A clinical and molecular analysis of childhood-onset hereditary spastic paraplegias with novel variants

Objectives Hereditary spastic paraplegias (HSP) are characterized by progressive degeneration of the corticospinal tract, leading to lower limb spasticity and weakness. The pure form presents with progressive spasticity, whereas complicated HSP involve additional neurological abnormalities. We aim to describe the clinical and genetic profiles of childhood-onset HSP and reveal novel variants in these very rare disorders.

Methods We retrospectively collected clinical and molecular diagnosis data from 24 patients with childhood-onset HSP; the patients came from 20 different families and attended three medical centers. Clinical exome or whole-exome sequencing was performed to identify causal genetic variants.

Results Three patients were diagnosed with pure HSP; the rest had the complicated form. In complicated HSP, intellectual disability, epilepsy, cerebellar signs, dystonia, and polyneuropathy were detected to varying degrees and in various combinations. The most common variants were in the ATL1 gene, followed by MAG and SPAST. Other causative genes were AP4B1, B4GALNT1, ERLIN1, KIF1A, KIF1C, MTRFR, PCYT2, SPG11, and SPG7; some of the variants in these genes were novel. MAG encoded myelin-associated glycoprotein, and all three patients with MAG variants had cerebellar signs without polyneuropathy. SPAST and ALT1 were associated with both the pure and complicated forms in our patients.

Conclusion The complicated form of childhood-onset HSP predominated in our patients. We demonstrated further evidence of genetic and phenotypic heterogeneity in our cohort, giving the first report of some novel variants. Although it has been described in some cases, we could not identify combined central–peripheral nervous system involvement in MAG-gene-affected patients.
Keywords: spasticity, ataxia, myeline-associated glycoprotein, MAG, ATL1