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PubMed1986

Evaluation of cell-mediated and humoral immunity in children suffering from spinal muscular atrophy.

A study of certain parameters of cellular and humoral immunity of 56 children with spinal muscular atrophy (SMA), treated in Children's Memorial Hospital, was undertaken to explain the observed frequent and serious respiratory tract infections. The main differences between a group of patients and the control group were found in the serum IgA and IgM concentrations, a number of peripheral B cells, and in the response to skin tests. Among all the methods applied, the skin tests seem to provide the best information concerning the child immunity system. The observed abnormalities were almost parallel to the severity of the SMA course.

B-Lymphocytes↗

PubMed2003

Neuropathological analysis in spinal muscular atrophy type II.

We performed a neuropathological analysis, including in situ nick end labeling (ISEL) and immunohistochemistry, of two cases of clinicogenetically confirmed infantile spinal muscular atrophy (SMA) type II. Both cases showed severe reduction of the motor neurons and gliosis in the spinal cord and brain stem, although the occurrences of central chromatolysis and ballooned neurons were not frequent. Clark's and lateral thalamic nuclei, which are usually altered in SMA type I, were spared, whereas Betz cells in the precentral gyrus and large myelinated fibers in the lateral funiculus were reduced in number. Regarding apoptosis, only the younger case demonstrated a few ISEL-positive nuclei in the dorsal horn, with reduced Bcl-x expression level in the Purkinje cells. Unlike SMA type I, the expression of neurofilaments was not disturbed and the reduction in synaptophysin expression level in the anterior horn was mild. An oxidative stress-related product was deposited in atrophic motor neurons in the spinal cord, and neurons with nuclei immunoreactive for 8-hydroxy-2'-deoxyguanosine were found in the lateral thalamus. In contrast, the expression of glial glutamate transporters was not altered. These data suggest that oxidative stress and, to a lesser extent, apoptotic cell death, but not disturbed neurofilament metabolism or excitotoxicity, may be involved in neurodegeneration in SMA type II.

Adult↗

PubMed1997

Expression of the SMN gene, the spinal muscular atrophy determining gene, in the mammalian central nervous system.

The survival motor neuron (SMN) gene is the putative disease gene for human spinal muscular atrophy (SMA), an autosomal recessive disorder characterized by progressive degeneration of lower motor neurons. Two copies of the gene, centromeric and telomeric, are present in the same 5q13 chromosomal region in humans. However, only the telomeric gene is affected in SMA. The SMN gene(s) encode(s) a novel protein of unknown function. To gain insights into the role of SMN in neurons, we have identified the SMN gene ortholog in the rat, and investigated SMN expression in the CNS of rat, monkey and humans by immunocytochemistry and in situ hybridization experiments. Antibodies against the SMN amino-terminus specifically recognized a single protein identical to the in vitro translation products of human and rat SMN cDNAs. The SMN gene transcript and product were widely but unevenly expressed throughout cerebral and spinal cord areas. The SMN protein was localized mainly in the cytoplasm of specific neuronal systems, and it was particularly expressed in lower motor neurons of newborn and adult animals. Likewise, a strong hybridization signal was detected in lamina IX of the spinal ventral horn. These results support the relevance of SMN for the motor neuron function and the pathogenetic role of the SMN gene in the neuronal degeneration associated with SMA.

Amino Acid Sequence↗

PubMed2026

Characteristics of early-onset, rapidly progressive scoliosis in spinal muscular atrophy type I treated with disease-modifying therapy -a multicenter retrospective study conducted in Japan.

In the era of disease-modifying therapy (DMT), almost all patients with spinal muscular atrophy (SMA) type I treated after onset, but before 6 months of age, develop early-onset, rapidly progressive scoliosis by 2 years of age, despite improvements in their motor function. Seven symptomatic patients with SMA type I who were treated before the age of 6 months were included in this retrospective observational study. Scoliosis had developed in all patients by 27 months of age. Among them, the patients who could stand with support or independently (standing patients; n = 3) tended to present with more progressive scoliosis than the sitters (n = 4). All standing patients demonstrated thoracic hyperkyphosis before or at the time of their scoliosis diagnosis. Despite receiving DMT, these patients continued to show residual key manifestations of SMA type I. Chronic difficulty maintaining posture due to trunk muscle weakness in the lying, sitting, or standing position was considered to be the main contributor to the development and progression of the scoliosis. The development and progression of such scoliosis, which begins in infancy, may be related to inappropriate postural management, which is not currently recognized as such by clinicians, caregivers, or guardians. In this population, it is important to closely monitor patients for such scoliosis from soon after the diagnosis of SMA. As this type of scoliosis progresses rapidly during the early developmental stage, when surgery is not possible, it is necessary to establish a proactive non-surgical management strategy for it.

Humans↗

PubMed2001

Depletion and sizes of motor units in spinal muscular atrophy.

Motor unit number estimation (MUNE) was applied to the biceps brachii muscles of 13 young patients (age 5--24 years) with spinal muscular atrophy (SMA) and the results compared with those of healthy control subjects matched for age and gender. In the SMA patients, all motor unit (MU) estimates fell below the control range, and there was good correspondence between the values for the two arms in the same subject. No correlation could be found between the MUNEs and the severity of the weakness. This unexpected result was attributed to the presence of small and normal-sized MUs in the muscles of patients, in addition to MUs that appeared to be considerably enlarged. The threefold mean increase in MU potential size was insufficient to compensate for the MU loss. In addition, the study confirmed that there are, on average, approximately 130 MUs in the healthy biceps brachii muscle.

Adolescent↗

PubMed1996

DNA fragmentation and BCL-2 expression in infantile spinal muscular atrophy.

Chromatin cleavage, a hallmark of apoptosis, was identified by in situ labeling in 55 +/- 7% of the muscle fibers in infantile spinal muscular atrophy (ISMA) and, to a lesser extent, in peripheral neuropathy indicating that DNA fragmentation is not specific to ISMA but a common feature in defect innervation. However, as DNA breaks are also known as a temporary process in differentiating myotubes DNA fragmentation may not always proceed to cell death. Therefore, it is currently not certain whether high rates of DNA fragmentation in ISMA are part of delayed muscle maturation due to neuronal defect or part of fibre breakdown. While atrophic muscle fibres in peripheral neuropathy displayed strong expression of bcl-2, a protein delaying onset of apoptosis, only 30% of the ISMA cases revealed weak bcl-2 expression assuming that immature muscle fibers are not able to produce a sufficient level of bcl-2.

Aged↗

PubMed2006

Enterostomy tube placement in children with spinal muscular atrophy type 1.

OBJECTIVE: To determine the major complication rate in the first 30 days after enterostomy tube insertion in infants with spinal muscular atrophy (SMA) type 1. STUDY DESIGN: A retrospective case review of all children with SMA type 1 who had a gastrostomy or gastrojejunostomy tube placed by the image-guided technique at the Hospital for Sick Children from 1994-2004. Major complications were classified as peritonitis, aspiration pneumonia, respiratory failure, nonelective admission to the pediatric intensive care unit, and death. RESULTS: Twelve children were identified as having SMA type 1 with an enterostomy tube insertion. The median age at tube insertion was 6.1 months (range 2.2 to 15.8 months). Major complications in the first 30 days after the procedure included aspiration pneumonia (5/12 patients [41.6%]), respiratory failure requiring admission to the pediatric intensive care unit (4/12 [33%]), and death (2/12 [16.7%]). Children with development of aspiration pneumonia were significantly older at time of tube insertion (P < .05) than those with no aspiration. CONCLUSIONS: Major complications including death are seen in children with SMA type 1 in the first 30 days after enterostomy tube insertion.

Enteral Nutrition↗

PubMed1981

Sensory ganglioneuropathy in infantile spinal muscular atrophy. Light and electronmicroscopic findings in two cases.

Light and electronmicroscopic findings in two cases. Neuropediatrics 12: 215-31 (1981). Two cases of infantile spinal muscular atrophy (Werdnig-Hoffmann disease) are described in unrelated children deceased at 11 months (acute clinical onset at 6 months) and 2 years (onset at birth). Severe respiratory difficulties, hypotonia, muscular weakness and depressed tendon reflexes were the main clinical features. Bulbar palsy, bilateral ptosis, pale optic discs and atactic movements of the hands were observed in the child deceased at 11 months. Besides severe loss of anterior horn cells and neurogenic muscle atrophy there was evidence of an extensive sensory involvement in both cases. Shrinkage, vacuolation as well as chromatolytic changes of dorsal root ganglion cells, together with the evidence of a primary axonal damage in sural nerve biopsies were interpreted in terms of ganglioneuropathy of the primary sensory neurons. An invasion of fibrous astrocytes into dorsal roots constituted another striking anomaly in one case as well as a pronounced degeneration of cranial nerves V and VIII in the other case, a finding not hitherto reported in Werdnig-Hoffmann disease.

Brain↗

PubMed2001

[Analysis of deletional damage in SMN1, SMN2, and NAIP genes in patients with spinal muscular atrophy in the northwestern region of Russia].

Polymerase chain reaction with subsequent SSCP (single-strand DNA conformational polymorphism) and restriction (BselI restriction endonuclease) analyses were used to type the DNA samples of affected individuals and their relatives from 23 Russian families with high risk of spinal muscular atrophy (SMA) residing in the northwestern region of Russia. Deletions of exon 7 of the SMN gene were found in 96% of the individuals examined. The frequency of homozygous deletion of exons 7 and 8 of the SMN1 gene was 65%. The frequency of homozygous isolated deletion of the SMN1 gene exon 7 among the SMA patients was 4.3%. Homozygous deletion of exon 5 of the NAIP gene was found in 22% of SMA patients. In SMA patients, a total of seven deletion types involving the SMN1, NAIP, and SMN2 genes were detected. Deletion of exons 7 and 8 of the SMN1 gene was the most common mutation associated with SMA in patients from the northwestern Russia.

Base Sequence↗

PubMedDate not supplied

A clinical study of childhood spinal muscular atrophy in Sicily: a review of 75 cases.

The aim of this study is to evaluate 75 patients affected by childhood-onset spinal muscular atrophy (SMA), using the diagnostic criteria and classification recently suggested by the International SMA Collaboration Consortium. Sex predominance, age of onset, clinical evaluation and other relevant clinical data of the disease are reported. These findings, as well as the role of the EMG and muscle biopsy as diagnostic tools, are discussed. The study suggests that the frequency of SMA in some areas of Sicily is high, possibly correlating with a relatively high gene frequency.

Age of Onset↗

PubMed2002

Specific interaction of Smn, the spinal muscular atrophy determining gene product, with hnRNP-R and gry-rbp/hnRNP-Q: a role for Smn in RNA processing in motor axons?

Spinal muscular atrophy (SMA), the most common hereditary motor neuron disease in children and young adults is caused by mutations in the telomeric survival motor neuron (SMN1) gene. The human genome, in contrast to mouse, contains a second SMN gene (SMN2) which codes for a gene product which is alternatively spliced at the C-terminus, but also gives rise to low levels of full-length SMN protein. The reason why reduced levels of the ubiquitously expressed SMN protein lead to specific motor neuron degeneration without affecting other cell types is still not understood. Using yeast two-hybrid techniques, we identified hnRNP-R and the highly related gry-rbp/hnRNP-Q as novel SMN interaction partners. These proteins have previously been identified in the context of RNA processing, in particular mRNA editing, transport and splicing. hnRNP-R and gry-rbp/hnRNP-Q interact with wild-type Smn but not with truncated or mutant Smn forms identified in SMA. Both proteins are widely expressed and developmentally regulated with expression peaking at E19 in mouse spinal cord. hnRNP-R binds RNA through its RNA recognition motif domains. Interestingly, hnRNP-R is predominantly located in axons of motor neurons and co-localizes with Smn in this cellular compartment. Thus, this finding could provide a key to understand a motor neuron-specific Smn function in SMA.

Amino Acid Sequence↗

PubMed2001

Muscle strength and motor function in children and adolescents with spinal muscular atrophy II and III.

The aim of this study was to quantify isometric muscle strength and motor function in children and adolescents with spinal muscular atrophy (SMA) and to analyse the impact of reduced muscle strength on motor function. Six children and adolescents with SMA II and eight with SMA IlI were assessed regarding isometric muscle strength and motor function. Isometric muscle strength was tested with a myometer and the values obtained were compared with normative data. Motor function was videotaped and 20 movements were scored according to a three-point scale. All of the assessed children and adolescents with SMA II and SMA III showed reduced muscle strength, but there were great differences within the group. The typical pattern of muscle weakness in SMA, with proximal weakness greater than distal and the lower limbs more affected than the upper, was also seen in these children. The muscle weakness affected motor function in all assessed children. Walking, transfer from lying or sitting to the standing position and stair-climbing were possible in some of the children, despite marked reduction of muscle strength. The study increases our knowledge concerning the degree of muscle weakness in children with SMA and the impact of muscle weakness on motor function. The results increase our possibilities of understanding the prerequisites for everyday life in these children and planning therapeutic interventions. Repeated assessments with the methods used in this study may be used to monitor the course of the disease and to evaluate the efficacy of treatment.

Activities of Daily Living↗

PubMed2006

[Self-produced locomotion and spatial cognition: a new light from spinal muscular atrophy].

Various studies have shown that occurrence of locomotion in infancy is correlated with the development of visuospatial cognitive competencies, suggesting that locomotor experience might play a central role in spatial development, especially in the realm of manual search for hidden objects. However, recent studies indicate that young children with spinal muscular atrophy (SMA), a hereditary neuromuscular disease which results in severe motor impairments, excel in some spatial cognitive skills. Indeed, striking cognitive performances are exhibited by young SMA children in some areas such as the ability to search successfully for hidden objects and the acquisition of the spatial vocabulary. The performances of SMA children suggest that, despite their total deprivation of locomotor experience, they have the capacity to acquire and use rich spatial representations. As a result, locomotor impairment does not appear to be a key risk factor for dramatic slowing down or deviation in the development of spatial search skills.

Child↗

PubMed2004

Coupled in vitro import of U snRNPs and SMN, the spinal muscular atrophy protein.

Cytoplasmic assembly of Sm-class small nuclear ribonucleoproteins (snRNPs) is a central process in eukaryotic gene expression. A large macromolecular complex containing the survival of motor neurons (SMN) protein is required for proper snRNP assembly in vivo. Defects in SMN function lead to a human neuromuscular disorder, spinal muscular atrophy (SMA). SMN protein localizes to both nuclear and cytoplasmic compartments, and a reduction in nuclear levels of SMN is correlated with the disease. The mechanism of SMN nuclear import, however, is unknown. Using digitonin-permeabilized cells, we show that SMN import depends on the presence of Sm snRNPs. Conversely, import of labeled U1 snRNPs was SMN complex dependent. Thus, import of SMN and U snRNPs are coupled in vitro. Furthermore, we identify nuclear import defects in SMA patient-derived SMN mutants, uncovering a potential mechanism for SMN dysfunction.

Carrier Proteins↗

PubMed1978

A genetic study of subacute and chronic spinal muscular atrophy in childhood. A nosological analysis of 124 index patients.

A genetic study of the subacute spinal muscular atrophies (SMA) of late infancy and early childhood has been undertaken. All such patients with chronic disease (with ages at onset up to 14 years, and excluding SMA Type I) known to 2 large Neurological Centres were reassessed clinically and genetically. There were 124 index patients (67 females and 57 males) and 17 secondary cases, which formed two consecutive unselected series. To investigate the genetic composition of this group, 4 nosological approaches were used; cluster analysis of clinical features of the disease, Haldane's sib-sib analysis on familial cases, interpretation of frequency distribution histograms, and a segregation analysis. A single autosomal recessive gene accounts for over 90% of cases, causes a clinical syndrome which manifests its first clinical signs before 5 years of age and in almost all cases before two years of age, but which is compatible with life into the third decade. Moderate intrafamilial discordance for some clinical features may be observed, but no genetic heterogeneity within this group was demonstrated. A small group of cases is caused by (a) new dominant mutation(s), or (b) is composed of phenocopies, or both. This relatively uncommon form may comprise the majority of late-presenting cases, and may account for all cases which manifest the first signs after 5 years of age. The spectrum of age-at-onset of this group cannot be determined at present, but the disease may be manifest before the age of two years; it is clinically indistinguishable from SMA caused by an autosomal recessive gene. The literature has been reviewed in the light of these findings. Empirical risks for use in genetic counselling are presented.

Child, Preschool↗

PubMed1976

Congenital total external ophthalmoplegia associated with infantile spinal muscular atrophy. Fine structure of extraocular muscle.

A case of total congenital external ophthalmoplegia associated with infantile spinal muscular atrophy is presented. In the first 29 months of life, ophthalmoplegia has remained complete. Ultrastructure of lateral rectus extraocular muscle indicates a neurogenic process as the basis of the ophthalmoplegia. Light microscopy alone is insufficient to distinguish primary "myopathic" from "neurogenic" disease in external eye muscles.

Child, Preschool↗

PubMed1994

Monoamine metabolites in the cerebrospinal fluid in infantile spinal muscular atrophy.

Analyses of tryptophan and tyrosine metabolites in cerebrospinal fluid were performed to examine an abnormality of the monoamine neurone system in severe infantile spinal muscular atrophy (SMA type I). The levels of 5-hydroxyindoleacetic acid and homovanillic acid were significantly lower than those in controls. Decreases in the concentration of 5-hydroxyindoleacetic acid and kynurenine seemed to be related to the severity of SMA type I. These results suggest that the monoamine neurone system may play a role in the pathophysiology of SMA type I.

Biogenic Monoamines↗

PubMed2001

Epidemiological survey of X-linked bulbar and spinal muscular atrophy, or Kennedy disease, in the province of Reggio Emilia, Italy.

Commencing with the work carried out during the epidemiological survey of amyotrophic lateral sclerosis in the period 1980-1992 and the pathology follow-up, we carried out a perspective incidence, prevalence and mortality survey of X-linked bulbar and spinal muscular atrophy (X-BSMA) in the province of Reggio Emilia in Northern Italy. Based on 11 patients (eight familial and three sporadic cases), the mean incidence per year for the period 1980 through 1997, as evaluated at the onset of symptoms, was 0.09 cases/100,000 for the total population and 0.19 cases/100,000 for the male population. On December 31, 1997, the prevalence rate was 1.6/100,000 for the total population and 3.3/100,000 for the male population. In the 18-year period of 1980-1997, the average yearly mortality rate was: 0.03 cases/100,000 per year for the total population and 0.06 cases/ 100,000 for the male population. The average age at onset was 44.8 +/- 10.1, and the average survival period was 27.3 +/- 2.3 years. The average age of the prevalence day was 58.9 +/- 14.9, and the average age at death was 71.3 +/- 4.7 years. Whereas the incidence rate of X-BSMA in the province of Reggio Emilia is 16 times lower that of amyotrophic lateral sclerosis (ALS), the incidence rate of progressive bulbar palsy in the male population is only slightly higher than X-BSMA; and the prevalence rate of ALS for males is two times the prevalence rate for X-BSMA, with overlapping of confidence intervals. X-BSMA is a rare disease, which is probably under-diagnosed, but due to the long survival period of this disease its frequency is not negligible. Because of the presence of sporadic cases or non-evident familial cases, it is appropriate to consider this diagnostic possibility in making a diagnosis of ALS in patients in whom lower motor neuron dysfunction or bulbar onset predominates.

Adult↗