Degeneration*
  • Spastic Paraplegia, Hereditary* / diagnosis
  • Spastic Paraplegia, Hereditary* / genetics
  • Spastic Paraplegia, Hereditary* / metabolism


  • SPG11 protein, human
  • Proteins