Newborn and carrier screening for spinal muscular atrophy

Abstract

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder caused by mutations in the survival motor neuron (SMN1) gene, affecting approximately 1 in 10,000 live births. The homozygous absence of SMN1 exon 7 has been observed in the majority of patients and is being utilized as a reliable and sensitive SMA diagnostic test. Treatment and prevention of SMA are complementary responses to the challenges presented by SMA. Even though a specific therapy for SMA is not currently available, a newborn screening test may allow the child to be enrolled in a clinical trial before irreversible neuronal loss occurs and enable patients to obtain more proactive treatments. Until an effective treatment is found to cure or arrest the progression of the disease, prevention of new cases through accurate diagnosis and carrier and prenatal diagnosis is of the utmost importance. The goal of population-based SMA carrier screening is to identify couples at risk for having a child with SMA, thus allowing carriers to make informed reproductive choices. During this study we performed two pilot projects addressing the clinical applicability of testing in the newborn period and carrier screening in the general population. We have demonstrated that an effective technology does exist for newborn screening of SMA. We also provide an estimate of the carrier frequency among individuals who accepted carrier screening, and report on patient's knowledge and attitudes toward SMA testing.

Baseline results of the NeuroNEXT spinal muscular atrophy infant biomarker study

“…Twenty‐seven healthy infants were enrolled within 12 months; 26 infants with SMA were enrolled concurrently over 22 months. Confirmation of the SMN1 exon 7 deletion and SMN2 copy number were performed as previously described 21. In addition, DNA from SMA subjects was screened for the SMN2 gene positive modifier mutation c.859G>C 22…”

Spinal Muscular Atrophy: A Clinical and Research Update

“…Moreover, despite the high carrier frequency, the incidence of spinal muscular atrophy is lower than expected. This finding may reflect that some fetuses have a 0/0 SMN1/SMN2 genotype (i.e., no SMN protein is present at all), which is known in other species to be embryonic lethal [10].…”

“…The potential for newborn screening of spinal muscular atrophy has been of great interest because the ideal time to initiate therapy would precede the initial degeneration of motor neurons, and newborn screening may help identify presymptomatic individuals [10,39]. Swoboda et al performed a prospective study in prenatally diagnosed infants with type I spinal muscular atrophy and found that, associated with the initial onset of signs or decline in function in these young infants, electrophysiologic evidence of precipitous denervation was detected (assessed with serial measurements of compound motor action potential amplitude and motor unit number estimation), suggesting that motor neuron loss occurs very early [56].…”

Spinal Muscular Atrophies

“…It has been postulated that this may reflect that some fetuses have a 0/0 SMN1/SMN2 genotype (ie, no SMN protein is present at all), which is known in other species to be embryonic lethal. 11 …”