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Results for “Muscular Atrophy, Spinal”

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PubMed1999

Allele-specific amplification for the diagnosis of autosomal recessive spinal muscular atrophy.

The SMN1 gene is homozygously deleted for at least exon 7, interrupted or converted to a non-functional telomeric copy in most cases of proximal spinal muscular atrophies. The presence of a pseudogene hampers direct detection of the exon 7 deletion. We describe a method for the detection of the of exon 7 deletion, based on the amplification refractory mutation system (ARMS), in a multiplex PCR with fluorescent-labelled primers. The gene and pseudogene amplification products differ in the dye bound and in their size, which allows distinction of both products on electrophoresis. The pseudogene is used as an internal control, and this method gives a clear and specific pattern for the patients. Amplification is achieved with 30 cycles, and specificity is retained up to 40 cycles.

Alleles↗

PubMed2005

Rapid diagnosis of spinal muscular atrophy using denaturing high-performance liquid chromatography.

OBJECTIVE: To introduce the application of denaturing high-performance liquid chromatography (DHPLC) in the diagnosis of childhood type spinal muscular atrophy (SMA). METHODS: Exon 7 and flanking area of survival motor neuron (SMN) gene were amplified by PCR in 1 standard sample, 25 normal individuals and 25 patients with SMA. The PCR products were then directly loaded onto the DHPLC system after denaturing and annealing. Different DNA segments were separated by changing the concentration of buffer A relative to that of buffer B. RESULTS: Different DNA segments were separable on the DHPLC chromatogram. Three peaks including SMN1/SMN2 heteroduplex peak, SMN2 homoduplex peak and SMN1 homoduplex peak were detected in 23 out of 25 normal individuals. Only SMN1 homoduplex peak was detected in 2 normal individuals and the standard sample, indicating the deletion of SMN2 On the contrary, only the SMN2 homoduplex peak was detected in 22 out of 25 patients with SMA, indicating deletion of SMN1. The three peaks as those of normal individuals were detected in the other 3 patients, indicating no SMN1 or SMN2 deletion. CONCLUSION: As a new technology for diagnosing SMA, DHPLC is sensitive, accurate, rapid and convenient.

Chromatography, High Pressure Liquid↗

PubMed2002

Pilot trial of albuterol in spinal muscular atrophy.

The aim of this pilot study was to evaluate the effect of albuterol in children with spinal muscular atrophy (SMA). Thirteen patients (five with SMA II and eight with SMA III) were given oral albuterol for 6 months. There was a significant increase in myometry, forced vital capacity, and lean body mass between the baseline and the 6-month assessments (p < 0.05). Albuterol may have a beneficial effect in patients with SMA without causing any significant adverse effects. Larger randomized, placebo-controlled trials are needed to confirm this observation.

Absorptiometry, Photon↗

PubMed2006

In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy.

Among a panel of histone deacetylase (HDAC) inhibitors investigated, suberoylanilide hydroxamic acid (SAHA) evolved as a potent and non-toxic candidate drug for the treatment of spinal muscular atrophy (SMA), an alpha-motoneurone disorder caused by insufficient survival motor neuron (SMN) protein levels. SAHA increased SMN levels at low micromolar concentrations in several neuroectodermal tissues, including rat hippocampal brain slices and motoneurone-rich cell fractions, and its therapeutic capacity was confirmed using a novel human brain slice culture assay. SAHA activated survival motor neuron gene 2 (SMN2), the target gene for SMA therapy, and inhibited HDACs at submicromolar doses, providing evidence that SAHA is more efficient than the HDAC inhibitor valproic acid, which is under clinical investigation for SMA treatment. In contrast to SAHA, the compounds m-Carboxycinnamic acid bis-Hydroxamide, suberoyl bishydroxamic acid and M344 displayed unfavourable toxicity profiles, whereas MS-275 failed to increase SMN levels. Clinical trials have revealed that SAHA, which is under investigation for cancer treatment, has a good oral bioavailability and is well tolerated, allowing in vivo concentrations shown to increase SMN levels to be achieved. Because SAHA crosses the blood-brain barrier, oral administration may allow deceleration of progressive alpha-motoneurone degeneration by epigenetic SMN2 gene activation.

Analysis of Variance↗

PubMed1996

Spinal muscular atrophy type II (intermediary) and III (Kugelberg-Welander). Evolution of 50 patients with physiotherapy and hydrotherapy in a swimming pool.

We added hydrotherapy to 50 patients with spinal muscular atrophy (SMA) who were being treated with individual conventional physiotherapy. Hydrotherapy performed at an approximate temperature of 30 degrees Celsius, twice a week, for thirty minutes in children and forty-five minutes in adults during a 2-year period. The outcome derived from this combined modality of treatment was rated according to physiotherapeutic evaluations, the MMT (Manual Muscular Test), and the Barthel Ladder. Patients were reevaluated at 2-month intervals. After two years of ongoing treatment, we were able to observe that the deformities in hip, knee and foot were progressive in all SMA Type II patients, and in some Type III. Muscle strength stabilized in most SMA Type III patients, and improved in some. MMT was not done in SMA Type II. In all patients we were able to detect an improvement in the Barthel Ladder scale. This study suggests that a measurable improvement in the quality of daily living may be obtained in patients with SMA Types II and III subjected to conventional physiotherapy when associated with hydrotherapy.

Adolescent↗

PubMed2002

[Kennedy syndrome--bulbo-spinal muscular atrophy].

Kennedy syndrome is a late-onset, bulbar-spinal type of muscular atrophy, with X-linked recessive inheritance. The characteristic features of the disease become prominent in the 4-5th decades: proximal muscle wasting and weakness, bulbar signs, fasciculations in skeletal muscles, subtle signs of endocrine dysfunction, such as gynaecomastia or testicular atrophy. The electrophysiological examinations are the keypoint to the diagnosis. Electroneurography shows normal conduction velocity in peripheral nerves, but the sensory nerves usually show axonal degeneration, which causes only very mild or subclinical neurological deficits. Electromyography shows chronic anterior horn cell degeneration in skeletal muscles. Molecular genetic diagnosis was introduced in 1991, when on abnormal expansion of CAG repeat was found in the first exon of the androgen receptor gene on chromosome X with a frequency of 100% in the affected population. Since the progression is very slow and these patients can expect a normal life span, it is essential to distinguish this syndrome from other, often more severe diseases, such as ALS. There is no proven therapy for Kennedy's disease yet. This is the first case of Kennedy's disease published in Hungary.

Adult↗

PubMed1997

Different entities of proximal spinal muscular atrophy within one family.

The molecular analysis of the survival motor neuron (SMN) gene and several closely flanking polymorphic markers in an atypical pedigree with four patients suffering from spinal muscular atrophy (SMA) over two generations has raised new aspects concerning the etiology and the molecular spectrum of autosomal recessive SMA. Three patients in two generations show homozygous deletions of exons 7 and 8 of the telomeric copy of SMN (telSMN), thus confirming the presence of autosomal recessive SMA, with localisation on chromosome 5q12. The fourth SMA patient with mild neurogenic atrophy (confirmed by muscle biopsy and electromyography) shows no homozygous deletion of telSMN but carries a heterozygous deletion of telSMN, as can be deduced from her two affected homozygously deleted children. No intragenic mutation has been identified in the remaining telSMN. In addition, she shares only one SMA chromosome with her affected brother, is haploidentical with two healthy brothers, and has a 31-year-old healthy son, who has inherited an SMN-deleted paternal chromosome and the SMN non-deleted maternal chromosome. These results suggest that this patient either has a neurogenic atrophy of a different origin or exhibits an unusual heterozygous manifestation of SMA 5q12. Interestingly, the two haploidentical telSMN-deleted affected sibs in the second generation show a strikingly discordant clinical picture indicating that, in addition to telSMN mutations, other factors influence the phenotype of SMA in the reported pedigree.

Adult↗

PubMed1998

Correlation between the M and F wave characteristics and the innervated muscle strength in spinal muscular atrophy.

The purpose of this study is to elucidate the interrelation between the M and F wave characteristics of the median nerve and the grip power in patients with spinal muscular atrophy (SMA). The SMA patients showed decreased amplitudes of the M and F waves, decreased frequency of the F wave, and an increase of the F/M ratio as compared with the normative values. The F wave frequency and the amplitudes of M and F waves, which showed a significant linear correlation with each other, became lower in accordance with the decrease of grip power. The properties of M and F waves strongly correlated with the number of surviving motor neurons which would be fewer in those severely affected by SMA.

Adolescent↗

PubMed2004

A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis.

Motor neuron diseases (MNDs) are a group of neurodegenerative disorders with involvement of upper and/or lower motor neurons, such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), progressive bulbar palsy, and primary lateral sclerosis. Recently, we have mapped a new locus for an atypical form of ALS/MND (atypical amyotrophic lateral sclerosis [ALS8]) at 20q13.3 in a large white Brazilian family. Here, we report the finding of a novel missense mutation in the vesicle-associated membrane protein/synaptobrevin-associated membrane protein B (VAPB) gene in patients from this family. Subsequently, the same mutation was identified in patients from six additional kindreds but with different clinical courses, such as ALS8, late-onset SMA, and typical severe ALS with rapid progression. Although it was not possible to link all these families, haplotype analysis suggests a founder effect. Members of the vesicle-associated proteins are intracellular membrane proteins that can associate with microtubules and that have been shown to have a function in membrane transport. These data suggest that clinically variable MNDs may be caused by a dysfunction in intracellular membrane trafficking.

Adult↗

PubMed1998

Analysis of creatine kinase activity in 504 patients with proximal spinal muscular atrophy types I-III from the point of view of progression and severity.

Mild to moderately elevated creatine kinase (CK) activity is a frequent biochemical finding in proximal spinal muscular atrophy (SMA). In a collaborative study on all types of childhood and juvenile onset SMA, we analysed the CK activity of 504 SMA patients (138 type I, 127 type II, 144 type IIIa, and 95 type IIIb patients). Under the assumption of a lognormal distribution of CK activity as the most appropriate statistical model, CK levels were transformed into logarithms and compared by standard deviation scores = CK-SDS (log). CK activity was statistically different between early and later onset SMA: in SMA I and II, about one-third of patients showed CK-SDS (log) >2 SD, the analysis of the means did not show significant differences. In SMA III, CK-SDS (log) was significantly higher (p < 0.01) than in the two other groups, which was most pronounced in SMA IIIb. More than 90% of SMA IIIb patients showed CK-SDS (log) values >2 vs. 57% in SMA IIIa. As similar values were obtained for a subgroup of 100 patients in whom the diagnosis of autosomal recessive SMA was confirmed by a deletion of the telomeric copy of the survival motor neuron gene, our results can be considered representative for SMA I-III. There was no correlation between CK level and disease duration. The fact that patients were ambulatory or chair-bound had no influence on CK activity in type III SMA. There was no sex influence in SMA I, II and IIIa. The observed higher male values in the group SMA IIIb are most likely the result of a lack of female patients with onset after puberty.

Adolescent↗

PubMed1984

Late-childhood-onset spinal muscular atrophy in three Melanesian families in Papua New guinea.

Late-childhood-onset spinal muscular atrophy (SMA) with rapid progression from proximal to distal muscle groups and leading to severe incapacity or death in adolescence or early adult life, was studied in two Melanesian families in Papua New Guinea. Probable SMA with cardiomyopathy was observed in a 12-year-old boy in a related family. The pattern of inheritance in the study group did not conform to any of the conventional Mendelian modes and it was conjectured that the disease was expressed in heterozygote carriers of the SMA gene only when an allelomorphic activator gene was present.

Adolescent↗

PubMed1986

A rapidly progressive autosomal dominant scapulohumeral form of spinal muscular atrophy.

Three patients from a large pedigree are described who had autosomal dominant spinal muscular atrophy that became manifest between the end of the fourth and the sixth decade. The disease progressed rapidly without evidence of corticospinal tract dysfunction, and within 3 years the patients died from respiratory failure.

Adult↗

PubMed1997

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

We conducted molecular analysis of two candidate genes for spinal muscular atrophy (SMA), the survival motor neuron gene (SMN) and the neuronal apoptosis inhibitory protein gene (NAIP), in 16 Japanese patients with SMA and compared the phenotypic features of SMA in these patients with the corresponding genotypes. Exons 7 and/or 8 of SMN were homozygously deleted in 11 SMA type I (Werdnig-Hoffmann disease) patients, two SMA type II patients and one SMA type III patient. Exons 5 and 6 of NAIP were homozygously deleted in six SMA type I patients. No patient had a deletion in NAIP without a deletion in SMN. Mechanical ventilation was required during the first 7 months of life in the SMA type I patients who had a deletion in both SMN and NAIP. Ventilatory support was initiated within 2 years after birth in patients who had a deletion in SMN but not in NAIP. We detected homozygous deletion of exon 5 of NAIP in the unaffected mothers of two SMA type I patients. In these families, the patients exhibited a deletion in both SMN and NAIP. The parents and unaffected siblings of these patients did not have a deletion in SMN. The present findings support the hypothesis that SMN deletion plays an important role in the development of SMA and suggest that combined deletion of both SMN and NAIP may be relevant for determining the disease severity.

Asian People↗

PubMed1987

Promotion of ambulation of patients with spinal muscular atrophy by early fitting of knee-ankle-foot orthoses.

Seven children with spinal muscular atrophy aged between 20 months and four years, none of whom had ever walked, were fitted with knee-ankle-foot orthoses. All the children could sit unsupported and therefore were at point 9 on the Vignos functional scale. Two children achieved autonomous walking, three assisted walking and the remaining two could stand without aid. During the follow-up period there was no progression of weakness and neither scoliosis nor contractures developed.

Braces↗

PubMed2006

An approximately 140-kb deletion associated with feline spinal muscular atrophy implies an essential LIX1 function for motor neuron survival.

The leading genetic cause of infant mortality is spinal muscular atrophy (SMA), a clinically and genetically heterogeneous group of disorders. Previously we described a domestic cat model of autosomal recessive, juvenile-onset SMA similar to human SMA type III. Here we report results of a whole-genome scan for linkage in the feline SMA pedigree using recently developed species-specific and comparative mapping resources. We identified a novel SMA gene candidate, LIX1, in an approximately140-kb deletion on feline chromosome A1q in a region of conserved synteny to human chromosome 5q15. Though LIX1 function is unknown, the predicted secondary structure is compatible with a role in RNA metabolism. LIX1 expression is largely restricted to the central nervous system, primarily in spinal motor neurons, thus offering explanation of the tissue restriction of pathology in feline SMA. An exon sequence screen of 25 human SMA cases, not otherwise explicable by mutations at the SMN1 locus, failed to identify comparable LIX1 mutations. Nonetheless, a LIX1-associated etiology in feline SMA implicates a previously undetected mechanism of motor neuron maintenance and mandates consideration of LIX1 as a candidate gene in human SMA when SMN1 mutations are not found.

Animals↗

PubMed2002

Spinal muscular atrophy with congenital fractures: postmortem analysis.

We present a male infant with congenital fractures and features typical of spinal muscular atrophy. Mid-shaft fractures of the left humerus and both femurs occurred in utero. The patient died at 8 months of age following recurrent respiratory tract infections. His peripheral electrophysiologic studies were consistent with anterior horn cell disease. Molecular genetic studies were negative for the SMN gene. At autopsy, extensive anterior horn cell loss was present. There was extensive disease of skeletal muscle with relative sparing of the diaphragm. This patient represents a further case of this rare and fatal disease.

Cyclic AMP Response Element-Binding Protein↗

PubMed2004

Pilot trial of phenylbutyrate in spinal muscular atrophy.

The aim of this study was to evaluate tolerability and efficacy of phenylbutyrate (PB) in patients with spinal muscular atrophy (SMA). Ten patients with SMA type II confirmed by DNA studies (age range 2.6-12.7 years, mean age 6.01) were started on oral PB (triButyrate) in powder or tablets. The dosage was 500 mg/kg per day (maximum dose 19 g/d), divided in five doses (every 4 h, skipping one night-dose) using an intermittent schedule (7 days on and 7 days off). Measures of efficacy were the change in motor function from baseline to 3 and 9 weeks, by means of the Hammersmith functional motor scale. In children older than 5 years, muscle strength, assessed by myometry, and forced vital capacity were also measured. We found a significant increase in the scores of the Hammersmith functional scale between the baseline and both 3-weeks (P < 0.012) and 9-weeks assessments (P < 0.004). Our results indicate that PB might be beneficial to SMA patients without producing any major side effect. Larger prospective randomised, double-blind, placebo controlled trials are needed to confirm these preliminary findings.

Child↗

PubMed1994

Paternal isodisomy for chromosome 5 in a child with spinal muscular atrophy.

Paternal isodisomy for chromosome 5 was detected in a 2-year-old boy with type III spinal muscular atrophy (SMA), an autosomal recessive degenerative disorder of alpha motor neurons, known to map to 5q11.2-13.3. Examination of 17 short-sequence repeat polymorphisms spanning 5p15.1-15.3 to 5q33.3-qter produced no evidence of maternally inherited alleles. Cytogenetic analysis revealed a normal male karyotype, and FISH with probes closely flanking the SMA locus confirmed the presence of two copies of chromosome 5. No developmental abnormalities, other than those attributable to classical childhood-onset SMA, were present. While the absence of a maternally derived chromosome 5 could have produced the symptoms of SMA through the mechanisms of genomic imprinting, the lack of more global developmental abnormalities would be unusual. Paternal transmission of two copies of a defective gene at the SMA locus seems to be the most likely cause of disease, but proof of this will have to await the identification of the SMA gene. While uniparental isodisomy is a rare event, it must be considered as a possible mechanism involved in SMA when conducting prenatal testing and counseling for this disorder.

Alleles↗