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PubMed1995

Mapping of retrotransposon sequences in the unstable region surrounding the spinal muscular atrophy locus in 5q13.

The mutation that underlies the autosomal recessive disorder spinal muscular atrophy (SMA) is located on chromosome 5q13. Recent studies show that SMA patients frequently have deletions and rearrangements in this region compared to normal controls. During the isolation of candidate cDNAs for the disease, we identified a sequence that shows high homology to the THE-1 retrotransposon gene family. Using YAC fragmentation techniques, we have refined the localization of this sequence to the domain known to show instability in SMA patients. The implication of these results for the mechanism of the mutation in SMA is discussed.

Base Sequence↗

PubMed1993

A tool for the molecular analysis of an early lethal disease: slide-PCR in spinal muscular atrophy patients.

DNA was recovered from sections of muscle biopsies of 20 spinal muscular atrophy (SMA) patients fixed on microscopic slides and stored from one to 20 years at room temperature. Microsatellite DNA markers tightly linked to the SMA locus were amplified using the polymerase chain reaction (PCR) to obtain specific amplified products. The procedure was successful in all cases, and allowed prenatal diagnosis in one at-risk pregnancy. In our hands this procedure is quick, sensitive and reproducible.

Alleles↗

PubMed1995

A sublocus of the multicopy microsatellite marker CMS1 maps proximal to spinal muscular atrophy (SMA) as shown by recombinant analysis.

The critical region containing the spinal muscular atrophy (SMA) gene is flanked by the 5q11-q13 markers, D5S435 and D5S557, as determined by linkage analysis. Here we present the results of an analysis of a Dutch SMA family with the multicopy microsatellite marker CMS1. A crossover is revealed in the critical SMA region. We conclude that at least one of the CMS1 subloci maps proximal to the SMA gene. This reduces the minimal SMA region from approximately 1.4 Mb to 600-700 kb.

Chromosome Mapping↗

PubMed2002

Spinal muscular atrophy genetic testing experience at an academic medical center.

Approximately 94% of spinal muscular atrophy (SMA) patients lack both copies of SMN1 exon 7. We report our SMA genetic testing experience (total 1281 cases), using SMA linkage analysis (32 families), SMA diagnostic testing by PCR-RFLP (restriction fragment length polymorphism) to detect the homozygous absence of SMN1 exon 7 (and exon 8) (533 cases), and an assay to determine copy number of SMN1 exon 7 (SMN1 gene dosage analysis) (716 cases). SMN1 gene dosage analysis is used for SMA carrier testing as well as for the confirmation of a heterozygous SMN1 deletion in symptomatic individuals who do not lack both copies of SMN1. We conclude that comprehensive SMA testing, including SMN1 deletion analysis, SMN1 gene dosage analysis, and linkage analysis, offers the most complete evaluation of SMA patients and their families.

Chromosome Mapping↗

PubMed1997

De novo rearrangements found in 2% of index patients with spinal muscular atrophy: mutational mechanisms, parental origin, mutation rate, and implications for genetic counseling.

Spinal muscular atrophy (SMA) is a relatively common autosomal recessive neuromuscular disorder. We have identified de novo rearrangements in 7 (approximately 2%) index patients from 340 informative SMA families. In each, the rearrangements resulted in the absence of the telomeric copy of the survival motor neuron (SMN) gene (telSMN), in two cases accompanied by the loss of the neuronal apoptosis-inhibitory protein gene . Haplotype analysis revealed unequal recombination in four cases, with loss of markers Ag1-CA and C212, which are near the 5' ends of the SMN genes. In one case, an interchromosomal rearrangement involving both the SMN genes and a regrouping of Ag1-CA and C212 alleles must have occurred, suggesting either interchromosomal gene conversion or double recombination. In two cases, no such rearrangement was observed, but loss of telSMN plus Ag1-CA and C212 alleles in one case suggested intrachromosomal deletion or gene conversion. In six of the seven cases, the de novo rearrangement had occurred during paternal meiosis. Direct detection of de novo SMA mutations by molecular genetic means has allowed us to estimate for the first time the mutation rate for a recessive disorder in humans. The sex-averaged rate of 1.1 x 10(-4), arrived at in a proband-based approach, compares well with the rate of 0.9 x 10(-4) expected under a mutation-selection equilibrium for SMA. These findings have important implications for genetic counseling and prenatal diagnosis in that they emphasize the relevance of indirect genotype analysis in combination with direct SMN-gene deletion testing in SMA families.

Alleles↗

PubMed1998

Intragenic telSMN mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number.

The autosomal recessive neuromuscular disorder proximal spinal muscular atrophy (SMA) is caused by the loss or mutation of the survival motor neuron (SMN) gene, which exists in two nearly identical copies, telomeric SMN (telSMN) and centromeric SMN (cenSMN). Exon 7 of the telSMN gene is homozygously absent in approximately 95% of SMA patients, whereas loss of cenSMN does not cause SMA. We searched for other telSMN mutations among 23 SMA compound heterozygotes, using heteroduplex analysis. We identified telSMN mutations in 11 of these unrelated SMA-like individuals who carry a single copy of telSMN: these include two frameshift mutations (800ins11 and 542delGT) and three missense mutations (A2G, S262I, and T274I). The telSMN mutations identified to date cluster at the 3' end, in a region containing sites for SMN oligomerization and binding of Sm proteins. Interestingly, the novel A2G missense mutation occurs outside this conserved carboxy-terminal domain, closely upstream of an SIP1 (SMN-interacting protein 1) binding site. In three patients, the A2G mutation was found to be on the same allele as a rare polymorphism in the 5' UTR, providing evidence for a founder chromosome; Ag1-CA marker data also support evidence of an ancestral origin for the 800ins11 and 542delGT mutations. We note that telSMN missense mutations are associated with milder disease in our patients and that the severe type I SMA phenotype caused by frameshift mutations can be ameliorated by an increase in cenSMN gene copy number.

Alleles↗

PubMed2005

In vitro restoration of functional SMN protein in human trophoblast cells affected by spinal muscular atrophy by small fragment homologous replacement.

The majority of patients affected by spinal muscular atrophy (SMA) have deletion of the survival of motor neuron 1 (SMN1) gene, but they retain a "nonfunctional" copy of the duplicate gene (SMN2) in their genome. SMN2 produces defective SMN protein because of a C --> T transition in exon 7, which causes the skipping of exon 7 during SMN mRNA maturation. Many attempts have been made to correct altered SMN gene expression and to increase the level of normal SMN protein, but to date an effective treatment for this disease has not been established. Small Fragment Homologous Replacement (SFHR) is a site-specific gene modification approach that has the potential to maintain the genomic organization necessary for expression. The target modification in the genome is mediated by small DNA fragments (SDFs) 400-800 bp in length. In this study we used SFHR to induce a T --> C transition at codon 280 in exon 7 of the SMN2 gene in order to produce an increase in functional SMN protein. SDFs were transfected in vitro into cells obtained from five human fetal chorionic villi of embryos, homozygous for the SMN1 deletion, by either electroporation or microinjection. Transfected SMA cells showed an increase of up to 53% in full-length SMN mRNA compared with untransfected controls, as detected by real-time polymerase chain reaction. Consistent with the RNA data, immunocytochemistry and immunoblotting revealed a significant 2-fold increase in wild-type SMN protein. Furthermore, genotype and phenotype of transfected cells remained stable after several in vitro passages, demonstrating the stability of the correction over time.

Cells, Cultured↗

PubMed1977

High incidence of spinal muscular atrophy type I (Werdnig - Hoffmann disease) in the Karaite community in Israel.

Spinal muscular atrophy (S.M.A.) type I (Infantile werdnig - Hoffmann Disease) was found in 4:1,600 (1:400) infants of the Egyptian Karaite community. This group constitutes a representative sample of the Egyptian Karaite community in Israel, which numbers at present somewhat more than 7,000. The community existed as a religious and reproductive isolate for over 10 centuries. The very high gene frequency, 0.05 for the autosomal recessive gene of S.M.A. type I, is probably the result of genetic drift.

Child, Preschool↗

PubMed2006

Randomized, double-blind, placebo-controlled trial of phenylbutyrate in spinal muscular atrophy.

OBJECTIVE: To assess the efficacy of phenylbutyrate (PB) in patients with spinal muscular atrophy in a randomized, double-blind, placebo-controlled trial involving 10 Italian centers. METHODS: One hundred seven children were assigned to receive PB (500 mg/kg/day) or matching placebo on an intermittent regimen (7 days on/7 days off) for 13 weeks. The Hammersmith functional motor scale (primary outcome measure), myometry, and forced vital capacity were assessed at baseline and at weeks 5 and 13. RESULTS: Between January and September 2004, 107 patients aged 30 to 154 months were enrolled. PB was well tolerated, with only one child withdrawing because of adverse events. Mean improvement in functional score was 0.60 in the PB arm and 0.73 in placebo arm (p = 0.70). Changes in the secondary endpoints were also similar in the two study arms. CONCLUSIONS: Phenylbutyrate was not effective at the regimen, schedule, and duration used in this study.

Child↗

PubMed2003

Deletion of the SMN1 and NAIP genes in Vietnamese patients with spinal muscular atrophy.

The SMN1 and NAIP genes are related to the development of spinal muscular atrophy (SMA), which is characterized by degeneration of motor neurons leading to progressive muscular weakness and atrophy. The SMN1 gene is homozygously deleted in most SMA patients, and now recognized as a responsible gene for SMA. The NAIP gene is often deleted in the SMA patients with the severest form of SMA, and now considered to be a modifying factor of the severity of SMA. Our previous study of five Vietnamese SMA patients showed that the SMN1 gene deletion was detected in one patient, although the NAIP gene deletion was not detected in any patients. In this study, we analyzed 12 Vietnamese SMA patients who were not enrolled in the previous study. The SMN1 gene was homozygously deleted in six out of 12 patients, and the NAIP gene deletion was detected in five patients. Taken together with our previous data, the SMN1 gene deletion was detected in seven out of 17 Vietnamese SMA patients and the NAIP gene deletion in five out of 17 Vietnamese SMA patients. These studies suggest that the SMN1 and NAIP gene deletions are not rare in Vietnamese SMA patients. Thus, the confirmation of SMA-related gene deletion will also be a useful tool for the diagnosis of SMA in Vietnam.

Asian People↗

PubMedDate not supplied

Facioscapulohumeral type spinal muscular atrophy: report of a case.

A case of muscular weakness and atrophy with a facioscapulohumeral distribution is described in this report. The neurogenic origin, as judged from the results of laboratory studies, is discussed. The diagnosis and classification of the spinal muscular atrophy syndrome are also discussed. Facioscapulohumeral type spinal muscular atrophy is thought to constitute a distinct form of spinal muscular atrophy.

Adolescent↗

PubMed2003

Classical infantile spinal muscular atrophy with SMN deficiency causes sensory neuronopathy.

OBJECTIVE: Classic infantile spinal muscular atrophy (SMA) is believed to be a purely motor disorder, affecting neurons of the spinal anterior horn and nuclei of the lower cranial nerves. Other organ malformations or peripheral nerve involvement have been regarded as exclusion criteria for infantile SMA. Whether SMN protein deficiency can also lead to loss of sensory neurons has not been systematically addressed. METHODS: The authors evaluated the sural nerve biopsies of 19 patients with infantile SMA of varying severity. The diagnosis of SMA was confirmed by the presence of a homozygous deletion of the SMN1 gene in all patients. RESULTS: In seven unrelated infants with SMA type I, axonal degeneration of the sural nerve was noted. Five patients showed abnormal sensory conduction, thus prompting sural nerve biopsy. Sural nerves showed different degrees of axonal loss: fiber density ranged from 3.482 to 22.076/mm2 and was markedly reduced in four patients. There was no evidence of primary demyelination: the ratio of total myelinated fiber thickness to axon diameter (g-ratio) was normal in the patients examined. In seven patients with SMA II and five patients with SMA III, no sural nerve alterations were seen, and conduction velocity was normal. In addition to SMN1 gene deletions, homozygous NAIP gene deletions were detected in six out of seven infants with peripheral neuropathy, whereas there was no evidence of a large deletion including the multicopy markers C212 and Ag1-CA in two out of three families tested. CONCLUSIONS: In this series of patients with SMA I through III who underwent sural nerve biopsy, there was significant sensory nerve pathology in severely affected patients with SMA type I, whereas there were no sensory nerve alterations clinically or morphologically in patients with milder SMA type II or III.

Axons↗

PubMed2005

Prenatal diagnosis of spinal muscular atrophy in Chinese by genetic analysis of fetal cells.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of anterior horn cells of the spinal cord. The survival motor neuron gene is SMA-determining gene deleted in approximately 95% of SMA patients. This study was undertaken to predict prenatal SMA efficiently and rapidly in families with previously affected child. METHODS: Prenatal diagnosis was made in 8 fetuses with a family history of SMA. Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used for the detection of the survival motor neuron gene. RESULTS: The survival motor neuron gene was not found in 6 fetuses, ruling out the diagnosis of SMA. Two fetuses were detected positive and the pregnancies were terminated. CONCLUSION: Our method is effective and convenient in prenatal diagnosis of SMA.

Adult↗

PubMed1978

Incidence, prevalence, and gene frequency studies of chronic childhood spinal muscular atrophy.

A total population study of chronic childhood spinal muscular atrophy (arrested Werdnig-Hoffmann disease, Kugelberg-Welander disease, SMA type II and III) was undertaken in north-east England to establish gene and carrier frequencies, incidence, and prevalence. The incidence of this disease was 1 in 24 100 live births. Prevalence was 1.20 per 100,000 of the general population. A technique for estimating an autosomal recessive gene frequency in the known presence of dominant new mutations (or phenocopies), using data from a segregation analysis, is described. Gene frequency was in the range (0.00451 to 0.00659 (95% confidence limits), with a working estimate of 0.0055. Carrier rates for the autosomal recessive gene concerned were 1 in 76 to 1 in 111 (95%) confidence limits), with a working estimate of 1 in 90 for genetic counselling purposes.

Child, Preschool↗

PubMed1982

[Proximal spinal muscular atrophies].

The author observed 24 patients with proximal spinal muscular atrophies (PSMA) 15 of whom were suffering from Kugelberg-Welander's disease, and 9 from the intermediate form. In addition to the conventional neurological examinations carried out in all the patients, 11 patients were also examined electroneuromyographically. A genetic analysis of affected families was performed. The analysis showed that the disease forms being studied were inherited according to the autosomo-recessive type: this was in agreement with literary data. The age of the disease onset, the clinical manifestations of the disease, particularly, the character of the atrophies and their prevalent localization; the course and the degree of the disease progress, and the prognosis were also analyzed. The author discusses the character of the electroneuromyograms that showed a typical picture of motoneuron affection, while the conductivity of motor nerves remained normal, though showed signs of an increase of motor unit parameters with a decrease of the number of voluntarily-activated units, i.e. a diminution of mobilization. The degree of the EMG amplitude lowering during voluntary muscular contractions correlated with the disease gravity. The speed of the impulse conduction was normal. The data presented may be of a certain significance for medico-genetic consultations.

Diagnosis, Differential↗

PubMed1985

Diaphragmatic paralysis due to spinal muscular atrophy. An unrecognised cause of respiratory failure in infancy?

An unusual form of spinal muscular atrophy presenting with respiratory failure was observed in four infants from two families. In one, whose death was attributed to pneumonia, the diagnosis was inferred retrospectively after two siblings died from an identical illness and were shown to have diaphragmatic paralysis and the typical electrophysiological and histological features of spinal muscular atrophy. Other signs of skeletal muscular weakness were absent or inconspicuous. The fourth, unrelated infant presented in an identical way but has survived for over a year on a ventilator. Two months after the onset of respiratory paralysis, more extensive skeletal muscular weakness was seen. Other infants, dying of unexplained respiratory illness, may have this disorder and some may be included in the miscellany of disorders that constitute the sudden infant death syndrome.

Female↗

PubMed2005

[Spinal muscular atrophy. A 4-year prospective, multicenter, longitudinal study (168 cases)].

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterised by motoneuron degeneration in the anterior horn of the spinal cord and in the bulbar nuclei. The various types of SMA are linked to the 5q13 locus in 95 % of cases. In the absence of an effective specific treatment, orthopaedic and respiratory management can significantly improve the prognosis. To study the contemporary natural history of SMA and to identify clinical and non invasive prognostic criteria, 168 patients with SMA were recruited in 6 hospital units (Lille, Lyon, Marseille, Paris) during a 4-year prospective multicenter follow-up study (1998-2002). Follow-up has now lasted at least 4 years in 151 cases (90%), and 24 of these patients have died Disease outcome was appraised by using three criteria: muscle strength, the sum of the motor function and examination index (IFM), the respiratory muscle paralysis index (IMR), and the dorsal decubitus forced vital capacity/theoretical index (ICV/CT). Statistical analysis showed a significant worsening (about 20%) of the three criteria during follow-up. The motor function and examination index (IFM) is particularly interesting: the difference between initial and final status was significant in all age groups and in all three types of the disease. The IFM may thus be useful as the main outcome measure during therapeutic trials.

Adolescent↗

PubMed2002

Spinal muscular atrophy: state-of-the-art and therapeutic perspectives.

Proximal spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans caused by degeneration of alpha motor neurons in the anterior horns of the spinal cord. This affects voluntary movements, leading to muscle weakness and atrophy. SMA is caused by homozygous deletions/mutations in the survival motor neuron gene 1 (SMN1). The severity of the phenotype is modulated by the copy number of SMN2 and by other yet unknown factors. SMN2 is affected by a critical non-translational nucleotide exchange in exon 7 that disrupts an exonic splicing enhancer. In consequence SMN2 produces mainly alternatively spliced mRNA that lacks exon 7. Trans-activating factors such as Htra2-beta1, as well as various drugs like sodium butyrate or aclarubicin, are able to restore the full-length SMN2 RNA to large amounts. Since each SMA patient carries at least one SMN2 copy, reconstitution of full-length SMN2 protein is an exciting strategy for somatic gene therapy in SMA patients.

Animals↗