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PubMed1989

[Clinical electrophysiological studies of peroneal muscular atrophy--report of 32 cases].

Clinical, electromyography (EMG) and nerve conduction velocity (NCV) features of 32 cases with peroneal muscular atrophy (PMA) are reported. Twenty of the cases showed remarkably slow NCV: median SNCV (Fing 1-W) X = 21.0 m/s, (Fing 3-W) X = 22.7 m/s, motor latency (ML) X = 7.3 ms; tibial SNCV (hallux-ankle) X = 22.2 m/s and ML = X = 8.1 ms, which were consistent with Type 1 PMA. Twelve cases showed normal or moderately slow NCV: median SNCV (Fing 1-W) X = 41.9 m/s, (Fing 3-W) X = 47.0 m/s and ML X = 3.2 ms; tibial SNCV (halluxankle) X = 32.5 m/s and ML X = 4.8 ms which were consistent with Type 2 PMA. The difference between these two groups was very significant (P less than 0.01). Sural nerve biopsy performed in 6 cases showed that 5 corresponded with NCV classification. We conclude that careful NCV examination is necessary for classification of PMA.

Adolescent↗
PubMed1995

A new mutation in the HEXA gene associated with a spinal muscular atrophy phenotype.

We describe two adult siblings who had had mild GM2 gangliosidosis since childhood. They presented with spinal muscular atrophy and dysarthria, and one sibling also had mental disturbances. Laboratory studies established the diagnosis of the B1 variant of GM2 gangliosidosis, because the hexosaminidase (Hex) A deficiency was not present upon testing with the unsulfated synthetic substrate 4-methylumbelliferyl N-acetylglucosaminide. HEXA gene analysis proved that the patients are compound heterozygotes for the previously identified G533-->A mutation and for a new mutation, G1171-->A, at exon 11. This new mutation affects a conserved amino acid and results in a Val-->Met substitution at position 391 of the HEXA gene. Full sequence of the alpha-subunit cDNA of Hex A revealed no other mutation. Assays for Hex A activities in patients suspected of having GM2 gangliosidosis should be performed with the sulfated substrate 4-methylumbelliferyl N-acetylglucosamine 6-sulfate.

Adult↗
PubMed2001

Osteoclast-stimulating factor interacts with the spinal muscular atrophy gene product to stimulate osteoclast formation.

We have recently identified and cloned an intracellular peptide termed osteoclast-stimulating factor (OSF) that increases osteoclast (OCL) formation and bone resorption through a cellular signal transduction cascade, possibly through its interaction with c-Src or related family members. To further identify participants in the OSF signaling cascade, we used yeast two-hybrid screening with Saccharomyces cerevisiae, and we found that the 40-kDa spinal muscular atrophy disease-determining gene product, survival motor neuron (SMN), interacts with the OSF-Src homology 3 domain. Reverse transcription-polymerase chain reaction analysis of SMN mRNA expression in cells of the OCL lineage demonstrates that expression of the exon 7 splice variant of SMN is restricted to mature OCLs, whereas the unspliced transcript was expressed in OCL precursors as well as mature OCLs. Treatment of murine bone marrow cultures with conditioned media (5% (v/v)) from 293 cells transiently expressing the SMN cDNA significantly increased OCL formation, compared with treatment with conditioned media from mock-transfected cells. Furthermore, OCL-stimulatory activity by OSF or SMN was abolished by antisense constructs to SMN or OSF, respectively. These data confirm the participation of SMN in the OSF-enhanced expression of an OCL stimulator. OSF-SMN interaction may provide more insights into novel cellular signaling mechanisms that may play an important role in congenital bone fractures associated with type I spinal muscular atrophy disease.

Animals↗
PubMed1994

Duchenne muscular dystrophy and spinal muscular atrophy type I segregating in the same family.

We report on a family with two severe neuromuscular diseases: Duchenne muscular dystrophy (DMD) and acute infantile spinal muscular atrophy (SMA I). One boy has DMD, and his brother died of SMA I at 11 months of age. Both boys had received the same DMD allele from their mother. Analysis of dystrophin by immunohistochemistry and Western blot showed complete lack of dystrophin in both brothers. The mother had a partial deficiency of dystrophin. The boy with SMA I had increased levels of creatine kinase in serum, compatible with DMD, but the muscle biopsy and post-mortem examination of the spinal cord showed the typical changes of SMA I. There were no cytogenetic abnormalities explaining the occurrence of both DMD and SMA I in this family. Molecular genetic prenatal diagnosis of DMD and SMA I, using analysis of RFLPs and dinucleotide repeats, has been performed in one foetus in the family. The results showed that the foetus had a high risk of developing SMA I. An abortion was planned but the pregnancy was terminated by miscarriage.

Adolescent↗
PubMed2000

[Autosomal dominant adult-onset spinal muscular atrophy with vocal cord paralysis: a case report].

This report concerns a 41-year-old female case of spinal muscular atrophy (SMA) associated with vocal cord paralysis. Her parents were not consanguineous. Her maternal grandmother and younger brother were suspected of having SMA. At age 37, she first experienced gait disturbance and began to have slowly progressive dysarthria and weakness of the extremities. Neurological examination revealed that she had inspiratory stridor, dysarthria and proximal muscular weakness of the extremities. Achilles tendon reflexes were absent, while there were no pathological reflexes or sensory disturbances. She showed a waddling gait and Gowers' sign. The laboratory data indicated mild elevation of serum CK. The nerve conduction study was normal, while the electromyographic study and muscle biopsy revealed neurogenic changes. We diagnosed the case as adult onset SMA of the autosomal dominant type. Laryngoscopy revealed that the patient had vocal cord paralysis, which was predominant in abductor muscles and of the posterior paralysis type according to the categories established by Isozaki. Genetic analysis showed no mutations in the genes of the neuronal apoptosis inhibitory protein and of the survival motor neuron.

Adult↗
PubMed2004

Gene conversion events in adult-onset spinal muscular atrophy.

OBJECTIVE: To investigate the possible occurrence of a conversion event in three patients with adult-onset spinal muscular atrophy (SMA) type IV, which represents the mildest form within the spectrum of the SMA phenotype. MATERIAL AND METHODS: We observed three patients with adult onset SMA and apparent isolated deletion of telomeric survival motor neuron (SMN1) exon 7. To distinguish between a deletion and a sequence conversion event of exon 7, these patients were analyzed in greater detail by a simple PCR-based assay. RESULTS: Analysis by DdeI digestion showed products for both telomeric and centromeric copies of exon 8. These findings indicated a gene conversion event as the site for primer R111 was retained at least in one of two alleles. CONCLUSIONS: These results provide first evidence that a conversion event may be also associated with adult-onset SMA, and further support the notion that a gene conversion event is usually associated with a milder SMA phenotype and a later onset of disease.

Adult↗
PubMed1993

Advanced EMG techniques in diagnostics of spinal muscular atrophies and motor neuron disease--magnetic stimulation, single fiber EMG and macro EMG.

Motor neuron disease (MND) and spinal muscular atrophies (SMA) are difficult to diagnose with classical EMG methods because significant findings appear relatively late and both groups of diseases show neurogenic type of record differing only in a relatively greater amount of fasciculations and higher amplitude of motor unit potential (MUP) in MND compared with SMA. We examined 12 patients with MND-amyotrophic lateral sclerosis and 7 patients with SMA type III and IV according to Swash with advanced EMG techniques-magnetic stimulation, single fiber and macro EMG. With transcranial magnetic stimulation, a significant prolongation of cortical latency was found in MND (P < 0.0001 right hand and P < 0.0005 left hand) against SMA, where it was almost normal. With single fiber EMG, mean jitter was less markedly increased in MND (P < 0.05 against SMA) and fiber density was lower in MND (P < 0.005). With macro EMG, no significant difference was found in either macro amplitude or area. Macro fiber density was also lower in MND (P < 0.005). Advanced EMG techniques proved to differentiate clearly the III. (Kugelberg-Welander) and IV. (adult) type of SMA from MND-amyotrophic lateral sclerosis.

Adult↗
PubMed2001

Allele-specific amplification for preimplantation genetic diagnosis (PGD) of spinal muscular atrophy.

We have developed a new allele-specific amplification method for the preimplantation genetic diagnosis (PGD) of spinal muscular atrophy (SMA; Werdnig-Hoffmann disease) from a single cell. This method is based on the detection of the deletion of exon 7 of the telomeric copy of the survival motor neurone (SMN(t)) gene. An oligonucleotide was designed to be specific to the SMN(t) nucleotidic sequence with exonic mismatch G (for SMN(t))-->A (for SMN(c)) at its 3' end. This test produces reliable PCR products in 95% of single lymphoblasts (85/88) tested as well as in 16/16 blastomeres from normal controls. Specificity analysis showed that we were able to detect homozygous deletion of the SMN(t) gene in 99% of single lymphoblasts (103/104) from a SMA patient. No contamination was detected in 68 blanks tested. Multiple cell and DNA dilution analysis revealed that the test is accurate and specific up to 100 pg DNA and should thus also be suitable for PGD at the blastocyst stage. This rapid procedure requires a single round of fluorescent PCR and no restriction digestion, while previously described single cell methods include nested PCR followed by restriction enzyme digestion. Two PGD cycles for SMA using this procedure were performed in our centre.

Adult↗
PubMed2004

Pilot trial of phenylbutyrate in spinal muscular atrophy.

The aim of this study was to evaluate tolerability and efficacy of phenylbutyrate (PB) in patients with spinal muscular atrophy (SMA). Ten patients with SMA type II confirmed by DNA studies (age range 2.6-12.7 years, mean age 6.01) were started on oral PB (triButyrate) in powder or tablets. The dosage was 500 mg/kg per day (maximum dose 19 g/d), divided in five doses (every 4 h, skipping one night-dose) using an intermittent schedule (7 days on and 7 days off). Measures of efficacy were the change in motor function from baseline to 3 and 9 weeks, by means of the Hammersmith functional motor scale. In children older than 5 years, muscle strength, assessed by myometry, and forced vital capacity were also measured. We found a significant increase in the scores of the Hammersmith functional scale between the baseline and both 3-weeks (P < 0.012) and 9-weeks assessments (P < 0.004). Our results indicate that PB might be beneficial to SMA patients without producing any major side effect. Larger prospective randomised, double-blind, placebo controlled trials are needed to confirm these preliminary findings.

Child↗
PubMed1994

Paternal isodisomy for chromosome 5 in a child with spinal muscular atrophy.

Paternal isodisomy for chromosome 5 was detected in a 2-year-old boy with type III spinal muscular atrophy (SMA), an autosomal recessive degenerative disorder of alpha motor neurons, known to map to 5q11.2-13.3. Examination of 17 short-sequence repeat polymorphisms spanning 5p15.1-15.3 to 5q33.3-qter produced no evidence of maternally inherited alleles. Cytogenetic analysis revealed a normal male karyotype, and FISH with probes closely flanking the SMA locus confirmed the presence of two copies of chromosome 5. No developmental abnormalities, other than those attributable to classical childhood-onset SMA, were present. While the absence of a maternally derived chromosome 5 could have produced the symptoms of SMA through the mechanisms of genomic imprinting, the lack of more global developmental abnormalities would be unusual. Paternal transmission of two copies of a defective gene at the SMA locus seems to be the most likely cause of disease, but proof of this will have to await the identification of the SMA gene. While uniparental isodisomy is a rare event, it must be considered as a possible mechanism involved in SMA when conducting prenatal testing and counseling for this disorder.

Alleles↗
PubMed1981

Spinal and cranial motor nerve roots in amyotrophic lateral sclerosis and X-linked recessive bulbospinal muscular atrophy: morphometric and teased-fiber study.

Amyotrophic lateral sclerosis (ALS) and adult onset X-linked recessive bulbospinal muscular atrophy (SPMA), constituting the category of adult onset form of motor neuron disease, were analyzed on motor nerve roots. The results of morphometric analysis on ventral spinal roots (VSR) of all spinal segments from ALS and SPMA revealed the following three findings: (1) the large-myelinated alpha-motoneuron fibers were markedly decreased in number throughout all segments; (2) thin-myelinated autonomic preganglionic fibers were almost completely preserved; (3) small-intermediate-myelinated fibers which are considered to correspond to gamma-motoneuron fibers were generally well preserved in ALS, but decreased by one-half to one-third in SPMA. However, all the components of the nerve roots of the oculomotor, trochlear, and abducent nerves were completely preserved in both ALS and SPMA. Moreover, the teased-fiber study showed that the regenerating-sprouting process rarely occurred in the VSR of ALS and SPMA. The present study suggested that the site of the primary lesion seems to be in the alpha-motoneuron fibers in motor neuron diseases, such as ALS or SPMA. However, the marked discrepancy in the pathologic change in the alpha-motoneuron fibers in the VSR and the nerve roots innervating the external ocular muscles was noteworthy.

Amyotrophic Lateral Sclerosis↗
PubMed2006

An approximately 140-kb deletion associated with feline spinal muscular atrophy implies an essential LIX1 function for motor neuron survival.

The leading genetic cause of infant mortality is spinal muscular atrophy (SMA), a clinically and genetically heterogeneous group of disorders. Previously we described a domestic cat model of autosomal recessive, juvenile-onset SMA similar to human SMA type III. Here we report results of a whole-genome scan for linkage in the feline SMA pedigree using recently developed species-specific and comparative mapping resources. We identified a novel SMA gene candidate, LIX1, in an approximately140-kb deletion on feline chromosome A1q in a region of conserved synteny to human chromosome 5q15. Though LIX1 function is unknown, the predicted secondary structure is compatible with a role in RNA metabolism. LIX1 expression is largely restricted to the central nervous system, primarily in spinal motor neurons, thus offering explanation of the tissue restriction of pathology in feline SMA. An exon sequence screen of 25 human SMA cases, not otherwise explicable by mutations at the SMN1 locus, failed to identify comparable LIX1 mutations. Nonetheless, a LIX1-associated etiology in feline SMA implicates a previously undetected mechanism of motor neuron maintenance and mandates consideration of LIX1 as a candidate gene in human SMA when SMN1 mutations are not found.

Animals↗
PubMed1994

Large linkage analysis in 100 families with autosomal recessive spinal muscular atrophy (SMA) and 11 CEPH families using 15 polymorphic loci in the region 5q11.2-q13.3.

The autosomal recessive proximal spinal muscular atrophy (SMA) gene was mapped to the region 5q11.2-q13.3 in 1990. Here, we present a large genetic linkage study of 100 SMA families and 11 CEPH families using 14 polymorphic simple sequence repeats (SSRs) and one RFLP in the region 5q11.2-q13.3. The genetic interval between the closest SMA flanking loci D5S435 and D5S557 comprises 1 cM at zmax = 27.94. Two recombinants were identified between the SMA gene and the closest telomeric marker D5S557 (theta = 0.02 at zmax = 8.63). The first places the SMA gene centromeric to this marker; the second suggests a double recombinant at D5S557, which is very unlikely. More likely explanations are discussed in the paper. No recombinant was found between D5S435 and the SMA gene (theta = 0.00 at zmax = 25.36). We localized a recently described polymorphic marker, D5S351 (Hudson et al., 1992), close to the SMA (theta = 0.00 at zmax = 19.01) and the 3'MAP1B gene (theta = 0.01 at zmax = 38.76). Due to its high PIC value of 0.70, it represents a very useful marker for prenatal diagnosis. In addition, we developed a new reverse primer for the nearest centromeric locus D5S435 (Soares et al., 1993), a useful marker for prenatal diagnosis, which has been very difficult to amplify in the past. Three of the markers presented here are newly developed polymorphic SSRs (one tetranucleotide repeat, D5S507/W15CATT, and two dinucleotide repeats, D5S544/C88.2GT and D5S682/C88.3GT). These markers are too far from the SMA gene to be relevant for cloning; nevertheless, as part of the human genome project, they are contributing to the fine genetic mapping of the region 5q11.2-q13.3. The most likely order of the loci based on two-point and multipoint linkage analyses as well as on specific recombination events and physical mapping studies is D5S76-D5S507- D5S6-D5S125-D5S680-D5S435-SMA-D5S557- D5S351-5'MAP1B-3'MAP1B-JK53CA1/2-(D5S127- D5S39)-(D5S544-D5S682). In general, the genetic distances obtained from the SMA and CEPH families are comparable.

Base Sequence↗
PubMed1997

Proximal and distal spinal muscular atrophy in one family: molecular genetic studies provide further evidence for the non-allelic origin of both diseases.

We present the results of clinical and molecular genetic investigations of a family in which the father suffers from distal spinal muscular atrophy and the younger son is affected by infantile autosomal recessive SMA type I. The molecular analysis of the SMN gene showed homozygous deletions of telSMN exons 7 and 8 in the son only. This was probably the result of a new mutation in the paternal haplotype, since the affected boy did not inherit one copy of the marker Ag1-CA. These results indicate that distal and proximal SMA in this family are not caused by the same gene on chromosome 5q.

Adult↗
PubMedDate not supplied

[Changes in the neural conduction in spinal muscular atrophy of the Kennedy type].

Sensory conduction velocity of median and sural nerves was examined in 6 patients with spinal muscular atrophy (SMA) of Kennedy type. In all patients, except the youngest one, slight slowing of sensory conduction velocity and marked decrease of potential amplitude was observed. These changes might suggest that the Kennedy type of SMA differs from another types of SMA and, may be, does not fit into "pure" motoneuron disease.

Adult↗
PubMed1997

Body composition determined with MR in patients with Duchenne muscular dystrophy, spinal muscular atrophy, and normal subjects.

Magnetic resonance imaging was used to determine total fat mass of patients with neuromuscular disorders, accounting for intramuscular fat. Nineteen boys aged 9 to 12 (eight with Duchenne muscular dystrophy, three with type II spinal muscular atrophy and eight control subjects) underwent whole-body magnetic resonance imaging examination and anthropometric measurements. Whole-body fat mass was deduced from automated analysis of images normalized by a reference signal. Intramuscular and subcutaneous fat masses were deduced from manual analysis of twelve reference slices. Affected children significantly differed from control subjects for higher total fat mass, mostly related to intramuscular fat mass. Shorter protocols validated from whole-body data were shown to be more accurate than fat mass estimation derived from anthropometric measurements.

Adipose Tissue↗
PubMed1992

Genotyping of spinal muscular atrophy families with linked DNA probes.

We report on linkage analysis and haplotype characterization in 40 Italian families with spinal muscular atrophy (SMA). The investigated loci included D5S6, D5S112, D5S39, and D5S76. No evidence of unlinked families was found. Thirty-two (80%) of the examined families were fully informative for prenatal diagnosis and carrier detection. The frequencies of individual alleles did not differ between SMA and normal chromosomes.

Adult↗