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PubMed1997

Spinal muscular atrophy--clinical and genetic correlations.

A clinical and molecular genetic study of nearly 500 patients with proximal spinal muscular atrophy (SMA) was undertaken. On the basis of defined achieved milestones, survival probabilities in type I (never able to sit), type II (able to sit but not to walk) and the probability of being ambulatory in type III (achieved ability to walk) SMA for a total of 445 patients with SMA are given. Specific deletions of the survival motor neuron (SMN) gene were found in 96% type I, 94% type II and 82% type III in a total of 191 patients, while four SMA type IV patients with an age of onset beyond 30 years were not deleted. The SMN gene obviously plays an important role in the pathogenesis of SMA but there is evidence that the SMN gene is not the SMA gene itself. The demonstration of SMN deletions in healthy siblings of affected persons, the high intrafamilial similarity of the clinical course on the background of a broad clinical spectrum of proximal SMA and the demonstration of different mutations causing different clinical manifestations in single pedigrees indicate that additional genetic factors might be relevant. Linkage studies, as well as the analysis of the SMN gene, recognised that SMA variants (with severe arthogryposis or cerebellar or diaphragmatic involvement) are not linked to chromosome 5q markers.

Chromosome Aberrations↗
PubMed1995

Neonatal spinal muscular atrophy with diaphragmatic paralysis is unlinked to 5q11.2-q13.

Two sibs affected by the severe neonatal form of spinal muscular atrophy (SMA) with diaphragmatic paralysis are described. The two sibs were discordant for the haplotypes determined by DNA markers flanking the SMA locus. This supports non-linkage of SMA to chromosome 5 in this family and indicates that the uncommon SMA type I variant associated with early onset respiratory failure maps outside the 5q11.2-q13.3 region.

Adult↗
PubMed1989

[Familial spinal muscular atrophy of the Kugelberg-Welander type].

The patients was a 16-year old girl with the spinal muscular atrophy. Clinical laboratory and genetic investigations were performed. A close relative of the proband suffering from the same ailment was found in analysing the genealogic tree. Enzymatic study (creatine phosphokinase, lactic dehydrogenase) of the proband and her parents proved the autosome-recessive type of inheriting the disorder.

Adolescent↗
PubMed1997

Clinical application of the molecular diagnosis of spinal muscular atrophy: deletions of neuronal apoptosis inhibitor protein and survival motor neuron genes.

The molecular genetic diagnosis of spinal muscular atrophy (SMA) has recently been complicated by the identification of two candidate genes, which are often deleted in affected individuals but are also occasionally deleted in apparently unaffected carriers. We present a compilation of genotypes, from our laboratory and recent reports, for the survival motor neuron (SMN) and neuronal apoptosis inhibitor protein (NAIP) genes. Bayesian analyses were used to generate probabilities for SMA when deletions are present or absent in SMN. We found that when the SMN(T) exon 7 is deleted, the probability of SMA can reach greater than 98% in some populations, and when SMN(T) is present, the probability of SMA is approximately 17 times less than the prior population risk. Deletion of NAIP exon 5, as well as SMN(T) exon 7, is associated with a 5-fold increased risk of type I SMA. Case studies are used to illustrate differing disease risks for pre- and postnatal testing, depending on the presence of information about clinical status or molecular results. These analyses demonstrate that deletion screening of candidate genes can be a powerful tool in the diagnosis of SMA.

Cyclic AMP Response Element-Binding Protein↗
PubMed1997

[Electromyogram (EMG) and muscle biopsy in patients with chronic spinal muscular atrophy].

The clinicopathological changes were investigated by electromyogram (EMG) and muscle biopsy in 30 cases of chronic spinal muscular atrophy. The results showed that the denervating changes were demonstrated in EMG in all patients but two. The light microscope discovered manifestation of neurogenic atrophy, and the electron microscope revealed a reduction of myofibrils, thickening and wavy appearance of Z-lines and dilation of mitochondria and endoplasmic reticula.

Adolescent↗
PubMed2005

Is spinal muscular atrophy the result of defects in motor neuron processes?

The hereditary neurodegenerative disease spinal muscular atrophy (SMA) with childhood onset is one of the most common genetic causes of infant mortality. The disease is characterized by selective loss of spinal cord motor neurons leading to muscle atrophy and is the result of mutations in the survival motor neuron (SMN) gene. The SMN protein has been implicated in diverse nuclear processes including splicing, ribosome formation and gene transcription. Even though the genetic basis of SMA is well understood, it is not clear how defects in these ubiquitous processes result in motor neuron degeneration leaving other tissues unaffected. Recent evidence from animal and cell culture models of SMA points to roles for SMN in neurite outgrowth and axonal transport. Disruption of these functions might be particularly detrimental to motor neurons given their high metabolic demands and precise connectivity requirements, thus providing a possible explanation for the specificity of motor neuron susceptibility in SMA. Understanding the molecular mechanisms of SMN activity in neuronal processes may generate new targets for future therapeutic strategies.

Animals↗
PubMedDate not supplied

A clinical and genetic study of spinal muscular atrophy.

AIMS: This study evaluates clinical, electromyography (EMG) and genetic analysis of consecutive patients with spinal muscular atrophy (SMA) in a tertiary care adult neurology practice in India. METHODS: Consecutive patients with SMA attending the neurology out patient department during 2001-2003 were included. They were subjected to a detailed clinical examination, nerve conduction and EMG and muscle biopsy. Clinically patients were classified into generalised and segmental SMA. SMN gene deletion study was carried out in all the patients. RESULTS: There were 15 patients with type III and type IV SMA and 15 with segmental SMA (Hirayama disease). The age ranged between 5 and 23 years in type III SMA, 33-50 years in type IV SMA and 16-30 years in Hirayama disease (HD). The latter was found exclusively in males. Family history was observed in 1 patient each in all the groups. In SMA III mother and brother were affected, in SMA IV two siblings and in HD one brother had similar disease. One type III SMA family was associated with deafness and one type IV family had strong association with maturity onset diabetes in young. The EMG was characterised by lack of fibrillations in all type III and IV SMA patients except 1 whereas in HD, 11 out of 15 had fibrillations suggesting ongoing denervation. The EMG was suggestive of reinnervation in generalised SMA in both upper and lower limb muscles where as these abnormalities were restricted to C7-T1 mytomes in HD. Muscle biopsy in 10 patients with generalised SMA revealed group atrophy in all, and loss of fascicular architecture in 3, clumping of nuclei in 7 and hypertrophic fibers in 4. SMN1 gene deletion was present in 3 patients with type III but none in type IV and HD. CONCLUSION: SMN gene deletion was positive in 33% type III SMA whereas it was negative in type IV and HD. Presence of HD only in males may be consistent with X-linked disorder.

Adolescent↗
PubMed1984

[Clinical picture, pathogenesis and geneology of hereditary progressive spinal muscular atrophies].

A clinical-genealogical and electromyographic investigation of 142 patients with spinal muscular atrophies demonstrated a heterogeneous nature of spinal amyotrophies. A group of amyotrophies was specified as determined by the degeneration of only motor cells of the anterior corns. This group includes Werdnig-Hoffmann's infantile spinal amyotrophy, late childhood spinal amyotrophy, Kugelberg-Welander's juvenile amyotrophy, and late distal spinal amyotrophy. The group of spinal neural amyotrophies is made up of the clinical variants which are characterized by the parallel involvement of spinal motor cells and their axons. Spinal neural amyotrophies include the autosomal-recessive childhood and the autosomal-dominant juvenile variants.

Child↗
PubMed2002

Correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy: three SMN2 copies fail to rescue some patients from the disease severity.

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder that is characterized by degeneration of the anterior horn cells of the spinal cord, which leads to the axial and limb weakness associated with muscle atrophy. SMA is classified into three groups based on the clinical severity: type I (severe), type II (intermediate) and type III (mild). All three clinical subtypes of SMA are caused by mutations of the SMN1 gene. More than 95 % of SMA patients show homozygous deletion of SMN1. It is thought that SMN2, which is a highly homologous gene of SMN1, compensates for the SMN1 deletion to some degree. To clarify the relationship between SMN2 and the disease severity of SMA, we performed fluorescence-based quantitative polymerase chain reaction assay of the copy number of SMN2 in 27 patients (11 type I and 16 type II-III) homozygous for SMN1 deletion. The SMN2 copy number in type II-III patients was 3.1 +/- 0.3 (mean +/- SD), which is significantly higher than that observed in type I patients, 2.2 +/- 0.6 (P < 0.01). However, three of the 11 type I patients carried 3 SMN2 copies. A type I patient with 3 SMN2 copies was studied further. RT-PCR analysis of the patient showed a trace of full-length SMN2 mRNA species, but a large amount of the truncated SMN2 mRNA species lacking exon 7. In conclusion, SMN2 alleles are not functionally equivalent among SMA patients, although in general the SMN2 copy number is correlated with the severity of SMA. Genetic background influencing splicing mechanisms of the SMN2 gene may be more critical in some SMA patients.

Adolescent↗
PubMed2005

Sleep-disordered breathing in spinal muscular atrophy types 1 and 2.

OBJECTIVE: Our aim was to assess the respiratory pattern during sleep in patients affected by spinal muscular atrophy types 1 and 2 and to compare their apnea-hypopnea indices with those of controls. DESIGN: All consecutively referred patients underwent polysomnography. Sleep stages were defined as either wake, quiet sleep (QS), or active sleep (AS). As measures of thoracoabdominal coordination, we measured: phase angle during QS and AS (Ph Angle QS and AS), phase relation during inspiration and expiration during QS and AS: (Ph RIB QS, Ph RIB AS, Ph REB QS; Ph REB AS) and the apnea-hypopnea index. RESULTS: The 14 consecutively referred infants and small children (age, 11.7 +/- 11.4 mos) showed a higher apnea-hypopnea index (P < 0.001), Ph Angle QS (P < 0.001), Ph Angle AS (P < 0.001), Ph RIB QS (P < 0.001), Ph RIB AS (P < 0.001), Ph REB QS (P < 0.001), and Ph REB AS (P < 0.001) compared with 28 healthy controls (age, 10.1 +/- 8.9 mos). CONCLUSIONS: Patients affected by types 1 and 2 spinal muscular atrophy had significantly higher apnea-hypopnea indices than controls. Thoracoabdominal asynchrony was present during the inspiratory and expiratory phases in both quiet and active sleep. Measures of thoracoabdominal coordination may be useful for the evaluation and monitoring of therapeutic interventions for these patients.

Case-Control Studies↗
PubMed1979

Use of the ECG in the diagnosis of childhood spinal muscular atrophy.

The appearance of tremors in patients with childhood, chronic spinal muscular atrophy has been known for years. We were struck by the presence of a "muscle tremor" artifact in the ECGs of all our patients with this diagnosis. This observation has not been noted previously. The consistency of this finding in patients with this disease is the basis for this report.

Adolescent↗
PubMed1992

[Spinal muscular atrophy in Braunvieh calves].

Clinical, neurophysiological and histopathological findings of sixteen cases of spinal muscular atrophy in calves are described. The first clinical signs usually were noticed at 2-6 weeks of age. The animals showed weakness in the hindquarters, trembling and ultimate recumbency. There was a marked muscular atrophy in all four extremities. In addition, secondary bronchopneumonia was evident in 11 cases. Histopathological lesions consisted of degenerative changes in the neurons of the ventral horns and the axons of the spinal cord as well as degeneration of nerve axons in the extremities. Neurophysiological measurements revealed spontaneous activity in the muscles of the limbs. The conditions is autosomal recessive. So far 11 bulls have been identified and excluded from breeding.

Animals↗
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↗
PubMed1995

Identification of multiple transcribed sequences from the spinal muscular atrophy region of human chromosome 5.

We report the isolation and characterization of novel expressed sequences from the spinal muscular atrophy (SMA) region on human chromosome 5q13. Based on the sequence homology studies these cDNAs were grouped in four classes, one of which shows extensive homologies with the beta-glucuronidase (BG) gene, differing in exon arrangement. The other cDNAs do not show any strong homology with known DNA sequences.

Base Sequence↗
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

The spinal muscular atrophy disease gene product, SMN, and its associated protein SIP1 are in a complex with spliceosomal snRNP proteins.

Spinal muscular atrophy (SMA), one of the most common fatal autosomal recessive diseases, is characterized by degeneration of motor neurons and muscular atrophy. The SMA disease gene, termed Survival of Motor Neurons (SMN), is deleted or mutated in over 98% of SMA patients. The function of the SMN protein is unknown. We found that SMN is tightly associated with a novel protein, SIP1, and together they form a specific complex with several spliceosomal snRNP proteins. SMN interacts directly with several of the snRNP Sm core proteins, including B, D1-3, and E. Interestingly, SIP1 has significant sequence similarity with Brr1, a yeast protein critical for snRNP biogenesis. These findings suggest a role for SMN and SIP1 in spliceosomal snRNP biogenesis and function and provide a likely molecular mechanism for the cause of SMA.

3T3 Cells↗
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↗