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PubMed1999

Preimplantation genetic diagnosis for spinal muscular atrophy type I.

OBJECTIVE: Couples with children who have spinal muscular atrophy type I (SMA) face a 25% risk of having affected offspring with spontaneous conception. Preimplantation genetic testing (PGT) is possible for the deletions in the survival motor neuron (SMN) gene that have been identified in 98% of SMA type I cases. PGT would provide new reproductive options for families at risk for SMA. METHODS: Three couples with previously affected children confirmed by DNA testing each underwent in vitro fertilization (IVF) and PGT of the resulting embryos. One or two blastomeres were biopsied from each embryo and analyzed for deletions in exons 7 and 8 of the SMN gene. RESULTS: Nine embryos were predicted to be unaffected, three to be affected, and one embryo could not be interpreted. One of three patients receiving transfer of unaffected embryos became pregnant with twins. CONCLUSIONS: Preimplantation genetic testing provides a means for couples at risk for spinal muscular atrophy type I to reduce their chance of initiating an affected pregnancy.

Adult↗
PubMed1993

Intramedullary astrocytoma presenting as spinal muscular atrophy.

We present a 6-year-old patient with a spinal cord tumor who had been followed with the diagnosis of spinal muscular atrophy since the age of 23 months. Reasons for reevaluating the diagnosis of spinal muscular atrophy were the early onset of scoliosis, the slight asymmetry in weakness of extremities, and the appearance of urinary retention in the last 3 days. Magnetic resonance imaging revealed a very long, intramedullary tumor extending from the level of the seventh cervical segment to the conus medullaris, later reported to be a grade I astrocytoma. We therefore recommend that magnetic resonance imaging, a noninvasive and sensitive technique for intraspinal pathologies, be performed in every patient with an atypical form of spinal muscular atrophy.

Age of Onset↗
PubMedDate not supplied

[Heart involvement in progressive spinal muscular atrophy. A review of the literature and case histories in childhood].

There are few cardiological studies in progressive spinal muscular atrophy and mainly concern subjects affected by the juvenile form (Kugelberg-Welander disease). The presence of a cardiomyopathy has been reported in these patients but the cardiac involvement is often secondary to the chronic respiratory insufficiency typical of the disease. We performed a retrospective study in our Institute on 43 patients, age range 3 months to 3 years, 37 of which presented type I (Werdnig-Hoffmann disease) and 6 type II (intermediate form) of the disease. No clinical nor instrumental signs of cardiomyopathy were observed. However, ECG revealed signs of right ventricular overload in 37.3% of the patients, probably provoked by pulmonary hypertension due to respiration anomalies. The authors underline the importance of correct respiratory assistance to prevent onset of cardiological alterations.

Cardiomyopathies↗
PubMed1997

Deletion and conversion in spinal muscular atrophy patients: is there a relationship to severity?

The spinal muscular atrophy-determining gene, survival motor neuron (SMN), is present in two copies, telSMN and cenSMN, which can be distinguished by base-pair changes in exons 7 and 8. The telSMN gene is often absent in spinal muscular atrophy patients, which could be due to deletion or sequence conversion (telSMN conversion to cenSMN giving rise to two cenSMN genes). To test for conversion events in spinal muscular atrophy, we amplified a 1-kb fragment that spanned exons 7 and 8 of SMN from 5 patients who retained telSMN exon 8 but lacked exon 7. In all patients, sequence analysis demonstrated that cenSMN exon 7 was adjacent to telSMN exon 8, indicating conversion. All 5 patients with this mutation had type II or III spinal muscular atrophy, strongly supporting an association with chronic spinal muscular atrophy. We also identified 3 families in which 2 siblings had no detectable telSMN but presented with markedly different phenotypes. We suggest that sequence conversion is a common event in spinal muscular atrophy and is associated with the milder form of the disease. The severity, however, can be modified in either a positive or negative direction by other factors that influence splicing or expression of the sequence converted SMN gene.

Base Sequence↗
PubMed2006

Establishing a standardized therapeutic testing protocol for spinal muscular atrophy.

Several mice models have been created for spinal muscular atrophy (SMA); however, there is still no standard preclinical testing system for the disease. We previously generated type III-specific SMA model mice, which might be suitable for use as a preclinical therapeutic testing system for SMA. To establish such a system and test its applicability, we first created a testing protocol and then applied it as a means to investigate the use of valproic acid (VPA) as a possible treatment for SMA. These SMA mice revealed tail/ear/foot deformity, muscle atrophy, poorer motor performances, smaller compound muscle action potential and lower spinal motoneuron density at the age of 9 to 12 months in comparison with age-matched wild-type littermate mice. In addition, VPA attenuates motoneuron death, increases spinal SMN protein level and partially normalizes motor function in SMA mice. These results suggest that the testing protocol developed here is well suited for use as a standardized preclinical therapeutic testing system for SMA.

Animals↗
PubMed2003

Evoked potentials in spinal muscular atrophy.

Visual evoked potentials, brainstem evoked responses, and somatosensory evoked potentials were evaluated in 22 children with spinal muscular atrophy, types I and II. Eleven of the children had the severe form of spinal muscular atrophy (type I) and 11 children had the intermediate form (type II). The results of visual evoked potentials, brainstem evoked responses, and somatosensory evoked potentials were compared with those obtained in a control group. Statistical analysis showed abnormalities in the different sensory modalities. A significant increase in the visual evoked potential latencies was observed and was found more often in patients with spinal muscular atrophy type I. Alterations of the somatosensory thalamocortical responses were also observed, as well as a delay in the central conduction time. Although spinal muscular atrophy is usually considered to be a purely motor disorder involving neurons of the spinal anterior horn and nuclei of the lower cranial nerves, lesions of the posterior roots, spinal ganglia, ascending tracts, lateral geniculated corpus, and thalamus have been reported. Our results suggest that sensory neuron degeneration occurs more commonly in spinal muscular atrophy than previously thought and that this process probably develops more slowly than motoneuron degeneration. Such degeneration may be associated with brain atrophy.

Adolescent↗
PubMed1997

Deletions in the SMN and NAIP genes in patients with spinal muscular atrophy in Croatia.

Two genes, i.e. survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) have been mapped to the SMA region of chromosome 5q13. Both genes are frequently deleted or truncated in SMA patients. We have studied 26 patients with SMA types I-III, 29 first relatives, and 14 subjects with mild adult-onset type IV. DNA deletion genotypes were determined by PCR techniques amplifying exons 7 and 8 of SMN, and exon 5 of NAIP gene which distinguish SMN and NAIP telomeric copy from a non-pathogenic gene homologue as a centromeric copy. Results revealed the homozygous deletions of exon 7 and 8 of the SMN gene and exon 5 of the NAIP gene in 3/3 infants with SMA I and in 1/20 with SMA type II. Exons 7 and 8 of the SMN gene were homozygously deleted in 10/20 and only exon 7 in 6/20 children with SMA type II. The overall percentage of deletion cases observed was 77% in children with SMA types I-III. Adult patients with type IV SMA showed no homozygous deletion of exons 7, 8 and 5 of the SMN and NAIP genes. Also, all relatives had both a telomeric and centromeric SMN and NAIP copy. Deletion analysis of SMN and NAIP genes are a significant diagnostic tool, because there are clinical entities resembling SMA which most likely have another pathogenetic background.

Adult↗
PubMed2001

Molecular genetic study of a childhood form of spinal muscular atrophy.

Molecular genetic studies were performed in 28 cases of childhood-onset spinal muscular atrophy (24 unrelated families). This consisted of type 1 (severe) (n = 5), type 2 (intermediate form) (n = 8), and type 3 (mild) (n = 15). Deletion of exons 7 and 8 of the SMNt gene was found in 100%, 100%, and 93%, respectively, in type 1, 2, and 3 spinal muscular atrophy. Deletion of exons 5 and 6 of the NAIP gene was found in 3 of 5 (60%) of type 1 and none of the type 2 and 3 cases. None of the 32 asymptomatic relatives had homozygous deletions in the SMNt and NAIP genes. Thus, the role of the NAIP gene needs to be specifically defined in spinal muscular atrophy. In a suspected case of spinal muscular atrophy, deletion of the SMNt gene is a useful laboratory marker for confirmation of the diagnosis.

Adolescent↗
PubMed1995

Prenatal diagnosis of spinal muscular atrophy in Russia.

Ninety-two families with spinal muscular atrophy (SMA) applied for genetic counselling and further prenatal diagnosis. To minimize expenses, only one tightly linked informative marker was determined in the course of preliminary examination, and non-radioactive allele detection was preferably used. Four prenatal diagnoses of SMA type I, four of SMA type II, and one of SMA type III were made. This trial programme shows the considerable requirements, importance, and potential effectiveness of prenatal prediction of SMA in Russia.

Adolescent↗
PubMed2005

Increased susceptibility of spinal muscular atrophy fibroblasts to camptothecin-induced cell death.

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by deletions or mutations in the telomeric copy of the survival motor neuron (SMN1) gene. Although the SMN protein has been implicated in the biogenesis of ribonucleoprotein complexes and RNA processing, it is not clear how these functions contribute to the pathogenesis of SMA. To gain a further understanding of SMN function, we have investigated its role in cell survival in skin fibroblasts derived from SMA patients and age-matched controls. SMA fibroblasts exposed to camptothecin, a specific inhibitor of DNA topoisomerase I, consistently showed cell death at a lower concentration than normal controls. Treatment with other cell death-inducing agents did not cause differences in survival of SMA fibroblasts as compared with control fibroblasts. Camptothecin treatment resulted in activation of caspase-3 with generation of the caspase-3 cleavage product, poly ADP-ribose polymerase (PARP). Depletion of SMN protein by RNA interference in control fibroblasts increased caspase-3 activity, whereas transfection of SMA fibroblasts with wild-type SMN decreased caspase-3 activity. Our data demonstrate that SMA fibroblasts are more prone to some, but not all, death-stimuli. Vulnerability to death-stimuli is associated with decreased levels of SMN protein and is mediated by activation of caspase-3.

Atrophy↗
PubMed1995

Noninvasive long-term ventilatory support for individuals with spinal muscular atrophy and functional bulbar musculature.

Ten individuals with spinal muscular atrophy (SMA) and chronic ventilatory insufficiency were trained in the use of assisted coughing techniques and received intermittent positive pressure ventilation (IPPV) via oral and/or nasal interfaces for a mean of 5.3 (range = 1 to 17) years. During this time they had significantly fewer respiratory complications than before introduction of noninvasive respiratory muscle aids despite the fact that 6 of the 10 went on to require more than 20 hours per day of ventilator use with less than 2 hours of ventilator-free breathing time (VFBT). All except two noninvasive IPPV users had vital capacities (VCs) less than 13% of predicted normal. They could, however, communicate verbally and take nutrition by mouth. All of the patients remained in the community. Five patients were gainfully employed and four were in school. We conclude that noninvasive respiratory muscle aids including noninvasive IPPV and assisted coughing techniques are effective and practical alternatives to tracheostomy for SMA patients with ventilatory failure but functional bulbar musculature.

Activities of Daily Living↗
PubMed2003

Prenatal diagnosis of spinal muscular atrophy by genetic analysis of circulating fetal cells.

Spinal muscular atrophy (SMA) has a prevalence of one in 6000 births and a one in 40 heterozygote frequency. We aimed to develop a routine test for non-invasive prenatal diagnosis. We tested blood with ISET (isolation by size of epithelial tumour or trophoblastic cells) in 12 pregnant women whose babies were at risk of SMA. Using genetic analysis of fetal cells, we identified SMA in all nine isolated from the three mothers carrying an affected child. There was no mutation in any of the 26 fetal cells isolated from the nine women with an unaffected child. Our results show that non-invasive detection of genetic diseases by the analysis of maternal blood is feasible.

Female↗