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PubMed2002

Neuronal death is enhanced and begins during foetal development in type I spinal muscular atrophy spinal cord.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by mutations in the survival motor neurone gene (SMN). The degeneration and loss of the anterior horn cells is the major neuropathological finding in SMA, but the mechanism and timing of this abnormal motor neurone death remain unknown. A quantitative study was carried out comparing neuronal death in controls and SMA foetuses and neonates. Between 12 and 15 weeks of gestational age, a significant increase in nuclear DNA vulnerability, as revealed with the method of in situ end-labelling of nuclear DNA fragmentation, was detected in SMA foetuses and was reflected by a decrease in the number of neurones of the anterior horn. Neurones with nuclear DNA vulnerability are no longer detected at the end of the foetal period and the post-natal period. On the other hand, abnormal morphology of motor neurones, mainly early chromatolytic changes, was observed only after birth. Our findings indicate that in type I SMA, the absence or dysfunction of SMN is reflected by an enhanced neuronal death that is already detectable at 12 weeks, the earliest SMA foetal stage analysed. This is associated with a progressive loss of motor neurones towards the neonatal period. Given that a proportion of the remaining SMA motor neurones in the neonatal period appear with pathological findings not detected at earlier stages, it can be hypothesized that type I SMA results in differential age-dependent responses leading to cell death and motor neurone degeneration during development.

Anterior Horn Cells↗
PubMed2001

Aclarubicin treatment restores SMN levels to cells derived from type I spinal muscular atrophy patients.

Proximal spinal muscular atrophy (SMA) is a common motor neuron disorder caused by mutation of the telomeric survival of motor neuron gene SMN1. The centromeric survival of motor neuron SMN2 gene is retained in all SMA patients but does not produce sufficient SMN protein to prevent the development of clinical symptoms. The SMN1 and SMN2 genes differ functionally by a single nucleotide change. This change affects the efficiency with which exon 7 is incorporated into the mRNA transcript. Thus, SMN2 produces less full-length mRNA and protein than SMN1. We have screened a library of compounds in order to identify ones that can alter the splicing pattern of the SMN2 gene. Here, we report that the compound aclarubicin increases the retention of exon 7 into the SMN2 transcript. We show that aclarubicin effectively induces incorporation of exon 7 into SMN2 transcripts from the endogenous gene in type I SMA fibroblasts as well as into transcripts from a SMN2 minigene in the motor neuron cell line NSC34. In type I fibroblasts, treatment resulted in an increase in SMN protein and gems to normal levels. Our results suggest that alteration of splicing pattern represents a new approach to modification of gene expression in disease treatment and demonstrate the feasibility of high throughput screens to detect compounds that affect the splicing pattern of a gene.

Aclarubicin↗
PubMed2006

The benzamide M344, a novel histone deacetylase inhibitor, significantly increases SMN2 RNA/protein levels in spinal muscular atrophy cells.

Proximal spinal muscular atrophy (SMA) is a common autosomal recessively inherited neuromuscular disorder causing infant death in half of all patients. Homozygous loss of the survival motor neuron 1 (SMN1) gene causes SMA, whereas the number of the SMN2 copy genes modulates the severity of the disease. Due to a silent mutation within an exonic splicing enhancer, SMN2 mainly produces alternatively spliced transcripts lacking exon 7 and only approximately 10% of a full-length protein identical to SMN1. However, SMN2 represents a promising target for an SMA therapy. The correct splicing of SMN2 can be efficiently restored by over-expression of the splicing factor Htra2-beta1 as well as by exogenous factors like drugs that inhibit histone deacetylases (HDACs). Here we show that the novel benzamide M344, an HDAC inhibitor, up-regulates SMN2 protein expression in fibroblast cells derived from SMA patients up to 7-fold after 64 h of treatment. Moreover, M344 significantly raises the total number of gems/nucleus as well as the number of nuclei that contain gems. This is the strongest in vitro effect of a drug on the SMN protein level reported so far. The reversion of Delta7-SMN2 into FL-SMN2 transcripts as demonstrated by quantitative RT-PCR is most likely facilitated by elevated levels of Htra2-beta1. Investigations of the cytotoxicity of M344 using an MTT assay revealed toxic cell effects only at very high concentrations. In conclusion, M344 can be considered as highly potent HDAC inhibitor which is active at low doses and therefore represents a promising candidate for a causal therapy of SMA.

Alternative Splicing↗
PubMed2003

A phase 1 trial of riluzole in spinal muscular atrophy.

BACKGROUND: Severe spinal muscular atrophy (SMA) (Werdnig-Hoffmann disease, acute SMA, and SMA I) is a disease of the motor neuron characterized by onset before 6 months of age, failure ever to achieve sitting without support, and a life expectancy of 2 years or less. There is no known treatment for SMA, and, until recently, no therapeutic trials have been attempted. There is reason to believe that glutamate, an excitatory neurotransmitter, enhances programmed cell death of anterior horn cells. Riluzole, a glutamate inhibitor, has been shown to slow the rate of decline in patients with amyotrophic lateral sclerosis, another form of motor neuron disease. OBJECTIVES: To determine whether a glutamate inhibitor might be tolerated by infants with SMA and, furthermore, whether this medication could have a positive effect on life expectancy. DESIGN: Subjects with homozygous deletions of the survival motor neuron gene were recruited from pediatric neuromuscular clinics and randomized in a 2:1 ratio, 2 riluzole to 1 placebo. Neurologic examination was performed at the first visit by one of the investigators. Complete blood count, hepatic and renal screens, and urinalysis were performed at baseline, 2 weeks, 1 month, 2 months, 3 months, 6 months, and 9 months after drug or placebo was started. An electrocardiogram was done at baseline, 3 months, 6 months, and 12 months. Treatment was stopped after 9 months, and blood work was repeated at 12 months. Treatment was reinstituted at 1 year if requested by the parents. The enrollment goal was 30 patients; however, support from the pharmaceutical company was withdrawn when Rhone-Poulenc Rorer was taken over by Aventis. The investigational review boards of the participating centers approved the protocol and consent forms. RESULTS: Seven patients received riluzole and 3 received placebo medication. All 3 patients in the placebo group died (mean age, 9 months). Three of 7 who received active drug are still living at ages 513 years, 4 years, and 30 months. None of the 10 subjects experienced adverse effects or changes in laboratory test results. None showed any change in motor abilities. CONCLUSIONS: Riluzole appears to be safe in young children. This was a limited study with insufficient power to show a difference between the 2 groups. Because there is a suggestion of possible benefit in treated subjects, we recommend further study of riluzole in pediatric patients with SMA.

Age of Onset↗
PubMedDate not supplied

Localisation of the gene for a dominant congenital spinal muscular atrophy predominantly affecting the lower limbs to chromosome 12q23-q24.

Spinal muscular atrophies are a heterogeneous group of disorders. They differ in time of onset, clinical presentation, progression, severity and mode of inheritance. In 1985 a Dutch family was described with a dominant, non-progressive spinal muscular atrophy presenting at birth with arthrogryposis (MIM 600175). Linkage analysis was performed in this family. After having excluded the loci for Werdnig-Hoffmann's disease and for dominant distal spinal muscular atrophy with upper limb predominance, we were able to localise the gene to a 10 cM interval between the markers D12S78 and D12S1646 on chromosome 12q23-q24. Recently, dominant scapuloperoneal spinal muscular atrophy has been localised to an overlapping interval. However, the clinical appearances of scapuloperoneal spinal muscular atrophy and the present disorder make allelism unlikely. In 1994, a second Dutch family with a disorder similar to the present one was described. We excluded linkage to markers of the 12q23-q24 region in this family and thereby proved genetic heterogeneity of this type of dominant, congenital and nonprogressive spinal muscular atrophy.

Chromosome Mapping↗
PubMed2006

A feasibility study for the newborn screening of spinal muscular atrophy.

PURPOSE: The natural history of spinal muscular atrophy suggests that for maximum effect, therapeutics will need to be administered in the earliest phases of the disease. This will require the adoption of techniques for the genetic analysis of affected individuals at the newborn stage. Our objective was to examine the feasibility surrounding the newborn screening for spinal muscular atrophy. METHODS: We investigated the application of real-time polymerase chain reaction technology for newborn screening. A multiplex assay was designed to identify homozygous deletions in SMN1 exon 7 and validated using 266 samples with defined SMN1 and SMN2 copy numbers. Sensitivity and specificity were then evaluated as part of a newborn screening strategy using DNA from 153 blood spots. RESULTS: Real-time technology validation demonstrated correct exclusion of all normal and carrier samples, and identified the homozygous SMN1 exon 7 deletions in all 32 affected samples. In the series of blood spots, all 59 affected samples were correctly identified yielding an analytic sensitivity of 100%; 56 normal and 39 carrier samples were correctly excluded yielding an analytic specificity of 100% for this blood spot series. CONCLUSION: We demonstrate that effective molecular technology exists and that ethics may soon warrant the newborn screening of spinal muscular atrophy.

Computer Systems↗
PubMed2006

Correlation between deletion patterns of SMN and NAIP genes and the clinical features of spinal muscular atrophy in Indian patients.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder involving degeneration of anterior horn cells of spinal cord resulting in progressive muscle weakness and atrophy. AIMS: The molecular analysis of two marker genes for spinal muscular atrophy (SMA) i.e, the survival motor neuron gene (SMN) and the neuronal apoptosis inhibitory protein gene (NAIP) was conducted in 39 Indian patients with clinical symptoms of SMA. Out of these, 28 showed homozygous deletions and the phenotypic features of these SMA patients were compared with the corresponding genotypes. SETTINGS: A tertiary care teaching Hospital. DESIGN: This is a prospective hospital based study. MATERIALS AND METHODS: Polymerase chain reaction (PCR) combined with restriction fragment length polymorphism (RFLP) was used to detect the deletion of exon 7 and exon 8 of SMN1 gene, as well as multiplex PCR for exon 5 and 13 of NAIP gene. RESULTS: Exons 7 and 8 of SMN and NAIP (exon 5) were homozygously deleted in 73% of SMA I and 27% of SMA II patients. SMN exon 7 and 8 deletions without NAIP deletions were seen in 27% of type I SMA and 46% of SMA type II patients. Two patients of type III SMA showed single deletion of SMN exon 7 along with 27% of SMA type II patients. CONCLUSION: With the advent of molecular biology techniques, SMN gene deletion studies have become the first line of investigation for confirmation of a clinical diagnosis of SMA. The findings of homozygous deletions of exons 7 and/or 8 of SMN1 gene confirms the diagnosis of SMA, even in patients with atypical clinical features. Deletions of NAIP gene were mainly seen in severely affected patients, hence is useful for predicting the prognosis.

Adolescent↗
PubMed2000

[Triplet repeat disease, with particular emphasis of spinal and bulbar muscular atrophy (SBMA)].

Spinal and bulbar muscular atrophy (SBMA) is an X-linked neurodegenerative disease caused by the expansion of a CAG repeat in the first exon of the androgen receptor (AR) gene. To date, eight CAG-repeat diseases have been identified, including spinal and bulbar muscular atrophy (SBMA). Huntington's disease (HD), dentatorubralpallidoluysian atrophy (DRPLA) and five spinocerebellar ataxias (SCAs 1, 2, 3, 6, 7). These disorders likely share a common pathogenesis caused by the gain of a toxic function associated with the expanded polyglutamine tract. Several mechanisms have been postulated as a pathogenic process for neurodegeneration caused by the expanded polyglutamine tract. Processing of the polyglutamine containing proteins by proteases liberate truncated polyglutamine tract, which may cause neurodegeneration as demonstrated in transgenic mice and transfected cells. In addition to cellular toxicity, truncated and expanded polyglutamine tracts have been shown to form intranuclear inclusions (NI). The NIs formed by the disease protein are a common pathological feature of these diseases. In SBMA, NIs containing AR protein have been observed in regions of SBMA central nervous system susceptible to degenerations. Transcriptional factors or their cofactors, such as cerb or creb-binding protein (CBP) sequestrated in the NI may alter the major intracellular transcriptional signal transduction, and ultimately may result in neuronal degeneration. The ubiquitin-proteasome pathway may also contribute to the pathogenesis of CAG-repeat diseases. As for the therapeutic strategies, many possibilities have been demonstrated. Overexpression of Hsp70 and Hsp40 chaperones act together to protect a cultured neuronal cell model of SBMA from a cellular toxicity of expanded polyglutamine tract.

Animals↗
PubMed2004

Sleep disordered breathing in spinal muscular atrophy.

Sleep disordered breathing is a common but under-diagnosed complication causing sleep disturbance and daytime symptoms in children with spinal muscular atrophy. Non-invasive (positive pressure) ventilation is an established treatment of respiratory failure; its role in treatment of sleep disordered breathing though remains controversial. Aim of this study was to verify the hypothesis that nocturnal non-invasive ventilation has beneficial impact on breathing during sleep, sleep quality and daytime complaints in children with spinal muscular atrophy. Twelve children with spinal muscular atrophy type I or II (7.8+/-1.9 years) underwent polysomnography and were asked to fill out a symptom questionnaire. Seven patients (six with spinal muscular atrophy I and one with spinal muscular atrophy II) had sleep disordered breathing and received non-invasive ventilation during sleep. Five less severely affected patients (one with spinal muscular atrophy I and four with spinal muscular atrophy II) had no sleep disordered breathing and served as reference group. Patients were restudied after 6-12 months. In patients with sleep disordered breathing both sleep architecture and disease related symptoms were significantly worse than in the reference-group. Non-invasive ventilation during sleep completely eliminated disordered breathing, normalized sleep architecture and improved symptoms (P<0.05 for all). In children with spinal muscular atrophy sleep disordered breathing may cause relevant impairment of sleep and well-being. Both can be highly improved by nocturnal non-invasive ventilation.

Child↗
PubMed2005

Pathology of experimental disuse muscular atrophy in rats.

The relationship between structural changes and hyaluronic acid (HA) content in muscular atrophy is unknown. The objective of our study was to conduct multifaceted evaluations of the change in muscle extensibility in muscular atrophy, in terms of morphological aspects as well as from a biochemical viewpoint, including changes in intercellular substances. Using a muscular atrophy model of the soleus muscle in the cast-fixed limbs of Wistar rats, we examined changes in HA accompanying muscular atrophy. Compared with controls, the cast-fixed limbs showed histological evidence of muscular atrophy and electron microscopy indicated destruction of the fasciae. Measurement of the HA level in muscle tissue from cast-fixed rats indicated a reduction in concentration per unit of weight. In contrast, serum HA concentrations increased in the cast-fixed group compared with the control group, suggesting that HA present in the fasciae was released into the blood stream during muscular atrophy.

Animals↗
PubMed2002

Autosomal dominant distal spinal muscular atrophy: an Italian family not linked to 12q24 and 7p14.

Distal spinal muscular atrophy is genetically heterogeneous, as sporadic cases and both autosomal dominant and recessive inheritance have been described. An autosomal dominant distal spinal muscular atrophy with upper limb predominance has been mapped to chromosome 7p, and more recently, an autosomal dominant distal spinal muscular atrophy with lower limb predominance has been linked to chromosome 12q24. We describe a four generation Italian family with autosomal dominant distal spinal muscular atrophy starting between 8 and 30 years with weakness and atrophy of distal leg muscles. The older patients also presented sensorineural deafness. We performed genetic linkage analysis with microsatellite markers D12S366, D12S349, D12S86, D12S321, D12S1612, D12S1349, D12S342, PLA2A on chromosome 12q24 and D7S516, D7S2496, D7S632, D7S2252 on chromosome 7p14. No support for linkage to chromosome 12q24 and 7p14 was found in our family, confirming a genetic heterogeneity within autosomal dominant distal spinal muscular atrophy.

Adolescent↗
PubMed1994

Pulmonary function in spinal muscular atrophy.

We present the first prospective study on pulmonary function in spinal muscular atrophy patients. Seventy-seven spinal muscular atrophy patients, ages 5 to 18 years, from three centers, were studied with regard to forced vital capacity, using height as a predictor. Patients were categorized into four motor function categories. The highest-functioning group had normal or near-normal values, and those who sat with support had the lowest values. Those with intermediate function had intermediate values. Forced vital capacity was studied longitudinally in 40 spinal muscular atrophy patients for 1.1 to 4.4 years. Eighty-eight percent of patients grew in height, but only 35% showed an increase in height-adjusted forced vital capacity percent. In those patients with the least function, 100% lost height-adjusted forced vital capacity over time. In those patients with the highest function, 57% lost height-adjusted forced vital capacity. In addition, the basic forced vital capacity, not correlated to height, decreased in 43% of cases. These pulmonary function alterations appear to be important determinants for function and survival in spinal muscular atrophy patients.

Adolescent↗
PubMed2006

A modified Hammersmith functional motor scale for use in multi-center research on spinal muscular atrophy.

The Hammersmith functional motor scale for children with spinal muscular atrophy was modified to establish a standard measure of functional ability in children with non-ambulant spinal muscular atrophy types 2 and 3 in a longitudinal multi-center clinical trial. This study assessed the intra- and interrater reliability and the test-retest stability of a modified version of the scale. Both intra- and interrater reliability were established. Results indicate that the scale is reliable and stable over a 6 month period. Reliability was maintained when patient sample criteria were expanded to include children younger than 30 months and children with popliteal angles greater than 20 degrees . These data establish the modified Hammersmith functional motor scale for children with spinal muscular atrophy as a reliable instrument for use in multi-center treatment trials in non-ambulant spinal muscular atrophy children. Our data provides additional support for the use of original scale items in terms of ease of administration, usefulness and reliability, while incorporating modifications to optimize its use in a multi-center clinical research setting.

Child, Preschool↗
PubMed1975

Sensory system involvement in infantile spinal muscular atrophy.

Nine cases of infantile spinal muscular atrophy were studied post-mortem. Their ages at death ranged from 5 months to 10 years. In all cases severe loss of anterior horn cells in the spinal cord and neurogenic muscular atrophy were characteristic of this disease. In 6 cases there was also loss of myelin in the posterior columns particularly affecting the lumbar contribution. Sensory ganglia, especially from the lumbar region, contained nodules of Nageotte, indicating sensory neuron degeneration. These sensory abnormalities were more severe in the longer surviving cases. It seems possible that sensory neuron degeneration occurs more commonly in Werdnig-Hoffmann disease than has previously been supposed but that it is less severe and develops more slowly than motor neuron degeneration.

Anterior Horn Cells↗
PubMed1980

Classification of spinal muscular atrophies.

Clinical heterogeneity within the spinal muscular atrophies (SMA) has long been a source of confusion for questions of prognosis and genetic counselling. Comprehensive clinical and genetic analyses of 240 consecutive index cases from two English centres (The English SMA Study) have enabled some nosological questions to be resolved. The different SMA syndromes can be discriminated by (a) age at the first clinical signs of the disease, (b) pattern of muscle involvement, (c) age at death of other patients within an affected kindred, and (d) genetic evidence. Seven different SMA syndromes can be defined clinically and genetically; thirteen mutant genes are incriminated. Prevalence and incidence figures are presented. SMA type I (Werdnig-Hoffman disease) and chronic childhood SMA together comprise 74% of all SMA cases. The classification of the spinal muscular atrophies presented also provides the differential diagnosis for newly presenting cases.

Adolescent↗
PubMed2002

Clinical and genetic heterogeneity in peroneal muscular atrophy associated with vocal cord weakness.

BACKGROUND: The peroneal muscular atrophy syndrome is the most common inherited disorder of the peripheral nervous system and has extensive clinical and genetic heterogeneity. Cranial nerve involvement is rare, though there are distinct peroneal muscular atrophy syndromes in which vocal cord paralysis is a characteristic feature. Among these dHMN-VII and HMSN-IIC are clinically similar but are differentiated by sensory involvement in HMSN-IIC. The gene for dHMN-VII, designated DHMNVP, has been localised to chromosome 2q14, but the location of the gene for HMSN-IIC is currently unknown. It has been suggested that dHMN-VII and HMSN II-C are allelic disorders. OBJECTIVE: To assess the contribution of the dHMN-VII predisposition gene to peroneal muscular atrophy syndromes associated with vocal cord weakness. METHODS: Linkage analysis of microsatellite markers at chromosome 2q14 was undertaken on two families, one affected by HMSN-IIC and a second manifesting vocal cord paralysis and sensorineural deafness in addition to distal muscular atrophy. RESULTS: Two-point LOD scores at chromosome 2q14 markers encompassing the DHMNVP gene were negative in both families. CONCLUSIONS: These results suggest that at least one further gene predisposing to distal muscular weakness in association with vocal cord paralysis is likely to exist, and that dHMN-VII and HMSN-IIC are unlikely to be allelic disorders. Analyses of further HMSN-IIC families are required to confirm this.

Charcot-Marie-Tooth Disease↗
PubMed2000

Deletion of SMN and NAIP genes in Korean patients with spinal muscular atrophy.

Childhood-onset proximal spinal muscular atrophies (SMAs) are an autosomal recessive, clinically heterogeneous group of neuronopathies characterized by selective degeneration of anterior horn cells. The causative genes to be reported are survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP) genes. The deletion of telomeric copy of SMN (SMN(T)) gene was observed in over 95% of SMAs. The deletion rate of NAIP gene is 20-50% according to disease severity. The objective of this article is to genetically characterize the childhood-onset spinal muscular atrophy in Koreans. Five Korean families (14 constituents containing 5 probands) with SMA were included in this study. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used for the deletion analysis of SMN(T). Multiplex PCR method was used for NAIP analysis. Four probands showed deletion of SMNT gene. Deletion of SMN(C) (centromeric SMN) gene was found in one proband who did not show the deletion of SMN(T) gene and in the father of one proband who showed the deletion of SMN(T) gene. The deletion of NAIP gene was not found among all the studied individuals. The extent of deletion in Koreans was smaller than that in other studied population. PCR-RFLP deletion analysis can be applied to diagnose SMA and make a prenatal diagnosis.

Adolescent↗
PubMed1995

Genetic homogeneity between childhood-onset and adult-onset autosomal recessive spinal muscular atrophy.

Molecular diagnosis of childhood proximal spinal muscular atrophy has been enhanced by the discovery of the survival motor neuron (SMN) gene, which is absent or truncated in 98.6% of patients. To determine whether deletion analysis of the SMN gene may also be diagnostic for adult-onset disease, we studied six patients and found deletions in all. This finding will facilitate the diagnosis of adult-onset spinal muscular atrophy, and provides evidence for genetic homogeneity between the clinically diverse adult and childhood forms of the disease.

Adult↗