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PubMed2004

Survival of motor neuron gene downregulation by RNAi: towards a cell culture model of spinal muscular atrophy.

Gene silencing with double-stranded RNA (RNAi) has proved useful for gene function studies, and should be especially well suited to studying diseases resulting in embryonal lethality where transgenic animal models are difficult to generate. We are applying this approach to the autosomal recessive disease spinal muscular atrophy (SMA). SMA is caused by mutations in the survival of motor neuron gene (SMN). The SMN protein is ubiquitously expressed and plays a role in RNA processing and its reduction in SMA ultimately leads to motor neuron degeneration in the spinal cord. The reasons for this motor neuron selectivity, however, are still unclear. SMN is essential for the viability of most eukaryotic organisms and this has made the generation of animal models of SMA extremely difficult. Here we describe a different approach to study SMN function using RNAi to silence SMN expression in cells. We designed double-stranded small interfering RNA (siRNA) targeted against murine Smn and transfected the murine embryonal terato-carcinoma cell line P19. The siRNAs reduced both Smn RNA and protein levels in the P19 cells compared to controls. These results illustrate that double-stranded RNA can be an effective gene silencing approach even in a protein that is essential for survival and highly expressed, and it could therefore be a valuable tool to study SMN function.

Animals↗

PubMed1995

Expression of developmentally regulated cytoskeleton and cell surface proteins in childhood spinal muscular atrophies.

Expression of some developmentally regulated cytoskeleton components (desmin, vimentin and myosin heavy chain isoforms) and cell surface proteins (including neural cell adhesion molecule (NCAM), its polysialylated (PSA) isoform and CD24) have been studied by immunohistochemical detection in a series of 23 infantile spinal muscular atrophies (SMA). According to the clinical classification established by Byers and Banker in 1961, 8 cases were type I SMA (Werdnig-Hoffmann's disease), 10 cases were type II (intermediate form), and 5 cases were type III (Kugelberg-Welander's disease). In 15 cases, the percentage of immunoreactive fibers with the various antibodies used has been quantified and the results correlated with clinical data. The aim of the study was to search for variations in the pattern of expression of the proteins to improve the accuracy of diagnosis and prognosis, and to gain an understanding of the pathological processes involved in SMA. The results showed that the pattern of expression of these cytoskeleton and cell surface proteins is abnormal in all types of SMA. However, it was strikingly different in type I and II SMA as opposed to type III. In type I and II SMA, strong NCAM and developmental myosin heavy chain (MHC) expression was observed in atrophic fibers. Numerous atrophic fibers co-expressed desmin and vimentin as well as slow and fast adult MHC. Very few of them expressed PSA NCAM, fetal MHC and CD24. In type III SMA, the number of fibers expressing NCAM, developmental MHC and co-expressing slow and fast adult MHC was low and virtually none of them expressed vimentin or desmin. These findings are in favor of a denervation process occurring very early in life, probably even in utero, in type I and II SMA and leading to a severe impairment of muscle fibers maturation. In contrast, in type III SMA, the process is initiated well after birth and affects mature muscle fibers. In all types of SMA, the ability of muscle fibers to regenerate is low, although some fibers may be reinnervated. Immunohistochemical data was not related to the patients follow-up and thus has no prognostic value.

Adolescent↗

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↗

PubMed2003

Role of gabapentin in spinal muscular atrophy: results of a multicenter, randomized Italian study.

Recent studies suggest that gabapentin has a neuroprotective effect in experimental models of motoneuron disease. We carried out a multicenter, randomized, controlled trial of gabapentin versus no treatment in 120 patients with type II or III spinal muscular atrophy for 12 months. We assessed maximum voluntary isometric contraction with a handheld myometer and calculated an arm megascore (summing elbow flexion, hand grip, and three-point pinch scores), and a leg megascore (summing knee flexion, knee extension, and foot extension scores). Forced vital capacity and timed tasks were also evaluated. Arm megascore improved by at least 30% in 24.6% of treated and 16.9% of untreated patients (relative risk = 1.45; 95% confidence interval = 0.71-2.97). The leg megascore improved by at least 30% in 37.7% of treated and 20.3% of untreated patients (relative risk = 1.85; 95% confidence interval = 1.02-3.37). We conclude that gabapentin produced a significant improvement in leg megascore at 6 months, which was more evident at 12 months, with a trend for improvement in arm megascore at 12 months. The treatment had no effect on forced vital capacity or timed functional tests.

Acetates↗

PubMed1991

Acute onset spinal muscular atrophy in siblings.

We describe two sisters who each presented in infancy with acute, severe, generalised weakness and are-flexia in association with an intercurrent infection. The clinical picture resembled acute polyneuritis, but EMG findings and the later clinical features were consistent with a diagnosis of spinal muscular atrophy. Although symptoms in SMA may be exacerbated by infection, immunisation or trauma, this unusual presentation of the condition in siblings suggests that this may constitute a genetically distinct subgroup of the disorder.

Acute Disease↗

PubMed1995

[Early myoclonic encephalopathy and spinal muscular atrophy type I].

The authors describe the case of a floppy baby with the typical features of early myoclonic encephalopathy, represented by erratic and partial myoclonus of early onset and electroencephalographical suppression-burst pattern. Muscle biopsy made it possible to recognize an important neurogenic pattern, suggesting a severe form of spinal muscular atrophy. The association of these two disorders has never been reported.

Brain↗

PubMed1986

Unusual pedigree patterns in seven families with spinal muscular atrophy; further evidence for the allelic model hypothesis.

Clinical and genetic findings are presented in 18 patients, from 7 pedigrees with different types of spinal muscular atrophy (SMA). The SMA diagnosis was based on EMG and muscle biopsy findings. All 7 pedigrees show an unusual genetic pattern, not consistent with simple autosomal recessive inheritance. Furthermore, in 6 of the 7 pedigrees different types of SMA were present within each pedigree. Our findings can be explained by an extension of a multiple alleles hypothesis originally described by Becker in 1964.

Alleles↗

PubMed1987

Cell adhesion molecule N-CAM is expressed by denervated myofibres in Werdnig-Hoffman and Kugelberg-Welander type spinal muscular atrophies.

Immunocytochemical analysis utilising antibody to neural cell adhesion molecule (N-CAM) was carried out on skeletal muscle biopsies from patients with childhood spinal muscular atrophy. Children with both Werdnig-Hoffmann and Kugelberg-Welander disease showed positive N-CAM reactivity. There were however differences in the N-CAM expression profiles in these two sets of patients. All myofibres were positive for N-CAM in the Werdnig-Hoffmann patients. This included both the normal sized fibres and the atrophic fibres. In contrast only the atrophic fibres were positive in the Kugelberg-Welander patients. No reactivity was found associated with the large hypertrophic fibres. It is likely that in the Werdnig-Hoffmann patients the positive N-CAM reactivity reflects unstable innervation of myofibres that had been previously innervated. A similar mechanism may operate in the Kugelberg-Welander patients, but the innervation of the hypertrophic fibres is more stable as they are able to repress N-CAM expression. These results contrast with a lack of N-CAM expression found previously on muscle biopsies from adults with denervation disease.

Antigens, Surface↗

PubMed2001

Fracture risk in patients with muscular dystrophy and spinal muscular atrophy.

We aimed at studying fracture risk in patients with Duchenne's muscular dystrophy (DMD), Becker's muscular dystrophy (BEMD), and spinal muscular atrophy type II and III (SMA II and III). A self-administered questionnaire was mailed to 293 patients with DMD, BEMD, SMA II or SMA III of which 229 returned the questionnaire. Each respondent was compared with an age- and gender-matched control subject. The mean age was 23.9 +/- 15.9 years for the patients and 23.3 +/- 16.5 years for the controls. There were significantly more fractures among patients than controls after the diagnosis was made (RR = 1.9), but not before. The patients had more fractures of the femurs, lower legs, and upper arms than the controls. Low energy fractures were more frequent in patients than controls (9% vs 0%). Many fractures in the femurs (40%), lower legs (35%), and feet and toes (44%) led to a permanent loss of function. Loss of ambulation was the major risk factor for fractures. In conclusion, fracture risk is increased in neuromuscular disease.

Adolescent↗

PubMed1994

Muscle biopsy in juvenile distal spinal muscular atrophy.

The myopathological changes in properly selected muscles can allow evaluation of the definite distribution of neuronogenic denervation which can probably not be found by clinical examination or EMG study of inadequate muscle sampling. We performed muscle biopsies in 13 Chinese patients with chronic juvenile monomelic motor neuron disease involving the distal part of the upper extremities. According to our findings and the literature review, the neurogenic changes selectively affected the muscles innervated by C7, 8 and T1 spinal nerves while sparing others. Consequently, the term 'juvenile lower cervical spinal muscular atrophy' is suggested.

Adolescent↗

PubMed2001

[Very severe spinal muscular atrophy--type 0. A cause of congenital multiple arthrogryposis].

A female infant born at term, with reduced fetal movements in utero, congenital multiple contractures, severe weakness at birth, and a short time of survival is described. The diagnosis was confirmed by identification of homozygous deletion of exons 7 and 8 of the SMNt gene. Severe spinal muscular atrophy should be considered in the differential diagnosis of reduced fetal movements.

Arthrogryposis↗

PubMed1981

Autosomal dominant late adult spinal muscular atrophy, type Finkel.

We describe clinical and genetic data from the study of two families with 80 members affected with the autosomal dominant, slowly progressive spinal muscular atrophy of late onset (average 48.8 years), first described by Finkel in 1962. Electromyography and muscle biopsy of a number of patients confirmed the neurogenic nature of the conditions. Unusual findings in this disorder were cramps, spontaneous fits of suffocation, and symptomatic myotonia. Other manifestations are slow loss of muscle strength and progressive proximal atrophy, which starts in the lower limbs and progresses to the upper limbs; hypoactive or absent tendinous reflexes; and generalized fasciculations. Sensory and cranial nerve function is unimpaired. Probabilities for genetic counseling are evaluated by means of a method adequate to the late-onset nature of the condition.

Diagnosis, Differential↗

PubMed1984

Single fiber electromyography in the differential diagnosis of myopathic limb girdle syndromes and chronic spinal muscular atrophy.

Single fiber electromyography ( SFEMG ) of the extensor digitorum communis muscle was performed on 20 patients with either myopathic limb girdle syndromes ( LGS ) or chronic spinal muscular atrophy ( CSMA ) to assess its value in the differential diagnosis of these disorders. Neurologic examinations (muscle biopsies, standard electromyography, or both) were reviewed in 16 patients and resulted in diagnosing LGS in 11 patients and CSMA in 5 patients. In four patients, discordance between EMG and biopsy, or mixed features of myopathy and neuropathy in either test, resulted in an indeterminate diagnosis. Two groups were discerned from SFEMG , one with higher fiber density, jitter, and percentage of abnormal pairs consistent with neuropathy and another with lower values consistent with myopathy. In all 16 patients, SFEMG confirmed the initial diagnosis, and in the four patients with indeterminate diagnoses, SFEMG suggested diagnoses of LGS in two patients and CSMA in two patients. Single fiber electromyography may be a useful diagnostic aid in the differential diagnosis of myopathic LGS and CSMA .

Adolescent↗

PubMed1980

Hereditary distal spinal muscular atrophy. A report on 34 cases and a review of the literature.

A description is given of 34 patients with the distal form of hereditary spinal muscular atrophy. This disorder constitutes one form of "peroneal muscular atrophy". It resembles types I and II hereditary motor and sensory neuropathy but differs from them in displaying less upper limb weakness, relative preservation of the tendon reflexes and an entirely normal clinical sensory examination. Motor nerve conduction velocity and sensory nerve action potentials are normal. Previous reports of this disorder are reviewed and compared with the present series.

Adolescent↗

PubMed1986

Localization of the gene for X-linked spinal muscular atrophy.

We used probes for DNA polymorphisms on the X chromosome to study genetic linkage in seven families with X-linked adult-onset spinal muscular atrophy. We found significant linkage to the marker DXYS1 on the proximal X chromosome long arm and loose linkage or nonlinkage to markers elsewhere. Our analysis localizes the gene defect for this form of anterior horn cell disease.

Adult↗

PubMed2002

SMN, the spinal muscular atrophy protein, forms a pre-import snRNP complex with snurportin1 and importin beta.

The survival of motor neuron (SMN) protein is mutated in patients with spinal muscular atrophy (SMA). SMN is part of a multiprotein complex required for biogenesis of the Sm class of small nuclear ribonucleoproteins (snRNPs). Following assembly of the Sm core domain, snRNPs are transported to the nucleus via importin beta. Sm snRNPs contain a nuclear localization signal (NLS) consisting of a 2,2,7-trimethylguanosine (TMG) cap and the Sm core. Snurportin1 (SPN) is the adaptor protein that recognizes both the TMG cap and importin beta. Here, we report that a mutant SPN construct lacking the importin beta binding domain (IBB), but containing an intact TMG cap-binding domain, localizes primarily to the nucleus, whereas full-length SPN localizes to the cytoplasm. The nuclear localization of the mutant SPN was not a result of passive diffusion through the nuclear pores. Importantly, we found that SPN interacts with SMN, Gemin3, Sm snRNPs and importin beta. In the presence of ribonucleases, the interactions with SMN and Sm proteins were abolished, indicating that snRNAs mediate this interplay. Cell fractionation studies showed that SPN binds preferentially to cytoplasmic SMN complexes. Notably, we found that SMN directly interacts with importin beta in a GST-pulldown assay, suggesting that the SMN complex might represent the Sm core NLS receptor predicted by previous studies. Therefore, we conclude that, following Sm protein assembly, the SMN complex persists until the final stages of cytoplasmic snRNP maturation and may provide somatic cell RNPs with an alternative NLS.

Carrier Proteins↗

PubMed1997

Congenital axonal neuropathy caused by deletions in the spinal muscular atrophy region.

Three newborn siblings presented with generalized weakness, asphyxia, facial diplegia, and external ophthalmoplegia. Electrophysiological testing showed inexcitability of motor and sensory nerves and myographic signs of denervation. Nerve biopsies and postmortem examination showed loss of myelinated fibers and axonal damage in sensory and mixed nerves. Many spinal motor neurons were chromatolytic although their number was normal. Molecular genetic investigations revealed a homozygous deletion of the survival motor neuron (SMN) gene and a loss of markers Ag1-CA and C212 in the paternal haplotype. These findings are consistent with the diagnosis of an unusually severe type of spinal muscular atrophy. Given the large extent of the deletion, it must be considered that the unusual severe phenotype with involvement of brainstem nuclei and afferent nerves might also be due to changes of yet unknown genes neighboring the SMN gene.

Axons↗

PubMed2000

An essential SMN interacting protein (SIP1) is not involved in the phenotypic variability of spinal muscular atrophy (SMA).

The survival motor neuron (SMN) protein and the SMN interacting protein 1 (SIP1) are part of a 300 kD protein complex with a crucial role in snRNP biogenesis and pre-mRNA splicing. Both proteins are colocalised in nuclear structures called gems and in the cytoplasm. Approximately 96% of patients with autosomal recessive spinal muscular atrophy (SMA) show mutations in the SMN1 gene, while about 4% fail to show any mutation, despite a typical SMA phenotype. Additionally, sibs with identical 5q13 homologs and homozygous absence of SMN1 can show variable phenotypes which suggest that SMA is modified by other, yet unknown factors. Since both genes, SMN1 and SIP1, belong to the same pathway and are part of the same protein complex, it is obvious to ask whether mutations within SIP1 are responsible for both the phenotypic variability and the appearance of non-SMN mutated SMA patients. First, we identified the chromosomal location of SIP1 and assigned it to chromosomal region 14q13-q21 by fluorescence in situ hybridisation. No SMA related disorder has yet been assigned to this chromosomal region. Next, we determined the exon-intron structure of the SIP1 gene which encompasses 10 exons and identified five transcription isoforms. We sequenced either RT-PCR products or genomic DNA covering the complete coding region from 23 typical SMA patients who had failed to show any SMN1 mutation. No mutation and no polymorphism was found within SIP1. Additionally, we sequenced RT-PCR products or genomic fragments of the entire SIP1 coding region from 26 sibs of 11 SMA families with identical genotypes (delta7SMN/delta7SMN or delta7SMN/other mutation) but different phenotypes and again no mutation was found. Finally, we performed quantitative analysis of RT-PCR products from the same 26 sibs. No difference in expression level of the five isoforms among phenotypically variable sibs was observed. Based on these data, we suggest that neither the phenotypic variability nor the 5q-unlinked SMA are caused by mutations within SIP1.

Alternative Splicing↗