Homozygous deletion in the SMN1 gene in asymptomatic individual - genetic counselling issues in SMA-risk families.

Spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders. The mode of inheritance of SMA is what determines the relatively low risk to off spring of affected persons, sibs of carriers of the pathogenic mutation or their more distant relatives. Nonetheless, the risk in question is increased beyond that in the population in general, thereby indicating the need for preventative measures to be taken in respect of SMA families. We present clinical characteristics of such a SMA-risk family. An apparently unaffected brother (patient) of the proband together with his pregnant wife sought genetic counselling about the SMA risk in their off spring. The estimated a priori risk was of about 0.5% (1 in 200). Molecular diagnostic tests performed in the patient indicated the presence of a homozygous deletion of the SMN1 gene identical to the one detected in the affected proband. The patient's wife was identified as a carrier of the deletion. The conditional risk for off spring of the couple was thus recalculated as 50% (1 in 2). Homozygous deletion of the SMN1 gene in unaffected individuals is a relatively rare event, yet one that nevertheless has significant impact on genetic counselling in SMA families. In these circumstances, molecular confirmation of SMA in such families allows for the provision of competent and reliable genetic advice, as well as for the introduction of secondary preventative measures. It also meets inclusion criteria as regards optional invasive prenatal diagnostic testing in families with a high (.25%) risk of the condition being present in the off spring.

Incidence of spinal muscular atrophy in Poland--more frequent than predicted?

BACKGROUND: The application of molecular methods has enhanced and enlarged the diagnostics of spinal muscular atrophy (SMA) and its carriership. It allows for reliable epidemiological studies which are of importance to demography and genetic counseling. METHODS: This study sought to evaluate the incidence of SMA in Poland, on the basis of the prevalence of the SMN1 gene deletion carrier state in the general population, as well as an analysis of all cases of SMA diagnosed in the years 1998-2005. RESULTS: The prevalence of the SMN1 gene deletion carrier state was estimated at 1 per 35 persons (17/600), yielding an incidence of SMA equal to 1 per 4,900. By contrast, the incidence of SMA based on the results of the meta-analysis was an estimated 1 per 7,127 in Warsaw and 1 per 9,320 persons across Poland, suggesting that some cases of SMA remain undiagnosed. SMA1 predominated among the diagnoses, accounting for 69% of all cases. CONCLUSION: A high prevalence of the SMN1 deletion carrier state in the general population indicates that SMA could be a more frequent disease than is predicted by the epidemiological data regarding diagnosed cases.

Phenotype modifiers of spinal muscular atrophy: the number of SMN2 gene copies, deletion in the NAIP gene and probably gender influence the course of the disease.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations of the SMN1 gene. It is characterized by significant phenotype variability. In this study, we analyzed possible phenotype modifiers of the disease - the size of the deletion in the SMA region, the number of SMN2 gene copies, as well as the effect of gender. Among the factors analyzed, two seem to influence the SMA phenotype: the number of SMN2 gene copies and a deletion in the NAIP gene. A higher number of SMN2 copies makes the clinical symptoms more benign, and the NAIP gene deletion is associated with a more severe phenotype. The influence of gender remains unclear. In a group of 1039 patients, 55% of whom were male, the greatest disproportion was in the SMA1 (F/M = 0.78) and SMA3b (F/M = 0.45) forms. In SMA1 a deletion in the NAIP gene was seen twice as frequently in girls compared to boys. In three patients, we observed genotypes atypical for the chronic forms of SMA: two patients with SMA3a and 3b had a deletion of the NAIP gene, and a third patient with SMA2 had one copy of the SMN2 gene.

Unaffected patients with a homozygous absence of the SMN1 gene.

In this report, we present three families in which we identified asymptomatic carriers of a homozygous absence of the SMN1 gene. In the first family, the bialleleic deletion was found in three of four siblings: two affected brothers (SMA type 3a and 3b) and a 25-years-old asymptomatic sister. All of them have four SMN2 copies. In the second family, four of six siblings are affected (three suffer from SMA2 and one from SMA3a), each with three SMN2 copies. The clinically asymptomatic 47-year-old father has the biallelic deletion and four SMN2 copies. In the third family, the biallelic SMN1 absence was found in a girl affected with SMA1 and in her healthy 53-years-old father who had five SMN2 copies. Our findings as well as those of other authors show that an increased number of SMN2 copies in healthy carriers of the biallelic SMN1 deletion is an important SMA phenotype modifier, but probably not the only one.

[Prenatal diagnosis of spinal muscular atrophy (SMA) -- indications, restrictions, interpretation of results]. / Diagnostyka prenatalna w rdzeniowym zaniku miesni. Wskazania, ograniczenia, interpretacja wuników.

INTRODUCTION: Proximal spinal muscular atrophy of childhood and adolescence (SMA) is a genetic autosomal recessive disease. Caused in 96.5% by deletion in the SMN1 gene. Owing to the homogeneity of the molecular defect. Secondary prophylaxis can readily be offered to families at risk of SMA. PATIENTS: Prenatal diagnosis of SMA was carried out in a group of 50 families. Which were divided into two subgroups: with high and relatively low genetic risk of SMA. In all, 55 prenatal tests were performed in the period 1998-2003. RESULTS: In the first group including 45 families at high genetic risk, 9 of the 50 tests were positive (18%). The diagnosis of SMA was tentative in 7 cases from this group and it was based only on the clinical picture (the affected children are not alive, therefore DNA samples are not available). Prenatal examination in 1 of these 7 families showed the SMA genotype. In the second subgroup including 5 families with relatively low genetic risk of SMA in none of the studies was there a biallelic deletion of exon 7 in the SMNI gene. Mainly parents of children with a severe form of SMA and having no healthy offspring asked for prenatal examination (73% of the families). CONCLUSIONS: Prenatal diagnosis could be offered to families even if the diagnosis of SMA was not genetically verified. The negative result should he then interpreted individually. Until the carrier test will not he introduced to routine procedures. prenatal diagnosis can be also offered to families at relatively low risk of SMA.

[Molecular pathogenesis of fragile X syndrome]. / Molekularna patogeneza zespolu lamliwego chromosomu X.

The fragile X syndrome is an X-linked genetic disorder; manifesting primarily as intellectual disability. The disease is caused by the absence of functional FMRP, a protein encoded by the FMR1 gene. The expansion of trinucleotide repeats within the first exon of the gene contributes to most cases of the syndrome. This review summarizes the present knowledge of the relationship between the molecular defect in the FMR1 gene and the clinical phenotype associated with disease.