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PubMed2006

Valproic acid promotes neurite outgrowth in PC12 cells independent from regulation of the survival of motoneuron protein.

Spinal muscular atrophy (SMA) is a neurodegenerative disorder of motoneurons. The disease is caused by deletions or mutations of the survival of motoneuron gene 1 (SMN1). The amount of protein expressed from the second gene, SMN2, correlated with the severity of the clinical phenotype. The histone deacetylase inhibitor valproic acid (VPA) has been shown to increase the total cellular amount of functional SMN protein and is therefore considered as a drug candidate for treatment of SMA. In this study, we analyzed the effects of VPA in PC12 cells, a model system for neuronal differentiation, with regard to neurite outgrowth and SMN expression. VPA promoted neurite outgrowth in PC12 cells. However, this effect did not correlate with upregulation of SMN protein levels, suggesting a SMN-independent mechanism for VPA regulation of neurite outgrowth.

Animals↗
PubMed2006

Splicing of a critical exon of human Survival Motor Neuron is regulated by a unique silencer element located in the last intron.

Humans have two nearly identical copies of the Survival Motor Neuron (SMN) gene, SMN1 and SMN2. In spinal muscular atrophy (SMA), SMN2 is not able to compensate for the loss of SMN1 due to exclusion of exon 7. Here we describe a novel inhibitory element located immediately downstream of the 5' splice site in intron 7. We call this element intronic splicing silencer N1 (ISS-N1). Deletion of ISS-N1 promoted exon 7 inclusion in mRNAs derived from the SMN2 minigene. Underlining the dominant role of ISS-N1 in exon 7 skipping, abrogation of a number of positive cis elements was tolerated when ISS-N1 was deleted. Confirming the silencer function of ISS-N1, an antisense oligonucleotide against ISS-N1 restored exon 7 inclusion in mRNAs derived from the SMN2 minigene or from endogenous SMN2. Consistently, this oligonucleotide increased the levels of SMN protein in SMA patient-derived cells that carry only the SMN2 gene. Our findings underscore for the first time the profound impact of an evolutionarily nonconserved intronic element on SMN2 exon 7 splicing. Considering that oligonucleotides annealing to intronic sequences do not interfere with exon-junction complex formation or mRNA transport and translation, ISS-N1 provides a very specific and efficient therapeutic target for antisense oligonucleotide-mediated correction of SMN2 splicing in SMA.

Alternative Splicing↗
PubMed1989

A hungarian study on Werdnig-Hoffmann disease.

The prevalence of Werdnig-Hoffmann disease was found to be 0.66 per 10,000 livebirths in Hungary from 1973 to 1980. However, the true prevalence is estimated to be 1 per 10,000 livebirths, which exceeds the level of a previously published English study. There was no higher fetal death rate in previous and subsequent pregnancies of index patients' mothers. The occurrence in sibs was 32%, probably because of greater ascertainment in families with more than one affected child.

Gene Frequency↗
PubMed1991

A new recessive syndrome of unusual facies and multiple structural abnormalities.

Two sibs with a similar pattern of dysmorphic facial features and multiple structural abnormalities are reported. Both had a normal karyotype. The parents are first cousins and neither shows any stigmata of the disorder. In view of the consanguinity and pattern of malformations, autosomal recessive inheritance seems likely.

Abnormalities, Multiple↗
PubMed1995

Lethal congenital contracture syndrome (LCCS), a fetal anterior horn cell disease, is not linked to the SMA 5q locus.

The lethal congenital contracture syndrome (LCCS) is an autosomal recessive syndrome (McKusick 253310) leading to perinatal death owing to early onset degeneration of the anterior horn motor neurones of the spinal cord. The neuropathological findings in the LCCS closely resemble those of spinal muscular atrophy (SMA). Since all the three types of SMA have been localised to the same gene locus on the long arm of chromosome 5, we analysed samples from seven families with 10 LCCS fetuses with the microsatellite markers assigned to the SMA 5q region. Linkage analyses between the SMA linked DNA markers and the disease allele in the LCCS families excluded the critical chromosomal region around the SMA locus as the critical chromosomal region for the LCCS locus.

Anterior Horn Cells↗
PubMed1998

Del(18p) shown to be a cryptic translocation using a multiprobe FISH assay for subtelomeric chromosome rearrangements.

We have previously described a fluorescence in situ hybridisation (FISH) assay for the simultaneous analysis of all human subtelomeric regions using a single microscope slide. Here we report the use of this multiprobe FISH assay in the study of a patient whose karyotype was reported by G banding analysis as 46,XX,del(18)(p11.2). Although the proband had some features suggestive of a chromosomal abnormality, relatively few of the specific features of del(18p) were present. She was a 37 year old female with mild distal spinal muscular atrophy (SMA), arthritis of the hands, an abnormal chest shape (pectus excavatum), and an unusual skin condition (keratosis pilaris). Reverse chromosome painting with degenerate oligonucleotide primer-polymerase chain reaction (DOP-PCR) amplified del(18p) chromosomes as a probe confirmed the abnormality as del(18p), with no evidence of any other chromosome involvement. Subsequently, the multiprobe FISH assay confirmed deletion of 18p subtelomeric sequence. However, the assay also showed that sequences corresponding to the 2p subtelomeric probe were present on the tip of the shortened 18p. The patient is therefore monosomic for 18p11.2-pter and trisomic for 2p25-pter, and the revised karyotype is 46,XX,der(18)t(2;18)(p25; p11.2). We believe that a proportion of all cases reported as telomeric deletions may be cryptic translocations involving other chromosome subtelomeric regions. Further studies such as this are necessary to define accurately the clinical characteristics associated with pure monosomy in chromosomal deletion syndromes.

Adult↗
PubMed1988

Estimation of the number of motor units based on macro-EMG.

The technique of the macro-EMG was used to estimate the number of motor units in the tibialis anterior muscles of healthy subjects in a wide range of ages, and of patients with myasthenia gravis and patients with amyotrophic lateral sclerosis or spinal muscular atrophy. The results obtained suggest a decrease in the number of motor units in the tibialis anterior muscle with increasing age in normal subjects. In myasthenic patients the motor unit count was within the normal range for their age group. Patients with motor neuron disorders on the average had a very low number of motor units.

Adult↗
PubMed2004

Activity-driven synaptic and axonal degeneration in canine motor neuron disease.

The role of neuronal activity in the pathogenesis of neurodegenerative disease is largely unknown. In this study, we examined the effects of increasing motor neuron activity on the pathogenesis of a canine version of inherited motor neuron disease (hereditary canine spinal muscular atrophy). Activity of motor neurons innervating the ankle extensor muscle medial gastrocnemius (MG) was increased by denervating close synergist muscles. In affected animals, 4 wk of synergist denervation accelerated loss of motor-unit function relative to control muscles and decreased motor axon conduction velocities. Slowing of axon conduction was greatest in the most distal portions of motor axons. Morphological analysis of neuromuscular junctions (NMJs) showed that these functional changes were associated with increased loss of intact innervation and with the appearance of significant motor axon and motor terminal sprouting. These effects were not observed in the MG muscles of age-matched, normal animals with synergist denervation for 5 wk. The results indicate that motor neuron action potential activity is a major contributing factor to the loss of motor-unit function and degeneration in inherited canine motor neuron disease.

Animals↗
PubMed2002

Reduced endplate currents underlie motor unit dysfunction in canine motor neuron disease.

Hereditary canine spinal muscular atrophy (HCSMA) is an autosomal dominant degenerative disorder of motor neurons. In homozygous animals, motor units produce decreased force output and fail during repetitive activity. Previous studies suggest that decreased efficacy of neuromuscular transmission underlies these abnormalities. To examine this, we recorded muscle fiber endplate currents (EPCs) and found reduced amplitudes and increased failures during nerve stimulation in homozygotes compared with wild-type controls. Comparison of EPC amplitudes with muscle fiber current thresholds indicate that many EPCs from homozygotes fall below threshold for activating muscle fibers but can be raised above threshold following potentiation. To determine whether axonal abnormalities might play a role in causing motor unit dysfunction, we examined the postnatal maturation of axonal conduction velocity in relation to the appearance of tetanic failure. We also examined intracellularly labeled motor neurons for evidence of axonal neurofilament accumulations, which are found in many instances of motor neuron disease including HCSMA. Despite the appearance of tetanic failure between 90 and 120 days, average motor axon conduction velocity increased with age in homozygotes and achieved adult levels. Normal correlations between motor neuron properties (including conduction velocity) and motor unit properties were also observed. Labeled proximal motor axons of several motor neurons that supplied failing motor units exhibited little or no evidence of axonal swellings. We conclude that decreased release of transmitter from motor terminals underlies motor unit dysfunction in HCSMA and that the mechanisms determining the maturation of axonal conduction velocity and the pattern of correlation between motor neuron and motor unit properties do not contribute to the appearance or evolution of motor unit dysfunction.

Aging↗
PubMed2006

[An unusual cause of failure of weaning from mechanical ventilation in an infant].

The weaning process is a critical phase in patients undergoing mechanical ventilation. This process can be hampered by numerous causes, such as neuromuscular diseases and spinal muscular atrophy (SMA). We present a 6-month-old boy with respiratory distress, fever, marked hypotonia without motor developmental milestones, and areflexia. The patient showed progressive respiratory distress requiring mechanical ventilation. Definitive weaning was not achieved and the boy died from respiratory failure. Partial autopsy was performed with a diagnosis of SMA and genetic study of the parents. Neuromuscular diseases are an infrequent cause of respiratory insufficiency in suckling infants. The differential diagnosis is made between axonal and motor neuron diseases. The diagnosis was confirmed by muscular biopsy and genetic study.

Fatal Outcome↗
PubMed1988

Descriptive epidemiology of some rare neurological diseases in Benghazi, Libya.

During a 4-year study period, January 1983 to December 1986, 24 patients (18 index cases) with spinal muscular atrophy (hereditary motor neuropathy, HMN), 9 with myasthenia gravis (MG), 6 with progressive supranuclear palsy (PSP), and 5 with subacute sclerosing panencephalitis (SSPE) were diagnosed in Benghazi. The HMN group comprised 6 acute infantile, 12 chronic childhood, and 3 each with adult-onset proximal, and distal forms of the disease. The crude average annual incidence of acute infantile HMN was 0.3/100,000 total population and 1/12,500 births in Benghazi. The crude prevalence rates of chronic childhood, adult-onset proximal, and distal types of HMN were 2.3, 0.6 and 0.6/100,000, respectively. The larger family size and the high rate of consanguineous marriages contribute to the high frequency of HMN in the study area. Distal HMN constituted 12.5% of the total cases. The adjusted average incidence of MG was 4.4/million/year, 2.1 for males and 6.8 for females. The female:male incidence ratio was 3.2:1. The crude average annual incidence rates/million inhabitants for PSP asnd SSPE were 3 and 2.4, respectively. The frequency of occurrence of SSPE among the subtropical Arab community under investigation is comparable with other surveys from the Middle East and Mediterranean region.

Adolescent↗
PubMedDate not supplied

Microsatellite polymorphisms for chromosome 5 bands q11.2-q13.3.

The genes for spinal muscular atrophy (SMA) and a possible subtype of schizophrenia (SCZD1) have been mapped to chromosome 5q11.2-q13.3. DNA markers have been mapped to 5q11.2-q13.3 using a hybrid cell line deleted for this region [Gilliam et al., Genomics 1989;5:940-944]. Genomic lambda clones for these markers facilitated the identification of highly polymorphic microsatellites. A total of ten microsatellites were identified and sequenced. Of these, seven were found to be polymorphic. Four had polymorphism information content values > 0.7. New polymorphic microsatellites were sequenced for D5S76, D5S125, D5S39, D5S127 and HEX-B. Two-point and multipoint analysis in non-CEPH pedigrees confirmed that the microsatellites were in tight linkage with each other. These new microsatellites will increase the efficiency of linkage analysis for these disorders.

Alleles↗
PubMed1993

Efficiency of various strategies and materials to generate new markers: saturating the region 5q11.2-q13.3 with 30 new randomly distributed clones.

Several different strategies and materials were used for saturating the region 5q11.2-q13.3 with new, randomly distributed markers: isolation of human clones from three chromosome-5-specific libraries (a BssHII endclone phage library from the somatic cell hybrid H64 and two total genomic phage libraries from radiation hybrids IH12 and IH132), as well as Alu-PCR from chromosome-5-specific radiation hybrids with overlapping fragments in the region around the spinal muscular atrophy locus, followed either by direct isolation of Alu-PCR products or hybridization of Alu-PCR products to chromosome-5-gridded cosmid libraries. 253 human phage and cosmid clones were mapped to various parts of chromosome 5 by deletion mapping to somatic cell hybrid panels. 30 of these clones were mapped into the region 5q11.2-q13.3, 9 of which are flanking rate cutting BssHII-sites, known to be, often, starting points for genes. They represent excellent starting material for the development of new polymorphic markers and sequence-tagged sites, for YAC screening and building of contigs, as well as for direct isolation of genes.

Animals↗
PubMed2005

New treatments for denervating diseases.

There has been considerable recent progress in understanding mechanisms by which gene mutations cause degeneration of motoneurons and peripheral nerves. Novel therapies inspired by these insights have begun to yield promising results in mouse models of these genetic diseases. Among these have been the use of small molecules or proteins to suppress gain-of-function mutations (eg, ascorbic acid for Charcot-Marie-Tooth disease type 1A) or to restore enzyme activities that are deficient because of loss-of-function mutations (eg, treatment of Fabry's disease with recombinant alpha-galactosidase or with low-molecular-weight alpha-galactosidase chaperones and treatment of spinal muscular atrophy with phenylbutyrate). Some of these therapies are already being tested in humans. Equally exciting is the prospect that small molecules and proteins will be identified that exert potent therapeutic effects in a broad spectrum of inherited and acquired motoneuron and peripheral nerve disorders.

Animals↗
PubMed1999

Carrell-Krusen Symposium invited lecture. Clinical trials in motor neuron diseases.

Although there is no truly effective disease-specific therapy for any of the motor neuron diseases, rapid progress in our understanding of the pathophysiology of some of these disorders is being made. In addition to progress in neuroscience, clinical trials of agents that appear to slow the progress of at least one of these diseases, amyotrophic lateral sclerosis, are beginning to show promising results. The first clinical trials in spinal muscular atrophy are currently underway. A number of other developments have raised the quality of clinical trials, which should improve their productivity and efficiency in the future.

Acetates↗
PubMed2005

SMN genotypes producing less SMN protein increase susceptibility to and severity of sporadic ALS.

BACKGROUND: ALS is believed to be multifactorial in origin with modifying genes affecting its clinical expression. Childhood-onset spinal muscular atrophy (SMA) is an autosomal recessive disorder of motor neurons, caused by mutations of the survival motor neuron (SMN) gene. The SMN gene exists in two highly homologous variants: SMN1, the causative gene responsible for the production of the majority of functional SMN protein, and SMN2, responsible for the production of less protein but sufficient for modifying the SMA phenotype. OBJECTIVE: To test whether SMN genotypes are associated with susceptibility to and severity of sporadic ALS. METHODS: We performed competitive quantitative PCR analysis for both SMN1 and SMN2 genes in 242 clinically well-defined ALS patients and 175 controls. The combined determination of SMN1 and SMN2 copies also allowed for an estimation of the level of SMN for each patient (estimated SMN protein level = SMN1 copy number + 0.20 x SMN2 copy number). RESULTS: One copy of SMN1 was associated with an increased risk of developing ALS (odds ratio = 4.1, 95% CI = 1.2 to 14.2, p = 0.02) and ALS patients carried fewer SMN2 copy numbers (p < 0.001). Sixty-one percent of patients had an estimated protein SMN level < or = 2.2 vs only 36% of controls (p = 0.0000004). Multivariate Cox regression analyses showed that lower SMN2 copy numbers and lower levels of estimated SMN protein (hazard ratio = 1.3, 95% CI = 1.1 to 1.6, p = 0.03) were associated with an increased mortality rate. CONCLUSIONS: SMN genotypes producing less SMN protein increase susceptibility to and severity of ALS.

Adult↗
PubMed2006

The G526R glycyl-tRNA synthetase gene mutation in distal hereditary motor neuropathy type V.

BACKGROUND: Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (dSMA) is a heterogeneous group of disorders characterized almost exclusively by degeneration of motor nerve fibers, predominantly in the distal part of the limbs. One subtype, dHMN type V (dHMN-V), is transmitted by autosomal dominant inheritance and predominantly involves the hands. It is allelic with Charcot-Marie-Tooth disease 2D (CMT2D), in which a similar phenotype is associated with sensory signs. Missense mutations in the glycyl-tRNA synthetase (GARS) gene have been recently reported in families with either dHMN-V, CMT2D, or both. METHODS: The authors searched for GARS mutations in eight dHMN-V families. RESULTS: The authors found the G526R missense mutation in three families (16 patients) of Algerian Sephardic Jewish origin. All patients shared a common disease haplotype, suggestive of a founder effect. The clinical phenotype consists of a slowly progressive, purely motor distal neuropathy. It starts in the hands in most patients, but also in both distal upper and lower limbs or in distal lower limbs alone. The age at onset in symptomatic individuals was between the second to fourth decades, but four mutation carriers were still asymptomatic, two of whom were already age 49 years. Electrophysiology showed that the motor fibers of the median nerve were the most affected in upper limbs. Sensory nerve action potentials were normal. CONCLUSIONS: The age at onset of patients with the G526R mutation in the GARS gene varied widely, but the clinical and electrophysiologic presentation was uniform and progressed slowly. Glycyl-tRNA synthetase mutations are a frequent cause of familial distal hereditary motor neuropathy type V but, because of the reduced penetrance of the disease, could also account for isolated cases.

Age of Onset↗