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PubMed2002

[The effect of MyoD family proteins on muscular atrophy induced by brachial plexus injury in rats].

OBJECTIVE: To study the changes of MyoD/myogenin expression in atrophic muscle after injury of brachial plexus among rats and to explore the role of proteins of MyoD family in denervation-induced muscular atrophy. METHODS: The brachial plexus was injured uniliterally among 24 SD rats. Then the rats were randomly divided into four groups treated by perfusion into the stomach with FGb 761 (extract of ginkgo leaf), creatine, clenbuterol, or distilled water (control group) at the dosage of 100 mg(-1).kg(-1).d(-1) for 8 weeks respectively. The changes of MyoD protein and myogenin were measured by Western blotting. The gene expression of MyoD and myogenin were determined by RT/PCR and Northern blotting. RESULTS: The expression of myogenin was upregulated within 24 hours after denervation then decreased in five days. On the seventh day, the expression of myogenin in the experimental side was weaker than in the control side. The expression of MyoD protein was downregulated soon after denervation. The expression of myogenin mRNA and MyoD was significantly downregulated after denervation. Clenbuterol, Egb, and creatine upregulated the expression of MyoD protein to a certain degree, creatine being the most effective and Egb being the least effective relatively. Clenbuterol and Egb upregulated the expression of myogenin in denervated muscle, clenbuterol being more effective. Creatine did not upregulate the expression of myogenin in denervated muscle remarkably. CONCLUSION: After denervation, the expression of MyoD protein and myogenin decreases, which plays an important role in atrophy of denervated muscle. EGb, creatine and clenbuterol retard the denervation-induced muscular atrophy by upregulating the expression of MyoD and/or myogenin.

Animals↗
PubMed1987

Static spinal muscular atrophy causing temporomandibular joint dysfunction.

A case of static spinal muscular atrophy is described. The patient presented with temporomandibular joint dysfunction. This case is unusual, not only from the perspective of clinical disease progression, but also that markedly elevated creatine kinase levels were demonstrated. Despite an obvious association of neuromuscular disorders and TMJ disease, reports of primary disorders of muscle and nerve which may predispose to this condition are rare. This case emphasizes the need for careful neuromuscular evaluation in all patients with TMJ dysfunction of nonarticular origin.

Adult↗
PubMed1999

[Study of NAIP gene in spinal muscular atrophy].

OBJECTIVE: Investigating the correlation between the genotype and spinal muscular atrophy(SMA) clinical phenotype. METHODS: Neuronal apoptosis inhibitory protein(NAIP) gene analysis was performed by PCR amplification of exon 5 in 13 unrelated SMA patients with deletions of SMN gene. RESULTS: Two Type-I patients(2 M5, 40%) lacked the NAIP exon 5. CONCLUSION: The results suggest a possible correlation between NAIP gene deletion and the disease severity of SMA.

Child↗
PubMed1998

Diagnosis of spinal muscular atrophy in an SMN non-deletion patient using a quantitative PCR screen and mutation analysis.

We report a child with clinical findings consistent with Werdnig-Hoffmann disease (spinal muscular atrophy type I) who was found not to have the homozygous absence of the survival motor neurone (SMN(T)) gene observed in approximately 95% of spinal muscular atrophy patients. A quantitative PCR based dosage assay for SMN(T) copy number showed that this patient possessed a single copy of the SMN(T) gene. Heteroduplex and sequence analysis of the remaining copy of SMN(T) showed a 2 base pair deletion within exon 4 which produces a frameshift and premature termination of the deduced SMN(T) protein. This protocol of initial SMN(T) gene dosage analysis followed by mutation detection allows identification of SMA compound heterozygotes (patients lacking one copy of SMN(T) and having another mutation in their other copy), thereby increasing the sensitivity of SMA molecular diagnosis.

Cyclic AMP Response Element-Binding Protein↗
PubMed1972

Pathology of peroneal muscular atrophy (Charcot-Marie-Tooth disease).

Four cases of peroneal muscular atrophy (Charcot-Marie-Tooth disease) are described in which observations were made from the necropsy examination of the central nervous system, the peripheral nervous system, and the skeletal muscles. The pattern of nerve degeneration in these various locations is described and the conclusion is drawn that the basis of the disease is a very chronic progressive neuropathy. To the pathological descriptions of previous observers is added the finding of fibrosis affecting the muscle spindles which was present in all four of the cases. The literature of the case reports with necropsy examination is reviewed.

Adult↗
PubMed1984

Progressive myoclonic epilepsy, nerve deafness and spinal muscular atrophy.

A boy of Finnish descent developed nerve deafness at six years of age, action myoclonus two years later, generalized myoclonic seizures when 16 years old and muscular atrophy at the age of 17 years. Bulbar palsy caused his death from inhalational pneumonia when he was 19 years old. Autopsy disclosed no significant changes in the cerebral cortex, thalamus, striatum, Purkinje cells or dentate nucleus. The most striking histological finding was degeneration of motor neurones in cranial nerves and anterior horns of the spinal cord, with neuroaxonal dystrophy of nucleus gracilis and cuneatus. While nerve deafness and spinal muscular atrophy have been recorded (each in different families) in association with progressive myoclonic epilepsy, the combination of these features has not previously been reported. Reasons are put forward for regarding all the system degenerations found in PME, including Unverricht-Lundborg disease (Baltic myoclonus) and the Ramsay Hunt syndrome, as variations of the same disorder.

Adult↗
PubMedDate not supplied

Molecular pathogenesis of spinal and bulbar muscular atrophy.

Studies of the molecular pathogenesis of spinal and bulbar muscular atrophy, as well as of the other polyglutamine repeat diseases, has led to an understanding of the role of protein accumulation in disease pathogenesis. Aggregation of the expanded repeat androgen receptor (AR), rather than playing a pathogenic role, likely reflects the insoluble nature of the misfolded AR. Proteolytic processing of the expanded AR at various stages of its metabolism may contribute to cellular toxicity through the enhancement of AR insolubility, and potentially through the disruption of normal proteolytic degradation processes. The finding that molecular chaperones not only promote solubility, but also enhance the degradation of expanded polyglutamines as well, make them promising targets for therapeutic development. Understanding the role of ligand binding in expanded AR metabolism may provide additional avenues of therapeutic manipulation as well.

Humans↗
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↗
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↗
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↗
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: 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↗
PubMed1988

Evaluation of immunoregulatory cells in Duchenne muscular dystrophy and spinal muscular atrophy among African and Indian patients.

Suppressor cells were assayed by numerical and functional tests in Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) among African and Indian children in order to contribute to an understanding of the pathogenesis of these neurological disorders. Peripheral blood mononuclears (PBM) were classified as total T cells and T cell subsets by the OKT series of monoclonal antibodies and as B cells by the presence of surface immunoglobulin. The suppressive effects of PBM pretreated with concanavalin A (Con A) on normal homologous phytohaemagglutinin (PHA) transformation of mononuclear cells was determined. PBM stimulation by PHA was also assessed. Patients with DMD had a significant increase (P = 0.0353) in the number of T suppressor/cytotoxic cells (1218 +/- 142 cells/mm3, mean +/- SE) as compared to controls (815 +/- 95 cells/mm3) and a significant reduction (P = 0.0282) in OKT4+ cells expressed as a percentage of OKT3+, 50% +/- 3 compared to 61% +/- 3. No differences were detected in any of the numerical assays employed in SMA as compared to controls, or within SMA patients according to severity of disease. Suppressor function and PHA transformation were normal in both groups of patients. No significant correlations were detected between numerical and functional assays of suppression. The implication of the results obtained for the role of immunoregulatory cells in the pathogenesis of DMD in these children is discussed.

Adolescent↗
PubMed1992

High-resolution genetic map around the spinal muscular atrophy (SMA) locus on chromosome 5.

Although autosomal recessive spinal muscular atrophy (SMA) has been mapped to chromosome 5q12-q13, there is for this region no genetic map based on highly informative markers. In this study we present the mapping of two previously reported microsatellite markers in 40 CEPH and 31 SMA pedigrees. We also describe the isolation of a new microsatellite marker at the D5S112 locus. The most likely order of markers (with recombination fractions given in parentheses) is 5cen-D5S6-(.02)-D5S125-(.04)-(JK53CA1/2,D5S11 2)-(.04)-D5S39-qter. The relative order of D5S6, D5S112, and D5S39 was confirmed by in situ hybridization. Multipoint linkage analysis in 31 SMA families indicates that the SMA locus lies in the 6-cM interval between D5S6 and JK53CA1/2, D5S112.

Base Sequence↗
PubMed1998

Treatment of type I spinal muscular atrophy with noninvasive ventilation and gastrostomy feeding.

Type I spinal muscular atrophy (SMA) is a rapidly progressive, degenerative neuromuscular disease of infancy. In severe SMA, weakness, hypotonia, and bulbar involvement lead to progressive respiratory insufficiency and swallowing dysfunction, which are frequently complicated by aspirations. There are few studies reported in the literature that address the respiratory management of type I SMA. This article reports the results of treating four patients with infantile SMA with noninvasive positive pressure ventilation and gastrostomy feeding. All patients had gastroesophageal reflux disease, which was managed medically. Despite these therapies, survival was only 1 to 3.5 months after presenting with severe aspirations. The treatment strategy, which can be effective in less rapidly progressive neuromuscular diseases, did not alter the very poor prognosis of type I SMA. The treatment options are reviewed, and a strategy designed to optimize quality of life for infants with this fatal disease is presented.

Deglutition Disorders↗
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↗
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↗
PubMedDate not supplied

Hip dislocation in patients with spinal muscular atrophy.

The propensity for hip dislocation in patients with spinal muscular atrophy (SMA) is well documented, but the appropriate treatment and even the long-term outcome of these hips in this patient population have not been well defined. The purpose of this study was to determine by long-term follow-up the natural history of dislocated hips in a cohort of SMA patients from a single institution. Pain and functional difficulties (positioning, skin and perineal care) were assessed and radiographs were reviewed in a total of 41 patients with a mean of 18 years of follow-up. Seventeen of 82 hips (21%) were dislocated in 14 patients and 20 hips were subluxed. Only two patients had any hip pain at follow-up, one had difficulty with seating, and no patients had difficulty with perineal care. Given the small number of patients with symptoms with dislocated hips, observation rather than surgical intervention seems warranted in SMA patients with hip dislocation.

Adolescent↗