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PubMed1984

Peroneal muscular atrophy with pyramidal features.

Twenty-five cases of peroneal muscular atrophy with pyramidal features from 15 families are described. This disorder has been referred to as hereditary motor and sensory neuropathy (HMSN) type V by Dyck. Onset was usually in the first two decades of life with difficulty in walking. The clinical syndrome superficially resembled that of HMSN types I and II with distal wasting and weakness involving the legs more than the arms. The tendon reflexes in the upper limbs and at the knee tended to be normal or increased but the ankle jerks were often absent. The plantar responses were extensor in 22 patients, absent in two and flexor in one. Increased tone and weakness in the proximal lower limb muscles were found in about 30% of cases. Mean motor nerve conduction velocity was lower than in normal controls and sensory nerve action potentials were reduced in amplitude or absent in two thirds of the patients studied. Inheritance was autosomal dominant in the majority of families. The disorder was slowly progressive but did not lead to severe disability.

Adolescent↗

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↗

PubMed1995

Exclusion of the gene locus for spinal muscular atrophy on chromosome 5q in a family with infantile olivopontocerebellar atrophy (OPCA) and anterior horn cell degeneration.

Two sisters with infantile OPCA plus spinal muscular atrophy (SMA) are reported. Both showed severe hypotonia and psychomotor delay from birth, and in addition, nystagmoid eye movements and vision impairment were evident. Cerebellar hypoplasia with cystic dilatation was seen by neuro-imaging methods. Pathoanatomically, a marked cerebellar hypoplasia and neuronal loss in the basal ganglia, brainstem and anterior horns were found in the deceased girl. Linkage studies with polymorphic markers of the region 5q11.2-q13.3 flanking the gene locus for infantile SMA showed identical parental haplotypes in the patients and their older healthy sister. It can be concluded that the gene locus for infantile SMA on chromosome 5q is not responsible for infantile OPCA plus anterior horn cell degeneration in the described family which might apply to this disorder in general.

Chromosome Mapping↗

PubMed2005

HyperIgEaemia in patients with juvenile muscular atrophy of the distal upper extremity (Hirayama disease).

BACKGROUND: Juvenile muscular atrophy of the distal upper extremity (Hirayama disease) is characterised by anterior horn cell loss in the lower cervical cord, presumably caused by anterior displacement of the dural sac during neck flexion. A recent report suggests that atopy and IgE may contribute to anterior horn damage. OBJECTIVE: To investigate whether IgE is a contributing factor in Hirayama disease. METHODS: Serum total IgE and allergen specific IgE were examined in 20 consecutive patients, and their correlations with clinical profiles investigated. RESULTS: Past or present history of allergy/atopy was found in only four patients (20%), but serum IgE was raised in 14 (70%). Patients with hyperIgEaemia had more severe clinical disabilities than those without (p = 0.01). In patients whose history of Hirayama disease was less than five years, serum total IgE was higher than in those with the disease for five years or more (p = 0.05). CONCLUSIONS: The results suggest that hyperIgEaemia is often associated with Hirayama disease and can facilitate its pathophysiology, particularly in the early phases of the disease. HyperIgEaemia does not appear to involve the anterior horn cells primarily.

Adolescent↗

PubMed2006

Mutant androgen receptor accumulation in spinal and bulbar muscular atrophy scrotal skin: a pathogenic marker.

OBJECTIVE: Spinal and bulbar muscular atrophy (SBMA) is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The nuclear accumulation of mutant AR is central to the pathogenesis of SBMA. Androgen deprivation with leuprorelin inhibits mutant AR accumulation, resulting in rescue of neuronal dysfunction in a mouse model of SBMA. This study aimed to investigate whether mutant AR accumulation in the scrotal skin is an appropriate biomarker of SBMA. METHODS: Immunohistochemistry of both scrotal skin and the spinal cord was performed on five autopsied SBMA cases. Neurological severity and scrotal skin findings were studied in another 13 patients. Five other patients received subcutaneous injections of leuprorelin and underwent scrotal skin biopsy. RESULTS: The degree of mutant AR accumulation in scrotal skin epithelial cells tended to be correlated with that in the spinal motor neurons in autopsy specimens, and it was well correlated with CAG repeat length and inversely correlated with the amyotrophic lateral sclerosis functional scale. Leuprorelin treatment inhibited mutant AR protein accumulation in the scrotal skin of SBMA patients. INTERPRETATION: These observations suggest that scrotal skin biopsy findings are a potent pathogenic marker of SBMA and can be a surrogate end point in therapeutic trials.

Adult↗

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↗

PubMed2006

Upper motor neuron involvement in X-linked recessive bulbospinal muscular atrophy.

OBJECTIVE: Clinicopathological findings of X-linked recessive bulbospinal muscular atrophy (SBMA) are indicative of lower motor neuron and primary sensory neuron involvement. The aim of our study was to investigate the presence of subclinical upper motor neuron (UMN) dysfunction in this disease. METHODS: Two siblings with clinical presentation, routine electrophysiological tests, histopathological features of muscle and nerve biopsies and genetic testing consistent with diagnosis of SBMA underwent transcranial magnetic stimulation (TMS). The analysed parameters were motor evoked potential (MEP) threshold, silent period (SP) and central motor conduction time. Intracortical inhibition with paired pulses from 1 to 6ms interstimulus intervals (ISIs) was evaluated in the older brother. RESULTS: MEP parameters were significantly altered in limb and cranial muscles and MEP suppression after paired stimulation significantly reduced in the older brother. MEP abnormalities were present in one lower limb, but SP abolished in all limbs, in the younger brother. CONCLUSIONS: Subclinical involvement of UMNs may be present in patients affected by SBMA. This finding suggests that the array of neuronal systems whose function may be affected by the pathogenic process of SBMA is larger than it was considered so far. SIGNIFICANCE: TMS is a sensitive diagnostic tool for the identification of UMN dysfunction and should be included in the diagnostic evaluation of patients with SBMA.

Aged↗

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↗

PubMed2026

Molecular diagnosis of spinal muscular atrophy: Experience in a pediatric hospital in Argentina.

Introduction. Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by the loss of the SMN1 gene, with a variable clinical spectrum determined primarily by the number of copies of the SMN2 gene. The development of new therapies underscores the importance of early molecular diagnosis and genotype-phenotype characterization. Objective. To describe 27 years of experience in the molecular diagnosis of SMA at a pediatric referral hospital in Argentina and to evaluate the correlation between SMN2 copy number and the SMA types.Population and methods. A retrospective descriptive study was conducted on 1060 pediatric patients with clinically suspected SMA who were evaluated between 1997 and 2024. Molecular diagnosis was performed using PCR-RFLP and, since 2012, MLPA to determine SMN1 and SMN2 copy number. Genotype-phenotype correlation was evaluated in 260 patients with complete clinical characterization. Results. The diagnosis was confirmed in 513 patients. A homozygous deletion of the SMN1 gene was detected in 99.6% of unrelated cases. The positivity rate increased over time. A significant correlation was observed between the number of SMN2 copies and the type of SMA, with milder phenotypes associated with a higher number of copies. Conclusion. Molecular diagnosis of SMA enabled accurate and timely characterization of patients, avoiding invasive procedures and optimizing therapeutic decision-making. Genotype-phenotype correlation is a fundamental tool for prognosis and clinical management, highlighting the importance of an interdisciplinary approach.

Argentina↗

PubMed1994

Two 5q13 simple tandem repeat loci are in linkage disequilibrium with type 1 spinal muscular atrophy.

The gene for the common recessive neuromuscular disorder spinal muscular atrophy (SMA) has been previously mapped to chromosome 5q. We report here linkage disequilibrium analyses of two polymorphic simple tandem repeat (STR) sequences which map into the critical region of 5q13 containing the SMA gene. The polymorphisms presented are constituents of CATT-1, a complex STR which is present in as many as four or more copies per chromosome 5. The PCR can amplify as many as eight CATT-1 products of different sizes from genomic DNA samples due to differing numbers of CA dinucleotides at each STR location (sublocus). Oligonucleotide primers for two of these subloci have been developed for specific PCR assays; a variety of allele sizes can be generated with each assay and, in some cases, no amplification products are detected due to null alleles. The genotyping of 149 SMA Type 1 chromosomes and 142 normal chromosomes from Canadian and American kindreds reveals the presence of significant linkage disequilibrium between the null allele of the sublocus referred to as CATT-40G1 and mutation(s) causing SMA Type 1 (Werdnig-Hoffmann disease). Allele 2 of the second sublocus, CATT-192F7, is also in linkage disequilibrium with SMA Type 1 although the degree of this association is less than that found for CATT-40G1. The proximal and distal STRs from the critical region, D5S435 and D5S351, showed no linkage disequilibrium with SMA. The data presented here will serve as a framework for future linkage disequilibrium analyses, expediting the final stage of the search for the SMA gene.

Alleles↗

PubMedDate not supplied

[Prenatal diagnosis of spinal muscular atrophy (SMA) -- indications, restrictions, interpretation of results].

INTRODUCTION: Proximal spinal muscular atrophy of childhood and adolescence (SMA) is a genetic autosomal recessive disease. Caused in 96.5% by deletion in the SMN1 gene. Owing to the homogeneity of the molecular defect. Secondary prophylaxis can readily be offered to families at risk of SMA. PATIENTS: Prenatal diagnosis of SMA was carried out in a group of 50 families. Which were divided into two subgroups: with high and relatively low genetic risk of SMA. In all, 55 prenatal tests were performed in the period 1998-2003. RESULTS: In the first group including 45 families at high genetic risk, 9 of the 50 tests were positive (18%). The diagnosis of SMA was tentative in 7 cases from this group and it was based only on the clinical picture (the affected children are not alive, therefore DNA samples are not available). Prenatal examination in 1 of these 7 families showed the SMA genotype. In the second subgroup including 5 families with relatively low genetic risk of SMA in none of the studies was there a biallelic deletion of exon 7 in the SMNI gene. Mainly parents of children with a severe form of SMA and having no healthy offspring asked for prenatal examination (73% of the families). CONCLUSIONS: Prenatal diagnosis could be offered to families even if the diagnosis of SMA was not genetically verified. The negative result should he then interpreted individually. Until the carrier test will not he introduced to routine procedures. prenatal diagnosis can be also offered to families at relatively low risk of SMA.

Adult↗

PubMed2003

Deletion of the SMN1 and NAIP genes in Vietnamese patients with spinal muscular atrophy.

The SMN1 and NAIP genes are related to the development of spinal muscular atrophy (SMA), which is characterized by degeneration of motor neurons leading to progressive muscular weakness and atrophy. The SMN1 gene is homozygously deleted in most SMA patients, and now recognized as a responsible gene for SMA. The NAIP gene is often deleted in the SMA patients with the severest form of SMA, and now considered to be a modifying factor of the severity of SMA. Our previous study of five Vietnamese SMA patients showed that the SMN1 gene deletion was detected in one patient, although the NAIP gene deletion was not detected in any patients. In this study, we analyzed 12 Vietnamese SMA patients who were not enrolled in the previous study. The SMN1 gene was homozygously deleted in six out of 12 patients, and the NAIP gene deletion was detected in five patients. Taken together with our previous data, the SMN1 gene deletion was detected in seven out of 17 Vietnamese SMA patients and the NAIP gene deletion in five out of 17 Vietnamese SMA patients. These studies suggest that the SMN1 and NAIP gene deletions are not rare in Vietnamese SMA patients. Thus, the confirmation of SMA-related gene deletion will also be a useful tool for the diagnosis of SMA in Vietnam.

Asian People↗

PubMedDate not supplied

[Family with progressive myelopathic muscular atrophy with proximal distribution and onset in adulthood].

The Authors present two brothers suffering from proximal progressive muscular atrophy arising in adulthood and describe its clinical, bioptic and electromyographic characteristics. Electromyographic and bioptic examinations demonstrate the neurogenic nature of the amyotrophy and localize the causal lesion at the level of the anterior horns of the spinal medulla. With regard to the differential diagnosis, the nosographic position of the disorder in question is described, and the hypothesis advanced that it may represents the late onset variety of Wohlfart-Kugelberg-Welander disease.

Amyotrophic Lateral Sclerosis↗

PubMed1995

Scoliosis and lung function in spinal muscular atrophy.

The notes and radiographs of 43 patients with a confirmed diagnosis of spinal muscular atrophy were reviewed. A significant inverse linear relationship between the severity of scoliosis and the percentage of predicted vital capacity and peak flow was found. The patients who stood had a significantly better lung function than patients who were confined to a wheelchair, and their scoliosis deteriorated significantly more slowly. Sixteen patients underwent surgical spinal stabilisation, 4 with Harrington instrumentation and 12 with segmental spinal instrumentation, at an average age of 12 years and 11 months. The average curve correction achieved was 40%. The decline in lung function seen pre-operatively was not only reversed, but a significant improvement was found at final follow-up.

Adolescent↗

PubMed2000

Maximal and minimal motor conduction velocity in amyotrophic lateral sclerosis and X-linked bulbospinal muscular atrophy measured by Harayama's collision method.

Measurement of the maximal (Vmax) and minimal (Vmin) motor nerve conduction velocities was performed in amyotrophic lateral sclerosis (ALS), bulbospinal muscular atrophy (BSMA), and control subjects. The collision method as described initially by Harayama and coworkers was used. This allowed for the correction of the velocity recovery effect (VRE) in Hopf's original method. The purpose of this study is to clarify the controversial results regarding the Vmin and the difference between Vmax and Vmin (Vmax-Vmin) in ALS and to compare these results with BSMA, and clarify the usefulness of Harayama's method. In ALS, a reduction of Vmax and Vmin, and an increase of Vmax-Vmin were found in both median and posterior tibial nerve. In BSMA, a reduction of Vmin and an increase of Vmax-Vmin in the median nerve were noted. Some patients whose results of conventional nerve conduction study were entirely within normal range showed abnormal results in Vmin and/or Vmax-Vmin. These results suggest that the correction of VRE is essential to determine a Vmin, and motor fibers with abnormally slow conduction velocities were present in ALS and BSMA. Harayama's collision method is useful to detect abnormalities of motor fibers with submaximal conduction velocities.

Adult↗

PubMed2002

Effect of treatment with nifedipine, an L-type calcium channel blocker, on muscular atrophy induced by hindlimb immobilization.

The purpose of this study was to investigate whether the prevention of calcium influx through L-type calcium channels contributed to the attenuation of muscular atrophy induced by hindlimb immobilization (HI) in a shortened position. Mice were divided into four groups (8 mice/group): control; nifedipine; HI; and HI with nifedipine. Mice received nifedipine at a dose of 5 mg/kg one day before and during the 8 days of HI. Quantitative alterations in the amount of myosin heavy chain (MyHC) and actin proteins in the soleus muscle were analyzed using SDS-PAGE. The weight of the soleus muscle decreased significantly by 40.8% (P<0.05) and 27.0% (P<0.05) after the hindlimb immobilization in the HI and HI with nifedipine groups, respectively, when compared to that of the control or nifedipine groups. Treatment with nifedipine alone appeared to have no effect on muscle mass or the amount of myofibrillar proteins. The level of MyHC proteins decreased significantly by 25.1% (P<0.001) and 17.4% (P<0.001) in the HI and HI with nifedipine groups, respectively. The level of MyHC protein in the HI with nifedipine group was significantly greater than that of the HI group (P<0.05), although there were no significant differences in the amount of actin protein. These findings suggest that nifedipine treatment may have a beneficial effect on muscular atrophy.

Actins↗

PubMedDate not supplied

Correlation of flexion contractures with upper extremity function and pain for spinal muscular atrophy and congenital myopathy patients.

To ascertain the patients' perception of the consequences of elbow flexion contractures and better understand the circumstances at their inception, we surveyed 405 spinal muscular atrophy and congenital myopathy patients. Diagrams of various elbow angles and questions concerning the effect of elbow contractures on daily activities were part of the survey. Of 108 completed responses, effectively a 24% response rate, 49 reported elbow flexion contractures. Thirteen of the 49 patients reported first noting them during extended periods of inactivity. Elbow flexion contractures greater than 25 degrees were intractable and were reported to hamper 17% (77 of 410) of specifically considered daily activities for the 49 subjects. Twenty-nine of the 49 (59%) subjects with contractures complained of contracture-associated hindrance of at least one daily function. Perceived contracture-associated difficulties increased significantly as a function of contracture severity. Elbow contractures were perceived to be useful by 12% of the respondents. The correlation between contracture severity and upper limb discomfort was also striking. We conclude that elbow flexion contractures are common and perceived to be associated with disability and discomfort for about one-half of spinal muscular atrophy and congenital myopathy patients.

Activities of Daily Living↗

PubMedDate not supplied

Spinal motoneuron function in lower motor neuron disease: normal corticomotoneuronal and peripheral Ia EPSPs in patients with spinal muscular atrophy.

Responses of single tibialis anterior motor units to transcranial magnetic stimulation and to a synchronized Ia volley evoked by peripheral electrical nerve stimulation were obtained in patients with distal spinal muscular atrophy and compared to normal controls. Estimations of excitatory postsynaptic potential (EPSPs) by cross-correlations revealed no difference in rise time of EPSPs for both groups of subjects despite considerable changes in macro-EMG parameters of the motor units studied in patients with spinal muscular atrophy (SMA). The results indicate that voluntarily activated spinal motoneurons in SMA are capable of normal excitatory responses to transcranial magnetic as well as peripheral Ia stimulation.

Action Potentials↗