Spectrum of Phenotypes in SMA Patients With 4 Copies in the French Population: Registre SMA France.

BACKGROUND AND OBJECTIVES

Clinical phenotype and course of individuals with 4 copies of the gene are insufficiently described, and presymptomatic treatment remains controversial.

METHODS

This is a cohort study that analyzed data from SMA patients with zero SMN1 and 4 SMN2 copies collected in the "Registre SMA France" to describe epidemiology, clinical presentation, and course.

RESULTS

A total of 140 of 1,112 patients with SMA carried 4 copies (16% of those with available copy number). The median age at onset was 3.5 years (6 months-20 years), and the median follow-up was 32 years. Twelve patients (8.6%) did not walk independently (SMA2). Of them, most were able to stand or walk with support (72%). Independent walking was acquired in 91% (123 SMA3, 5 SMA4), and one-third of them lost this ability (median 16 years). Loss of ambulation was significantly earlier in children with onset before 3 years (SMA3a). There was a significant predominance of male participants in the whole cohort (63%) and in subcohorts (SMA2, 83%; SMA3, 61%; adult population, 68%). There was a significant lower risk for female participants to lose ambulation ( = 0.01). Sixty-five percent of patients used a wheelchair. Scoliosis surgery and ventilation were required in less than 15%.

DISCUSSION

Most SMA patients with 4 copies in the French population show an onset during childhood and a progressive course with absence or loss of ambulation before adulthood. Presymptomatic treatment seems an acceptable option to consider, although identification of individual pejorative markers of early or severe phenotypes would allow more targeted approaches. Our results and literature suggest a gender effect in this population.

TRIAL REGISTRATION INFORMATION

NCT04177134.