201P Natural history of spinal muscular atrophy patients with 3 and 4 copies of SMN2 gene – data from the national Spanish registry (CUIDAME).

Spinal muscular atrophy (SMA) is caused by biallelic mutations of SMN1 gene, with wide spectrum of phenotypes. One of the best-known disease modifiers is a paralogous SMN2 gene and its copy numbers. Other well-known genetic modifiers are the c.859G>C andc.835-44A>G variants in SMN2. SMA was classified in 4 clinical types (1-4) depending on the acquisition of motor milestones, but there is a significant overlap in their clinical characteristics and genetic background, especially in late-onset patients. Moreover, with the approval of disease-modifying therapies (DMT), new phenotypes are arising, which do not fit with the traditional classification. In this context, describing the natural history according to the number of SMN2 copies and other well-known genetic modifiers has become more and more important. In this study, patients with 3 or 4 SMN2 copies included in the national Spanish registry for SMA (CUIDAME) who signed informed consent were assessed. The age of acquisition and loss of four main motor milestones (head control, sitting without support, walking with and without support) and other important milestones (scoliosis surgery, first long bone fracture and ventilation initiation) was collected with well-known SMN2 genetic modifiers and sex. Data on natural history were collected retrospectively from questionnaires and medical records and prospectively on subsequent clinical visits until treatment initiation. Multivariable models will be used to assess the influence of genetic modifiers and sex in the acquisition and loss of motor milestones. As for April 2024 253 patients with 3 SMN2 copies and 71 patients with 4 SMN2 copies were identified in the CUIDAME registry. Data on their natural history and the influence of sex and genetic modifiers will be presented. The description of SMA natural history according to genetic modifiers and sex will be key to predict the prognosis of asymptomatic untreated carriers and to assess the long-term efficacy of DMT. [ABSTRACT FROM AUTHOR]