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PubMed2003

Reliability of 4 outcome measures in pediatric spinal muscular atrophy.

BACKGROUND: Spinal muscular atrophy is a common neurologic disorder of infants and children with a high mortality rate. Clinical trials have not been attempted in this population until recently. OBJECTIVE: To demonstrate that 4 outcome measures are reliable for use in clinical trials in patients with spinal muscular atrophy. DESIGN, SETTING, PATIENTS: Thirty-eight children with spinal muscular atrophy who fulfilled inclusion and exclusion criteria were enrolled at 5 pediatric centers for a reliability study. Paired samples statistics were performed comparing results of the qualifying variance visit with a fourth visit. MAIN OUTCOME MEASURES: Quantitative muscle testing and the Gross Motor Function Measure. RESULTS: Thirty-four patients and 7 evaluators completed the study. Thirteen patients were aged 2 through 4 years and 21 were 5 through 17 years. The Gross Motor Function Measure was completed by 34 subjects. Six variables for pulmonary function tests were measured in 20 subjects. Quantitative muscle testing was performed on 21 subjects in 8 muscle groups. Thirty-three subjects completed the PedsQL Neuromuscular Module for Parents. The intraclass correlation coefficient and Bradley-Blackwood procedures indicated a very high level of agreement between measures. CONCLUSION: The Gross Motor Function Measure, pulmonary function tests, quantitative muscle testing, and quality of life are reliable outcome measures for clinical trials in pediatric spinal muscular atrophy.

Adolescent↗
PubMedDate not supplied

Infantile olivopontocerebellar atrophy with spinal muscular atrophy (infantile OPCA + SMA).

We report three siblings (two boys and girl) with familial (autosomal recessive) infantile olivopontocerebellar atrophy (OPCA) associated with lower motoneuron involvement. Brain autopsy findings in two of the children revealed a multisystem degeneration characterized by marked hypoplasia of phylogenetically new parts of the brain stem (basis pontis and inferior olivary nuclei) associated with hypoplasia of the neocerebellum, both cerebellar and cerebral peduncle. All three infants died before six months of age. The clinical features are characterized by severe hypotonia, areflexia, failure to thrive, respiratory insufficiency in all cases, cardiomyopathy and dislocated hips at birth in two of the three siblings. Extensive serum, urinary and leukocyte enzyme assays in the second infant failed to disclose a specific metabolic abnormality. The diagnosis of OPCA was established prior to death by Magnetic Resonance Imaging (MRI) in the youngest infant. Since OPCA represents a heterogeneous group of diseases, correlation of neuropathologic, clinical, genetic and MRI findings at early stages of evolution becomes crucial in the understanding of the nosology of OPCA and its variants.

Female↗
PubMed2002

Outcome measures for pediatric spinal muscular atrophy.

BACKGROUND: Spinal muscular atrophy (SMA) is a genetic disease of the anterior horn cell with a frequency of 8 per 100 000 live births and a high rate of mortality during infancy. The American Spinal Muscular Atrophy Randomized Trials (AmSMART) Group is an organization of 5 centers formed to perform clinical trials in children with SMA. OBJECTIVE: To devise reliable methods to measure strength, motor function, lung function, and quality of life for use as outcome measures in children with SMA. SETTING: Tertiary referral center, pediatric neurology department. PATIENTS AND METHODS: Twelve children with SMA aged 2 to 14 years were enrolled in a reliability study of 4 outcome measures: quantitative muscle testing (in children >5 years), gross motor function measure, pulmonary function tests, and quality of life. The Richmond Quantitative Measurement System was used to test grip, knee flexion and extension, and elbow flexion. Gross motor function measure was performed as described, and pulmonary function tests were measured using the KoKo system. Quality of life was assessed via the PedsQL and the PedsQL Neuromuscular Module for patients and parents. RESULTS: Ten children fulfilled the inclusion criteria and completed at least 3 visits with 3 evaluators in 6 months. Using a weighted kappa, the gross motor function measure showed high interrater reliability. Quantitative muscle testing showed greater variability among the weakest children; the findings for pulmonary function tests and quality of life were inconclusive. The PedsQL Neuromuscular Module for parents had moderately high reliability. CONCLUSION: A tool for motor function may be more useful in clinical trials of childhood SMA than one for quantitative muscle strength.

Adolescent↗
PubMed1996

[Distal spinal muscular atrophy].

Chronic spinal muscular atrophy usually presents in childhood or adolescence, generally as predominant proximal muscle weakness. Other less common forms involving distal muscles can be either partial or generalized and their prognosis is relatively good. At least three well-defined types can be identified: a) a form located in the upper extremities that typically affects young men, is not familial and is highly prevalent in Asia; b) a more generalized form that can be either familial or isolated and that resembles Charcot-Marie-Tooth disease in the distribution of muscle weakness and prognosis, and c) another generalized form that starts in and mainly involves the upper extremities, is inherited in an autosomal dominant manner and is accompanied by laryngeal involvement. We review the literature and describe 27 patients with distal spinal muscular atrophy resembling Charcot-Marie-Tooth disease.

Adolescent↗
PubMed2000

The role of SMN in spinal muscular atrophy.

Childhood spinal muscular atrophy (SMA) is a common autosomal recessive disorder which is characterized by muscle weakness due to degeneration of motoneurons in the spinal cord and brainstem nuclei. Positional cloning strategies have revealed several gene candidates including the genes for the survival motoneuron (SMN) and the neuronal apoptosis inhibitory protein (NAIP). Both genes are duplicated on chromosome 5. Homozygous deletions/mutations of the telomeric SMN gene, which is expressed from both copies on human chromosome 5, are associated with the disease. Recent reports suggest involvement of the SMN protein in the formation of spliceosomal particles in the cytoplasm and in the regeneration of spliceosomes in the nucleus. These data put spinal muscular atrophy into a growing group of disorders of RNA metabolism which also include fragile-X syndrome and myotonic dystrophy. Relevance of these previous data for the pathogenesis of the disease are discussed in this review.

Animals↗
PubMed2005

Hydroxyurea enhances SMN2 gene expression in spinal muscular atrophy cells.

Spinal muscular atrophy (SMA) is a motor neuron disease caused by dysfunction of the survival motor neuron (SMN) gene. Human SMN gene is present in duplicated copies: SMN1 and SMN2. More than 95% of patients with SMA lack a functional SMN1 but retain at least one copy of SMN2. Unlike SMN1, SMN2 is primarily transcribed into truncated messenger RNA and produces low levels of SMN protein. We tested a therapeutic strategy by treating cultured lymphocytes from patients with SMA with hydroxyurea to modify SMN2 gene expression and to increase the production of SMN protein. Twenty lymphoblastoid cell lines (15 SMA and 5 control lines) were treated with hydroxyurea at 5 concentrations (0.5, 5, 50, 500, and 5,000 microg/ml) and 3 time points (24, 48, and 72 hours). SMN2 gene copy numbers were determined using real-time quantitative polymerase chain reaction. Hydroxyurea treatment resulted in a time-related and dose-dependent increase in the ratio of full-length to truncated SMN messenger RNA. SMN protein levels and intranuclear gems also were significantly increased in these hydroxyurea-treated cells. The SMN2 gene copy number correlated inversely with the SMA phenotypic severity. This study provides the first evidence for a therapeutic indication of hydroxyurea in SMA.

Blotting, Western↗
PubMed1994

A multicopy dinucleotide marker that maps close to the spinal muscular atrophy gene.

Spinal muscular atrophy (SMA) is a common autosomal recessive disorder resulting in loss of motor neurons. The interval containing the SMA gene has been defined by linkage analysis as 5qcen-D5S435-SMA-D5S557-5qter. We have isolated a new dinucleotide repeat marker, CATT1, that lies between these two closest markers. The marker CATT1 has 16 alleles and is highly polymorphic. The marker can have 1 to 4 (or more) copies per chromosome, giving rise to individuals with up to 8 (or more) alleles. All of the subloci map between the markers D5S557 and D5S435 and lie in close proximity to one another. The marker CATT1 is linked to the SMA gene with a lod score of Zmax = 34.42 at theta = 0 and crosses all available recombinants. Certain alleles occurred more frequently in either the SMA or normal populations, indicating significant allelic association between CATT1 and the SMA locus. Haplotype analysis combining U.S. and Canadian SMA families reveals that one haplotype group (VII) occurs significantly more frequently in the SMA population than in the normal. This confirms the allelic association of CATT1 with the SMA locus.

Alleles↗
PubMed1994

Linkage mapping of the spinal muscular atrophy gene.

Spinal muscular atrophy (SMA) is a common autosomal recessive disorder resulting in loss of motor neurons. We have performed linkage analysis on a panel of families using nine markers that are closely linked to the SMA gene. The highest lod score was obtained with the marker D5S351 (Zmax = 10.04 at theta = O excluding two unlinked families, and Zmax = 8.77 at theta = 0.007 with all families). One type III family did not show linkage to the 5q13 markers, and in one type I consanguineous family the affected individual did not show homozygosity except for the marker D5S435. Three recombinants were identified with the closet centromeric marker, D5S435, which position the gene telomeric of this marker. These recombinants will facilitate finer mapping of the location of the SMA gene. Lastly, two families provide strong evidence for a remarkable variability in presentation of the SMA phenotype, with the age at onset in one family varying from 17 months to 13 years.

Adolescent↗
PubMed2006

Fine-mapping and candidate gene analysis of bovine spinal muscular atrophy.

Bovine spinal muscular atrophy (SMA), an autosomal recessive neurodegenerative disease, has been mapped at moderate resolution to the distal part of Chromosome 24. In this article we confirm this location and fine-map the SMA locus to an interval of approximately 0.8 cM at the very distal end of BTA24. Despite remarkable similarity to human SMA, the causative gene SMN can be excluded in bovine SMA. However, the interval where the disease now has been mapped contains BCL2, like SMN an antiapoptotic factor, and shown to bind to SMN. Moreover, knockout mice lacking the BCL2 gene show rapid motor neuron degeneration with early postnatal onset, as observed in bovine SMA. A comparative cattle/human map of the distal end of BTA24, based on the emerging bovine genome sequencing data, shows conserved synteny to HSA18 with hints of a segmental duplication and pericentric inversion just after the last available bovine marker DIK4971. This synteny lets us conclude that SMA is in immediate vicinity of the telomere. Candidate gene analysis of BCL2, however, excludes most of this gene, except its promoter region, and draws attention to the neighboring gene VPS4B, part of the endosomal protein-sorting machinery ESCRT-III which is involved in several neurodegenerative diseases.

Animals↗
PubMed2002

Genetic testing and risk assessment for spinal muscular atrophy (SMA).

Spinal muscular atrophy (SMA) is one of the most common autosomal recessive diseases, affecting approximately 1 in 10,000 live births, and with a carrier frequency of approximately 1 in 50. Because of gene deletion or conversion, SMN1 exon 7 is homozygously absent in approximately 94% of patients with clinically typical SMA. Approximately 30 small intragenic SMN1 mutations have also been described. These mutations are present in many of the approximately 6% of SMA patients who do not lack both copies of SMN1, whereas SMA of other patients without a homozygous absence of SMN1 is unrelated to SMN1. A commonly used polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) assay can be used to detect a homozygous absence of SMN1 exon 7. SMN gene dosage analyses, which can determine the copy numbers of SMN1 and SMN2 (an SMN1 homolog and a modifier for SMA), have been developed for SMA carrier testing and to confirm that SMN1 is heterozygously absent in symptomatic individuals who do not lack both copies of SMN1. In conjunction with SMN gene dosage analysis, linkage analysis remains an important component of SMA genetic testing in certain circumstances. Genetic risk assessment is an essential and integral component of SMA genetic testing and impacts genetic counseling both before and after genetic testing is performed. Comprehensive SMA genetic testing, comprising PCR-RFLP assay, SMN gene dosage analysis, and linkage analysis, combined with appropriate genetic risk assessment and genetic counseling, offers the most complete evaluation of SMA patients and their families at this time. New technologies, such as haploid analysis techniques, may be widely available in the future.

Arthrogryposis↗
PubMed2006

Novel aminoglycosides increase SMN levels in spinal muscular atrophy fibroblasts.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. SMA is caused by the homozygous absence of survival motor neuron-1 (SMN1). SMN2, a nearly identical copy gene, is retained in all SMA patients and encodes an identical protein as SMN1; however, SMN1 and SMN2 differ by a silent C to T transition which results in the production of an alternatively spliced isoform (SMNDelta7), which encodes a defective protein, demonstrating that the absence of the short peptide encoded by SMN exon 7 is critical in SMA development. Previously, we have shown that for some functions heterologous sequences can compensate for the exon 7 peptide, suggesting that the SMN C-terminus functions non-specifically. Consistent with this hypothesis, we now identify novel aminoglycosides that can induce SMN protein levels in patient fibroblasts. This hypothesis was supported, in part, by a novel fluorescent SMN read-through assay. Interestingly, however, through the development of a SMN exon 7-specific antibody, results suggested that levels of normal full-length SMN might also be elevated by aminoglycoside treatment. These results demonstrate that the compounds that promote read-through may provide an alternative platform for the discovery of compounds that induce SMN protein levels.

Aminoglycosides↗
PubMed1995

A novel cDNA detects homozygous microdeletions in greater than 50% of type I spinal muscular atrophy patients.

Spinal muscular atrophy (SMA) is the second most common lethal, autosomal recessive disease in Caucasians (after cystic fibrosis). Childhood SMAs are divided into three groups (type I, II and III), which are allelic variants of the same locus in a region of approximately 850 kb in chromosome 5q12-q13, containing multiple copies of a novel, chromosome 5-specific repeat as well as many atypical pseudogenes. This has hampered the identification of candidate genes. We have identified several coding sequences unique to the SMA region. A genomic fragment detected by one cDNA is homozygously deleted in 17/29 (58%) of type I SMA patients. Of 235 unaffected individuals examined, only two showed the deletion and both are carriers of SMA. Our results suggest that deletion of at least part of this novel gene is directly related to the phenotype of SMA.

Base Sequence↗
PubMed1998

SMN oligomerization defect correlates with spinal muscular atrophy severity.

Spinal muscular atrophy (SMA) is a motor-neuron disorder resulting from anterior-horn-cell death. The autosomal recessive form has a carrier frequency of 1 in 50 and is the most common genetic cause of infant death. SMA is categorized as types I-III, ranging from severe to mild, based upon age of onset and clinical course. Two closely flanking copies of the survival motor neuron (SMN) gene are on chromosome 5q13 (ref. 1). The telomeric SMN (SMN1) copy is homozygously deleted or converted in >95% of SMA patients, while a small number of SMA disease alleles contain missense mutations within the carboxy terminus. We have identified a modular oligomerization domain within exon 6 of SMN1. All previously identified missense mutations map within or immediately adjacent to this domain. Comparison of wild-type to mutant SMN proteins of type I, II and III SMA patients showed a direct correlation between oligomerization and clinical type. Moreover, the most abundant centromeric SMN product, which encodes exons 1-6 but not 7, demonstrated reduced self-association. These findings identify decreased SMN self-association as a biochemical defect in SMA, and imply that disease severity is proportional to the intracellular concentration of oligomerization-competent SMN proteins.

Cyclic AMP Response Element-Binding Protein↗
PubMed2001

Spinal muscular atrophy.

The spinal muscular atrophies are a group of mostly inherited disorders selectively affecting the lower motor neuron. There is a wide degree of clinical and genetic heterogeneity that must be taken into account when giving prognostic information. Autosomal recessive childhood proximal SMA is the commonest form and is due to mutations in a gene encoding a novel protein, SMN, that appears to play a critical role in RNA metabolism but has also been shown to interact with actin-binding proteins and mediators of programmed cell death. The identification of the genetic basis of SMA has resulted in advances for prenatal diagnosis and in new insights into motor neuron biology. The chromosomal location of two of the rarer dominant forms of SMA has been found. Identification of the molecular pathophysiology of lower motor neuron syndromes can be expected to aid in the development of therapy for these disabling disorders.

Adult↗
PubMed2003

A transgene carrying an A2G missense mutation in the SMN gene modulates phenotypic severity in mice with severe (type I) spinal muscular atrophy.

5q spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and the leading genetic cause of infantile death. Patients lack a functional survival of motor neurons (SMN1) gene, but carry one or more copies of the highly homologous SMN2 gene. A homozygous knockout of the single murine Smn gene is embryonic lethal. Here we report that in the absence of the SMN2 gene, a mutant SMN A2G transgene is unable to rescue the embryonic lethality. In its presence, the A2G transgene delays the onset of motor neuron loss, resulting in mice with mild SMA. We suggest that only in the presence of low levels of full-length SMN is the A2G transgene able to form partially functional higher order SMN complexes essential for its functions. Mild SMA mice exhibit motor neuron degeneration, muscle atrophy, and abnormal EMGs. Animals homozygous for the mutant transgene are less severely affected than heterozygotes. This demonstrates the importance of SMN levels in SMA even if the protein is expressed from a mutant allele. Our mild SMA mice will be useful in (a) determining the effect of missense mutations in vivo and in motor neurons and (b) testing potential therapies in SMA.

Animals↗
PubMed2003

Development of a gene therapy strategy for the restoration of survival motor neuron protein expression: implications for spinal muscular atrophy therapy.

Spinal muscular atrophy (SMA) is a motor neuron degeneration disorder, and manifests itself in patients as muscle weakness and paralysis that ultimately leads to death. Currently, there is no effective treatment for this disease. As a first step in developing a treatment for SMA, we are examining whether delivery of the gene encoding survival motor neuron (SMN) protein to primary fibroblast cell lines derived from SMA patients can lead to restoration of nuclear-staining foci, called gems, which are absent in patients with severe SMA. Using adenovirus-mediated gene delivery, we show that SMN can be efficiently expressed in patient fibroblasts, and leads to restoration of nuclear gems, which are thought to be important for the functional rescue of the SMA phenotype. The number of gems per cell is equal to or greater than those found in fibroblasts of normal individuals. Furthermore, ectopic expression of SMN also caused relocalization of Gemin2, an SMN-interacting protein, to gems. Overall, this work is the first demonstration of the feasibility of virus-based delivery of the SMN-coding gene to restore the normal SMN expression pattern in SMA patient-derived cells, and holds promise for gene therapy of SMA, as a potential long-term therapy for this devastating childhood disease.

Adenoviridae↗
PubMed1993

High resolution physical map of the region surrounding the spinal muscular atrophy gene.

Spinal muscular atrophy (SMA) is the second most common lethal, autosomal recessive disease in Caucasians, second only to cystic fibrosis. In an effort to identify the causative gene in SMA, we have used radiation hybrid (RH) mapping to prepare a high resolution physical map of the proximal region of chromosome 5 (5q11-13) which contains the SMA gene. The map of the SMA region, which spans approximately 4 Mb, contains 19 loci including 9 polymorphic DNA markers, 8 monomorphic sequence tagged sites (STS) and two genes. Based upon the RH map the two polymorphic loci which most closely flank the SMA locus were estimated to be separated by approximately 750 kb. Using two different directional cloning schemes, several new clones between the genetic markers which most closely flank SMA were isolated. These new clones within the SMA candidate region, together with cosmid clones prepared from one RH hybrid which retains an approximately 1 Mb segment spanning the SMA region as its only human DNA, will greatly facilitate efforts to identify the gene for SMA. In addition, analysis of cloned DNA segments from within the SMA candidate region has identified the presence of a novel, chromosome 5-specific, low copy repeated sequence which is distributed throughout the region containing the SMA gene as well as in at least four other regions of chromosome 5. Whether or not these novel repeated sequences throughout the SMA region are involved in the disease remains to be determined.

Animals↗