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PubMed2003

The gene for HMSN2C maps to 12q23-24: a region of neuromuscular disorders.

BACKGROUND: Hereditary motor and sensory neuropathy type 2C (HMSN2C, Charcot-Marie-Tooth 2C [CMT2C]) is an autosomal dominant motor and sensory neuropathy involving limb, diaphragm, vocal cord, and intercostal muscles. OBJECTIVE: To identify the chromosome localization for this disorder in one large American family of English and Scottish ethnicity. METHODS: Variable clinical severity led the authors to combine several approaches to accurately identify affected patients. Genome-wide two-point linkage analysis, high-definition mapping, and multipoint and recombinant haplotype analyses were performed. Mutation analysis of the triplet repeat region of ataxin-2 was also carried out. RESULTS: The initial genome-wide scan identified a region at 12q24, and fine mapping provided a maximal lod score of 4.73 (D12S1645 and D12S1583 at theta = 0.01 and 0, respectively). With multipoint analysis, a higher lod score of 5.17 was obtained and localized to the same region at 119.0 cM. Haplotype analysis narrowed the region to approximately 5.0 cM between D12S1646,D12S1330 and D12S105,D12S1339 (12q23.3-24.21). Ataxin-2, the gene responsible for spinocerebellar ataxia type 2 (SCA2), localizes to this region, but no triplet repeat expansion or point mutations within the repeat were found. CONCLUSIONS: The gene for HMSN2C maps to 12q23-24. This region is associated with SCA2, scapuloperoneal spinal muscular atrophy, and congenital distal spinal muscular atrophy. Further studies are needed to demonstrate the specific gene alteration and its relationship with nearby genes.

Age of Onset↗
PubMed1993

Heterotopic neurons in amyotrophic lateral sclerosis.

Heterotopic neurons in ALS have suggested aberrant neuronal migration during development. We studied 10 cases with ALS, 10 normal controls, and 10 cases with anterior horn cell disease, including spinal muscular atrophy and acute and remote poliomyelitis. There was no excess of heterotopic neurons in ALS compared with either control group and therefore no failure of neuronal migration in ALS.

Adolescent↗
PubMed1999

Spinal muscular atrophy-like picture, cardiomyopathy, and cytochrome c oxidase deficiency.

The authors report a child with a spinal muscular atrophy (SMA)-like picture, cardiomyopathy, and cytochrome c oxidase (COX) deficiency. Electromyography and muscle biopsy showed findings typical of SMA. However, COX staining of the muscle was negative. DNA analysis did not detect deletions in the survival motor neuron (SMN) gene. The lactate and lactate-to-pyruvate ratios were increased in blood and CSF. COX activity was decreased in muscle and fibroblasts. Western blot analysis showed reduced contents for all COX subunits. Patients with clinical features resembling SMA but with an intact SMN gene should be screened for a mitochondrial disorder.

Blotting, Western↗
PubMed2003

Defects in dynein linked to motor neuron degeneration in mice.

Although the causative genetic mutations for a subset of some of the most prevalent human motor neurodegenerative diseases have been identified, the exact molecular mechanisms behind motor neuron and associated muscular loss in these disorders remain an unsolved mystery. In a recent issue of Science, two mutagenesis-derived mouse mutants are described that contain missense mutations in the gene encoding the cytoplasmic dynein heavy-chain protein, which is part of a major cellular motor complex involved in retrograde axonal transport. These mutations result in progressive motor neuron degeneration in heterozygous animals and Lewy-like inclusion bodies in the homozygotes resembling those that occur in related human pathologies such as amyotrophic lateral sclerosis, spinal muscular atrophy, and spinal-bulbar muscular atrophy. This discovery opens up the exciting possibility that similar mutations may be involved in these human disease states.

Animals↗
PubMed1990

[An association of Werdnig-Hoffman disease and pregnancy: apropos of an unusual case].

The authors describe the first case in the literature of pregnancy in a twenty year old patient suffering from Werdnig Hoffman's disease. This is pure progressive spinal muscular atrophy which involves respiratory and locomotor functions. It brings into consideration several problems of respiration and in particular of genetics to be considered in this case, and we report that pregnancy was well tolerated in the patient who had a severe physical handicap.

Adult↗
PubMed1988

The effect of peripheral nerve injury on immature motor and sensory neurons and on muscle fibres. Possible relation to the histogenesis of Werdnig-Hoffmann disease.

Sciatic nerve section in newborn rats causes loss of almost all motoneurons and of two thirds of the sensory neurons. Single motor axons may regenerate but they innervate only few muscle fibres. The nonreinnervated fibres vanish and are replaced by fat cells. The reinnervated muscle fibres are overloaded, hypertrophy, and eventually necrotize. Their satellite cells regenerate new fibres; most of them develop aneurally and then disappear. The muscles, if reinnervated at all, after 1 year consist of a mixture of hypertrophic fibres, non-innervated regenerates, and fat cells, and resemble muscle from patients with infantile spinal muscular atrophy Werdnig-Hoffmann. In immature rat muscles, restricted reinnervation and functional overload of the few innervated fibres maintain a self-enhancing process which eventually leads to the replacement of the entire muscle by fat tissue. It is suggested that Werdnig-Hoffmann disease starts during fetal life and that similar mechanisms are operative. The clinical progression would then depend on the extent of degeneration due to overload and on regeneration and reinnervation in the muscles rather than on the rate of continuous loss of anterior horn cells. Immature motoneurons in rat die when they loose contact with their target; one might therefore speculate that the primary lesion in Werdnig-Hoffmann disease is peripheral rather than central, and that lack of neuronotorophic influences causes the loss of anterior horn cells.

Animals↗
PubMed1996

Differential pattern in tissue-specific somatic mosaicism of expanded CAG trinucleotide repeats in dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, and X-linked recessive spinal and bulbar muscular atrophy.

We investigated the somatic mosaicism of trinucleotide repeat expansion in the neural and nonneural tissues of a dentatorubral-pallidoluysian atrophy (DRPLA), Machado-Joseph disease (MJD), and spinal and bulbar muscular atrophy (SBMA) patient and their correlation to the topographical distribution of the pathological involvement. The spatial pattern of tissue-specific somatic mosaicism in the CAG repeat size was significantly different among the DRPLA, MJD and SBMA patients. The size of the major bands of the mutant CAG repeat allele was significantly smaller in the cerebellar cortex in both DRPLA and MJD patients by 6 and 2 repeat units respectively and larger in the colon and liver of DRPLA by 5 repeats or more. There were also 1-2 repeat-sized small variations of major band size among the neural tissues in DRPLA. In contrast, there was no tissue-specific variation of major bands of CAG repeats and diversity of extra bands among the examined tissues including the cerebellum in the SBMA patient. There was no parallel occurrence of tissue-specific CAG instability and severity of neuropathological involvement in the neural and nonneural tissues of DRPLA, MJD and SBMA patients. Lack of significant tissue-specific somatic mosaicism in SBMA including the cerebellar cortex may suggest that CAG repeat expansion in the mutant androgen receptor gene is far more stable compared with that in DRPLA and MJD as well as those reported in Huntington's disease.

Adult↗
PubMed1997

Cloning, characterization, and copy number of the murine survival motor neuron gene: homolog of the spinal muscular atrophy-determining gene.

Because of a 500-kb inverted duplication, there are two copies of the survival motor neuron (SMN) gene in humans, cenSMN and telSMN. Both genes produce identical ubiquitously expressed transcripts; however, only mutations in telSMN are responsible for spinal muscular atrophy (SMA), the second most common autosomal recessive childhood disease. We have cloned the murine homolog Smn and mapped the gene to Chromosome 13 within the conserved syntenic region of human chromosome 5q13. We show that the Smn transcript (1.4 kb) is expressed as early as embryonic day 7. In contrast to humans, we found no evidence of alternative splicing. The predicted amino acid sequence between mouse and human SMN is 82% identical, and a putative nuclear localization signal is conserved. FISH data indicate that the duplication of the SMA region observed in humans is not present in the mouse. We also found no evidence of multiple Smn genes using Southern blot hybridization and single-strand conformation analysis. Using these methods, we detected at least four copies of Naip exon 5 clustering distal to Smn. Finally, three biallelic markers were identified within the Smn coding region; two are silent polymorphisms, whereas the third changes a cysteine residue to a tyrosine residue in exon 7. Overall, our results indicate that Smn is single copy within the mouse genome, which should facilitate gene disruption experiments to create an animal model of SMA.

Amino Acid Sequence↗
PubMed1996

[Study of androgen receptor expression and neuronal vulnerability in X-linked spinal and bulbar muscular atrophy].

X-linked spinal and bulbar muscular atrophy (SBMA), a rare adult onset form of motor neuron disease, is clinically characterized by slowly progressive muscle weakness and atrophy, and endocrinopathy such as gynecomastia, testicular atrophy and oligospermia. Androgens are known to play an important role in motor neuron growth, development and regeneration. The genetic mutation of androgen receptor (AR) gene in SBMA has been disclosed and thought to lead to degeneration of lower motor neurons. However, the mechanism of neuronal death and the basis for the regional specificity of neuropathology observed in SBMA are not clear. At first, we proved the existence of androgen receptor (AR) in the motor neurons of the rat spinal cord by the immunohistochemical stain and Western blotting. The possibility that AR protein in spinal cord is expressed in tissue-specific form is proposed, being different from other androgen-dependent tissue. Northern blotting data showed that AR is expressed in not only rat spinal cord but also cerebrum and cerebellum, which are spared in SBMA. Then, specimens from 2 SBMA patients were examined and compared with those from normal controls (n = 4). AR was widely expressed in central nervous system. Anterior horn cells, which are severely affected in SBMA, were stained intensely. Even the remaining atrophic motor neurons in SBMA had AR. To our interest, the neurons of cranial nerves III, IV, VI, dentate nucleus, posterior horn and Onufrowicz nucleus etc., which are spared in SBMA, contained AR moderately. These data did not show any difference between SBMA and controls. Our immunohistochemical study showed that not only the neurons affected in SBMA but the unaffected in this disease process express AR. The question why motor neurons are selectively involved in SBMA if AR is present in almost neurons should further be clarified.

Aged↗
PubMed1999

Sporadic amyotrophic lateral sclerosis of long duration mimicking spinal progressive muscular atrophy: a clinicopathological study.

We report an autopsy case of amyotrophic lateral sclerosis (ALS) clinically diagnosed as spinal progressive muscular atrophy (SPMA). The patient was a Japanese woman without hereditary burden. She developed muscle weakness of the distal part of the left lower extremity at age 42, followed by muscle weakness and atrophy of the right lower extremity and upper extremities. At age 57, she needed transient ventilatory support. Slight weakness in the facial muscles and fasciculation of the tongue appeared at age 60. At age 61, she died of sudden respiratory arrest. During the clinical course, neurological examination revealed neither Babinski signs nor hyperreflexia. The neuropathological examination revealed not only neuronal loss with gliosis in the facial nucleus, hypoglossal nucleus, and anterior horns of the spinal cord, but also loss of Betz cells and degeneration of the pyramidal tracts. Based on these clinicopathological findings and review of literature, we conclude that sporadic ALS mimicking SPMA is present.

Amyotrophic Lateral Sclerosis↗
PubMed1992

A novel primer extension method to detect the number of CAG repeats in the androgen receptor gene in families with X-linked spinal and bulbar muscular atrophy.

X-linked spinal and bulbar muscular atrophy (SBMA), an adult-onset form of motor neuron disease, was recently reported to be caused by amplification of the CAG repeats in the androgen receptor gene. We report here a simple and rapid strategy to detect the precise number of the CAGs. After the DNA fragment containing the CAG repeats is amplified by the polymerase chain reaction, a primer extension is carried out; the extension of the end-labelled reverse primer adjacent to 3' end of CAG repeats stops at the first T after CAG repeats with the incorporation of dideoxy ATP in the reaction mixture. The resultant primer products are analysed by denaturing polyacrylamide gel electrophoresis and autoradiography. This method could be quite useful to detect not only CAG repeats in SBMA but also other polymorphic dinucleotide and trinucleotide repeats.

Adult↗
PubMed1991

Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy.

X-linked spinal and bulbar muscular atrophy (Kennedy's disease) is an adult-onset form of motorneuron disease which may be associated with signs of androgen insensitivity. We have now investigated whether the androgen receptor gene on the proximal long arm of the X chromosome is a candidate gene for this disease. In patient samples we found androgen receptor gene mutations with increased size of a polymorphic tandem CAG repeat in the coding region. These amplified repeats were absolutely associated with the disease, being present in 35 unrelated patients and none of 75 controls. They segregated with the disease in 15 families, with no recombination in 61 meioses (the maximum log likelihood ratio (lod score) is 13.2 at a recombination rate of 0). The association is unlikely to be due to linkage disequilibrium, because 11 different disease alleles were observed. We conclude that enlargement of the CAG repeat in the androgen receptor gene is probably the cause of this disorder.

Base Sequence↗