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PubMed2003

Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1).

Autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1) is the second anterior horn cell disease in infants in which the genetic defect has been defined. SMARD1 results from mutations in the gene encoding the immunoglobulin micro-binding protein 2 (IGHMBP2) on chromosome 11q13. Our aim was to review the clinical features of 29 infants affected with SMARD1 and report on 26 novel IGHMBP2 mutations. Intrauterine growth retardation, weak cry, and foot deformities were the earliest symptoms of SMARD1. Most patients presented at the age of 1 to 6 months with respiratory distress due to diaphragmatic paralysis and progressive muscle weakness with predominantly distal lower limb muscle involvement. Sensory and autonomic nerves are also affected. Because of the poor prognosis, there is a demand for prenatal diagnosis, and clear diagnostic criteria for infantile SMARD1 are needed. The diagnosis of SMARD1 should be considered in infants with non-5q spinal muscular atrophy, neuropathy, and muscle weakness and/or respiratory distress of unclear cause. Furthermore, consanguineous parents of a child with sudden infant death syndrome should be examined for IGHMBP2 mutations.

Carrier Proteins↗

PubMed2003

Spinal muscular atrophies reveal motor neuron vulnerability to defects in ribonucleoprotein handling.

PURPOSE OF REVIEW: Many forms of spinal muscular atrophy, a pure lower motor neuron disease, have been characterized clinically but the molecular basis of most of these is unknown. In this article we review recent developments in our understanding of the spinal muscular atrophies and how this knowledge has revealed important new insights into the causes of motor neuron vulnerability which may ultimately lead to novel therapies for this untreatable group of disorders. RECENT FINDINGS: The identification of the genetic basis of two forms of autosomal recessive spinal muscular atrophy has revealed that lower motor neurons appear to have a specific vulnerability to defects in RNA metabolism. Most notably, the survival motor neuron protein, deficient in the most common form of spinal muscular atrophy, plays a multifunctional role in ribonucleoprotein metabolism and pre-messenger RNA splicing. The role of this protein in motor neurons is currently under intense study. The identification of two other spinal muscular atrophy-causing genes has provided support for the central role of components of the RNA metabolic pathway in determining motor neuron survival. SUMMARY: Understanding the molecular basis of lower motor neuron vulnerability in disorders such as spinal muscular atrophy will ultimately allow these disabling disorders to be treated. In addition we can expect to learn much about basic neuronal biology and about the pathways that are relevant to more common neurodegenerative disorders such as amyotrophic lateral sclerosis.

Animals↗

PubMed1989

Scoliosis in spinal muscular atrophy: natural history and management.

This is a report on the natural history of 109 patients with infantile spinal muscular atrophy (SMA). All 18 children with the severe form died, as did five of the 52 with the intermediate form. Functional ability was more or less stable in the 47 living patients with the intermediate form, but 16 of the 39 with mild SMA lost the ability to walk. Ventilatory function was severely impaired in those with intermediate SMA: orthopaedic treatment for scoliosis in this group did not prevent the curves from worsening with age. Scoliosis was also severe in patients with mild SMA who had stopped walking: surgical treatment in six cases resulted in stable correction of the spine, with functional and cosmetic improvement and without impairment of respiratory function.

Adolescent↗

PubMed2003

Anaesthesia for caesarean section in a patient with spinal muscular atrophy.

This report describes a 33-year-old primigravid woman with spinal muscular atrophy Type III (Kugelberg-Welander syndrome). Elective caesarean section was performed at 38 weeks gestation under spinal anaesthesia. The implications of spinal muscular atrophy for anaesthesia for caesarean section are described.

Adult↗

PubMed1992

Spinal muscular atrophy: new thoughts on the pathogenesis and classification schema.

We have established the first prospective, collaborative study of spinal muscular atrophy, the second most common neuromuscular disease of childhood. One hundred and forty-one patients have been evaluated on at least four occasions over a 3-year period. The patients have been grouped by age of onset, as well as by function at the time of initial evaluation. The muscle strength of 96 patients aged 5 years or older was evaluated at 6-month intervals using a fixed myometry system. The new observations made are: (1) The present classification schema is not valid; for example, 49 patients with onset of weakness before 6 months of age (type I or Werdnig-Hoffmann disease), whose life span is said to be only 2 to 4 years, participated in the study and are 4 months to 31 years of age. (2) Thirty-seven patients were evaluated over an 18-month period. None lost strength during this time but four lost function. Although the period of observation was short, the results suggest that the loss of function in patients with spinal muscular atrophy might be explained by a process other than cell death that allows patient strength to be maintained and simultaneously prevents the motor unit from achieving its normal adult potential.

Adolescent↗

PubMed2003

A simple method for diagnosis of autosomal recessive spinal muscular atrophy by denaturing high-performance liquid chromatography.

Autosomal recessive spinal muscular atrophy is caused by mutations in the survival motoneuron (SMN) gene. There are two nearly identical copies of this gene present on chromosome 5q13; however, only the telomeric copy of this gene is affected in spinal muscular atrophy. In this study, we describe a new method to detect SMN gene deletion by denaturing high-performance liquid chromatography, which is also simple to perform but is faster and more specific.

Chromatography, High Pressure Liquid↗

PubMed1994

An investigation of genetic heterogeneity and linkage disequilibrium in 161 families with spinal muscular atrophy.

We performed linkage analysis of 161 families with spinal muscular atrophy (SMA) in which affected individuals suffer from the intermediate or mild form of the disease (Types II or III). Markers for six loci encompassing the chromosome 5q11.2-q13.3 region were typed. The best map location for the disease locus was found to be between D5S6 and MAP1B. The corresponding 1 lod unit support intervals is confined to this interval and spans 0.5 cM. The data strongly support the hypothesis of linkage heterogeneity (likelihood ratio, 1.14 x 10(4)), with 5% of the families unlinked. Four families have a probability of less than 50% of segregating the SMA gene linked to the region 5q11.2-q13.3. A likelihood approach to test for linkage disequilibrium revealed no significant departure from Hardy-Weinberg equilibrium with any marker under study.

Alleles↗

PubMed2006

Spinal muscular atrophy and therapeutic prospects.

The molecular genetic basis of spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the loss of function of the survival motor neuron gene (SMN1). The SMN2 gene, a nearly identical copy of SMN1, has been detected as a promising target for SMA therapy. Both genes are ubiquitously expressed and encode identical proteins, but markedly differ in their splicing patterns: While SMN1 produces full-length (FL)-SMN transcripts only, the majority of SMN2 transcripts lacks exon 7. Transcriptional SMN2 activation or modulation of its splicing pattern to increase FL-SMN levels is believed to be clinically beneficial and therefore a crucial challenge in SMA research. Drugs such as valproic acid, phenylbutyrate, sodium butyrate, M344 and SAHA that mainly act as histone deacetylase inhibitors can mediate both: they stimulate the SMN2 gene transcription and/or restore the splicing pattern, thereby elevating the levels of FL-SMN2 protein. Preliminary phase II clinical trials and individual experimental curative approaches SMA patients show promising results. However, phase III double-blind placebo controlled clinical trials have to finally prove the efficacy of these drugs.

Alternative Splicing↗

PubMed2003

Mapping of the bovine spinal muscular atrophy locus to Chromosome 24.

A hereditary form of spinal muscular atrophy (SMA) caused by an autosomal recessive gene has been reported for American Brown-Swiss cattle and in advanced backcrosses between American Brown-Swiss and many European brown cattle breeds. Bovine SMA (bovSMA) bears remarkable resemblance to the human SMA (SMA1). Affected homozygous calves also show progressive symmetric weakness and neurogenic atrophy of proximal muscles. The condition is characterized by severe muscle atrophy, quadriparesis, and sternal recumbency as result of neurogenic atrophy. We report on the localization of the gene causing bovSMA within a genomic interval between the microsatellite marker URB031 and the telomeric end of bovine Chromosome (Chr) 24 (BTA24). Linkage analysis of a complex pedigree of German Braunvieh cattle revealed a recombination fraction of 0.06 and a three-point lod score of 11.82. The results of linkage and haplotyping analysis enable a marker-assisted selection against bovSMA based on four microsatellite markers most telomeric on BTA24 to a moderate accuracy of 89-94%. So far, this region is not orthologous to any human chromosome segments responsible for twelve distinct disease phenotypes of autosomal neuropathies. Our results indicate the apoptosis-inhibiting protein BCL2 as the most promising positional candidate gene causing bovSMA. Our findings offer an attractive animal model for a better understanding of human forms of SMA and for a probable anti-apoptotic synergy of SMN-BCL2 aggregates in mammals.

Animals↗

PubMed1996

Deletion analysis of the SMN and NAIP genes in Kuwaiti patients with spinal muscular atrophy.

Two genes are known to be involved in spinal muscular atrophy (SMA), namely, SMN (survival motor neuron) and NAIP (neuronal apoptosis inhibitory protein). Deletion analysis of these genes has been reported for many ethnic groups. We have extended this analysis to include 15 Arabic patients (11 unrelated cases of type I, which represent practically all of the patients diagnosed within the last 2 years in Kuwait, and 4 type-II cases from a single kinship). Also, 41 healthy relatives (parents and sibs) and 44 control individuals of Arabic origin were analyzed. The homozygous deletions of exons 7 and 8 of the SMN gene were found in all SMA patients studied. Exon 5 of NAIP was homozygously absent in all type-I patients, but was retained in type-II cases. Among members of SMA families, one mother was found to be homozygously deleted for NAIP. All of the control individuals had both normal SMN and NAIP. Our results are in agreement with the general consensus that the incidence of NAIP deletion is higher in the more severe SMA cases. Furthermore, they suggest that SMA type-I chromosomes, with the dual deletion of the SMN and NAIP genes, are more common in Arabs than in patients of other ethnic origin.

Arabs↗

PubMed1989

Differential diagnosis between amyotrophic lateral sclerosis and spinal muscular atrophy by skin involvement.

Amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) might be clinical variants caused by the same etiology, or different diseases altogether. We studied the skin in 12 patients with ALS and 7 patients with SMA. The "delayed return phenomenon" (DRP) was observed only in ALS patients. On light microscopy, collagen bundles in ALS dermis were seen to be less numerous, thinner and more loosely woven than in SMA. Electron microscopy revealed that in ALS (1) collagen fibers became thinner as the disease lasted longer, and (2) collagen bundles were separated by much more amorphous material. These findings were not observed in SMA. Our observations show that ALS may be distinguished from SMA by the presence of abnormal dermal collagen. Therefore, we suggest that comparable clinical and pathological skin analysis is the most important diagnostic tool in differentiating between ALS and SMA.

Adult↗

PubMed2006

Spinal muscular atrophy: from gene to therapy.

The molecular basis of spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disorder, is the homozygous loss of the survival motor neuron gene 1 (SMN1). A nearly identical copy of the SMN1 gene, called SMN2, modulates the disease severity. The functional difference between both genes is a translationally silent mutation that, however, disrupts an exonic splicing enhancer causing exon 7 skipping in most SMN2 transcripts. Only 10% of SMN2 transcripts encode functional full-length protein identical to SMN1. Transcriptional activation, facilitation of correct SMN2 splicing, or stabilization of the protein are considered as strategies for SMA therapy. Among various drugs, histone deacetylase inhibitors such as valproic acid (VPA) or 4-phenylbutyrate (PBA) have been shown to increase SMN2-derived RNA and protein levels. Recently, in vivo activation of the SMN gene was shown in VPA-treated SMA patients and carriers. Clinical trials are underway to investigate the effect of VPA and PBA on motor function in SMA patients.

Animals↗

PubMed1998

A novel function for SMN, the spinal muscular atrophy disease gene product, in pre-mRNA splicing.

Spinal muscular atrophy (SMA) is a common motor neuron degenerative disease that results from reduced levels of, or mutations in, the Survival of Motor Neurons (SMN) protein. SMN is found in the cytoplasm and the nucleus where it is concentrated in gems. SMN interacts with spliceosomal snRNP proteins and is critical for snRNP assembly in the cytoplasm. We show that a dominant-negative mutant SMN (SMNdeltaN27) causes a dramatic reorganization of snRNPs in the nucleus. Furthermore, SMNdeltaN27 inhibits pre-mRNA splicing in vitro, while wild-type SMN stimulates splicing. SMN mutants found in SMA patients cannot stimulate splicing. These findings demonstrate that SMN plays a crucial role in the generation of the pre-mRNA splicing machinery and thus in mRNA biogenesis, and they link the function of SMN in this pathway to SMA.

Autoantigens↗

PubMed1999

SMN mutants of spinal muscular atrophy patients are defective in binding to snRNP proteins.

Spinal muscular atrophy (SMA) is a common motor neuron degenerative disease and the leading genetic cause of death of young children. The survival of motor neurons (SMN) gene, the SMA disease gene, is homozygously deleted or mutated in more than 98% of SMA patients. The SMN protein interacts with itself, with SMN-interacting protein 1, and with several spliceosomal small nuclear ribonucleoprotein (snRNP) Sm proteins. A complex containing SMN plays a critical role in spliceosomal snRNP assembly and in pre-mRNA splicing. SMN mutants found in SMA patients show reduced self-association and lack the capacity to regenerate the splicing machinery. Here we demonstrate that SMN mutants found in SMA patients are defective in binding to Sm proteins. Moreover, we show that SMN, but not mutants found in SMA patients, can form large oligomers and that SMN oligomerization is required for high-affinity binding to spliceosomal snRNP Sm proteins. These findings directly link the impaired interaction between SMN and Sm proteins to a defect in snRNP metabolism and to SMA.

Autoantigens↗

PubMed1997

Quantification, by solid-phase minisequencing, of the telomeric and centromeric copies of the survival motor neuron gene in families with spinal muscular atrophy.

In an analysis of 30 families affected by spinal muscular atrophy (SMA) we have used the solid-phase minisequencing method to determine the ratio between the number of telomeric and centromeric copies of the survival motor neuron gene (SMN and cBCD541 respectively) on normal and SMA chromosomes. This has enabled us to establish haplotypes with regard to SMN and cBCD541, and estimate their frequencies, on both types of chromosomes. Six predominant haplotypes were identified, three for normal chromosomes and three for SMA chromosomes, characterized by having 0, 1, or 2 copies, respectively, of cBCD541. We found evidence for the presence of patients homozygous for a deletion of SMN and with only one copy of cBCD541, but found none deleted for all copies of this gene. Several asymptomatic carriers of SMA with only a single copy of SMN and no copy of cBCD541 were identified. We could not confirm the hypothesis that the presence of more copies of cBCD541 is correlated to a less severe course of the disease. The frequencies of haplotypes characterized by having 0, 1, or 2 copies, respectively, of cBCD541 were found to differ significantly between normal and SMA chromosomes. This distribution can be explained by an underrepresentation of the haplotype completely lacking SMN genes, which is expected to cause early embryonic death in homozygotes. This first report of a direct haplotype analysis of SMN and cBCD541 should help clarify the role of cBCD541 in the pathogenesis of SMA.

Centromere↗

PubMed2005

Bovine spinal muscular atrophy: AFG3L2 is not a positional candidate gene.

Bovine spinal muscular atrophy (BSMA) is a neurodegenerative disorder, which is widespread in Brown Swiss cattle. Main symptoms of the disease are muscular atrophy and recumbency. Affected calves die within few days or weeks. BSMA seems to be inherited as a recessive trait and the disease allele appears to have a common origin. In this study, a pedigree with 30 affected BSMA calves was used to genetically localize the BSMA locus. Linkage analysis was performed between microsatellite markers of seven chromosomes, where the homologous genes of human neurodegenerative disorders are located according to comparative mapping data, and the disease genotype. BSMA was mapped to chromosome 24 confirming the recently published localization (Medugorac et al. 2003). The candidate gene AFG3L2 was physically mapped to chromosome 24q24 using fluorescence in situ hybridization. Due to their different localizations AFG3L2 is not a positional candidate for BSMA. An informative marker localized on the telomeric side of the BSMA locus would be beneficial for marker-assisted selection as well as searching for the causative gene. However, finding a marker distal to BSMA locus is difficult because of its position at the end of the chromosome.

Adenosine Triphosphatases↗

PubMed2001

Prenatal diagnosis of spinal muscular atrophy in Turkish families.

Prenatal diagnosis of childhood proximal spinal muscular atrophy (SMA) is carried out by the detection of homozygous deletions of survival motor neuron (SMN; exons 7 and 8) and neuronal apoptosis inhibitory protein (NAIP; exons 5 and 6) genes located in 5q13 chromosomal region. In Hacettepe University, Department of Medical Biology, 203 postnatal molecular diagnoses of SMA have been carried out since October 1994 and prenatal diagnosis in subsequent pregnancies to couples who previously had an affected child became possible. Between January 1996 and December 1999 totally 41 SMA families were analyzed by detecting homozygous deletions of SMN and NAIP genes for prenatal counseling. Fetal DNAs were obtained from amniotic fluid and chorionic villus samples. 8/41 (20%) fetal samples were found to be affected and these pregnancies were terminated. It was interesting to find that 2 fetuses had only SMN deletions, however their affected siblings had both SMN and NAIP gene deletions.

Cyclic AMP Response Element-Binding Protein↗

PubMed1993

[A case of distal spinal muscular atrophy].

A 13-year-old boy with distal spinal muscular atrophy was reported. He noted atrophy of the bilateral legs since 11 years old. Ankle jerk was brisk and pes cavus was observed. Needle EMG of the leg showed denervation pattern. Muscle biopsy of the gastrocnemius muscle revealed large group atrophy and fiber type grouping. MCV, SCV and results of sural nerve biopsy were normal. We diagnosed his disorder as distal muscular atrophy. The essential lesion of this disease was supposed to be in the anterior horn cells.

Adolescent↗