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Pulmonary function assessment in patients with spinal muscular atrophy type II and type III.

In this study, we used a spirometer to measure pulmonary function of 48 patients (4.3 to 34 years old), with type II and type III spinal muscular atrophy (SMA) and compared our findings according to the two SMA types, sex, functional grade, and degree of scoliosis. SMA patients were stratified into three groups based on severity and the age at which the symptoms began: type I, type II, and type III SMA patients were also classified into four functional grades depending upon whether they were able to 1) sit with support, 2) sit independently, 3) walk with assistance, or 4) walk independently. A restrictive pattern was found in all SMA patients who were found to have impaired lung function. The highest functional group had normal or nearly normal pulmonary functions. The lowest functional group, however, were found to have the worst pulmonary functions. Patients with type III SMA had better lung function than type II. We found a significant inverse relationship between pulmonary function and scoliosis, but no significant difference in pulmonary functioning with respect to gender. As the functional grade decreases, chest care needs to be intensified to prevent respiratory tract infections.

Adolescent↗
PubMed1977

Chronic spinal muscular atrophy simulating facioscapulohumeral type and limb-girdle type of muscular dystrophy. Report of two cases.

Two cases of chronic spinal muscular atrophy simulating the clinical picture of the facioscapulohumeral type and limb-girdle type of muscular dystrophy are reported. Both patients had a waddling gait, Gowers' maneuver in arising, terminal atrophies and pseudohypertrophies of some muscles, marked fasciculations, and fascicular tremor. The electromyogram revealed signs of anterior horn cell disease. Calf muscle biopsy (case 2) revealed 'myopathic' changes.

Chronic Disease↗
PubMed2002

Respiratory support in spinal muscular atrophy type I: a survey of physician practices and attitudes.

OBJECTIVE: To determine whether there is variability in the attitudes and practices of physicians regarding treatment of respiratory failure in children with spinal muscular atrophy type I (SMA type I) and, if so, whether this variation is associated with professional training. METHODS: This was a descriptive, cross-sectional survey mailed to a randomly selected subset of the Child Neurology Society, pediatric members of the Society of Critical Care Medicine and to the membership of the Pediatric Interest Section of the American Academy of Physical Medicine and Rehabilitation. A scenario of a child with SMA type I in respiratory distress was followed by questions that explored practices and attitudes regarding mechanical ventilation. RESULTS: Fifty-seven percent of intensivists (75 of 132), 39% physiatrists (61 of 155), and 34% of neurologists (61 of 155) responded. Specialists differed as to whether they offered and/or recommended respiratory support to patients with SMA type I. Intensivists were less likely to offer and recommend tracheostomy than physiatrists. Intensivists were also significantly less likely than physiatrists to agree with statements supporting the ethical necessity of noninvasive mechanical ventilation (NIMV) and intubation in the setting of an acute respiratory illness, and NIMV and tracheostomy in the setting of chronic respiratory failure. Although parallel differences were found between physiatrists and neurologists regarding their attitudes toward mechanical ventilation, no significant differences were detected between intensivists and neurologists. Finally, physicians who reported that a high percentage of their patients with SMA type I received "comfort care only" also tended to view mechanical ventilation, ie, use of NIMV for chronic respiratory failure, use of intubation for an acute respiratory infection, and use of tracheostomy for chronic respiratory failure as an unreasonable intervention in most circumstances. CONCLUSIONS: We found a wide variation in physician practice regarding the mechanical ventilation of patients with SMA type I. This study suggests a wide variation not only in what is recommended but also in what is actually offered to families of these children. Furthermore, the study suggests that physician training and attitudes affect recommendations regarding mechanical ventilation and ultimately family decision making.

Attitude of Health Personnel↗
PubMed1984

Cluster of acute infantile spinal muscular atrophy (Werdnig-Hoffmann disease) in a limited area of Reunion Island.

A retrospective study of Werdnig-Hoffmann disease (spinal muscular atrophy type I) was undertaken on Reunion Island. Nineteen WH cases born between 1969 and 1980 were recorded belonging to thirteen sibships of the European population of the island. Genealogical analysis, going back to the XVIIth century (1642), showed a relationship among the 13 families, which were derived from a common ancestral pair. A founder effect is the most probable explanation for the concentration of Werdnig-Hoffmann disease in the area.

Adolescent↗
PubMed1997

The survival motor neuron protein in spinal muscular atrophy.

The 38 kDa survival motor neuron (SMN) protein is encoded by two ubiquitously expressed genes: telomeric SMN (SMN(T)) and centromeric SMN (SMN(C)). Mutations in SMN(T), but not SMN(C), cause proximal spinal muscular atrophy (SMA), an autosomal recessive disorder that results in loss of motor neurons. SMN is found in the cytoplasm and nucleus. The nuclear form is located in structures termed gems. Using a panel of anti-SMN antibodies, we demonstrate that the SMN protein is expressed from both the SMN(T) and SMN(C) genes. Western blot analysis of fibroblasts from SMA patients with various clinical severities of SMA showed a moderate reduction in the amount of SMN protein, particularly in type I (most severe) patients. Immunocytochemical analysis of SMA patient fibroblasts indicates a significant reduction in the number of gems in type I SMA patients and a correlation of the number of gems with clinical severity. This correlation to phenotype using primary fibroblasts may serve as a useful diagnostic tool in an easily accessible tissue. SMN is expressed at high levels in brain, kidney and liver, moderate levels in skeletal and cardiac muscle, and low levels in fibroblasts and lymphocytes. In SMA patients, the SMN level was moderately reduced in muscle and lymphoblasts. In contrast, SMN was expressed at high levels in spinal cord from normals and non-SMA disease controls, but was reduced 100-fold in spinal cord from type I patients. The marked reduction of SMN in type I SMA spinal cords is consistent with the features of this motor neuron disease. We suggest that disruption of SMN(T) in type I patients results in loss of SMN from motor neurons, resulting in the degeneration of these neurons.

Animals↗
PubMed1978

Infantile spinal muscular atrophy. Unusual fiber typing and distribution in a muscle biopsy.

A right gastrocnemius muscle biopsy of a 13-month-old floppy male infant, which appeared at a more advanced age to suffer from an infantile spinal muscular atrophy, showed unusual histochemical changes: the chequer-board distribution was replaced by three groups of muscle fibers with a same mean narrow diameter of 12.5 micrometer. The smallest groups could easily be recognized as type I and type IIB fibers, while the largest group, involving more than 75% of the whole biopsy, revealed an intermediate hybrid fiber population, which would be classified as type I, if based on their phosphorylase and myofibrillar ATPase activities alone. The pathogenesis of this unusual finding is discussed.

Histocytochemistry↗
PubMed2001

Hybrids monosomal for human chromosome 5 reveal the presence of a spinal muscular atrophy (SMA) carrier with two SMN1 copies on one chromosome.

We have analyzed the survival motor neuron gene (SMN1) dosage in 100 parents of children with homozygous SMN1 deletions. Of these parents, 96 (96%) demonstrated the expected one-copy SMN1 carrier genotype. However, four parents (4%) were observed to have a normal two-copy SMN1 dosage. The presence of two intact SMN1 genes in the parent of an affected child indicates either the occurrence of a de novo mutation event or a situation in which one chromosome has two copies of SMN1, whereas the other is null. We have separated individual chromosomes from two of these parents with two-copy SMN1 dosage by somatic cell hybridization and have employed a modified quantitative dosage assay to provide direct evidence that one parent is a two-copy/ zero-copy SMN1 carrier, whereas the other parent had an affected child as the result of a de novo mutation. These findings are important for assessing the recurrence risk of parents of children with spinal muscular atrophy and for providing accurate family counseling.

Autoradiography↗
PubMed2005

Regular exercise prolongs survival in a type 2 spinal muscular atrophy model mouse.

Several studies indicate that physical exercise is likely to be neuroprotective, even in the case of neuromuscular disease. In the present work, we evaluated the efficiency of running-based training on type 2 spinal muscular atrophy (SMA)-like mice. The model used in this study is an SMN (survival motor neuron)-null mouse carrying one copy of a transgene of human SMN2. The running-induced benefits sustained the motor function and the life span of the type 2 SMA-like mice by 57.3%. We showed that the extent of neuronal death is reduced in the lumbar anterior horn of the spinal cord of running-trained mice in comparison with untrained animals. Notably, exercise enhanced motoneuron survival. We showed that the running-mediated neuroprotection is related to a change of the alternative splicing pattern of exon 7 in the SMN2 gene, leading to increased amounts of exon 7-containing transcripts in the spinal cord of trained mice. In addition, analysis at the level of two muscles from the calf, the slow-twitch soleus and the fast-twitch plantaris, showed an overall conserved muscle phenotype in running-trained animals. These data provide the first evidence for the beneficial effect of exercise in SMA and might lead to important therapeutic developments for human SMA patients.

Animals↗
PubMed1999

No evidence of association between apolipoprotein E genotype and phenotypic severity in childhood onset proximal spinal muscular atrophy.

The survival motor neuron (SMN) gene is present in two copies on chromosome 5q13 and the evidence is now compelling that mutations in the telomeric copy (SMNt) of the gene underlie childhood onset proximal spinal muscular atrophy (SMA). There is a correlation between the number of centromeric SMN gene copies (SMNc) and the clinical severity of the disease but this relationship is not absolute. Allelic variants of the apolipoprotein E (APOE) gene encoded on chromosome 19q are known to influence the prognosis and risk in a number of neurological disorders. We have therefore genotyped 166 unrelated cases of SMA to determine whether the presence of specific APOE genotypes correlates with severity of disease. The study failed to show the influence of any particular APOE genotype on disease severity, with specifically APOE epsilon4 being no more common in the milder SMA forms and APOE epsilon2 not over represented in type I SMA. A limited study of 23 SMA families also failed to show any influence of APOE genotype on SMA disease severity. Factors other than APOE genotype must therefore be responsible for determining SMA disease severity.

Apolipoprotein E2↗
PubMed2006

An infant with hypoplastic left heart syndrome and spinal muscular atrophy.

We report an infant with hypoplastic left heart syndrome consisting of mitral valvar atresia, aortic valvar atresia, hypoplasia of the aortic arch and coarctation of the aorta, who demonstrated respiratory failure and global hypotonia, and who was eventually diagnosed with spinal muscular atrophy.

Angiography↗
PubMed1979

Chronic form of childhood spinal muscular atrophy. Are the problems of its genetics really solved?

The authors discuss the differences between the two large series of chronic childhood spinal muscular atrophies (SMA)--their own comprising 273 cases, and that of Pearn et al. comprising 141 cases. The main difference concerns the predominance of males in the clinically milder later-onset group in the present series. The data of Pearn et al. (1978a, b) are quite different. The reason for the discrepancies is apparently a different selection of material. The present material is highly selective in favour of chronic cases, and Kugelberg-Welander cases are well-represented, whereas the percentage of Kugelberg-Welander cases in the material of Pearn et al. was very small. Differences in selection also appear to be responsible for discordance in observations regarding influence of sex on the course of the disease. The present data seem to support the view that most of the cases revealing chronic forms of SMA (both mild and severe) are not distinct genetically. However, the possible existence of a distinct subgroup in which sex influence is strongly expressed is not excluded.

Adolescent↗
PubMed1985

Chronic proximal spinal muscular atrophy of childhood and adolescence: problems of classification and genetic counselling.

Results obtained from a study of 354 cases of chronic proximal spinal muscular atrophy of childhood and adolescence suggest that the condition is not as homogeneous as it was previously thought. A tentative classification based on our results is proposed. Estimates of genetic risks are provided, taking into account the sex and age at clinical onset. In our opinion these factors are more reliable than the data hitherto available because they are based on a considerably larger series.

Adolescent↗
PubMed1980

Mitochondrial functions in chronic spinal muscular atrophy.

We determined the respiration rate, respiratory control and ADP/O ratios, with different substrates in mitochondria isolated from seven patients with chronic spinal muscular atrophy and compared them with normal human muscle. In all cases studied, a severe alteration of the respiratory control with variable derangement of oxidative phosphorylation was found. Similar findings have been described in other neuromuscular disorders including the so-called "mitochondrial myopathy". We believe that this disturbance of mitochondrial function is non specific and only the hypermetabolic syndrome of Luft could be considered biochemically as a "mitochondrial myopathy", a disorder selectively involving mitochondria of skeletal muscle.

Adolescent↗
PubMed1978

Distal chronic spinal muscular atrophy involving the hands.

Six patients are described with a history of slowly progressive wasting of the muscle of the hands and forearms extending over periods of up to 20 years. The clinical, radiological, and electrophysiological findings were consistent with a diagnosis of chronic anterior horn cell degeneration. It is suggested that the patients are affected by a form of distal chronic spinal muscular atrophy affecting the hands.

Action Potentials↗
PubMed1976

International collaborative study of the spinal muscular atrophies. Part 2. Analysis of genetic data.

Most of the cases in the present study are of the juvenile onset, proximal form of spinal muscular atrophy. The results of the study indicate that the majority of these cases are due to one or more autosomal recessive genes, with very few being inherited as a dominant trait. Affected individuals very widely in the severity of the disease. When 2 or more sibs are affected, they tend to be similar as regards severity, but there are a substantial number of sibships in which this is not so. The data are consistent with either a single gene, with a wide range of expressivity due to the effects of other genes and/or environmental influences, or 2 or more genes, but with considerable overlap in their expression.

Adolescent↗
PubMed1978

A clinical study of chronic childhood spinal muscular atrophy. A review of 141 cases.

The case histories and clinical details of 141 children (67 males and 74 females) with chronic childhood spinal muscular atrophy (SMA) have been reviewed. Hundred of these children were alive at the time of the study. The cases comprise a consecutive unselected series of all with this disease who presented to two large English neurological centres over a 10-year tracing period. Chronic childhood SMA is defined here as a progressive disease of anterior horn cells with initial proximal selectivity, which does not of itself cause death before 18 months of age. Clinical signs are first manifest between birth and 8 years of age, but in 95% before 3 years. Cumulative frequency tables for motor skills are presented; 46% of children never walked, even with orthopaedic aids; 37.6% were able to walk unaided at some stage. No child was able to run after 12 years of age. Late-presenting sporadic cases retain motor skills longer than do familial cases. A sex influence on the clinical course of the disease has been demonstrated, males being more severely affected. Cumulative frequency curves for age-at-onset and age-at-presentation have been compiled. A sib of an affected index case, still clinically normal at 2 years of age, has passed 90 percent of his risk period; the use of such cumulative frequency curves for studies of carrier-frequency and incidence is discussed. The median age at death for this disease exceeds 10 years. The range encompassed by the clinical spectrum is discussed.

Adolescent↗
PubMed2006

Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes.

Humans have two nearly identical copies of the survival motor neuron (SMN ) gene, SMN1 and SMN2. Homozygous loss of SMN1 causes spinal muscular atrophy (SMA). SMN2 is unable to prevent the disease due to skipping of exon 7. Using a systematic approach of in vivo selection, we have previously demonstrated that a weak 5' splice site (ss) serves as the major cause of skipping of SMN2 exon 7. Here we show the inhibitory impact of RNA structure on the weak 5' ss of exon 7. We call this structure terminal stem-loop 2 (TSL2). Confirming the inhibitory nature of TSL2, point mutations that destabilize TSL2 promote exon 7 inclusion in SMN2, whereas strengthening of TSL2 promotes exon 7 skipping even in SMN1. We also demonstrate that TSL2 negatively affects the recruitment of U1snRNP at the 5' ss of exon 7. Using enzymatic structure probing, we confirm that the sequence at the junction of exon 7/intron 7 folds into TSL2 and show that mutations in TSL2 cause predicted structural changes in this region. Our findings reveal for the first time the critical role of RNA structure in regulation of alternative splicing of human SMN.

Alternative Splicing↗