Ivón Cuscó

SMN2 copy number predicts acute or chronic spinal muscular atrophy but does not account for intrafamilial variability in siblings

AbstractSpinal muscular atrophy (SMA) is an autosomal recessive disorder that affects motor neurons. It is caused by mutations in the survival motor neuron gene 1 (SMN1). The SMN2 gene, which is the highly homologous SMN1 copy that is present in all the patients, is unable to prevent the disease. An SMN2 dosage method was applied to 45 patients with the three SMA types (I–III) and to four pairs of siblings with chronic SMA (II–III) and different phenotypes. Our results confirm that the SMN2 copy number plays a key role in predicting acute or chronic SMA. However, siblings with different SMA phenotypes show an identical SMN2 copy number and identical markers, indicating that the genetic background around the SMA locus is insufficient to account for the intrafamilial variability. In our results, age of onset appears to be the most important predictor of disease severity in affected members of the same family.Given that SMN2 is regarded as a target for potential pharmacological therapies in SMA, the identification of genetic factors other than the SMN genes is necessary to better understand the pathogenesis of the disease in order to implement additional therapeutic approaches.

Detection of novel mutations in the SMN Tudor domain in type I SMA patients.

The authors present a complete SMN gene analysis in four type I unrelated spinal muscular atrophy patients who retained one copy of the SMN1 gene. Two intragenic point mutations were identified in exon 3 (I116F, Q136E), affecting a very conserved region with the Tudor domain of SMN1. The remaining two patients showed no alterations in the SMN1 coding sequences although a transcription defect was detected in one of them, corroborating the existence of non-functional SMN1 genes.

Prenatal diagnosis for risk of spinal muscular atrophy

Objectives Prenatal diagnosis of spinal muscular atrophy is usually performed in high risk couples by detection of a homozygous deletion in the survival motor neurone gene (SMN1). However, other relatives at risk of being carriers very often request genetic counselling and the possibility of prenatal diagnosis. The aim of this study was to validate a SMN1 gene quantitative test to help the couples formed by one spinal muscular atrophy carrier and a partner of the general population (1/200 potential risk) to achieve a less ambiguous risk result for the pregnancy.

Should gamete donors be tested for spinal muscular atrophy

OBJECTIVE To report two cases of spinal muscular atrophy (SMA) after artificial insemination and to discuss why genetic screening of the disease may be justified in gamete donors. DESIGN Case report. SETTING Academic departments of genetics and obstetrics. PATIENT(S) A 32-year-old woman with two successive assisted pregnancies. INTERVENTION(S) Molecular studies of the SMN1 (survival motor neuron), the determining gene of the disease. MAIN OUTCOME MEASURE(S); Prenatal testing to detect a homozygous deletion of the SMN1 gene; carrier diagnosis by quantitative analysis to detect a single or double dose of exon 7 in the SMN1 gene. RESULT(S) After a first assisted pregnancy, an SMA child with a homozygous deletion of the SMN1 gene was born. In the second assisted pregnancy, using sperm from a different donor, a fetus with a homozygous deletion of SMN1 was detected. Carrier status in the donor was confirmed by a single dose of SMN1 in the quantitative analysis. CONCLUSION(S) Genetic screening of SMA carrier status by quantitative analysis of the SMN1 gene should be performed in gamete donors when the recipient is a known carrier. Cost-benefit analysis should be made to consider the inclusion of the test in prospective gamete donor programs.

Choline acetyltransferase expression does not identify early pathogenic events in fetal SMA spinal cord

We investigated the expression of choline acetyltransferase, a specific marker for cholinergic neurons, in control and spinal muscular atrophy fetuses and newborns. By immunoblot we observed at 12 and 15 weeks a similar pattern of choline acetyltransferase expression in spinal muscular atrophy with respect to controls, although at 22 weeks this expression was reduced, probably due to a smaller number of motor neurons in the spinal muscular atrophy spinal cord. By immunohistochemistry, the counting of positive and negative motor neurons for choline acetyltransferase immunostaining in control and spinal muscular atrophy fetuses showed a similar proportion at all stages analyzed. The choline acetyltransferase-negative motor neurons were of similar appearance in both groups. After birth, chromatolytic motor neurons were detected in spinal muscular atrophy, all of which were choline acetyltransferase-negative. Our results in spinal muscular atrophy fetuses indicate that choline acetyltransferase immunostaining does not identify early events in neuronal pathogenesis and suggest that the spinal muscular atrophy surviving motor neurons may not be dysfunctional during this period. Furthermore, spinal muscular atrophy choline acetyltransferase-negative motor neurons showed detectable pathological changes only after birth, indicating that choline acetyltransferase is a late marker for motor neuron degeneration and not a primary contributing factor in this process.

Correlation between SMA type and SMN2 copy number revisited: an analysis of 625 unrelated spanish patients and a compilation of 2,834 reported cases

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss or mutations in SMN1. According to age of onset, achieved motor abilities, and life span, SMA patients are classified into type I (never sit), II (never walk unaided) or III (achieve independent walking abilities). SMN2, the highly homologous copy of SMN1, is considered the most important phenotypic modifier of the disease. Determination of SMN2 copy number is essential to establish careful genotype-phenotype correlations, predict disease evolution, and to stratify patients for clinical trials. We have determined SMN2 copy numbers in 625 unrelated Spanish SMA patients with loss or mutation of both copies of SMN1 and a clear assignation of the SMA type by clinical criteria. Furthermore, we compiled data from relevant worldwide reports that link SMN2 copy number with SMA severity published from 1999 to date (2834 patients with different ethnic and geographic backgrounds). Altogether, we have assembled a database with a total of 3459 patients to delineate more universal prognostic rules regarding the influence of SMN2 copy number on SMA phenotype. This issue is crucial in the present scenario of therapeutic advances with the perspective of SMA neonatal screening and early diagnosis to initiate treatments.