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PubMed2003

Transgenic mouse models of spinal and bulbar muscular atrophy (SBMA).

Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. Only males develop symptoms, while female carriers usually are asymptomatic. A specific treatment for SBMA has not been established. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine (polyQ) tract, in the first exon of the androgen receptor (AR) gene. The pathologic hallmark is nuclear inclusions (NIs) containing the mutant and truncated AR with expanded polyQ in the residual motor neurons in the brainstem and spinal cord as well as in some other visceral organs. Several transgenic (Tg) mouse models have been created for studying the pathogenesis of SBMA. The Tg mouse model carrying pure 239 CAGs under human AR promoter and another model carrying truncated AR with expanded CAGs show motor impairment and nuclear NIs in spinal motor neurons. Interestingly, Tg mice carrying full-length human AR with expanded polyQ demonstrate progressive motor impairment and neurogenic pathology as well as sexual difference of phenotypes. These models recapitulate the phenotypic expression observed in SBMA. The ligand-dependent nuclear localization of the mutant AR is found to be involved in the disease mechanism, and hormonal therapy is suggested to be a therapeutic approach applicable to SBMA.

Animals↗
PubMed2002

Molecular genetic analyses of five Vietnamese patients with spinal muscular atrophy.

Most patients with spinal muscular atrophy (SMA) have been reported to show homozygous deletion of the gene responsible for SMA, SMN1. However, whether SMA patients homozygous for the SMN1 deletion exist in Southeast Asian countries, including Vietnam, remains to be determined, because molecular genetic analyses of SMA patients from these countries have not been reported. In this preliminary study, we analyzed five Vietnamese SMA patients and found that SMN1 gene exons 7 and 8 were completely absent in one of them, a 6-month-old girl with hypotonic muscles. Thus, SMN1 deletion can be a cause of SMA in Vietnam, although other genetic abnormalities should be considered as etiological factors in many cases. In conclusion, we identified a homozygous deletion of the SMN1 gene in a Vietnamese SMA patient. Since the number of the patients analyzed in this study was very limited, it is too early to determine whether SMN1 deletion is not a main cause of SMA in Vietnam.

Adolescent↗
PubMed2006

Pathogenesis, animal models and therapeutics in spinal and bulbar muscular atrophy (SBMA).

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neurodegenerative disease characterized by slowly progressive muscle weakness and atrophy of bulbar, facial, and limb muscles. The cause of SBMA is expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, in the first exon of the androgen receptor (AR) gene. SBMA chiefly occurs in adult males, whereas neurological symptoms are rarely detected in females having mutant AR gene. The cardinal histopathological finding of SBMA is loss of lower motor neurons in the anterior horn of spinal cord as well as in brainstem motor nuclei. Animal models carrying human mutant AR gene recapitulate polyglutamine-mediated motor neuron degeneration, providing clues to the pathogenesis of SBMA. There is increasing evidence that testosterone, the ligand of AR, plays a pivotal role in the pathogenesis of neurodegeneration in SBMA. The striking success of androgen deprivation therapy in SBMA mouse models has been translated into clinical trials. In addition, elucidation of pathophysiology using animal models leads to emergence of candidate drugs to treat this devastating disease: HSP inducer, Hsp90 inhibitor, and histone deacetylase inhibitor. Utilizing biomarkers such as scrotal skin biopsy would improve efficacy of clinical trials to verify the results from animal studies. Advances in basic and clinical researches on SBMA are now paving the way for clinical application of potential therapeutics.

Animals↗
PubMed2005

Genotype-phenotype correlation of SMN locus genes in spinal muscular atrophy patients from India.

Spinal muscular atrophy has been classified into four groups based on the age of onset and clinical severity of the disease. Homozygous deletion in SMN1 gene causes the disease but the clinical severity may be modified by copy number of homologous gene SMN2 as well as the extent of deletion at SMN locus. In the view of scarcity of genotype and phenotype correlation data from India, this study has been undertaken to determine that correlation in SMA patients by using the SMN and NAIP genes and two polymorphic markers C212 and C272 located in this region. Two to four alleles of the markers C212 and C272 were observed in normal individuals. However, majority of Type I patients showed only one allele from both markers whereas in Type II and III patients, 2-3 alleles were observed. The SMN2 copy number in our type III patients showed that patients carry 3-5 copies of SMN2 gene. Our results suggest that extent of deletions encompassing H4F5, SMN1, NAIP and copy number of SMN2 gene can modify the SMA phenotype, thus accounting for the different clinical subtypes of the disease.

Adolescent↗
PubMed2000

[Molecular basis of spinal muscular atrophy: th SMN gene].

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration and loss of motor neurons of the anterior horn of the spinal cord. The clinical manifestations include proximal symmetric weakness and progressive atrophy of muscle. SMA is classified by age of onset, severity of symptoms, and evolution in three groups: type I, severe or Werdnig-Hoffmann disease, type II or intermediate and type III, moderate-mild, Kugelberg-Welander disease. The identification of the SMN1 gene as determinant of SMA opened new alternatives to study the disease. Most of the patients have deletions and conversion of SMN1 and in a small number of cases, point mutations were detected. There is no obvious genotype-phenotype correlation because homozygous absence of SMN1 was associated to a wide spectrum of manifestations from congenital disease to non symptomatic cases. Modifier factors, such as the number of copies of SMN2, could influence the phenotype. Other possible modifier genes are under study. The SMN gene is expressed in various neuronal populations. However, only motor neurons are responsible for the manifestations of the disease. The SMN protein is part of a complex with various proteins involved in the splicing reaction. This apparent essential function for all cells could be critical in motor neurons. When SMN1 is absent or dysfunctional, the motor neurons could be more sensitive because they have an increased transcription activity. In this situation, other cells and tissues could be protected by genetic or cellular factors still undiscovered.

Alleles↗
PubMed1998

Identification of a candidate modifying gene for spinal muscular atrophy by comparative genomics.

Spinal muscular atrophy (SMA) is a common recessive disorder characterized by the loss of lower motor neurons in the spinal cord. The disease has been classified into three types based on age of onset and severity. SMA I-III all map to chromosome 5q13 (refs 2,3), and nearly all patients display deletions or gene conversions of the survival motor neuron (SMN1) gene. Some correlation has been established between SMN protein levels and disease course; nevertheless, the genetic basis for SMA phenotypic variability remains unclear, and it has been postulated that the loss of an additional modifying factor contributes to the severity of type I SMA. Using comparative genomics to screen for such a factor among evolutionarily conserved sequences between mouse and human, we have identified a novel transcript, H4F5, which lies closer to SMN1 than any previously identified gene in the region. A multi-copy microsatellite marker that is deleted in more than 90% of type I SMA chromosomes is embedded in an intron of this gene, indicating that H4F5 is also highly deleted in type I SMA chromosomes, and thus is a candidate phenotypic modifier for SMA.

Amino Acid Sequence↗
PubMed2005

SMN1 dosage analysis in spinal muscular atrophy from India.

BACKGROUND: Spinal muscular atrophy (SMA) represents the second most common fatal autosomal recessive disorder after cystic fibrosis. Due to the high carrier frequency, the burden of this genetic disorder is very heavy in developing countries like India. As there is no cure or effective treatment, genetic counseling becomes very important in disease management. SMN1 dosage analysis results can be utilized for identifying carriers before offering prenatal diagnosis in the context of genetic counseling. METHODS: In the present study we analyzed the carrier status of parents and sibs of proven SMA patients. In addition, SMN1 copy number was determined in suspected SMA patients and parents of children with a clinical diagnosis of SMA. RESULTS: Twenty nine DNA samples were analyzed by quantitative PCR to determine the number of SMN1 gene copies present, and 17 of these were found to have one SMN1 gene copy. The parents of confirmed SMA patients were found to be obligate carriers of the disease. Dosage analysis was useful in ruling out clinical suspicion of SMA in four patients. In a family with history of a deceased floppy infant and two abortions, both parents were found to be carriers of SMA and prenatal diagnosis could be offered in future pregnancies. CONCLUSION: SMN1 copy number analysis is an important parameter for identification of couples at risk for having a child affected with SMA and reduces unwarranted prenatal diagnosis for SMA. The dosage analysis is also useful for the counseling of clinically suspected SMA with a negative diagnostic SMA test.

Child↗
PubMed2003

Behavioural problems in children and adolescents with spinal muscular atrophy and their siblings.

Spinal muscular atrophy (SMA) is a chronic illness characterized by loss of motor function. The aim of the study was to investigate behavioural adjustment in 96 children and adolescents with SMA (47 males, 49 females; mean age 11 years 2 months, range 6 to 18 years). Forty-five non-affected siblings (26 males, 19 females; mean age 11 years 6 months, range 6 to 18 years) and 59 normally developing children (33 males, 26 females; mean age 10 years 8 months, range 6 to 18 years) were recruited as control participants. Behavioural symptoms were measured with the Child Behaviour Checklist (CBCL) and disorders were assessed with a structured psychiatric interview (Kinder-DIPS). Of the patients with SMA, 12.5% fulfilled the criteria for an ICD-10 or DSM-IV diagnosis, with separation anxiety disorder being the most common diagnosis. The CBCL total score was in the clinical range for 11.5% of patients, 20% of the siblings, and 11.7% of the control children; the externalizing score rates were 2.1%, 22.2%, and 11.9% respectively; the internalizing score 18.9%, 24.4%, and 13.6% respectively. Comorbid psychopathology was not influenced by sex, IQ, nor severity of SMA, and only externalizing behaviour was correlated to age. In conclusion, children and adolescents with SMA are characterized by a low psychiatric comorbidity not different from control individuals. The group with the highest rate of behavioural problems and with the greatest need for intervention were the non-affected siblings who had a two- to threefold higher rate of behavioural problems than the normative population.

Adolescent↗
PubMed1993

Alterations in neurofilament mRNA in hereditary canine spinal muscular atrophy.

BACKGROUND: Hereditary canine spinal muscular atrophy (HCSMA) is a dominantly inherited motor neuron disease in which distal axonal caliber is reduced in lower motor neurons. Because several animal models show that neurofilament protein gene expression is a major determinant of axonal caliber, we began an examination of neurofilament gene expression in HCSMA early in the clinical disease to determine whether this family of proteins was selectively affected and could thus possibly contribute to the morphologic and functional alterations characteristic of the disease. EXPERIMENTAL DESIGN: We used quantitative in situ hybridization to compare levels of mRNA encoding neurofilament protein subunits in lateral ventral horn neurons from the cervical spinal cord enlargement (C7-C8) in 10-week-old homozygous HCSMA and control dogs. Each slide contained a spinal cord section from a control and an HCSMA dog in order to make within-slide comparisons. The mean number of grains/neuron and the mean neuronal grain density for the HCSMA section were divided by that value for the control section on each slide. The means of these ratios for each mRNA species (i.e., neurofilament subunits and total polyadenylated mRNA (poly-A+) were then compared statistically. RESULTS: The levels of mRNA encoding the low molecular weight neurofilament protein subunit were significantly different from levels of mRNA encoding the high molecular weight neurofilament protein subunit and poly-A+ mRNA in dogs with HCSMA compared with control dogs. The neuronal levels of poly-A+ mRNA were comparable in dogs with HCSMA and controls. CONCLUSIONS: If neurofilament protein subunit levels are found to follow the mRNA levels in this animal model, our results would suggest that decreased expression of the low molecular weight neurofilament gene is sufficient to inhibit neurofilament function, i.e., maintenance of axonal caliber, probably by disrupting normal neurofilament assembly.

Animals↗
PubMed2005

Molecular and functional analysis of intragenic SMN1 mutations in patients with spinal muscular atrophy.

The autosomal recessive spinal muscular atrophy (SMA), a neuromuscular disease and frequent cause of early death in childhood, is caused in 96% of patients by homozygous absence of the survival motor neuron gene (SMN1). The severity of the disease is mainly determined by the copy number of SMN2, a copy gene which predominantly produces exon 7-skipped transcripts and only low amount of full-length transcripts that encode for a protein identical to SMN1. Only about 4% of SMA patients bear one SMN1 copy with an intragenic mutation. A comprehensive molecular genetic analysis of 34 SMA patients who carry one SMN1 gene is presented, including 18 that were previously published. Haplotype analysis with the microsatellite markers Ag1-CA and C212 in these SMA families turned out to be a reliable accessory method in predicting known SMN1 mutations in SMA patients carrying one SMN1 copy. Five novel missense mutations were identified that are localized in: exon 2a c.88G>A (p.D30N) and c.131A>T (p.D44V); exon 3 c.283G>C (p.G95R) and c.332C>G (p.A111G); and exon 6 c.784A>G (p.S262G), respectively. The survival motor neuron (SMN) protein has been shown to be a component of a large complex (termed the SMN complex) that promotes the formation of spliceosomal U small nuclear ribonucleoproteins (snRNPs). Within this complex, SMN forms oligomers and directly interacts via its N-terminus with SMN-interacting protein 1 (SIP1) and via its central Tudor domain with spliceosomal (Sm) proteins. We performed in vitro interaction studies to test whether SMA-causing missense mutations identified in this study interfere with the reported interactions of SMN. Our results show that mutations p.G95R and p.A111G reduce SMN binding to Sm proteins, further confirming the previous finding that the Tudor domain is the essential binding site of SMN to Sm-proteins. However, all mutations, including those in exon 2a, a region shown to be important for the binding of SMN to SIP1, do not disturb the interaction of SMN to SIP1.

Adolescent↗
PubMed1996

Molecular basis of phenotypic heterogeneity in siblings with spinal muscular atrophy.

We report on a family with childhood-onset spinal muscular atrophy with intrafamilial phenotypic variation. Typical of a large majority of such patients, both the child with spinal muscular atrophy type I and the child with type II were missing both copies of the survival motor neuron telomeric gene (SMN(T)). The more severely affected child, however, showed genotypic evidence consistent with the de novo loss of DNA sequence in addition to that inherited by both affected children. These data suggest that the intrafamilial phenotypic variation in this family results from a new mutation event in the more severely affected child. Examples of intrafamilial phenotypic variability are quite rare, but some reports exist in the spinal muscular atrophy literature. We present evidence that one explanation for this phenomenon is the occurrence of de novo deletion events at the highly unstable disease locus.

Alleles↗
PubMed1977

Chronic spinal muscular atrophy simulating facioscapulohumeral type and limb-girdle type of muscular dystrophy. Report of two cases.

Two cases of chronic spinal muscular atrophy simulating the clinical picture of the facioscapulohumeral type and limb-girdle type of muscular dystrophy are reported. Both patients had a waddling gait, Gowers' maneuver in arising, terminal atrophies and pseudohypertrophies of some muscles, marked fasciculations, and fascicular tremor. The electromyogram revealed signs of anterior horn cell disease. Calf muscle biopsy (case 2) revealed 'myopathic' changes.

Chronic Disease↗
PubMed1971

The genetic heterogeneity of spinal muscular atrophy (SMA).

The clinical picture of the spinal muscular atrophy varies greatly with respect to age of onset, speed of progression, severity and distribution of muscular atrophy, weakness and contractures, yet cases occurring within a family usually show concordant clinical features. Thus, genetic heterogeneity has to be assumed. This is supported by the various genetic transmission patterns (autosomal dominant, recessive, X-linked recessive) found by accurate pedigree analysis.

Age Factors↗
PubMed1994

Spinal muscular atrophy in calves of the Red Danish dairy breed.

Pathological and genetic aspects of spinal muscular atrophy in Red Danish dairy cattle are described. A total of 312 calves suspected of having the condition was reported in the Danish Bovine Genetic Disease Programme, 162 of them were examined post mortem and spinal muscular atrophy was diagnosed in 82 of these. Seventy-five per cent of the affected calves had bronchopneumonia. The diagnosis of spinal muscular atrophy was based on histopathological examinations of the spinal cord and musculature. The lesions were primarily characterised by degeneration of the spinal cord motor neurons with neuronophagia and denervation muscular atrophy. The ages of the affected calves varied from those recumbent from birth to a 21-week-old calf. All the necropsied cases appeared in a clearly familial pattern and could be traced back to American Brown Swiss bulls.

Animals↗
PubMed1989

Functional activities in spinal muscular atrophy patients after spinal fusion.

Spinal muscular atrophy patients present with weakness, greater in the proximal muscles, leading to scoliosis and limited upper extremity function. The purpose of this study is to identify unique aspects of these patients and to understand how spinal fusion affects their function. Forty patients underwent Harrington or Luque rod instrumentation with functional evaluations preoperatively and 2 and 5 years postoperatively. Biomechanical assessment of function is important. Flexibility of the spine is functionally advantageous because distal strength is used to align weaker proximal segments. Postoperatively, lack of spinal flexibility resulted in a decline in gross motor function and increased use of UE aids due to a change in the trunk position in the weaker patients. The stronger patients' activities were maintained. Earlier mobilization in patients with Luque procedures did not improve postoperative function.

Activities of Daily Living↗
PubMed1990

Genetic homogeneity between acute and chronic forms of spinal muscular atrophy.

The childhood-onset spinal muscular atrophies (SMAs) describe a heterogeneous group of disorders that selectively affect the alpha motoneuron. We have shown that chronic childhood-onset SMA (SMA II and III) maps to a single locus on chromosome 5q. Acute SMA (SMA Type I/Werdnig-Hoffmann/severe/infantile) is the main cause of heritable infant mortality. Mapping the acute SMA locus by conventional methods is complicated by the rapidly fatal course of the disease and its recessive mode of inheritance. We present here the typing of four inbred acute-SMA families with DNA markers on chromosome 5q and analysis of these together with acute families from our previous study to demonstrate genetic homogeneity between the acute and chronic forms of SMA. The data indicate that the acute SMA locus maps to chromosome 5q11.2-13.3. Two families seem unlinked to 5q markers, raising the possibility of genetic heterogeneity or disease misclassification within the acute and chronic family sets.

Acute Disease↗
PubMed1972

Spinal motor neurones in murine muscular dystrophy and spinal muscular atrophy. A quantitative histological study.

Recent electrophysiological studies of human and mouse muscular dystrophy have prompted the hypothesis that both are of neurogenic rather than myogenic origin. A decreased number of spinal motor neurones might be expected if this hypothesis were correct. The total number of neurones in the anterior grey horns of seven normal mice, six Bar Harbor 129 strain dystrophic mice, and six mice suffering from genetically-determined spinal muscular atrophy have been counted. The number of neurones in the cell types believed to include the motor neurones was significantly reduced to 13 to 71% of normal in mice with spinal muscular atrophy. In mice with muscular dystrophy, the number of anterior horn neurones was higher rather than lower than normal. The significance of these findings is discussed.

Animals↗