[Increased occurrence of "sporadic" spinal progressive muscular atrophy in infancy].
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Child↗
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Results for “Muscular Atrophy, Spinal”
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Cell types required to efficiently innervate human muscle cells in vitro.
Previous studies carried out in our laboratory have shown that myofibers formed by fusion of muscle satellite cells from donors with spinal muscular atrophy (SMA) type I or II undergo a characteristic degeneration 1.5-3 weeks after innervation with rat embryonic spinal cord explants. The only cells responsible for degeneration of innervated cocultures are SMA muscle satellite cells. In order to study the kinetics of nerve and muscle cell degeneration in nerve-muscle cocultures implicating SMA muscle cells, we attempted to simplify the nervous component of the coculture and identify the nerve cell types necessary for a successful innervation. We demonstrate here that motoneurons alone were unable to innervate myotubes. However, when three cell types (motoneurons, sensory neurons, and Schwann cells) were added onto a reconstituted muscular component consisting of cloned muscle satellite cells and cloned muscular fibroblasts, myotubes contracted, indicating that functional neuromuscular junctions were formed. We concluded that the three cell types were required for a successful innervation. Moreover, we studied the effects of culture medium conditioned by different combinations of nerve cells on innervation; we observed that physical contacts among sensory neurons, motoneurons, and myotubes are required for a successful innervation; in contrast Schwann cells can be replaced by a Schwann-cell-conditioned medium, indicating that these cells produce a putative soluble "innervation-promoting factor." Obviously such a reconstituted system does not reflect the in vivo situation but it allows the formation of functional motor synapses and could therefore allow us to elucidate neuromuscular disease pathogenesis, especially that of spinal muscular atrophy.
Adolescent↗
X-linked spinal and bulbar muscular atrophy of late onset (Kennedy-Stefanis disease?).
X-linked spinal and bulbar muscular atrophy of late onset is a rare variety of motor neuron disease. In this report a Greek family with 2 affected brothers is described. It is interesting that all Greek cases of this disease originate from a small group of Greek islands. Transient fatigue is an additional feature of the disease which is manifested sometimes before other symptoms are apparent. The progression of the disease appears to be faster than in spinal muscular atrophy of Wohlfart-Kugelberg-Welander. Regarding the name of this disorder, we propose the descriptive term, 'X-linked spinal and bulbar atrophy of late onset' or 'Kennedy-Stefanis disease.
Brain Diseases↗
Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world.
SBMA (spinal and bulbar muscular atrophy), also called Kennedy disease, is an X-chromosomal recessive adult-onset neurodegenerative disorder caused by death of the spinal and bulbar motor neurones and dorsal root ganglia. Patients may also show signs of partial androgen insensitivity. SBMA is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene on the X-chromosome. Our previous study suggested that all the Nordic patients with SBMA originated from an ancient Nordic founder mutation, but the new intragenic SNP marker ARd12 revealed that the Danish patients derive their disease chromosome from another ancestor. In search of relationships between patients from different countries, we haplotyped altogether 123 SBMA families from different parts of the world for two intragenic markers and 16 microsatellites spanning 25 cM around the AR gene. The fact that different SBMA founder haplotypes were found in patients from around the world implies that the CAG repeat expansion mutation has not been a unique event. No expansion-prone haplotype could be detected. Trinucleotide diseases often show correlation between the repeat length and the severity and earlier onset of the disease. The longer the repeat, the more severe the symptoms are and the onset of the disease is earlier. A negative correlation between the CAG repeat length and the age of onset was found in the 95 SBMA patients with defined ages at onset.
Exons↗
Genetics of pediatric neuromuscular disease.
Our understanding of the neuromuscular disorders of childhood has been rapidly expanding. This is mostly because of the discovery of the underlying genetic loci for the vast majority of these diseases and the abnormal proteins produced caused by these mutations. Spinal muscular atrophy is the second most frequent autosomal recessive disease of childhood and the most fatal. It has been mapped to chromosome 5q11.2-13.3, an area with three distinct genes associated with spinal muscular atrophy. Charcot-Marie-Tooth is the most common inherited peripheral neuropathy. Three genes encoding for myelin proteins and one for a nuclear protein have been associated with this group of disorders. Finally, since dystrophin was cloned in 1986, many proteins assisting dystrophin in anchoring the muscle cytoskeleton to the extracellular matrix have been discovered. Mutations in these genes lead to various forms of muscular dystrophy.
Child↗
Analysis of the CAG repeat region of the androgen receptor gene in a kindred with X-linked spinal and bulbar muscular atrophy.
Herein we describe a family with X-linked spinal and bulbar muscular atrophy (SBMA or Kennedy's disease), an adult onset neuromuscular disease characterized by slow progression, predominant proximal and bulbar muscle weakness. One frequent association is the appearance of gynecomastia. This disorder was previously shown to be linked to the locus DXYS1 on the proximal long arm of the X chromosome. Recently, a report implicated a mutation at the N-terminus of the androgen receptor gene involving amplification of CAG repeats as the cause of X-linked SBMA. We studied this region of the androgen receptor in a kindred clinically suspected but not confirmed of having X-linked SBMA by the polymerase chain reaction (PCR) followed by Southern analysis and DNA sequencing. The mutated allele was found to have an increased number of 51 CAG repeats confirming the clinical diagnosis of SBMA. Normal individuals revealed 23 repeat numbers within the normal range, while another unrelated X-linked SBMA patient had an enlarged CAG repeat region. The carrier or disease status could be established or confirmed in 12 individuals of this family on the basis of detecting normal and disease alleles reflected by the number of CAG repeats.
Adult↗
Inhibition of apoptosis by Z-VAD-fmk in SMN-depleted S2 cells.
Spinal muscular atrophy is an autosomal recessive motor neuron degenerative disorder, caused by the loss of telomeric copy of the survival motor neuron gene (SMN1). To better understand how motor neurons are targeted in Spinal muscular atrophy patients, it is important to study the role of SMN protein in cell death. In this report, we employed RNA interference (RNAi) to study the loss-of-function of SMN in Drosophila S2 cells. A 601-base pair double-stranded RNA (dsRNA) of Drosophila SMN (dSMN) was used for silencing the dSMN. Our data indicate that dSMN RNAi resulted in more than 90% reduction of both RNA and protein. Further analysis of S2 cells by cell death ELISA and flow cytometry assays revealed that reduction of dSMN expression significantly increased apoptosis. The cell death mediated by SMN depletion is caspase-dependent and specifically due to the activation of the endogenous caspases, DRONC and DRICE. Significantly, the effect of dSMN RNAi was reversed by a peptide caspase inhibitor, Z-VAD-fmk. These results suggest that dSMN is involved in signal pathways of apoptotic cell death in Drosophila. Hence, the model system of reduced SMN expression by RNAi in Drosophila could be exploited for identification of therapeutic targets.
Amino Acid Chloromethyl Ketones↗
Mitochondrial respiratory chain dysfunction in various neuromuscular diseases.
The mitochondrial respiratory chain function and the occurrence of mitochondrial respiratory chain dysfunction were determined in various neuromuscular diseases. The mitochondrial complexes I-V and citrate synthase in the skeletal muscle taken from 75 orthopaedic surgical patients excluding neuromuscular diseases (control subjects) and 26 patients with various neuromuscular diseases (7 patients with Duchenne muscular dystrophy, 3 patients with spinal muscular atrophy, 6 patients with mitochondrial diseases, 7 patients with type II fibre atrophy and 3 patients with neuropathy) were assayed. Of 26 patients, results of analysis of 3 patients (1 Duchenne muscular dystrophy, 1 spinal muscular atrophy and 1 type II fibre atrophy) were excluded because the citrate synthase activities in their muscle homogenate were less than third percentile of the normal controls. As compared to the control subjects by using Student's t-test, all studied groups of patients had significantly lower activities of more than one or two mitochondrial complexes (p<0.05). However, a significantly higher activity of mitochondrial complex I was observed in patients with mitochondrial diseases (p<0.05). These findings will require further study to elucidate the pathogenesis and role of secondary mitochondrial respiratory chain dysfunction in such neuromuscular diseases.
Adolescent↗
X-linked bulbospinal muscular atrophy (Kennedy's syndrome): a report of three cases.
Two cases of X-linked bulbo-spinal muscular atrophy and one sporadic case with the same clinical features are presented. All three cases were extensively studied by electrophysiological methods. One of the patients showed some transient weakness, which was partly improved by pyridostigmin. In this patient the Decrement test and jitter revealed a mild degree of motor-end plate dysfunction. Clinical and electrophysiological findings obtained from all three patients suggest that in Kennedy syndrome cell bodies of group IA muscle afferents are also affected selectively, with other peripheral afferents.
Electromyography↗
Cloning and characterization of the multiple murine homologues of NAIP (neuronal apoptosis inhibitory protein).
The spinal muscular atrophies (SMAs), characterized by degeneration of spinal cord motor neurons, are among the most common autosomal recessive disorders. We have previously reported the characterization of an SMA-associated gene designated NAIP (neuronal apoptosis inhibitory protein). This gene, which encodes a protein homologous to the baculoviral inhibitor of apoptosis proteins, is deleted in a significant proportion of individuals with type I SMA, is expressed in motor neurons, and inhibits apoptosis both in vitro and in vivo. Here we present the cloning and characterization of multiple copies of the mouse homologue of NAIP, Naip1-Naip6. Our analysis of the genomic organization of Naip indicated the existence of a minimum of six distinct Naip loci in the 129/SvJ mouse strain. However, Southern blot analysis revealed that only three of these loci contained the 5'UTR element essential for translation in the CNS. The coding region of one of these three potentially functional loci (Naip1) demonstrates 77% homology to NAIP at the nucleotide level and 68% identity at the amino acid level.
Animals↗
Changes in the distribution of fast and slow forms of troponin I in some neuromuscular disorders.
As judged from the atrophy of the muscle cells, the distribution of slow and fast troponin I in type I and type II cells in peripheral neuropathies in the adults (24-67 years of age) was unaffected for long periods after denervation. Reinnervation by fast or slow nerve in chronic neuropathies usually resulted in typical fibre type grouping with complete segregation of slow and fast troponin I in type I and type II cells, respectively. Intermediate fibres (slow and fast troponin I in the same cell) were present during the course of transformation. Unlike peripheral neuropathies, the number of cells staining for slow troponin I in the very atrophic fascicles in spinal muscular atrophy was considerably reduced. The synthesis of fast troponin I was stimulated in original type I cells containing slow troponin I. These observations support the experimental data (Dhoot and Perry 1982b) that the suppression of fast troponin I in type I or presumptive type I cells requires innervation by the slow nerve. Its absence results in an increased expression of fast troponin I in cells that originally contained only slow troponin I. Once suppressed, fast troponin I is absent in type I cells even after long periods of experimental denervation or cases of human peripheral neuropathies but not so in the cases of spinal muscular atrophy.
Adult↗
Double cortical stimulation in amyotrophic lateral sclerosis.
OBJECTIVE: Transcranial double magnetic stimulation on the motor cortex was used to investigate central motor tract function in 16 patients with amyotrophic lateral sclerosis, five with spinal muscular atrophy, and 16 age matched normal controls. METHODS: Surface EMG responses were recorded from the relaxed abductor pollicis brevis (APB) muscle. RESULTS: Responses to test stimuli were markedly attenuated by a subthreshold conditioning stimulus given at a condition-test (C-T) interval of 1-4 ms in normal controls and patients with spinal muscular atrophy, but attenuation was mild in patients with amyotrophic lateral sclerosis. In the normal controls this suppression was caused by activation of the intracortical inhibitory mechanism because responses to electrical test stimuli and the H wave were not suppressed by the same magnetic subthreshold conditioning stimulus. In amyotrophic lateral sclerosis the effect of the conditioning cortical stimulus on the H wave was also in the normal range. CONCLUSION: The intracortical inhibitory mechanism may be impaired in patients with amyotrophic lateral sclerosis.
Aged↗
[From gene to disease; 'survival' motor neuron protein and hereditary proximal spinal muscle atrophy].
The majority of patients with hereditary proximal spinal muscular atrophy (SMA) have a homozygous deletion of the survival motor neuron gene (SMN1). The number of SMN2 gene copies modifies the phenotype, which ranges from a lethal infantile disorder to an adult-onset disease causing mild impairment and disability. The SMN protein plays a role in an apparently essential cell metabolism process, the splicing of pre-mRNA in the spliceosomes. Why SMN1 deletions are only clinically expressed in motor neuron cells and not in other cell types is still unknown. DNA analysis, prenatal diagnosis and carrier testing as means of diagnosing SMA are all routinely available in the Netherlands and are currently performed at the DNA laboratory of the University of Groningen.
Adult↗
[Conduction velocity in peripheral nerves in healthy and sick children].
Conduction velocity was determined in motor fibres of peripheral nerves in healthy children aged from 4 months to 15 years and in children with spinal muscular atrophy, untreated phenylketonuria, myopathies and infantile cerebral palsy. Conduction velocity equalling that in adults is reached in the ulnar and peroneal nerves at the age of about 3 years, in the median nerve somewhat later (at the age of 4-5 years). In cases of untreated phenylketonuria, myopathies and infantile cerebral palsy conduction velocity was about normal. In spinal muscular atrophy decreased conduction velocity in the youngest children may indicate delayed myelination of peripheral nerves.
Adolescent↗
The Long Haul: Microtubule Motors as the Essential Supply Line for Neuronal Longevity.
The extreme morphology and polarised architecture of neurons require the highly sophisticated microtubule transport system for both construction and lifelong survival. Genomic evidence from an expanding landscape of human mutations supports the essential role of the microtubule transport machinery. During neurodevelopment, mutations disrupt the proliferation and migration of neuronal precursors, as well as the initial establishment of polarity. In the mature nervous system, the reliance on microtubule transport shifts to the long-term maintenance of axon integrity and synaptic proteostasis. Across the motor proteins responsible for long distance transport in neurons, mutations highlight a specific vulnerability of long axons to transport failure in Hereditary Spastic Paraplegia (HSP), Charcot Marie Tooth disease Type 2 (CMT2), Spinal Muscular Atrophy (SMA), Perry Syndrome, and Amyotrophic Lateral Sclerosis (ALS) amongst others. Due to the role of microtubule motors in development and maintenance, there is frequently a phenotypic spectrum within a single gene of the microtubule transport system. For example, mutations in dynein motors are linked both to malformations of cortical development and specific motor neuron loss in SMA-LED (Spinal Muscular Atrophy with Lower Extremity Predominance). By synthesising genetic evidence, this review illustrates how specific molecular failures, ranging from motor-domain kinetics to cargo binding, can inform our understanding of neuronal homeostasis. Ultimately, we argue that microtubule transport is not merely a cellular utility, but a key determinant of neuronal longevity.
Humans↗
Postoperative use of a cough-assist device in avoiding prolonged intubation.
Postoperative management following major surgery in patients with neuromuscular disorders associated with scoliosis is frequently complicated by sputum retention and ventilatory failure. This report demonstrates the successful perioperative management of an 11-yr-old boy with type II spinal muscular atrophy undergoing a single-stage posterior spinal fusion procedure. Use of an MI-E device was able to successfully treat sputum retention and avoid a tracheostomy.
Child↗
The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing.
The coactivator-associated arginine methyltransferase CARM1 is recruited by many different transcription factors as a positive regulator. To understand the mechanism by which CARM1 functions, we sought to isolate its substrates. We developed a small-pool screening approach for this purpose and identified CA150, SAP49, SmB, and U1C as splicing factors that are specifically methylated by CARM1. We further showed that CA150, a molecule that links transcription to splicing, interacts with the Tudor domain of the spinal muscular atrophy protein SMN in a CARM1-dependent fashion. Experiments with an exogenous splicing reporter and the endogenous CD44 gene revealed that CARM1 promotes exon skipping in an enzyme-dependent manner. The identification of splicing factors that are methylated by CARM1, and protein-protein interactions that are regulated by CARM1, strongly implicates this enzyme in the regulation of alternative splicing and points toward its involvement in spinal muscular atrophy pathogenesis.
Alternative Splicing↗
Blood loss in Duchenne muscular dystrophy: vascular smooth muscle dysfunction?
Patients with Duchenne muscular dystrophy (DMD) tend to bleed more during surgery than do patients with other conditions. A retrospective analysis of blood loss after spinal surgery for scoliosis was therefore undertaken in 102 patients undergoing surgery in the senior author's unit. These included 48 patients with DMD, 26 patients with spinal muscular atrophy, and a miscellaneous group of 28 other patients most of whom had idiopathic scoliosis. For each patient the age at surgery, estimated blood volume, duration of operation, Cobb angle, and number of vertebrae fused were recorded and compared. Expression of dystrophin in skeletal muscle and the underlying gene mutation were also determined. The estimated blood loss in patients with DMD was significantly higher than that in patients with spinal muscular atrophy undergoing the same or similar procedure (P < 0.005) and was also significantly greater than that of the third group, which consisted mostly of patients with idiopathic scoliosis (P < 0.0005). Blood loss in the patient group with DMD showed a significant relationship with duration of surgery (P < 0.05). As most patients expressed no dystrophin, this did not correlate with the estimated blood loss. There was also no correlation between the estimated blood loss and the type of gene mutation found causing DMD. The authors' previous observations confirm the increased blood loss in patients with DMD who undergo scoliosis surgery. Because children with DMD lack dystrophin in all muscle types, including smooth muscle, the excessive blood loss may be because of a poor vascular smooth muscle vaso-constrictive response due to a lack of dystrophin.
Adolescent↗