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PubMed1998

Axonal neuropathy and predominance of type II myofibers in infantile spinal muscular atrophy.

Two affected siblings with infantile spinal muscular atrophy (SMA I) presented with generalized muscular hypotonia, which progressed to early death. Quadriceps muscle biopsy did not show the typical neurogenic pattern of spinal muscular atrophy. The histochemical fiber type determination revealed a predominance of type II fibers without type I hypertrophy, an unprecedented finding in spinal muscular atrophy. Sural nerve biopsy exhibited findings typical for axonal neuropathy. In one patient, electrical stimulation of peripheral nerves showed an inexcitability of motor and sensory nerves. Genetic studies revealed homozygous deletions of the telomeric survival motor neuron (SMN) gene and the neuronal apoptosis inhibitory protein (NAIP) gene in the affected children. This is the second case report of molecular genetically proven spinal muscular atrophy associated with axonal neuropathy. We conclude atypical findings on muscle biopsy and evidence of axonal neuropathy are compatible with the diagnosis of infantile spinal muscular atrophy.

Adult↗
PubMed2003

Molecular and cellular basis of spinal muscular atrophy.

Autosomal recessive spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle atrophy combined with motor neuron degeneration. SMA is caused by homozygous mutation or loss of the telomeric copy of the survival of motor neuron gene (SMN). The SMN gene is localized as an inverted repeat on chromosome 5q13. Both gene copies (SMN1 and SMN2) are expressed, but they differ in the expression of full-length protein. SMN2 gene preferentially gives rise to a truncated and less stable version of the SMN protein and thus can not compensate for SMN1 loss or mutations unless it is not present in multiple copies. The SMN protein is part of multiprotein complexes in the cytoplasm and the nucleus of all cell types. These complexes are involved in assembly of spliceosomal snRNPs. SMN interacts with RNA polymerase II and other binding proteins, indicating that the SMN protein is involved in messenger and ribosomal RNA transcription and processing. The analysis of animal models for SMA could help to identify the pathophysiological changes that are responsible for spinal muscular atrophy.

Animals↗
PubMed1995

Neurogenic FSH muscular atrophy.

Neurogenic facioscapulohumeral (FSH) muscular atrophy is a distinct entity from FSH muscular dystrophy. Is the gene(s) responsible for the disease identical with or different from that for FSH dystrophy?

Adult↗
PubMed1982

Pathology of motor neurons in accelerated hereditary canine spinal muscular atrophy.

Hereditary canine spinal muscular atrophy is a dominantly inherited lower motor neuron disease with three phenotypic variants: accelerated, intermediate, and chronic. Pups with the accelerated disease develop weakness by 1.5 months and are quadriparetic by 3 months. The motor neurons of selected brainstem nuclei and ventral horn of the spinal cord are characterized by chromatolysis and by neurofibrillary abnormalities in perikarya, dendrites, and, most strikingly, proximal axons. Dendrites and axons are segmentally enlarged by accumulations of maloriented fascicles of neurofilaments; the axonal swelling usually involve internodes and are delimited by the initial segment or nodes of Ranvier. The disorganized neurofilaments appear to entrap mitochondria and other particular organelles. We have hypothesized that the neurofibrillary changes in this genetic disorder in dogs is associated with an abnormality of the cytoskeletal constituents of motor neurons. Hereditary canine spinal muscular atrophy shows features in common with human motor neuron disease.

Animals↗
PubMed1998

Somatic mosaicism of the expanded CAG trinucleotide repeat in mRNAs for the responsible gene of Machado-Joseph disease (MJD), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal and bulbar muscular atrophy (SBMA).

The CAG trinucleotide repeats in mRNAs for the responsible genes of Machado-Joseph disease (MJD), dentatorubral-pallidoluysian atrophy (DRPLA), and X-linked spinal and bulbal muscular atrophy (SBMA) were examined in various neural and nonneural tissues of affected individuals. The tissue-specific variation of expanded CAG repeat alleles were apparent for mRNAs of all three genes. The expanded CAG repeats of the mRNA were shorter in the cerebellum than in other regions of the central nervous system in DRPLA and MJD, but not in SBMA, and were longer in the liver and colon in MJD. Transcripts of the responsible genes with expanded CAG repeats were detected in all tissues studied, and the tissue-specific variation in the CAG repeat size of the mRNA did not correlate with the tissue-specific severity of pathological involvement in these diseases.

Adult↗
PubMed2000

Reduced survival motor neuron (Smn) gene dose in mice leads to motor neuron degeneration: an animal model for spinal muscular atrophy type III.

Spinal muscular atrophy (SMA) is caused by deletion or specific mutations of the telomeric survival motor neuron ( SMN ) gene on human chromosome 5. The human SMN gene, in contrast to the Smn gene in mouse, is duplicated and the centromeric copy on chromosome 5 codes for transcripts which preferentially lead to C-terminally truncated SMN protein. Here we show that a 46% reduction of Smn protein levels in the spinal cord of Smn heterozygous mice leads to a marked loss of the cytoplasmic Smn pool and motor neuron degeneration resembling spinal muscular atrophy type 3. Smn heterozygous mice described here thus represent a model for the human disease. These mice could allow screening for SMA therapies and help in gaining further understanding of the pathophysiological events leading to motor neuron degeneration in SMA.

Animals↗
PubMed2005

A family with early-onset and rapidly progressive X-linked spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is an X-linked, late-onset neuroendocrine disorder resulting from an expansion of a CAG repeat in the androgen receptor gene. Reported here is a detailed phenotypic study in a series of seven patients from the same family with SBMA with 50 to 54 CAG repeats, juvenile onset (mean age at onset 13 years [8 to 15 years]), and rapid progression leading to compromised ambulation in the mid-20s.

Adolescent↗
PubMed2006

Mutation of gene in spinal muscular atrophy respiratory distress type I.

Spinal muscular atrophy with respiratory distress type I (SMARD1, MIM #604 320) is an uncommon variant of infantile spinal muscular atrophy type I. Distinguishing features include diaphragmatic palsy, early-onset distal limb wasting, and contracture. This report describes a Chinese male with typical features of spinal muscular atrophy with respiratory distress type I. Direct sequencing of the causative gene, the immunoglobulin mu-binding protein 2 (IGHMBP2) gene, revealed the presence of a novel frameshift mutation caused by deletion of G in exon 13 and a single base pair substitution of G to A in exon 12 resulting in substitution of isoleucine for valine.

DNA-Binding Proteins↗
PubMed2005

Finger cold-induced vasodilatation, sympathetic skin response, and R-R interval variation in patients with progressive spinal muscular atrophy.

To elucidate autonomic function in spinal muscular atrophy, we evaluated finger cold-induced vasodilatation, sympathetic skin response, and R-R interval variation in 10 patients with spinal muscular atrophy: 7 of type 1, 2 of type 2, and 1 of type 3. Results of finger cold-induced vasodilatation, sympathetic skin response, and R-R interval variation were compared with those of healthy children. Finger cold-induced vasodilatation was abnormal in 6 of 10 patients with spinal muscular atrophy; it was normal in the healthy children. The mean sympathetic skin response latency and amplitude did not differ significantly from those of the healthy children. Amplitudes of sympathetic skin response to sound stimulation were absent or low in all six patients with spinal muscular atrophy. No significant difference was found in the mean R-R interval variation of patients with spinal muscular atrophy and healthy children. Results show that some patients with spinal muscular atrophy have autonomic dysfunction, especially sympathetic nerve hyperactivity, that resembles dysfunction observed in amyotrophic lateral sclerosis.

Adolescent↗
PubMed2004

Spinal muscular atrophy: molecular genetics and diagnostics.

Spinal muscular atrophy is one of the most common autosomal recessive diseases, affecting approximately one in 10,000 live births and with a carrier frequency of approximately one in 50. Spinal muscular atrophy is caused by a deficiency of the ubiquitous protein survival of motor neuron (SMN), which is encoded by the SMN genes, SMN1 and SMN2. Due to a single nucleotide polymorphism (840C>T), SMN2 produces less full-length transcript than SMN1 and cannot entirely prevent neuronal cell death at physiologic gene dosages. The 38-kDa SMN protein comprises 294 amino acids and is involved in the biogenesis of uridine-rich small nuclear ribonucleoproteins, facilitating their cytoplasmic assembly into the spliceosome. Various animal models have been developed to study the pathogenesis of spinal muscular atrophy, as well as to test novel therapeutics. Common PCR-restriction fragment length polymorphism assays can detect the homozygous absence of SMN1 in approximately 94% of patients with clinically typical spinal muscular atrophy. SMN gene dosage analysis can determine the copy number of SMN1 to detect carriers and patients heterozygous for the absence of SMN1. Due to the genetic complexity and the high carrier frequency, accurate risk assessment and genetic counseling are particularly important. Comprehensive SMA genetic testing, combined with appropriate genetic counseling and risk assessment, provides the most complete evaluation of patients and their families at this time. New technologies, such as monosomal analysis techniques, may be widely available in the future.

Animals↗
PubMed2007

Mitochondrial respiratory complex I deficiency simulating spinal muscular atrophy.

Two female patients with clinical features resembling spinal muscular atrophy were presented. Patient 1 presented with hypotonia and proximal weakness of extremities at age 4 months. Electromyography revealed motor neuronopathy suggestive of spinal muscular atrophy. Patient 2 presented with severe hypotonia, motor weakness, and joint contractures since birth. Muscle biopsy findings were consistent with spinal muscular atrophy. However, deletions in the survival motor neuron gene and the neuronal apoptosis inhibitor protein gene were not found in both patients. They finally manifested clinical features unlike spinal muscular atrophy: epileptic seizure, cardiomyopathy, and spasticity. The clinical course of each patient was not like that of spinal muscular atrophy type I. Mitochondrial respiratory chain complex enzyme activities in cultured skin fibroblasts were measured. Respiratory complex I enzyme activity was decreased, suggestive of isolated complex I deficiency in both patients. In conclusion, in patients who have clinical features resembling spinal muscular atrophy but no deletions in the spinal muscular atrophy gene, the possibility of the mitochondrial respiratory chain complex I deficiency should be considered.

Cardiomyopathies↗
PubMed1976

Chronic spinal muscular atrophy of facioscapulohumeral type.

Chronic spinal muscular atrophy of FSH type affecting a mother and her son and daughter is reported. The relevant literature is reviewed and the relation between this conditon and Kugelberg-Welander (K-W) disease is discussed. Chronic spinal muscular atrophy of FSH type is considered to be a different entity from the eponymous K-W disease. Each type of muscular dystrophy, e.g. limb-girdle, FSH, distal, ocular, or oculopharyngeal type, has its counterpart of nuclear origin. A classification of the chronic spinal muscular atrophies is suggested following the classification of muscular dystrophy.

Action Potentials↗
PubMed2004

Expression profiling in spinal muscular atrophy reveals an RNA binding protein deficit.

Spinal muscular atrophy is a common neuromuscular disorder caused by deletions or mutations within the survival motor neuron gene. The reason for specific motor neuron loss within the disease is still unclear. Expression profiling has been carried out in two models of spinal muscular atrophy; the heterozygote mouse model and human primary muscle cultures from a spinal muscular atrophy patient. A group of RNA binding proteins are up-regulated in spinal muscular atrophy motor neurons. One such protein, BRUNOL3, is highly expressed within spinal cord and muscle and also at the same developmental stage as survival motor neuron. The differential expression of Brunol3 has been confirmed with real-time RT-PCR in spinal cord and muscle of three different models of spinal muscular atrophy. BRUNOL3 has been shown to co-localise with survival motor neuron in the nuclei of neuronal cells and to co-immunoprecipitate with Smn in mouse brain. This is the first time that a link has been established between RNA binding proteins and survival motor neuron within motor neurons.

Adolescent↗
PubMed1991

Calf hypertrophy in spinal muscular atrophy.

Two unusual variants of spinal muscular atrophy with gross calf hypertrophy of adolescent onset were studied clinically, electrophysiologically and histologically. There have been reports of several variants within this group of spinal muscular atrophies. In Singapore we encountered 2 patients who had an unusual variant of spinal muscular atrophy not well recognised previously with only 3 reports recorded to date. Our cases presented with gross calf hypertrophy and a slowly progressive clinical course. Nerve conduction studies were normal but electromyogram and muscle biopsies revealed a chronic denervation problem of probable central origin.

Adult↗
PubMed2004

Phenotypic variability in siblings with type III spinal muscular atrophy.

Autosomal recessive spinal muscular atrophy (SMA) shows substantial phenotypic variability, presenting at a variety of ages from infancy to adult life. Diagnostic difficulties may arise because SMA sometimes produces a dystrophic or myopathic phenotype rather than classical neurogenic abnormalities. Two brothers are described who illustrate this principle and highlight the increasing importance of molecular genetics in investigating patients with neuromuscular diseases. The findings are discussed in the light of recent observations in a mouse model of SMA.

Adolescent↗
PubMed2001

Treatment of spinal muscular atrophy by sodium butyrate.

Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of the anterior horn cells of the spinal cord, leading to muscular paralysis with muscular atrophy. No effective treatment of this disorder is presently available. Studies of the correlation between disease severity and the amount of survival motor neuron (SMN) protein have shown an inverse relationship. We report that sodium butyrate effectively increases the amount of exon 7-containing SMN protein in SMA lymphoid cell lines by changing the alternative splicing pattern of exon 7 in the SMN2 gene. In vivo, sodium butyrate treatment of SMA-like mice resulted in increased expression of SMN protein in motor neurons of the spinal cord and resulted in significant improvement of SMA clinical symptoms. Oral administration of sodium butyrate to intercrosses of heterozygous pregnant knockout-transgenic SMA-like mice decreased the birth rate of severe types of SMA-like mice, and SMA symptoms were ameliorated for all three types of SMA-like mice. These results suggest that sodium butyrate may be an effective drug for the treatment of human SMA patients.

Abnormalities, Multiple↗
PubMed1995

Autosomal dominant distal spinal muscular atrophy in four generations.

Distal spinal muscular atrophy is a rare lower motor neuron disorder that may be difficult to distinguish clinically from type II Charcot-Marie-Tooth disease. We report on clinical and pathologic findings in 13 members of a four-generation extended family with autosomal dominant distal spinal muscular atrophy. The patients developed a slowly progressive lower motor neuron disorder involving mainly the distal lower extremities; onset was from the second to fourth decades. Electromyography and muscle biopsy findings were indicative of motor denervation. Combined silver/cholinesterase/immunocytochemical staining of intramuscular nerve revealed abundant collateral axonal branching in mild disease but marked loss of terminal motor endplate innervation in the more severe state, suggesting decreased growth of motor axon collaterals with disease progression. Multipoint DNA linkage analysis showed that this family's disorder is not linked to the chromosome 5q11.2-13.3 spinal muscular atrophy locus.

Adolescent↗
PubMed2005

Spinal muscular atrophy: a delayed development hypothesis.

Spinal muscular atrophy is an inherited neuromuscular disorder. The gene responsible for the disease has been identified and named the SMN gene. This review is prompted by recent advances in understanding cellular function of the SMN gene and its gene product and by the increasing evidence that maturation of all parts of the neuromuscular system is delayed in spinal muscular atrophy patients. We suggest that the timing of developmental changes in motoneurons and muscles is critical for their survival. Delayed maturation of either motoneuron or muscle can cause these cells to die so the molecules that are involved in controlling their rate of maturation are crucial for normal development. We suggest that SMN gene/protein is one such molecule, because the neuromuscular system develops more slowly in spinal muscular atrophy patients, where SMN protein is absent, and in animals models, where SMN protein is reduced.

Child↗