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PubMed2003

Spinal muscular atrophies reveal motor neuron vulnerability to defects in ribonucleoprotein handling.

PURPOSE OF REVIEW: Many forms of spinal muscular atrophy, a pure lower motor neuron disease, have been characterized clinically but the molecular basis of most of these is unknown. In this article we review recent developments in our understanding of the spinal muscular atrophies and how this knowledge has revealed important new insights into the causes of motor neuron vulnerability which may ultimately lead to novel therapies for this untreatable group of disorders. RECENT FINDINGS: The identification of the genetic basis of two forms of autosomal recessive spinal muscular atrophy has revealed that lower motor neurons appear to have a specific vulnerability to defects in RNA metabolism. Most notably, the survival motor neuron protein, deficient in the most common form of spinal muscular atrophy, plays a multifunctional role in ribonucleoprotein metabolism and pre-messenger RNA splicing. The role of this protein in motor neurons is currently under intense study. The identification of two other spinal muscular atrophy-causing genes has provided support for the central role of components of the RNA metabolic pathway in determining motor neuron survival. SUMMARY: Understanding the molecular basis of lower motor neuron vulnerability in disorders such as spinal muscular atrophy will ultimately allow these disabling disorders to be treated. In addition we can expect to learn much about basic neuronal biology and about the pathways that are relevant to more common neurodegenerative disorders such as amyotrophic lateral sclerosis.

Animals↗
PubMed2005

Physical complaints in ageing persons with spinal muscular atrophy.

OBJECTIVE: While life expectancy is improving for persons with spinal muscular atrophy, new physical complaints may arise. To investigate this, we studied persons with a long duration and severe course (high functional limitations) of the disease. DESIGN: Cross-sectional descriptive study. SUBJECTS/PATIENTS: Persons with spinal muscular atrophy. METHODS: Questionnaires and structured interviews on prevalence of physical complaints and their duration. Of 190 questionnaires 99 were returned; of 23 persons (with the longest disease duration and high functional limitation level) selected for structured medical interviews 9 participated. RESULTS: Patterns common within and different between the different types of spinal muscular atrophy were identified. Of the 10 most common complaints, types 1-2 had a significantly higher prevalence of kyphoscoliosis, difficulty in coughing, joint contractures and voice/speech problems, while type 3 had a significantly higher prevalence of fatigue. No statistically significant correlation was found between the appearance of physical complaints and disease duration. However, sleeping and swallowing problems were in the 5 most common complaints with the shortest mean time of appearance. The structured interview revealed hypermobility in the hand, suffusion of the eyes, and itching as new complaints with high prevalence. CONCLUSION: There are indications that the frequency of less well-known physical complaints increases with ageing.

Adult↗
PubMed2003

Evoked potentials in spinal muscular atrophy.

Visual evoked potentials, brainstem evoked responses, and somatosensory evoked potentials were evaluated in 22 children with spinal muscular atrophy, types I and II. Eleven of the children had the severe form of spinal muscular atrophy (type I) and 11 children had the intermediate form (type II). The results of visual evoked potentials, brainstem evoked responses, and somatosensory evoked potentials were compared with those obtained in a control group. Statistical analysis showed abnormalities in the different sensory modalities. A significant increase in the visual evoked potential latencies was observed and was found more often in patients with spinal muscular atrophy type I. Alterations of the somatosensory thalamocortical responses were also observed, as well as a delay in the central conduction time. Although spinal muscular atrophy is usually considered to be a purely motor disorder involving neurons of the spinal anterior horn and nuclei of the lower cranial nerves, lesions of the posterior roots, spinal ganglia, ascending tracts, lateral geniculated corpus, and thalamus have been reported. Our results suggest that sensory neuron degeneration occurs more commonly in spinal muscular atrophy than previously thought and that this process probably develops more slowly than motoneuron degeneration. Such degeneration may be associated with brain atrophy.

Adolescent↗
PubMed1973

Oculopharyngeal involvement in familial neurogenic muscular atrophy.

A Japanese family with progressive spinal muscular atrophy is presented. Seven members in two generations were affected and the mode of inheritance was probably an autosomal recessive trait. A characteristic feature of this family was the presence of oculopharyngeal involvement in some of the affected members, in addition to the variable distribution of muscular atrophy among each of the affected members, such as mainly proximal or distal atrophies in the limbs. In one case the oculopharyngeal weakness appeared without limb involvement. The changes in the extremities were thought to be of neurogenic origin, and so was the progressive external ophthalmoplegia seen characteristically in these cases, although the latter was similar to ocular myopathy.

Action Potentials↗
PubMed1984

Rehabilitative operation for motor neuron disease: tendon transfer for segmental muscular atrophy of the upper extremities.

Segmental spinal muscular atrophy of adolescence is a clinical syndrome that can be distinguished from the more common forms of motor neuron disease. A patient with this syndrome who was no longer able to care for herself is described. After selective tendon transfers in her right upper extremity, she has been able to perform many of the activities of daily living. This improved function has been maintained for more than 2 years. We suggest that transfer of tendons and muscles may be indicated in selected patients with slowly progressive muscular atrophy.

Activities of Daily Living↗
PubMed1986

[Deafness as a symptom of neural muscular atrophy (Charcot-Marie-Tooth disease)].

Peroneal muscular atrophy (Charcot-Marie-Tooth-disease) is a hereditary disease of the peripheral motor and sensory neurons. In most patients the distal extremities are affected but involvement of the cranial nerves has also been described. We describe a 58 year old patient suffering from this disease accompanied by bilateral hearing loss. Audiometric examinations over a period of 10 years showed no progression and indicate a neural hearing loss. This was finally verified by auditory potentials (EAEP); J V and J III were prolonged, indicating a neural origin of hearing loss. Thus the lesion must be localised to the cranial nerves or brainstem and represent a symptom of the peroneal muscular atrophy.

Audiometry, Pure-Tone↗
PubMedDate not supplied

[Spinal muscular atrophy associated with olivopontocerebellar hypoplasia. A case report].

INTRODUCTION: Spinal muscular atrophy is a frequent neurodegenerative disease in infancy. Nevertheless, its association with olivopontocerebellar hypoplasia is rare. CASE REPORT: We describe a case displaying clinical symptoms that included respiratory failure, dysmorphias, hypotonia, deep tendon areflexia and respiratory complications, like the cases described in the literature. In the genetic study it was not possible to find the motor neuron gene surviving from the infantile muscular atrophy. The neuropathological disorders found in the necropsy study were olivopontocerebellar hypoplasia with intense neuronal loss (fundamentally from Purkinje cells and from the granular layer of the cerebellum, olivary nuclei and pons), replacement gliosis and degeneration of the motor cells in the anterior horn of the spinal cord. Death occurred due to a respiratory complication in the 11th postnatal month. CONCLUSIONS: The paper describes the clinical-pathological study and the genetic study of a female patient who died at the age of 11 months after being diagnosed as presumably suffering from Werdnig-Hoffman disease. The autopsy revealed an olivopontocerebellar hypoplasia, which is a morphological trait that is not associated with the above-mentioned entity. The microscopic study revealed extensive areas of gliosis and neuronal loss. We conclude with the diagnosis of spinal muscular atrophy associated with olivopontocerebellar hypoplasia, which is a rare clinical entity with very few case reports and whose genetic defect is still unknown. We also review the extant literature related to this case.

Abnormalities, Multiple↗
PubMed1991

[Pathological anatomy of the heart in myopathies and infantile muscular atrophies].

In progressive muscular dystrophy, the heart is always affected and presents characteristic histological lesions: irregular, diffuse and intense rearrangements predominantly in the left ventricle, the septum and conductive tissue, consisting of wide, poorly vascularized fibrous bands, that are destructive but without an inflammatory aspect. The remaining myocardium is dystrophic with degeneration of the fibers (hyalin, atrophic or hypertrophic) with irregular nuclei. Plaques of adipose tissue are found under the epicardium within the heart wall. Sometimes, a fibrous thickening of the intracoronary arteries is observed without modification of the intima, but vascular lesions are not systematically seen. In congenital muscular dystrophy, cardiomyopathy certainly exists, but there is no histological description. Half of the patients suffering from myopathy with intracytoplasmic inclusions also have dystrophic and fibrotic cardiac involvement. Congenital myopathies may have their own specific cardiomyopathy, as in central core myopathy, nemaline (rod) myopathy and especially myotubular myopathy, where involvement is common. Werdnig-Hoffmann disease types I and II do not affect the heart. In contrast, several cases of fibrotic lesions have been described in KugelbergWelander disease.

Adolescent↗
PubMed2002

Spinal muscular atrophy among the Roma (Gypsies) in Bulgaria and Hungary.

Spinal muscular atrophy is one of the most common autosomal recessive disorders, classified into three major clinical forms. It is caused mainly by deletions or gene conversions of the telomeric survival motor neuron gene (SMN1) on human chromosome 5. We have conducted molecular studies of the disorder in genetically isolated Romani (Gypsy) communities in Bulgaria and Hungary, where spinal muscular atrophy appears to have different prevalence and both mild and severe spinal muscular atrophy phenotypes have been diagnosed. We have observed three distinct genetic defects which, in different combinations, lead to different forms of the disease. The similar chromosomal background on which the different mutations occur suggests a common origin and founder effect, with rearrangements of a single ancestral chromosome resulting in a diversity of molecular defects.

Bulgaria↗
PubMed1975

A clinical and genetic study of chronic proximal spinal muscular atrophy.

A study of chronic proximal spinal muscular atrophy was undertaken with the main aim of obtaining empirical recurrence risks for genetic counselling. Thirty-eight patients and their families were studied. Of these, 33 had similar clinical features and onset of disease in infancy or childhood. A division of these 33 patients by onset before or after 2 years (which was equivalent to whether or not they ever walked normally) gave recurrence risks for sibs which were higher with early onset. Among the sibs of patients with onset before 2 years, the incidence of disease was 1 in 5, due to most patients having an autosomal recessive disorder. A few patients, however, were thought to represent new dominant mutations. Among the families of index patients with onset after 2 years, the incidence of disease in sibs was only 1 in 15, but among their children it as 1 in 8. Both autosomal recessive and autosomal dominant forms therefore occurred in this age group, but it was concluded that nearly half the patients with onset after 2 had non-genetic motor neuron disease. The autosomal recessive form of chronic spinal muscular atrophy generally had onset before 2 years, but occasionally after 2. About a third of the patients never walked, and about half were in wheelchairs by age 10. No genetic heterogeneity within this form was demonstrated. Three remaining patients had distinctive clinical features associated with their proximal weakness, external ophthalmoplegia in one, dysarthria in another, and joint contractures in a third. Only 2 patients had onset in adult life, one of a probable recessive disorder and the other a probable dominant disorder.

Age Factors↗
PubMed1992

A novel primer extension method to detect the number of CAG repeats in the androgen receptor gene in families with X-linked spinal and bulbar muscular atrophy.

X-linked spinal and bulbar muscular atrophy (SBMA), an adult-onset form of motor neuron disease, was recently reported to be caused by amplification of the CAG repeats in the androgen receptor gene. We report here a simple and rapid strategy to detect the precise number of the CAGs. After the DNA fragment containing the CAG repeats is amplified by the polymerase chain reaction, a primer extension is carried out; the extension of the end-labelled reverse primer adjacent to 3' end of CAG repeats stops at the first T after CAG repeats with the incorporation of dideoxy ATP in the reaction mixture. The resultant primer products are analysed by denaturing polyacrylamide gel electrophoresis and autoradiography. This method could be quite useful to detect not only CAG repeats in SBMA but also other polymorphic dinucleotide and trinucleotide repeats.

Adult↗
PubMed1991

Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy.

X-linked spinal and bulbar muscular atrophy (Kennedy's disease) is an adult-onset form of motorneuron disease which may be associated with signs of androgen insensitivity. We have now investigated whether the androgen receptor gene on the proximal long arm of the X chromosome is a candidate gene for this disease. In patient samples we found androgen receptor gene mutations with increased size of a polymorphic tandem CAG repeat in the coding region. These amplified repeats were absolutely associated with the disease, being present in 35 unrelated patients and none of 75 controls. They segregated with the disease in 15 families, with no recombination in 61 meioses (the maximum log likelihood ratio (lod score) is 13.2 at a recombination rate of 0). The association is unlikely to be due to linkage disequilibrium, because 11 different disease alleles were observed. We conclude that enlargement of the CAG repeat in the androgen receptor gene is probably the cause of this disorder.

Base Sequence↗
PubMed2001

Molecular genetic study of a childhood form of spinal muscular atrophy.

Molecular genetic studies were performed in 28 cases of childhood-onset spinal muscular atrophy (24 unrelated families). This consisted of type 1 (severe) (n = 5), type 2 (intermediate form) (n = 8), and type 3 (mild) (n = 15). Deletion of exons 7 and 8 of the SMNt gene was found in 100%, 100%, and 93%, respectively, in type 1, 2, and 3 spinal muscular atrophy. Deletion of exons 5 and 6 of the NAIP gene was found in 3 of 5 (60%) of type 1 and none of the type 2 and 3 cases. None of the 32 asymptomatic relatives had homozygous deletions in the SMNt and NAIP genes. Thus, the role of the NAIP gene needs to be specifically defined in spinal muscular atrophy. In a suspected case of spinal muscular atrophy, deletion of the SMNt gene is a useful laboratory marker for confirmation of the diagnosis.

Adolescent↗
PubMed1997

Exclusion of the expansion of CAG/CTG repeats at thirteen loci on chromosome 12 as a candidate genetic mutation in scapuloperoneal spinal muscular atrophy with anticipation.

Scapuloperoneal spinal muscular atrophy (SPSMA) is a neuromuscular disorder characterized by weakness in the distribution of shoulder girdle and peroneal muscles. We have previously described a large New England kindred with autosomal dominant SPSMA and have subsequently linked this family trait to 12q24.1-q24.31. In this family, disease expression becomes more severe and progressive in successive generations, suggesting genetic anticipation. Accordingly, we have investigated the thirteen known CAG/CTG repeat loci on chromosome 12 that could be tested by using the polymerase chain reaction as candidate genetic mutations in SPSMA. None of these loci is expanded.

Age of Onset↗
PubMed1999

Spinal muscular atrophy. Incidence in Iceland.

Spinal muscular atrophy (SMA) is among the commonest degenerative disorders of the nervous system in childhood. This is an inherited autosomal recessive disease which results in premature death of anterior horn cells of the spinal cord and is manifested by progressive weakness and atrophy of skeletal muscles. Few studies have looked at the frequency of the disease in a defined population. We identified all patients diagnosed with SMA in Iceland during a 15-year period. The diagnosis is based on typical symptoms and supported by results of electromyography/nerve conduction studies and muscle biopsy. The average annual incidence was 13.7 per 100,000 live births for all types of SMA, which is similar to that reported in other population-based studies.

Adolescent↗
PubMed2002

SMN1 gene study in three families in which ALS and spinal muscular atrophy co-exist.

Spinal muscular atrophy (SMA) is caused by SMN1 gene deletions or mutations, and ALS is the most frequent motor neuron condition in adults. The authors describe three families in which ALS and SMA coexist. The authors found that no SOD1 mutation was found within these families; all three ALS cases had at least two SMN1 copies; and an abnormal SMN1 gene locus did not explain the co-occurrence of these two motor neuron disorders in these families.

Amyotrophic Lateral Sclerosis↗
PubMed1990

Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2-13.3.

SPINAL muscular atrophy (SMA) describes a group of heritable degenerative diseases that selectively affect the alpha-motor neuron. Childhood-onset SMAs rank second in frequency to cystic fibrosis among autosomal recessive disorders, and are the leading cause of heritable infant mortality. Predictions that genetic heterogeneity underlies the differences between types of SMA, together with the aggressive nature of the most-severe infantile form, make linkage analysis of SMA potentially complex. We have now analysed 13 clinically heterogeneous SMA families. We find that 'chronic' childhood-onset SMA (including intermediate SMA or SMA type II, and Kugelberg-Welander or SMA type III) is genetically homogeneous, mapping to chromosomal region 5q11.2-13.3.

Adolescent↗
PubMed1993

Two novel microsatellite markers for prenatal prediction of spinal muscular atrophy (SMA).

Autosomal recessive spinal muscular atrophy (SMA) has been mapped to a 6-cM interval on chromosome 5q12-13.3, flanked proximally by locus D5S6 and distally by locus D5S112. In this study we describe the isolation of two new microsatellite markers (EF1/2a and EF13/14) near locus D5S125, which lies 2 cM distal to D5S6. We show by linkage analysis and the study of the recombinants in 55 SMA pedigrees that the disease lies in the 4-cM interval between EF1/2a and D5S112. Fluorescence in situ analysis of cosmids from D5S6, EF1/2 and D5S112 confirms the genetic order and relative distance of markers. The microsatellites EF1/2a and EF13/14 are the first highly polymorphic PCR-based proximal markers in SMA to be described, and will be of value in prenatal prediction of the disorder.

Base Sequence↗