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PubMed2004

Expression profiling in spinal muscular atrophy reveals an RNA binding protein deficit.

Spinal muscular atrophy is a common neuromuscular disorder caused by deletions or mutations within the survival motor neuron gene. The reason for specific motor neuron loss within the disease is still unclear. Expression profiling has been carried out in two models of spinal muscular atrophy; the heterozygote mouse model and human primary muscle cultures from a spinal muscular atrophy patient. A group of RNA binding proteins are up-regulated in spinal muscular atrophy motor neurons. One such protein, BRUNOL3, is highly expressed within spinal cord and muscle and also at the same developmental stage as survival motor neuron. The differential expression of Brunol3 has been confirmed with real-time RT-PCR in spinal cord and muscle of three different models of spinal muscular atrophy. BRUNOL3 has been shown to co-localise with survival motor neuron in the nuclei of neuronal cells and to co-immunoprecipitate with Smn in mouse brain. This is the first time that a link has been established between RNA binding proteins and survival motor neuron within motor neurons.

Adolescent↗

PubMed2000

[Genetically confirmed spinal muscular atrophy type III with epilepsy, cerebral hypoperfusion, and parahippocampal gyrus atrophy].

We report a 37-year-old female with spinal muscular atrophy (SMA) type III and central nervous system (CNS) involvement. She showed gait disturbance at the age of 12 years, and difficulty of squatting at the age of 19. On examination at the age of 22, she had proximal muscle weakness and atrophy, fasciculation, normal sensory system and elevated creatine kinase in the serum. She was diagnosed as having SMA type III based on clinical, electrophysiological, and muscle biopsy findings. She suffered from subacute necrotizing lymphadenitis at the age of 23 and from epilepsy at the age of 33. Magnetic resonance imaging showed atrophy of parahippocampal gyrus with right side predominance. Single photon emission computed tomography (SPECT) using I123-IMP showed decreased accumulations of I123-IMP in the temporal lobes with left side predominance. Electroencephalogram showed theta wave without epileptic burst. SMA gene analysis revealed deletion of exon 7 and 8 in survival motor neuron (SMN) gene. A few patients with SMA and CNS involvement have been reported without genetic diagnosis. This is the first report of genetically confirmed SMA patient with CNS involvement. SMN gene is distributed not only in spinal cord but also in brain. The CNS involvement detected in this patient may be related to the loss of SMN gene function, although coincidental association of SMA and the CNS abnormalities is still considered in this atypical case.

Adult↗

PubMed1992

Medical therapy in spinal muscular atrophy: a realistic expectation?

The hereditary spinal muscular atrophies (SMA) type I-III belong to those diseases for which even the thought of medical therapy seems forbidden. Two neurotrophic factors are, however, now known to exert a markedly stimulating effect on survival of motor neurons in vivo! In principle such factors may become available by recombinant DNA techniques for experiments in animal models of SMA and if these experiments are successful for clinical trials in man. Medical therapy in SMA should aim primarily at patients early in the rapidly progressive phase of their disease, before massive loss of motoneuron has taken place.

Adrenocorticotropic Hormone↗

PubMed2005

Type I spinal muscular atrophy can mimic sensory-motor axonal neuropathy.

Spinal muscular atrophy is a group of allelic autosomal recessive disorders characterized by progressive motoneuron loss, symmetric weakness, and skeletal muscle atrophy. It is traditionally considered a pure lower motoneuron disorder, for which a current definitive diagnosis is now possible by molecular genetic testing. We report two newborns with a clinical phenotype consistent with that of spinal muscular atrophy type I and nerve conduction studies and electromyography suggesting more extensive sensory involvement than classically described with spinal muscular atrophy. Molecular testing confirmed spinal muscular atrophy in patient 1 but not in patient 2. Thus, in the setting of a suspected congenital axonal neuropathy, molecular testing might be necessary to distinguish spinal muscular atrophy type I from infantile polyneuropathy.

Diagnosis, Differential↗

PubMed1998

Congenital autosomal dominant distal spinal muscular atrophy.

We present a father and son with congenital foot deformity. The father at age 41 years used crutches and the son at 7 years walked unaided. Both had atrophy and weakness of lower leg muscles and mild proximal and hand intrinsic weakness. Knee and ankle myotactic reflexes were absent and sensation was intact. Creatine kinase level was normal, nerve conduction studies wer normal and electromyography showed chronic neurogenic change. In both, nerve biopsies were normal and muscle biopsies showed type 1 predominance. The boy's serum hexosaminidase, spinal MRI and SMN gene were normal. This may be the first well documented example of congenital autosomal dominant distal spinal muscular atrophy affecting legs and arms.

Adult↗

PubMed1980

Classification of spinal muscular atrophies.

Clinical heterogeneity within the spinal muscular atrophies (SMA) has long been a source of confusion for questions of prognosis and genetic counselling. Comprehensive clinical and genetic analyses of 240 consecutive index cases from two English centres (The English SMA Study) have enabled some nosological questions to be resolved. The different SMA syndromes can be discriminated by (a) age at the first clinical signs of the disease, (b) pattern of muscle involvement, (c) age at death of other patients within an affected kindred, and (d) genetic evidence. Seven different SMA syndromes can be defined clinically and genetically; thirteen mutant genes are incriminated. Prevalence and incidence figures are presented. SMA type I (Werdnig-Hoffman disease) and chronic childhood SMA together comprise 74% of all SMA cases. The classification of the spinal muscular atrophies presented also provides the differential diagnosis for newly presenting cases.

Adolescent↗

PubMed1988

A follow-up study of 60 cases of chronic spinal muscular atrophy.

60 cases of chronic spinal muscular atrophy (CSMA) were followed-up for a period varying from 5 to 40 years. The neuromuscular impairment was evaluated by Norris' ALS score, both at the time of last examination and retrospectively at the time of diagnosis. Age at onset of symptoms was the most important factor in the progression of the neuromuscular damage. Monomelic or asymmetric location of symptoms at the time of diagnosis and duration of the disease were not significantly correlated to the worsening of ALS score.

Adult↗

PubMed2005

Determinants of exon 7 splicing in the spinal muscular atrophy genes, SMN1 and SMN2.

Spinal muscular atrophy is a neurodegenerative disorder caused by the deletion or mutation of the survival-of-motor-neuron gene, SMN1. An SMN1 paralog, SMN2, differs by a C-->T transition in exon 7 that causes substantial skipping of this exon, such that SMN2 expresses only low levels of functional protein. A better understanding of SMN splicing mechanisms should facilitate the development of drugs that increase survival motor neuron (SMN) protein levels by improving SMN2 exon 7 inclusion. In addition, exonic mutations that cause defective splicing give rise to many genetic diseases, and the SMN1/2 system is a useful paradigm for understanding exon-identity determinants and alternative-splicing mechanisms. Skipping of SMN2 exon 7 was previously attributed either to the loss of an SF2/ASF-dependent exonic splicing enhancer or to the creation of an hnRNP A/B-dependent exonic splicing silencer, as a result of the C-->T transition. We report the extensive testing of the enhancer-loss and silencer-gain models by mutagenesis, RNA interference, overexpression, RNA splicing, and RNA-protein interaction experiments. Our results support the enhancer-loss model but also demonstrate that hnRNP A/B proteins antagonize SF2/ASF-dependent ESE activity and promote exon 7 skipping by a mechanism that is independent of the C-->T transition and is, therefore, common to both SMN1 and SMN2. Our findings explain the basis of defective SMN2 splicing, illustrate the fine balance between positive and negative determinants of exon identity and alternative splicing, and underscore the importance of antagonistic splicing factors and exonic elements in a disease context.

Base Sequence↗

PubMedDate not supplied

Screening of deletions in SMN, NAIP and BTF2p44 genes in Turkish spinal muscular atrophy patients.

Deletions of the spinal muscular atrophy (SMA)-determining gene, SMN1, NAIP, and a third multicopy gene, BTF2p44tel were investigated in 60 unrelated Turkish SMA patients. SMN1 was deleted for at least exons 7 and 8 in 85% of the Turkish SMA patients. The NAIP gene was deleted in 75 and 33% of type I and type II SMA patients, respectively. Analysis of the 5'end of the BTF2p44tel gene indicated the extension of deletion in 13.3% of the cases, mainly in type I patients. Deletions of the NAIP and BTF2p44tel genes were detected in 1.3 and 3.9% of carrriers, respectively, in Turkish SMA families. Two patients were detected to harbor the hybrid SMN gene, one type II with deletion of the NAIP gene, and one type III without deletion of the NAIP gene.

Chromosomes, Human, Pair 5↗

PubMed1995

Deletions of the survival motor neuron gene in unaffected siblings of patients with spinal muscular atrophy.

DNA studies in 103 spinal muscular atrophy (SMA) patients from The Netherlands revealed homozygosity for a survival motor neuron (SMN) deletion in 96 (93%) of 103. Neuronal apoptosis inhibitory protein deletions were found in 38 (37%) of 103 and occurred most frequently in SMA type I. SMN deletions have not yet been described to occur in healthy subjects. In this study, however, four unaffected sibs from two SMA families showed homozygosity for SMN deletions. Homozygosity for an SMN deletion in unaffected persons seems to be very rare. Therefore, demonstration of a homozygous SMN deletion in a clinically presumed SMA patient should be considered as a confirmation of the diagnosis, whether or not SMN is in fact the causal gene for SMA.

DNA↗

PubMed1992

Werdnig-Hoffmann disease and chronic distal spinal muscular atrophy with apparent autosomal dominant inheritance.

We report on a family in which both Werdnig-Hoffmann disease (severe infantile-onset spinal muscular atrophy) and chronic distal spinal muscular atrophy occurred, with apparent autosomal dominant inheritance. The female proband clinically had Werdnig-Hoffmann disease and died at 10 months. In their second decade of life, the proband's father and his 2 brothers developed bilateral progressive atrophy and weakness of the hands and mild weakness in the distal parts of the legs. Their mother had no symptoms or signs of motor neuron disease but electromyography revealed distal denervation of the limbs. While the family studies suggest autosomal dominant inheritance, it is possible that the proband's condition was influenced by a maternally derived allelic or modifying trait.

Adult↗

PubMed2002

Spinal muscular atrophy: recent advances and future prospects.

Spinal muscular atrophies (SMA) are characterized by degeneration of lower motor neurons associated with muscle paralysis and atrophy. Childhood SMA is a frequent recessive autosomal disorder and represents one of the most common genetic causes of death in childhood. Mutations of the SMN1 gene are responsible for SMA. The knowledge of the genetic basis of SMA, a better understanding of SMN function, and the recent generation of SMA mouse models represent major advances in the field of SMA. These are starting points towards understanding the pathophysiology of SMA and developing therapeutic strategies for this devastating neurodegenerative disease, for which no curative treatment is known so far.

Adult↗

PubMed2006

Atypical presentations of spinal muscular atrophy type III (Kugelberg-Welander disease).

Spinal muscular atrophy type III (SMA III, Kugelberg-Welander disease) typically presents with symmetric proximal weakness, areflexia, and hypotonia. We present four children with spinal muscular atrophy type III who had atypical phenotypes. Three patients clearly had asymmetric weakness at presentation and two had upper motor neuron signs in the lower extremities (one patient had both features). Two of the patients had prolonged evaluations before the diagnosis was made. All patients had Gowers signs and two had pes planus. In patients with proximal muscle weakness the presence of asymmetrical weakness, upper motor neuron signs, or both, may be compatible with spinal muscular atrophy type III. The diagnosis of spinal muscular atrophy should be considered when other possibilities have been excluded.

Brain↗

PubMed2007

Mitochondrial respiratory complex I deficiency simulating spinal muscular atrophy.

Two female patients with clinical features resembling spinal muscular atrophy were presented. Patient 1 presented with hypotonia and proximal weakness of extremities at age 4 months. Electromyography revealed motor neuronopathy suggestive of spinal muscular atrophy. Patient 2 presented with severe hypotonia, motor weakness, and joint contractures since birth. Muscle biopsy findings were consistent with spinal muscular atrophy. However, deletions in the survival motor neuron gene and the neuronal apoptosis inhibitor protein gene were not found in both patients. They finally manifested clinical features unlike spinal muscular atrophy: epileptic seizure, cardiomyopathy, and spasticity. The clinical course of each patient was not like that of spinal muscular atrophy type I. Mitochondrial respiratory chain complex enzyme activities in cultured skin fibroblasts were measured. Respiratory complex I enzyme activity was decreased, suggestive of isolated complex I deficiency in both patients. In conclusion, in patients who have clinical features resembling spinal muscular atrophy but no deletions in the spinal muscular atrophy gene, the possibility of the mitochondrial respiratory chain complex I deficiency should be considered.

Cardiomyopathies↗

PubMed2005

The ultrastructure of peripheral nerve, motor end-plate and skeletal muscle in patients suffering from spinal muscular atrophy with respiratory distress type 1 (SMARD1).

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is genetically and clinically distinct from classic spinal muscular atrophy (SMA1). It results from mutations in the gene encoding immunoglobulin mu-binding protein 2 (IGHMBP2) on chromosome 11q13. Patients develop distally pronounced muscular weakness and early involvement of the diaphragm, resulting in respiratory failure. Sensory and autonomic nerves are also affected at later stages of the disease. We investigated peripheral nerves, skeletal muscles and neuromuscular junctions (NMJ) ultrastructurally in five unrelated patients and three siblings with genetically confirmed SMARD1. In mixed motor and sensory nerves we detected Wallerian degeneration and axonal atrophy similar to the ultrastructural findings described in SMA1. Isolated axonal atrophy was evident in purely sensory nerves. All investigated NMJ of patients with SMARD1 were dysmorphic and lacked a terminal axon. Moreover, we also observed characteristics of neuropathies, such as abnormalities in myelination, that have not been described in spinal muscular atrophies so far. Based on these findings we conclude that impairment of IGHMBP2 function leads to axonal degeneration, abnormal myelin formation, and motor end-plate degeneration.

Axons↗

PubMed2006

A feasibility study for the newborn screening of spinal muscular atrophy.

PURPOSE: The natural history of spinal muscular atrophy suggests that for maximum effect, therapeutics will need to be administered in the earliest phases of the disease. This will require the adoption of techniques for the genetic analysis of affected individuals at the newborn stage. Our objective was to examine the feasibility surrounding the newborn screening for spinal muscular atrophy. METHODS: We investigated the application of real-time polymerase chain reaction technology for newborn screening. A multiplex assay was designed to identify homozygous deletions in SMN1 exon 7 and validated using 266 samples with defined SMN1 and SMN2 copy numbers. Sensitivity and specificity were then evaluated as part of a newborn screening strategy using DNA from 153 blood spots. RESULTS: Real-time technology validation demonstrated correct exclusion of all normal and carrier samples, and identified the homozygous SMN1 exon 7 deletions in all 32 affected samples. In the series of blood spots, all 59 affected samples were correctly identified yielding an analytic sensitivity of 100%; 56 normal and 39 carrier samples were correctly excluded yielding an analytic specificity of 100% for this blood spot series. CONCLUSION: We demonstrate that effective molecular technology exists and that ethics may soon warrant the newborn screening of spinal muscular atrophy.

Computer Systems↗

PubMed1989

Surgical and functional results of spine fusion in spinal muscular atrophy.

From 1965 to 1987, 84 spinal muscular atrophy patients were followed at Rancho Los Amigos Medical Center (RLAMC). Twenty-seven patients were excluded from this study due to insufficient medical documentation (16), lack of follow-up (5), and death (6); leaving 57 patients in the general study group. Group I (34 patients) had posterior spinal fusion (PSF) with Harrington rod instrumentation (HRI); mean age at surgery was 12 years, average preoperative curve was 57 degrees, average postoperative correction was 42%, with a loss of correction of 9 degrees. The complication rate in this group was 35%. The average follow-up interval was 9 years (range, 4-19 years). Group II (six patients) underwent PSF with Luque segmental spinal instrumentation (SSI); mean age at surgery was 11 years, preoperative curves averaged 37 degrees, average postoperative correction was 42% with a loss of correction of 3 degrees. The complication rate in this group was 16%. Follow-up was 3.5 years. Physical therapy and occupational therapy evaluations were done preoperatively and postoperatively at 2- and 5-year intervals. Information was gathered in three categories: 1) ambulation, 2) equipment use, and 3) functional activities. After fusion, sitting tolerance was maintained but additional use of mobile arm supports, lapboards, and reaching aides was necessary for all patients. The ability to perform activities such as drinking, self-feeding, and self-hygiene declined during the 2 years immediately following surgery but improved by 5 years. Surgical patients never approached their preoperative skill levels. Therapy evaluations further demonstrated that there were no difference in function between either operative group.

Adolescent↗

PubMed1988

[Unusual complications at birth in a stillborn with spinal muscular atrophy].

A report is given on a premature stillborn with severe congenital spinal muscular atrophy, arthrogryposis multiplex congenita and hydrops fetalis. During delivery the head was spontaneously pulled off. The neuromuscular disease was the cause of this unusual complication. No alterations of collagenous fibres were found by light and electron microscopy in dermis, aorta or in the Achilles tendon. The hydrops fetalis was not of immunological nature.

Arthrogryposis↗