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. 2024 Dec;82(12):1-9.
doi: 10.1055/s-0044-1792096. Epub 2024 Dec 20.

A self-reported Brazilian registry of 5q-spinal muscular atrophy: data on natural history, genetic characteristics, and multidisciplinary care

Rodrigo Holanda Mendonça  1 , Juliane Suellen Arndt de Godoi  2 , Edmar Zanoteli  1
Affiliations

A self-reported Brazilian registry of 5q-spinal muscular atrophy: data on natural history, genetic characteristics, and multidisciplinary care

Rodrigo Holanda Mendonça et al. Arq Neuropsiquiatr. 2024 Dec.

Abstract
in English, Portuguese

Background: Spinal muscular atrophy linked to chromosome 5q (SMA-5q) is a neurodegenerative disorder caused by mutations in the SMN1 gene.

Objective: To describe the key demographic, clinical and genetic characteristics, as well as natural history data of patients with SMA-5q.

Methods: Up to January 2022, 706 patients with confirmed genetic diagnosis of SMA-5q, or their parents, completed a self-reported questionnaire on natural history, genetic characteristics, drug treatments, and multidisciplinary care.

Results: Most patients had type 1 SMA-5q (42%); with 33% having type 2, and 23% type 3. There were 667 patients (94.4%) with a homozygous SMN1-exon 7 deletion. Of the total, 131 (18.6%) patients had a previous family history of the disease, and the familial recurrence rate was higher in type 3 (25.6%). Type 1 patients had a mean age of 3 months at the onset of symptoms and a delay of more than 3 months until genetic diagnosis. The median survival of patients with type 1 without invasive ventilation was 27 months. Before 2018, the median age of use of invasive ventilation was 16 months and, after, most patients (71%) were not submitted to invasive ventilation. About 50% of patients with type 3 lost their walking ability by 37 years of age. Further, 384 (54.4%) patients had access to disease-modifying therapy, and 62.3% of type 1 patients were in treatment, compared with only 47.2% of type 2 and 31.9% of type 3 patients.

Conclusion: There is still a substantial diagnostic delay, especially in those patients with types 2 and 3 SMA-5q. However, the present study demonstrated prolonged survival, especially in type 1 patients.

Antecedentes: A atrofia muscular espinhal ligada ao cromossomo 5q (AME-5q) é uma doença neurodegenerativa causada por mutações no gene SMN1.

Objetivo: Descrever as principais características demográficas, clínicas e genéticas, assim como dados de história natural de pacientes com AME-5q no nosso meio. MéTODOS: Até janeiro de 2022, 706 pacientes com diagnóstico genético confirmado de AME-5q, ou seus pais, preencheram questionário sobre dados de história natural, características genéticas, tratamento medicamentoso e cuidados multidisciplinares.

Resultados: A maioria dos pacientes tinha AME-5q tipo 1 (42%); 33% tinham tipo 2 e 23% tipo 3. Deleção homozigótica no SMN1 foi notada em 667 pacientes (94,4%). Do total, 131 (18,6%) pacientes tinham história familiar prévia, e a taxa de recorrência familiar foi maior no tipo 3 (25,6%). Os pacientes com tipo 1 tinham idade média de 3 meses no início dos sintomas e atraso de mais de 3 meses até o diagnóstico genético. A sobrevida mediana de pacientes com tipo 1 sem ventilação invasiva foi de 27 meses. Antes de 2018, a idade mediana de uso de ventilação invasiva era de 16 meses e, após, a maioria dos pacientes (71%) não foi submetida a ventilação invasiva. Cerca de 50% dos pacientes com tipo 3 perderam a marcha em média aos 37 anos de idade. Além disso, 384 (54,4%) pacientes tiveram acesso a alguma terapia modificadora da doença; 62,3% dos pacientes tipo 1 estavam sendo tratados, comparados a 47.2% do tipo 2 e 31.9% do tipo 3. CONCLUSãO: Ainda existe um atraso substancial para o diagnóstico, especialmente nos pacientes com AME-5q tipos 2 e 3. Contudo, o presente estudo demonstrou sobrevida prolongada em pacientes tipo 1.

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Conflict of interest statement

RHM: Consultant advisory, talks, and subinvestigator of clinical trials for Biogen, Novartis, and Roche. JSAD: Nothing to declare. EZ: Consultant advisory, talks, and principal investigator for Biogen, Novartis, and Roche.

Figures

Figure 1
Figure 1
( A ) The distribution of SMA-5q types in the registry. ( B ) Gender distribution in the general group, and according to types and median age in each subtype. ( C ) The age distribution in type 1. ( D ) The age distribution in type 2.
Figure 2
Figure 2
( A ) The distribution of SMN2 copy number according to SMA-5q types in those with MLPA confirmation ( n  = 505, types 0 and 4 not included). ( B ) The proportion of previous family history of SMA-5q according to patients' type. Note a more significant proportion of recurrence cases in type 3.
Figure 3
Figure 3
( A ) The Kaplan-Meier curve for invasive ventilation-free survival in patients with type 1 according to SMN2 copy number. For patients with two copies of SMN2 , the median time was 24 months and did not differ significantly from those with three copies ( p  = 0.5). ( B ) The survival curve relative to the time until invasive ventilation of type 1 patients, according to birth year. In those born before 2018, the median time until invasive ventilation use was 16 months (IQR: 10–27), and for those born after 2018, it was not possible to estimate because less than 25% of patients achieved this outcome ( p  = 0.002).
Figure 4
Figure 4
( A ) The estimated curve of walking loss in SMA-5q type 3. About 50% of type 3 patients lost walking ability by 453 months (37 years) of age. ( B ) The Kaplan-Meier curve of gait loss in type 3 according to SMN2 copies. The outcome appeared to be earlier in those patients with three copies of SMN2 , a median of 36 years (first quartile of 15 years) compared with those with four copies, with a p -value close to statistical significance ( p  = 0.077).
Figure 5
Figure 5
( A ) The distribution of ventilatory support according to SMA-5q types. ( B ) The level of nutritional support/feeding route according to types.
See this image and copyright information in PMC

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