Variable severity of SMA in patients with four copies of the SMN2 gene

A study published using data from the SMA France register, set up in 2020, shows a wide variety of phenotypes in patients with SMN1-related proximal spinal muscular atrophy (SMA) with homozygous deletion of the SMN1 gene and four copies of the SMN2 gene, sometimes more severe than expected.

  • As of May 2023, 1,112 patients were registered in the SMA France registry.
  • Of these, 140 patients (16.1%) carried a homozygous deletion of the SMN1 gene and four copies of the SMN2 gene, including 123 with type III SMA, 12 with type II and five with type IV.
  • The median age of onset was 3.5 years and the median follow-up 32 years.
  • Symptoms appeared in childhood in most patients, before the age of three in 37.4% of type IIIs, with a progressive course of the disease.
  • Two-thirds of patients needed a wheelchair to get around.
  • The rates of use of scoliosis surgery and ventilation were less than 15%.
  • Problems with chewing and swallowing affected only 10.7% of patients.
  • Half the patients needed help at school or a carer for adults.
  • The overall phenotype was milder than expected for type II patients.
  • A gender effect is suggested by the predominance of males in the cohort (63%) and the more severe progression of the disease in males.

However, further in-depth studies are required, in particular to assess the value of presymptomatic treatment in this population presenting four copies of SMN2 and sometimes a more severe phenotype than expected.

 

Spectrum of Phenotypes in SMA Patients With 4 SMN2 Copies in the French Population: Registre SMA France Gerin L, Ropars J, Garcia-Uzquiano R et al. Neurol Genet. 2025 Apr.