Dados do Trabalho

Título

SPINAL MUSCULAR ATROPHY IN A INFANT CAUSED BY COMPOUND HETEROZYGOUS SMN1 MUTATIONS: A CASE REPORT

Apresentação do caso único

Patient E.V.A.R., female, evaluated by neuropediatrics at 1 year and 6 months of age during hospitalization for treatment of pneumonia due to extubation failure and hypotonia. At the time, she presented signs of supra and infraspinal involvement. The patient is a orphanage residet, with little past history data. A brain magnetic resonance imaging and screening for inborn errors of metabolism were performed, with normal results. Upon return to the outpatient clinic, progression of global hypotonia with a predominance of the proximal lower limbs, tongue fasciculation and hyporeflexia were observed. A panel for spinal muscular atrophy (SMA) was collected with a MLPA result of 1 copy (heterozygous deletion) in the region referring to exon 7 of SMN1 and 2 copies of SMN2. Complete sequencing of the SMN1 gene was performed and the variant c.346A>T, p.(Ile116Phe) was found. However, it was not possible to identify whether the deletion detected in the MLPA exam and the point mutation were in cis or trans, without possible parental investigation. It was decided to perform electroneuromyography, with neuromuscular impairment of the motor neuronopathy type, compatible with SMA. A splicing (maturation) modifier of SMN2 pre-mRNA was prescribed.

Discussão

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular degenerative disorder of lower motor neurons, leading to progressive weakness. The most common form of SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene located at 5q13. Most of SMA cases (95%) result from homozygous deletion SMN1 and 5% cases are caused by compound heterozygous mutation (a SMN1 deletion on one allele and a subtle mutation on the other). In patients with exon 7 deletion in one SMN1 allele, the exons 3 and 6 of the other allele should be prompt evaluated, as it seems to be a specific hot spot for small mutations. According to the age of onset and clinical severity, SMA is divided into five types, and there is an correlation between low SMN2 copy number results in a severe phenotype. For patients who presents deletion on one SMN1 allele and one mutation on the other allele, their clinical severity can be usually determined by the type and location of the mutation rather than SMN2 copy number.

Comentários finais

The incidence of point mutations in SMA is not high, but they represent a distinct way to study the gene function and its mechanisms of disease and hence could lead to novel therapeutic approaches to alleviate SMA progression.

Referências

Mendonça RH, Matsui C Jr, Polido GJ, Silva AMS, Kulikowski L, Torchio Dias A, Zanardo EA, Solla DJF, Gurgel-Giannetti J, de Moura ACML, Sampaio GPC, Oliveira ASB, de Souza PVS, Pinto WBVR, Gonçalves EA, Farias IB, Nardes F, Araújo APQC, Marques W Jr, Tomaselli PJ, Ribeiro MDO, Kitajima JP, Paoli Monteiro F, Saute JAM, Becker MM, Saraiva-Pereira ML, Brusius-Facchin AC, van der Linden V, Florêncio RN, Barbosa AVS, Machado-Costa MC, Pessoa ALS, Souza LS, Franca MC Jr, Kok F, Reed UC, Zanoteli E. Intragenic variants in the SMN1 gene determine the clinical phenotype in 5q spinal muscular atrophy. Neurol Genet. 2020 Sep 1;6(5):e505. doi: 10.1212/NXG.0000000000000505. PMID: 33062891; PMCID: PMC7524579.

QU, Yu-jin; SONG, Fang; YANG, Yan-ling; JIN, Yu-wei; BAI, Jin-li. Compound heterozygous mutation in two unrelated cases of Chinese spinal muscular atrophy patients. Chinese Medical Journal 124(3):p 385-389, February 2011. | DOI: 10.3760/cma.j.issn.0366-6999.2011.03.012

Palavras Chave

Spinal muscular atrophy; Compound heterozygous mutation; SMN1