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PubMed1991

Continuous muscle activity and distal spinal muscular atrophy.

A young man presented with myokymias, cramp-like difficulty in muscle relaxation and peroneal atrophy. EMG studies revealed continuous muscle activity (CMA) manifested as grouped potentials and high frequency discharges. Sensory nerve conduction studies and sural nerve biopsy gave normal results, and he was thought to suffer from distal spinal muscular atrophy with CMA. This association suggests that the lower motor neuron may have an important role in the generation of the continuous muscle activity.

Adult↗

PubMed2002

Evaluation of muscle strength in patients with spinal muscular atrophy.

The first aim of this study was to evaluate the muscular strength in order to document the strength scores for patients with spinal muscular atrophy (SMA). The second aim was to analyze the differences in average strength score among the musculatures at various body parts. Twenty-five patients with type II SMA (mean age of 13.7 +/- 7.0 years) and 15 patients with type III SMA (mean age of 13.7 +/- 8.2 years) were enrolled to undergo a muscle strength evaluation using the method of manual muscle testing. For each patient, the strength of 71 muscle groups were graded using a numerical ordinal scale to obtain individual muscle group scores, average scores of the arms, legs, the musculatures around the limbs' joints, the arm flexors and extensors, and leg flexors and extensors. The data were analyzed using a statistic model of multivariate analysis of variance and paired t-test. All data were administrated respectively for type II and type III SMA. The results showed that in both types of patients, the trunk muscles and the musculatures around the hips possessed lower strength scores, whereas elbow flexors, wrist flexors and extensors, finger flexors, and diaphragms exhibited relatively higher strength scores. In type II SMA the average scores of the musculatures of the left side arms was lower than those of the right side at the joints of scapulas, elbows and wrists. Our data also showed the arm flexor scores were higher than the arm extensor scores in both types, whereas significant higher score of the leg flexor in comparison to the leg extensor was only found in the patients with type II SMA. The profiles of muscle strength and strength differences over various body parts in the patients with type II SMA as well as the type III SMA were obtained from this study.

Adolescent↗

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↗

PubMed1992

[Clinical and histochemical findings in spinal muscular atrophy].

The childhood form of the spinal muscular atrophy (SMA) is classically subdivided into three groups on the basis of a combination of age of onset, milestones of development and age of survival: acute Werdning-Hoffmann (type I), intermediate Werdnig-Hoffmann (type II) and Kugelberg-Welander disease (type III). Now we examined 7 cases of type I and 9 cases of type II on clinical and histochemical ground. Of the total of 16 cases, 5 cases had a family history of the disease. (1) In type I, three were males and 4 females. The onset was within 30 days and the disease was manifest before or at delivery in 3 cases. The progression was so severe. All cases were dead by 10 months. They showed generalized hypotonia, abnormal respiration and could not sit without support. In type II, five were males and 4 females. The onset of the disease was between the age of 3 and 15 months. The progression was slow. All patients couldn't walk by themselves at all but 7 of them had abilities to sit without support. Clinically it was easy to classify type I from type II. (2) The most characteristic histochemical findings of both types were group atrophy, fiber hypertrophy, fiber type predominance and fibrosis. Though there was a slight difference between two types in histological pattern, the basis was so similar. There is controversy about the proper classification of recessive childhood SMA. Now it is suggested that the majority of both acute and chronic cases are allelic, similar to the patterns of Duchenne and Becker forms of muscular dystrophy.

Biopsy↗

PubMed1996

[Juvenile and adult forms of spinal muscular atrophies].

We propose a classification system for spinal muscular atrophies (SMA) based on the distribution of clinical signs, paresis and atrophy, as well as on the location of the responsible gene and the resulting enzyme deficiency, whenever these are known. This highly practical classification system encompasses three large SMA groups, as follows. A) Generalized forms, many of which are hereditary, are generally transmitted in a recessive autosomal manner. The course of disease is more severe when symptoms manifest early. Patients whose symptoms first occur after the first year of life often reach adolescence and even adulthood, confirming a highly apparent congruence of intermediate and pseudomyopathic juvenile forms. The same genetic defect, deletion in the 5q11-13.3 locus, that is responsible for acute infantile SMA has been demonstrated in both the aforementioned forms. B) Focal forms are restricted and often isolated cases; when they are hereditary, the genetic profile is highly heterogeneous. Though the disease will not necessarily evolve, it may progress to a generalized form. Focal forms may be symetric, assymetric, spinal-bulbar or multisegmental. The genetic abnormality has been identified for only some forms, such as chronic bulbar-spinal amyotrophy linked to the X-chromosome, at whose location, Xq11, the androgenic receptor is found. C) Amyotrophic lateral sclerosis (ALS) manifests clinically in a variety of ways and may be isolated, familial, juvenile or associated. Familial ALS is related to a gene defect in the 21q22.1 location that codifies for the superoxide dismutase enzyme. One juvenile form of ALS is related to a defect in the 2q33-35 chromosome. Any type of SMA can be related to degenerative neuronal disease of the central nervous system, especially juvenile ALS with generalized SMA, although such a link is at present merely an attractive hypothesis. Specific bibliographic references are given for each SMA form. Figures are provided to illustrate most of the SMA forms included in this classification system, the patients being at this time older adolescents and adults whose disease has been in evidence over many years.

Adolescent↗

PubMed1990

Hereditary canine spinal muscular atrophy: canine motor neuron disease.

Motor neuron diseases, manifest as weakness and atrophy of skeletal muscles, occur in infancy, childhood, and adult life. Some forms of this disease are inherited. Motor neurons are selectively affected and exhibit cytoskeletal pathology, primarily enlargements of proximal axons by accumulations of transported neurofilaments. A motor neuron disease, hereditary canine spinal muscular atrophy, has been discovered in Brittany spaniels. The disease is inherited as an autosomal dominant characteristic and shows striking clinical and pathological features in common with human motor neuron disease. The availability of this excellent animal model of the human condition has allowed neurobiological investigations of the dynamics of structural and chemical pathologies of vulnerable neurons.

Animals↗

PubMed1999

Different molecular basis for spinal muscular atrophy in South African black patients.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder occurring at a rate of between 1/5,000 and 1/10,000 births in most European countries. The phenotype results from the degeneration of the anterior horn cells of the spinal cord, resulting in symmetrical muscle weakness and wasting. The disorder can be classified according to the severity of the disease and the age of onset into three major types. Two candidate SMA genes, NAIP and SMN, isolated from the 5q13 region, have been reported to be homozygously deleted in approximately 30% and >95% of SMA patients, respectively. Black SMA patients have been reported to have facial muscle weakness more commonly. This study aimed to determine the molecular basis of SMA in South African black SMA patients. The SMN gene was found to be homozygously deleted in 65.5% (19/29) of patients, significantly less frequently than in previous studies. Similarly, the NAIP gene was homozygously deleted in a smaller number, 14% (4/29) of patients; 47% (9/19) of SMN deletion patients appeared to have deletions of telomeric exon 7, but not exon 8. In at least six of these patients a gene conversion event has occurred. No detectable deletions were found in 35% (10/29) of patients. Haplotype analysis in the nondeletion patients, using six closely linked markers, provided no evidence for a founder mutation. No mutations were found in exons 3 and intron 6 through exon 8 by sequence analysis of these nondeletion patients. It is proposed that the differences in the SMA phenotype observed in black patients may in part be explained by a different molecular basis.

Black People↗

PubMed2003

Downregulation of Bcl-2 proteins in type I spinal muscular atrophy motor neurons during fetal development.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by mutations in the survival motor neuron gene. The degeneration and loss of the anterior horn cells constitute the major neuropathological finding in SMA, although the mechanism and timing of this abnormal motor neuron death remain unknown. It has recently been reported that the fetal SMA spinal cord shows a significant increase in cells with DNA fragmentation, suggesting that the programmed cell death is aberrantly increased in type I SMA during development. We have analyzed 2 antiapoptotic proteins, Bcl-2 and Bcl-X, by Western blot and immunohistochemistry screening for differential expression in control and SMA fetal spinal cords. Expression of these proteins was found in various neuronal populations and structures of the developing spinal cord. At 15 weeks, motor neurons of SMA fetuses showed a marked decrease in the levels of Bcl-2 and a delay in the expression of Bcl-X in comparison with controls. The difference in the pattern and degree of expression is consistent with a role for both proteins in the aberrant programmed cell death observed in type I SMA.

Anterior Horn Cells↗

PubMed1989

Hereditary distal muscular atrophy with vocal cord paralysis and sensorineural hearing loss: a dominant form of spinal muscular atrophy?

In 1980 Young and Harper described a family with an unusual form of distal spinal muscular atrophy associated with vocal cord paralysis. We report a family with three similarly affected subjects. Progressive sensorineural hearing loss was an additional feature in our patients. Electrophysiological and histological investigations did not exclude an involvement of sensory neurones. Whether the classification of this dominant disorder with the spinal muscular atrophies is justified will depend on additional studies in further families.

Acoustic Impedance Tests↗

PubMed2005

Transmission ratio distortion in the spinal muscular atrophy locus: data from 314 prenatal tests.

BACKGROUND: Spinal muscular atrophy (SMA) is a recessive neurodegenerative disorder characterized by the loss of alpha-motor neurons in the spinal cord and subsequent death of motor neuron cells. SMA occurs with a frequency of 1 in 6,000 live births, with a carrier frequency of 1 in 40, and is a leading genetic cause of infant mortality. SMA is caused by loss or mutation of the telomeric survival motor neuron gene (SMN1), which is deleted in almost 94% of SMA patients OBJECTIVE: To analyze the transmission ratio at the SMA locus, examining the segregation of the SMN1-deleted alleles in 314 fetuses from carrier parents who requested prenatal testing for the disease. METHODS: Prenatal diagnosis of SMA in families at 25% risk of the disease has been performed on chorionic villous sampling specimens, through direct detection of the SMN1 gene mutation and linkage analysis using microsatellite markers from the 5q13 region. Analysis of the genotypic/allelic frequencies of the SMN1 gene was performed using the chi2 test, assuming a recessive mendelian inheritance. RESULTS: Of 314 fetuses analyzed, 95 were homozygous for the wild-type allele (30.3%), 154 were carriers (49.0%), and the remaining 65 were homozygous for the mutated allele (20.7%). Statistical analysis demonstrated that proportion of fetuses predicted with SMA is lower than 25% expected for a recessive disorder, resulting in a transmission rate of the SMN1-deleted allele deviant from the 50% expected in a random the segregation of a mendelian tract (p = 0.016) CONCLUSIONS: This is the first study to evaluate the genotypic frequencies at the spinal muscular atrophy (SMA) locus based on data derived from prenatal analysis, which are not subject to ascertainment bias. The analysis showed a transmission ratio distortion at the SMA locus in favor of the SMN1 wild-type alleles.

Chorionic Villi Sampling↗

PubMed1994

[Changes of some proteins expression of the spinal cord and muscles in infantile spinal muscular atrophy].

The various types of childhood spinal muscular atrophy (SMA) represent a spectrum of clinical disorders resulting from the degeneration of motor neurons (MN). The genetic defect has been recently localized to chromosome 5q in the region 11.2-13.3. Under normal conditions, half of the motor neurons die during embryonic development, while the remaining 50% survive to innervate muscle fibers and form neuromuscular junctions. Numerous studies using in vivo and in vitro models have shown that survival of MNs depends on the presence of trophic factors of neuronal and muscular origin. However, at the present time, no molecular mechanisms can be proposed to account for the nature and the sequence of the interactions leading to the formation and maintenance of a functional neuromuscular junction. To gain a better understanding of the SMA disorders, an alternative to genetic studies consists in analyzing the molecular mechanisms underlying this pathology. Variations in the expression of proteins, for instance, might reflect the pathological phenotype. We thought it possible to detect differences in the protein(s) which would correlate with the molecular deficit of childhood SMA. We, therefore, compared the patterns of human protein expression from normal controls and SMA spinal cord and muscle. Significant variations in the expression of some proteins, which have been quantified by a computerized Bio-Image electrophoresis system, have been found. In particular, two proteins, a and b (126 kDa and 112 kDa) which are very probably common to spinal cord and muscle show a marked increase of their expression in children with SMA.(ABSTRACT TRUNCATED AT 250 WORDS)

Child↗

PubMed1988

CT muscle scanning in the evaluation of patients with spinal muscular atrophy (SMA).

One hundred patients with spinal muscular atrophy (SMA) were assessed by CT scanning using a standardised technique. The spectrum of CT abnormality occurring in SMA was observed and by overall analysis the patients were divided into 4 groups. While the CT appearances of these groups correlated well with clinical assessment of severity of disease, the disease process was usually much more widespread than clinical examination suggested. CT abnormality was first observed in the leg and gluteal muscles, progressing to the posterior spinal, thigh, shoulder girdle and sternomastoid muscles. Hypertrophy of sartorius and gracilis was observed in a significant number of patients. Fascial planes were preserved in involved muscles in over half of the patients, even in late-stage disease. Asymmetrical muscle involvement was seen with increasing frequency as the disease process increased in extent as evaluated by CT scanning. There was no discernible difference in the CT appearances in those patients who clinically had limb-girdle, facioscapulohumeral or scapuloperoneal distribution of weakness.

Adolescent↗

PubMed1989

[Spinal muscular atrophy: disappearance of RNA fluorescence of degenerating motor neurons. An acridine orange study].

The histochemical distribution of nucleic acids has been studied in degenerating motor neurons of 9 children who died with spinal muscular atrophy, using the fluorochrome acridine orange. Ribonucleic acid (RNA) fluorescence disappeared abruptly from involved motor neurons without chromatolysis, attenuation of intensity, or other intermediate transitions that follow axotomy or hypoxic insults. We found a nearly identical pattern in 3 adults with amyotrophic lateral sclerosis. The findings in older subjects are complicated, however, by the presence of cytoplasmic lipofuscin. The autofluorescence of this pigment is inhibited by acridine orange. Our results support the hypothesis that spinal muscular atrophy is a disturbance of the genetically coded mechanism that arrests the programmed physiological death of surplus motor neuroblasts after a certain time in embryonic life, so that the normal lethal developmental process becomes pathological by persisting postnatally. A failure of RNA transcription seems to be primary and results in a failure of synthesis of neurotransmitters, of enzymes, and of cytoplasmic proteins. Consequent inanition leads to cell death.

Acridine Orange↗

PubMed1995

A recombination event occurring within two complex 5q13.1 microsatellite repeat polymorphisms suggests a telomeric mapping of spinal muscular atrophy.

The gene for the childhood spinal muscular atrophies (SMAs) has been mapped to 5q13.1. The interval containing the SMA gene has been defined by linkage analysis as 5qcen-D5S629-SMA-D5S557-5qter. We have identified a recombination event within this interval on a type-I SMA chromosome. The recombination maps to a region of multilocus microsatellite repeat (MSR) markers, and occurs between different subloci of two such markers, CMS-1 and 7613. While the possibility of a novel mutation caused by the recombination cannot be discounted, we believe when viewed in the context of a similar recombination in a Dutch SMA family, a centromeric boundary at the recombination site for the critical SMA interval is likely. This new proximal boundary would reduce the minimal region harboring the SMA locus from approximately 1.1 Mb to approximately 600 kb.

Alleles↗

PubMed2001

The predictive value of achieved motor milestones assessed in 441 patients with infantile spinal muscular atrophy types II and III.

Proximal spinal muscular atrophy (SMA) is classified into three main subtypes (I-III), defined by age at onset and achieved motor milestones. As age at onset can be very early in SMA II and III (IIIa, onset < 3 years) and does not necessarily correlate with prognosis, the question arises whether the child can be correctly assigned to a specific SMA type at the time of presentation based on the assessment of motor function. Therefore we studied the motor milestones in 175 SMA type II and 266 SMA type III patients. In SMA II, 73% of the patients sat within the normal age range (up to 9 months), the remainder learned to do so at ages between 10 and 30 months. In SMA III, the walking milestone was passed with delay (given an upper normal limit of 18 months) in 10% of all and 16% of SMA IIIa patients (median age 13 months, range 9-53 months). There was a correlation between late sitting and walking in SMA III, since those who sat after 9 months were responsible for the majority of delayed walkers. The median age when becoming chairbound did not differ between early-onset SMA III patients who walked with delay and those who walked within the normal age range (10.2 versus 10.5 years). In conclusion, a significant proportion of patients with early-onset SMA classified as SMA II on the basis of achieved motor function turned out to be SMA III at later follow-up. It is important to reassess a child in the first 2-4 years, to determine whether walking can be achieved with or without aids, as children who start to walk late have a similar favourable outcome for ambulation compared to earlier walkers.

Adolescent↗

PubMed2003

Riluzole attenuates spinal muscular atrophy disease progression in a mouse model.

Spinal muscular atrophy (SMA) is a motor neuron disease caused by mutations of the survival motor neuron 1 gene (SMN1). No curative treatment is available. Mutant mice carrying homozygous deletion of Smn exon 7 directed to neurons display a degenerative process of motor neurons similar to that found in human SMA. To test whether riluzole, which exhibits neurotrophic properties, might have a protective role in SMA, mutant mice were treated with it after the onset of the degenerative process. Riluzole improved median survival and exerted a protective effect against aberrant cytoskeletal organization of motor synaptic terminals but not against loss of proximal axons. These results demonstrate that the disease course of SMA can be attenuated after the onset of neuromuscular defects and may warrant further investigation in a therapeutic trial in SMA.

Animals↗

PubMed1989

Myosin heavy chain composition of muscle fibers in spinal muscular atrophy.

Muscle biopsies from 20 cases of spinal muscular atrophy (SMA), mostly diagnosed as Werdnig-Hoffmann (W-H) disease, were examined for myosin heavy chain (HC) composition. The fetal, fast, and slow heavy chains were characterized in the isolated muscle myosin, and in myosin of single, chemically skinned fibers, by electrophoresis in SDS-6% polyacrylamide gels and by immunoblot techniques, using specific antibodies directed to each main type of myosin HC. The fiber distribution of myosin HC isozymes was further investigated on muscle cryostat sections by an indirect immunofluorescent technique. Fetal myosin HC was found to be expressed in a subpopulation of severely atrophic fibers, alone or together with the slow form of myosin HC. Triangulated fibers of intermediate size contained fetal and fast myosin or fast myosin alone. The hypertrophic fibers were characterized by the predominant expression of slow myosin HC; but in some of these fibers, also low amounts of HC fetal were found to be expressed. These findings are discussed in relation to developmental transitions of myosin heavy chains in human muscle.

Child, Preschool↗

PubMed1998

Sequence of a 131-kb region of 5q13.1 containing the spinal muscular atrophy candidate genes SMN and NAIP.

The spinal muscular atrophies (SMA), which are characterized by motor neuron loss and progressive paralysis, are among the most common autosomal recessive disorders. The SMA region of chromosome 5q13.1 is distinguished by variable amplification of genomic sequence incorporating a number of genes and pseudogenes. Recently, two SMA candidate genes mapping to this area were identified: survival motor neuron (SMN) and neuronal apoptosis inhibitory protein (NAIP). The telomeric copy of SMN (SMNtel) is deleted in over 95% of cases of SMA, with NAIP deletions primarily seen in type I SMA. We present here 131 kb of genomic sequence from 5q13.1 incorporating both NAIP and SMNtel in addition to revisions of the original NAIP cDNA sequence. The Alu-rich NAIP-SMNtel interval contains the microsatellite polymorphisms that are deleted in as many as 80% of type I SMA chromosomes, focusing attention on this region in the pathogenesis of type I SMA.

Amino Acid Sequence↗