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At least 1,099 records · Page 61Linked to original sources
PubMed1998

Autosomal dominant distal spinal muscular atrophy type V (dSMA-V) and Charcot-Marie-Tooth disease type 2D (CMT2D) segregate within a single large kindred and map to a refined region on chromosome 7p15.

Two separate disorders, autosomal dominant distal spinal muscular atrophy type V (dSMA-V) characterized by marked bilateral weakness in the hands and atrophy of thenar eminence and the first interosseous muscle, and Charcot-Marie-Tooth disease type 2D (CMT2D) characterized by sensory deficits in addition to the upper limb weakness and wasting, have been independently linked to chromosome 7p. We identified a multigenerational Mongolian kindred with 17 members affected with either dSMA-V or CMT2D and mapped both syndromes to the same region on chromosome 7p15. A maximum two-point lod score of 4.74 at recombination fraction zero was obtained with marker D7S474. Tight linkage without recombination was also detected with markers D7S526 and D7S632. A multipoint lod score of 6.07 suggested that the gene is located between markers D7S526 and D7S474. A single conserved haplotype was associated with dSMA-V and CMT2D. Based on informative recombination events, the disease locus was placed between markers D7S516 and D7S1514 within the 7p15 band. Data obtained from this study suggest that a single gene is responsible for both syndromes, dSMA-V and CMT2D, and extend our knowledge of the candidate region.

Adult↗
PubMed2002

Trinucleotide repeat disease. The androgen receptor in spinal and bulbar muscular atrophy.

It has been more than 10 years since the discovery that the expansion of a simple CAG trinucleotide repeat within the coding region of the androgen receptor gene leads to the motor neuronopathy spinal and bulbar muscular atrophy (SBMA). A flurry of investigation into this and the other, more recently discovered, polyglutamine diseases has led to an understanding of many aspects of the molecular pathogenesis of this family of diseases. A characteristics pathological feature of the polyglutamine diseases is the occurrence in affected neurons of ubiquitinated aggregates; such aggregates also contain, among others, proteins involved in the folding and degradation of the mutant proteins. Aggregates themselves are likely not directly cytotoxic, but rather mark the accumulation of all or part of the mutant protein. Furthermore, aggregation occurs because of the inefficient clearance of the mutant protein by the ubiquitin-proteasome pathway for protein degradation. These findings are common to the polyglutamine diseases and reflect the general problem of folding/degrading expanded polyglutamines. In SBMA, the altered metabolism of the androgen receptor is ligand dependent. How the accumulation of the mutant protein causes neuronal dysfunction and disease is not well understood, but several cellular processes have been implicated. Although these findings provide insight into the toxic function of the expanded polyglutamine protein, additional investigations have led to the finding that intrinsic AR transactivational function is somewhat diminished in the presence of the expanded polyglutamine; this likely leads to the partial androgen insensitivity that characterizes patients with SBMA. The recent development of useful animal and cell models of SBMA will lead to increased understanding of disease pathogenesis, as well as to the development of new and better therapeutic strategies.

Animals↗
PubMed1978

Genetic studies of acute infantile spinal muscular atrophy (SMA type I). An analysis of sex ratios, segregation ratios, and sex influence.

An analysis of segregation and sex ratios, and of sex influence, was undertaken in a series of 78 index patients with acute infantile spinal muscular atrophy (SMA type I). The sex ratio of index patients was 2.0, and the excess of males was shown to occur principally among sporadic cases. The sex ratio of familial cases did not differ significantly from 1.0. The implications of this are discussed. No sex influence on age at onset, or on life expectancy, was present. The segregation ratio (Weinberg Proband method) was 0.29 for all index cases, and 0.26 for all cases excluding those referred specifically to a genetic counselling clinic. Autosomal recessivity is confirmed for this disease, with the probable inclusion of unrecognised male phenocopies in clinical series.

Acute Disease↗
PubMed1996

Transcriptional activation by the androgen receptor in X-linked spinal and bulbar muscular atrophy.

Polyglutamine tracts encoded by trinucleotide CAG repeats have been found in some transcription factors. Expansion of the polyglutamine tracts in the androgen receptor (AR) has been recognized as a cause of X-linked spinal and bulbar muscular atrophy (SBMA). To study the role of AR as a transcription factor in SBMA, we constructed AR genes encoding expanded polyglutamine tracts (repeat numbers = 52, 92, 132, and 212), and analyzed AR-induced transcriptional activation in NG108-15 cells. We found that AR-induced transcriptional activation gradually decreased with increasing glutamine repeat numbers, and polyglutamine expansion caused a specific reduction in transcription activity in motor neurons. However, the degree of reduction was slight in comparison with the normal AR gene and that of SBMA. Thus, subtle disorders of transcriptional control may occur in SBMA.

Animals↗
PubMed1979

Hereditary spinal muscular atrophy in Brittany Spaniels: clinical manifestations.

A progressive neurologic disease was identified in a family of closely related Britanny Spaniel dogs. The disease developed in dogs less than 1 year old and characteristically resulted in paraspinal and proximal pelvic limb muscular atrophy. Neurologic examination, electrodiagnostic testing, and histologic studies indicated that the disease results from motor horn cell degeneration. A colony of affected dogs was established, and breeding studies incriminated an inherited basis for the disease.

Animals↗
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↗
PubMed1994

[Cervical flexion-induced changes of motor evoked potentials by transcranial magnetic stimulation in a patient with Hirayama disease--juvenile muscular atrophy of unilateral upper extremity].

A 16-year-old girl noticed weakness in the left hand in 1990, which gradually progressed over the next 2 years but then stabilized. Her neurologic and electrophysiological signs were compatible with juvenile muscular atrophy of unilateral upper extremity (Hirayama disease). Cine MRIs demonstrated a mild cervical cord atrophy at the C6 spine level together with an engorged epidural vein at the C4-C6 extradural spaces during neck flexion. Transcranial magnetic stimulation over the motor cortex was carried out with a pickup placed on the contralateral abductor brevis muscle. While neck flexion was maintained, the amplitude of the evoked potentials steadily attenuated and the central motor conduction time lengthened as time passed. After 8 minutes, she began to feel some dullness in the left upper limb. These phenomena were reversible and were observed only on the affected limb. The above facts not only supported the presence of a reversible cortico-efferent dysfunction in Hirayama disease, but also appeared to justify the use of neck collars to treat those afflicted with this entity.

Adolescent↗
PubMed1994

Intestinal pseudo-obstruction in adult spinal muscular atrophy.

A 42-year-old woman with negative family history had the insidious onset of weakness in her lower extremities 8 years before, in 1983. The disorder slowly progressed to include cramps and muscle twitches. The diagnosis of adult spinal muscular atrophy (SMA) was made when electromyography showed large rapidly firing motor unit-potentials, positive waves, and fibrillation potentials, and when muscle biopsy of the quadriceps revealed severe alterations consistent with neurogenic atrophy. The patient also had severe chronic constipation for many years. More recently she had developed unremitting diarrhea. Gastrointestinal studies showed no evidence of peristaltic contractions in the rectum, delayed gastric emptying, and abnormal jejunal manometry with altered propagation of the migrating myoelectrical complex.

Adult↗
PubMed2006

A phenotypic-genetic study of a group of Polish patients with spinal and bulbar muscular atrophy.

We studied phenotype-genotype correlation in a group of Polish males with spinal and bulbar muscular atrophy (SBMA) and in female carriers. Eleven males with suspected SBMA phenotype and three suspected female carriers were examined. Male patients presented with the predominant signs of progressive, symmetrical distal limb weakness with amyotrophy, facial muscular weakness with orofacial fasciculations, nasal voice and slight dysphagia, gynaecomastia, decreased potency, as well as hand tremor and distal peripheral sensory disturbances in a few cases. One of the carriers presented with a 30-year history of fasciculations and minimal distal weakness and cramps in the legs, while the other two were asymptomatic. DNA analysis revealed expanded size of CAG repeats in Xq11-12 in the AR gene in 10 out of 11 men (range 45-52 CAG repeats) and in the women (range 46-48 CAG repeats). There was no correlation between CAG repeat size and the age of disease onset and duration of the disease. A rare, predominantly distal distribution of weakness and amyotrophy was found in our group of the SBMA patients (8 out of 11 cases) from three unrelated kindreds and also in the remaining two sporadic cases. The extended CAG repeats within families were stable.

Adult↗
PubMed1987

Extracts of muscle biopsies from patients with spinal muscular atrophies inhibit neurite outgrowth from spinal neurons.

Preparations derived from embryonic and neonatal chick muscle enhance neurite outgrowth when added to cultures of embryonic chick spinal neurons. In the presence of soluble extracts of biopsied muscle from 15 of 20 patients with spinal muscular atrophy (SMA), the in vitro neurite-promoting activity of neonatal chick muscle was inhibited. There was no comparable inhibition using extracts from 20 age-matched pathologic or morphologically normal controls. The neurite-promoting activity in media conditioned by embryonic myotubes was not inhibited by extracts of the SMA group.

Animals↗
PubMed2006

Aggregation and proteasome: the case of elongated polyglutamine aggregation in spinal and bulbar muscular atrophy.

Aggregates, a hallmark of most neurodegenerative diseases, may have different properties, and possibly different roles in neurodegeneration. We analysed ubiquitin-proteasome pathway functions during cytoplasmic aggregation in polyglutamine (polyQ) diseases, using a unique model of motor neuron disease, the SpinoBulbar Muscular Atrophy. The disease, which is linked to a polyQ tract elongation in the androgen receptor (ARpolyQ), has the interesting feature that ARpolyQ aggregation is triggered by the AR ligand, testosterone. Using immortalized motor neurons expressing ARpolyQ, we found that a proteasome reporter, YFPu, accumulated in absence of aggregates; testosterone treatment, which induced ARpolyQ aggregation, allowed the normal clearance of YFPu, suggesting that aggregation contributed to proteasome de-saturation, an effect not related to AR nuclear translocation. Using AR antagonists to modulate the kinetic of ARpolyQ aggregation, we demonstrated that aggregation, by removing the neurotoxic protein from the soluble compartment, protected the proteasome from an excess of misfolded protein to be processed.

Animals↗
PubMed2004

Carrier incidence for spinal muscular atrophy in southern Chinese.

A real time quantitative PCR (QPCR) method using TaqMan technology was used to assess the copy number of the two survival motor neuron genes (SMN1 and SMN2) on chromosome 5q13. This allows the accurate determination of carriers for spinal muscular atrophy (SMA), with one copy of SMN1. Analysis of 569 normal southern Chinese individuals revealed a carrier incidence of 1.6%, similar to that found in the western society. Study of 42 obligatory carriers showed a (2 + 0) genotype in two (4.8 %). In 27 SMA patients with homozygous deletion of the SMN1 gene, the number of SMN2 gene correlated with disease phenotype, with 68% of type II and III patients carrying three or more SMN2 genes, whilst the incidence of three or more SMN2 genes in the normal population was 1.57%.

Asian People↗