P-12

High phenotypic variability in two siblings with spinal muscular atrophy

Teresa Saraiva^I; Jorge Oliveira^I,III; Márcia E. Oliveira^I,III; Ana Soares^I; Rosário Santos^I,III; Ana Fortuna^I,III

^IUnidade de Genética Médica, Centro Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto - EPE, Porto, Portugal
^IIUnidade de Genética Molecular, Centro Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto - EPE, Porto, Portugal
^IIIUnidade Multidisciplinar de Investigação Biomédica (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto,Porto, Portugal

Introduction: Spinal muscular atrophy (SMA) is the second most common lethal autosomal recessive disease in caucasians after cystic fibrosis, with an estimated incidence in Portugal of 1 in 10.800 live births. SMA is a severe neuromuscular disease characterized by degeneration and loss of spinal and brain stem motor neurons (lower motor neurons), resulting in progressive proximal muscle weakness and atrophy. The disease-causing gene is the survival motor neuron 1 (SMN1) localized in 5q13. This gene has a highly homologous copy - SMN2 - differing in only 5 base pairs. While the SMN2 gene does not compensate entirely the loss of SMN1 in SMA patients, the number of SMN2 copies modulates the disease’s severity.

About 95% of patients have a homozygous deletion of exons 7 and 8 of SMN1. The remaining cases are compound heterozygotes for the deletion of SMN1 and an intragenic mutation in the other allele. Clinically  SMA  is  classified into four subtypes (I – IV) on the basis of age of onset, the maximum motor function achieved and survivorship. This classification is useful for prognosis and clinical management. Intrafamilial phenotypic variability is quite rare, but different SMA subtypes within the same family have been previously reported.

Case report: We present a family with two siblings diagnosed with SMA. They demonstrate a remarkable clinical variability and were classified with different SMA subtypes. The first patient, a 25 year-old  woman,  was  referred  to our genetic consultation with proximal limb weakness and difficulty in walking which started at 22 years of age. Her brother, 32 years old, is also affected with SMA but remarkably more severe in weakness. His limb weakness started at 5 years of age and significantly deteriorated to lose independent ambulation at the age of 7 years. Molecular genetic investigations revealed that both sibs have the same SMN1 genotype: compound heterozygosity for an SMN1 deletion and a novel point mutation [c.460C>T, (p.Gln154*)] in exon 3 of SMN1. MLPA technique revealed the presence of two SMN2 copies in both patients.

Conclusion: In this report we demonstrated the presence of intrafamilial phenotypic variability in two siblings classified with  different  SMA  subtypes.  This  variability  cannot  be explained by the number of SMN2 copies, since the siblings show an identical SMN2 copy number. These results are suggestive that other modifying factors may influence the phenotypic variability of SMA, such as gender-related factors, variants in other loci or modifier genes involved in regulating alternative splicing. Phenotypic discrepancies in SMA among siblings are major resources to identify such modifying factors, which may represent additional therapeutic targets and contribute towards a better understanding of SMA’s pathophysiology.