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PubMed2001

A direct interaction between the survival motor neuron protein and p53 and its relationship to spinal muscular atrophy.

Mutations in the SMN1 (survival motor neuron 1) gene cause spinal muscular atrophy (SMA). We now show that SMN protein, the SMN1 gene product, interacts directly with the tumor suppressor protein, p53. Pathogenic missense mutations in SMN reduce both self-association and p53 binding by SMN, and the extent of the reductions correlate with disease severity. The inactive, truncated form of SMN produced by the SMN2 gene in SMA patients fails to bind p53 efficiently. SMN and p53 co-localize in nuclear Cajal bodies, but p53 redistributes to the nucleolus in fibroblasts from SMA patients. These results suggest a functional interaction between SMN and p53, and the potential for apoptosis when this interaction is impaired may explain motor neuron death in SMA.

Apoptosis↗
PubMed1998

Caspase-3 cleaves the expanded androgen receptor protein of spinal and bulbar muscular atrophy in a polyglutamine repeat length-dependent manner.

Spinal and bulbar muscular atrophy (SBMA) is one of a group of human inherited neurodegenerative diseases caused by polyglutamine expansion. There is increasing evidence that generation of truncated proteins containing an expanded polyglutamine tract may be an important step in the pathogenesis of these disorders. We have previously demonstrated that the SBMA gene product, the androgen receptor (AR) protein, is toxic when truncated. We now report that in vitro translated full-length AR proteins containing different sized polyglutamine repeats (24, 65 and 97 repeats, respectively) are specifically cleaved by recombinant caspase-3, liberating a polyglutamine containing fragment, and that the susceptibility to cleavage is polyglutamine repeat length-dependent. These findings suggest that AR protein is one of the "death substrates" cleaved by caspase-3 and that caspase-3 might be involved in the pathogenesis of SBMA.

Bulbar Palsy, Progressive↗
PubMed2004

Association of spinal and bulbar muscular atrophy with myotonic dystrophy type 1.

A man with spinal and bulbar muscular atrophy (SBMA) had a short (CTG)n expansion in the myotonic dystrophy protein kinase gene as well as (CAG)n expansion in the androgen receptor gene in leukocytes. The patient had the characteristic clinical findings of SBMA, but none of myotonic dystrophy type 1 (DM1). All of his three children (a son and two daughters) had the DM1 phenotype with long (CTG)n expansions. The daughters also had heterozygous long (CAG)n expansions. Postmortem examination of the patient revealed the characteristic pathological changes of SBMA as well as muscle degeneration compatible with DM1. Gene analysis of the organs disclosed unstable long expansions of the (CTG)n repeats, in contrast to the stable (CAG)n expansions. We have assumed that SBMA and DM1 developed independently in our patient, but cannot exclude the possibility that interactive gene effects increased somatic instability.

Adult↗
PubMed1994

Survival of individuals with spinal muscular atrophy on ventilatory support.

Six ventilator-assisted individuals (VAIs) with spinal muscular atrophy (SMA) are described. All six survived by using intermittent positive pressure ventilation via an indwelling tracheostomy for a mean of 11.7 +/- 17.7 yr despite frequent episodes of mucus plugging and pneumonia. Four of the VAIs also received all nutrition via indwelling gastrostomy tubes because of severe bulbar muscle weakness. Four VAIs used tracheostomy intermittent positive pressure ventilation with their tracheostomy cuffs deflated and could communicate verbally. Five of the six VAIs remained institutionalized from the onset of ventilatory use. Two SMA VAIs survived for 15 and 4 yr, respectively, despite need for ventilatory support since early infancy. All four SMA VAIs who could communicate remained socially active and one, gainfully employed. We conclude that for patients with advanced SMA markedly prolonged survival is possible with ventilatory assistance despite severe respiratory and bulbar muscle dysfunction.

Activities of Daily Living↗
PubMed1993

Fine mapping and narrowing of the genetic interval of the spinal muscular atrophy region by linkage studies.

The gene for autosomal recessive proximal spinal muscular atrophy (SMA) has recently been mapped to chromosome 5q12.2-q13, within a genetic distance of about 6 cM, and is proximally flanked by the locus D5S6 and distally by D5S112. Here, we report linkage analyses in 64 SMA families with nine polymorphic markers closely linked to the SMA gene, which allowed us to narrow the SMA region to about 4 cM and to define a new proximal genetic border by the locus D5S125 (EF(TG/AG)n. Based on haplotype analysis and specific recombination events, the following order of the loci was determined: 5cen-D5S76-D5S6-D5S125-SMA-(5'MAP-1B-3'MAP- 1B)/D5S112-JK53CA1/2-(D5S39-D5S127)-5qter. The location of the SMA gene between D5S125 and MAP-1B is further supported by multipoint linkage analysis.

Cell Line, Transformed↗
PubMed1989

Skeletal muscle CK-B activity in neurogenic muscular atrophies.

Creatine kinase isoenzymes were determined in skeletal muscle biopsy specimens of 34 patients suffering from neurogenic muscular atrophies. The findings were compared: (1) with those of 38 control muscle samples and (2) with those in 41 muscular dystrophies and other myopathic conditions. The measurements were made by electrophoretic separation and elution of the isoenzymes and by immunoinhibition assay. The results showed that the total and specific CK activity were significantly decreased (P less than 0.005) in neurogenic atrophies in contrast to myopathic conditions where no differences from control levels were observed. This decrease was due to a decrease of the CK-M subunit activity, while the CK-B subunit was elevated. The muscle CK-MB activity was considerably elevated in muscular dystrophies (P less than 0.02) and myositis (P less than 0.001), but it was also slightly elevated in neurogenic conditions. The similarity of the muscle CK isoenzyme pattern in neurogenic atrophies and myotonic dystrophy was noted. These findings could possibly reflect considerable difference in the regeneration process of neurogenic atrophies and muscular dystrophies.

Biopsy↗
PubMed2001

Fracture risk in patients with muscular dystrophy and spinal muscular atrophy.

We aimed at studying fracture risk in patients with Duchenne's muscular dystrophy (DMD), Becker's muscular dystrophy (BEMD), and spinal muscular atrophy type II and III (SMA II and III). A self-administered questionnaire was mailed to 293 patients with DMD, BEMD, SMA II or SMA III of which 229 returned the questionnaire. Each respondent was compared with an age- and gender-matched control subject. The mean age was 23.9 +/- 15.9 years for the patients and 23.3 +/- 16.5 years for the controls. There were significantly more fractures among patients than controls after the diagnosis was made (RR = 1.9), but not before. The patients had more fractures of the femurs, lower legs, and upper arms than the controls. Low energy fractures were more frequent in patients than controls (9% vs 0%). Many fractures in the femurs (40%), lower legs (35%), and feet and toes (44%) led to a permanent loss of function. Loss of ambulation was the major risk factor for fractures. In conclusion, fracture risk is increased in neuromuscular disease.

Adolescent↗
PubMed1991

Linkage analysis in spinal muscular atrophy, by six closely flanking markers on chromosome 5.

The proximal spinal muscular atrophies (SMA) represent the second most common autosomal recessive disorder, after cystic fibrosis. The gene responsible for chronic SMA has recently been mapped to chromosome 5q by using genetic linkage studies. Among six markers mapping to this region, five were shown to be linked with the SMA locus in 39 chronic SMA families each containing at least two affected individuals. Multilocus analysis by the method of location score was used to establish the best estimate of the SMA gene location. Our data suggest that the most likely location for SMA is between loci D5S6 and D5S39. The genetic distances between these two markers are estimated to be 6.4 cM in males and 11.9 cM in females. Since meiosis were informative with D5S39 and D5S6 in 92% and 87% of SMA families, respectively, it is hoped that the present study will contribute to the calculation of genetic risk in SMA families.

Chromosome Mapping↗
PubMed1986

Long-term follow-up of spinal fusion in spinal muscular atrophy.

From 1966 to 1983, 11 females and eight males with spinal muscular atrophy were treated by arthrodesis. Seventeen of 19 patients were evaluated by follow-up physical examination, roentgenograms, and questionnaires. In order to compare long-term versus short-term results, changes in management, and factors contributing to morbidity and mortality, three groups were identified for study. Group I consisted of 11 patients operated between 1966 and 1983 and alive at follow-up evaluation. Group II consisted of five patients operated between 1980 and 1983. Group III consisted of three patients, all deceased at follow-up evaluation and operated before 1980. In Group I, the preoperative curve averaged 119 degrees and at final follow-up examination, 99 degrees. The average preoperative curve in Group II was 80 degrees and at follow-up examination, 49 degrees. Long-term follow-up vital capacities were obtained in nine patients. The average preoperative vital capacity was 1033 cm3, and the average vital capacity seven years postoperation was 860 cm3. Most patients reported improvement in sitting, balance, and comfort. All patients are wheelchair-bound, as they were before surgery. Few long-term respiratory problems were reported.

Adolescent↗
PubMed2006

Detection of spinal muscular atrophy carriers by nested polymerase chain reaction of single sperm cells.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder with a carrier frequency of approximately 1 in 40. Approximately 95% of patients have homozygous deletions of exon 7 and/or 8 of the SMN1 gene. Carrier testing for SMA is relatively complex and requires quantitative polymerase chain reaction (PCR) of genomic DNA to determine SMN1 copy number. The purpose of this study was to assess the feasibility of carrier testing for SMA in males, by nested PCR analysis of SMN1 deletions in single sperm cells. A nested PCR method was developed to amplify SMN1 exon 7 in single cells. Restriction enzyme digestion with DraI was used to differentiate between the highly homologous SMN1 and SMN2 genes. Single sperm cells from five known SMA carriers and six noncarriers were analyzed. Among the five carriers, a total of 132 single sperm cells were analyzed and SMN1 exon 7 deletion was detected in 68 cells (51.5%). In contrast, among the six noncarriers, a total of 136 single sperm cells were analyzed. Of these, an apparent SMN1 exon 7 deletion was detected in four sperm cells. This was interpreted as an allele dropout (ADO) rate of 2.9%. We conclude that nested PCR of SMN1 exon 7 is an accurate and reproducible method for detection of SMA male carriers with a SMN1 deletion.

Base Sequence↗
PubMed2003

Protein expression changes in spinal muscular atrophy revealed with a novel antibody array technology.

Autosomal recessive proximal spinal muscular atrophy (SMA) is a severe neurodegenerative disease of childhood causing weakness and wasting secondary to motor neuron dysfunction. Over 97% of cases are caused by deletions or mutations within the survival motor neuron (SMN) gene. The SMN protein is highly expressed within brain, spinal cord and muscle, and is decreased in SMA patients. It has been shown to have an important role in RNA metabolism, but the reason for the specific motor neuron loss is still unclear. We have used a novel antibody array technology to look for differences in the expression patterns of primary muscle cultures from a type II SMA patient and a normal control. A relatively small number of differences were found within a group of proteins that function as both RNA binding proteins and transcription factors. Interactions between a number of these proteins are well established, and three of them bind in turn to p53 which interacts with SMN. A number of the changes were confirmed with western blot analysis both in the primary muscle cultures and in skeletal muscle samples from SMA patients and controls. Changes at the mRNA level were also confirmed with oligonucleotide arrays. These results suggest that a common transcription pathway may be altered in the disease state, and suggests that down-regulation of transcription factors contributes to SMA pathogenesis.

Adolescent↗
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↗
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↗
PubMed2000

[A case of spinal muscular atrophy with marked calf hypertrophy and adolescent onset].

We report on a 41-year-old male patient with spinal muscular atrophy (SMA). He had slowly progressive muscular weakness and hypertrophic calves since 14 years of age. The upper arms were slightly, and the thighs moderately atrophic, but the calves were remarkably hypertrophic. There was muscle weakness of both the upper and lower limbs, being more proximal in distribution. He had a positive Gowers' sign and his gait was slightly waddling. Serum creatine kinase level was elevated (518IU/l). Electromyogram revealed a neurogenic pattern. Muscle biopsy of the left biceps brachii showed chronic neurogenic changes. Immunohistochemical examination and Western blot analysis using anti-dystrophin antibodies showed no abnormality. DNA analysis with multiplex PCR proved no deletion in the dystrophin gene, while deletions of exons 7 and 8 of the telomeric copy of survival motor neuron gene were detected. In 1978, Pearn et al. described a new variant syndrome of SMA, characterized by adolescent onset, gross hypertrophy of calves, and a slowly progressive clinical course. The present case is compatible with this syndrome. Therefore, it is suggested that this syndrome, mimicking Becker muscular dystrophy, is not an independent clinical entity, although the phenotype of this syndrome is different from that of typical SMA.

Adolescent↗
PubMed2026

Compound muscle action potential amplitudes in newborn screen positive spinal muscular atrophy.

OBJECTIVE: To evaluate the utility of compound muscle action potential (CMAP) amplitudes as biomarkers of disease severity in newborn screening (NBS)-positive infants with spinal muscular atrophy (SMA). METHODS: We conducted a retrospective review of 21 infants identified through SMA NBS (11 with 2 SMN2 copies and 10 with 3 SMN2 copies). Baseline and serial right median, ulnar, and fibular motor nerve CMAP amplitudes (millivolts, mV) were obtained during the study. Functional outcomes were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND). RESULTS: At baseline, infants with 2 SMN2 copies demonstrated significantly lower median, ulnar, and fibular CMAP amplitudes compared with infants with 3 SMN2 copies (p&#xa0;<&#xa0;0.05). In contrast, baseline CHOP-INTEND scores did not differ significantly between the two groups. Prior to genetic confirmation, a right median CMAP amplitude&#xa0;&#x2265;3.2&#xa0;mV predicted&#xa0;&#x2265;3 SMN2 copies. Following treatment, right median and fibular CMAP amplitudes demonstrated significant improvement over time, including in analyses accounting for SMN2 copies number. CONCLUSION: CMAP amplitudes obtained from multiple upper- and lower-extremity motor nerves provided objective electrophysiological measures that distinguished infants with two versus three SMN2 copies, despite similar baseline CHOP-INTEND scores. Furthermore, CMAP abnormalities were detectable in some cases before confirmatory genetic testing results became available. Serial CMAP measurements demonstrated significant longitudinal changes following treatment, whereas functional assessments approached ceiling values, supporting the potential value of electrophysiological monitoring in the era of disease-modifying therapies. SIGNIFICANCE: CMAP assessment is a useful adjunct in the evaluation of infants identified through SMA NBS.

Humans↗