Function changes in spinal muscular atrophy II and III

Russman, Barry S.; Buncher, C. Ralph; White, Michael L.; Samaha, Frederick J.; Iannaccone, ST

doi:10.1212/wnl.47.4.973

Cited by 99 publications

(71 citation statements)

References 5 publications

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“…However, trial design among patients with milder phenotypes is also challenged by the slowly progressive nature of the disease among this subset of patients, particularly ambulatory subjects with SMA. In studies looking at acquisition and loss of motor milestones such as walking among patients with SMA type 3, a slow functional loss is only observed by observation over a period of several years [Zerres et al 1997;Russman et al 1996;Zerres and Rudnik-Schoneborn, 1995]. Given that most patients with SMA will initially present during childhood, the effect of normal development with its potential for gain in function must also be considered.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic developments in spinal muscular atrophy

Sproule

Kaufmann

2010

Ther Adv Neurol Disord

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Spinal muscular atrophy (SMA), a potentially devastating disease marked by progressive weakness and muscle atrophy resulting from the dysfunction and loss of motor neurons of the spinal cord, has emerged in recent years as an attractive target for therapeutic intervention. Caused by a homozygous mutation to the Survival of Motor Neurons 1 (SMN1) gene on chromosome 5q, the severity of the clinical phenotype in SMA is modulated by the function of a related protein, Survival of Motor Neurons 2 (SMN2). SMN2 predominantly produces an unstable SMN transcript lacking exon 7; only about 10% of the transcription product produces a full-length, functional SMN protein. Several therapeutic strategies have targeted this gene with the goal of producing increased full-length SMN transcript, thereby modifying the underlying mechanism. Drugs that have increased SMN2 function, in vitro, are now explored for potential therapeutic benefit in this disease. Alternative approaches, including neuroprotective, muscle anabolic, gene and cell replacement strategies, also hold promise. The recent advances in preclinical research and the development of a wider range of animal models for SMA continue to provide cautious optimism that effective treatments for SMA will eventually emerge.

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Section: Introductionmentioning

confidence: 99%

Therapeutic developments in spinal muscular atrophy

Sproule

Kaufmann

2010

Ther Adv Neurol Disord

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“…Thus, scales targeted to assess functional ability with disease-specific and strength-specific tasks may have the potential to exceed direct measures of power in sensitivity and reliability [10][11][12]. In addition, functional testing to ascertain efficacy and monitor natural history has value [13,14]. Functional tests, however, are often limited by lack of sensitivity and/or the inability of the test to efficaciously monitor change over the full course/spectrum of the disease.…”

Section: Introductionmentioning

confidence: 99%

A modified Hammersmith functional motor scale for use in multi-center research on spinal muscular atrophy

Krosschell

Maczulski²,

Crawford

et al. 2006

Neuromuscular Disorders

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The Hammersmith functional motor scale for children with spinal muscular atrophy was modified to establish a standard measure of functional ability in children with non-ambulant spinal muscular atrophy types 2 and 3 in a longitudinal multi-center clinical trial. This study assessed the intra-and interrater reliability and the test-retest stability of a modified version of the scale. Both intra-and interrater reliability were established. Results indicate that the scale is reliable and stable over a 6 month period. Reliability was maintained when patient sample criteria were expanded to include children younger than 30 months and children with popliteal angles greater than 20°. These data establish the modified Hammersmith functional motor scale for children with spinal muscular atrophy as a reliable instrument for use in multi-center treatment trials in non-ambulant spinal muscular atrophy children. Our data provides additional support for the use of original scale items in terms of ease of administration, usefulness and reliability, while incorporating modifications to optimize its use in a multi-center clinical research setting.

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“…37,38 Type III patients are diagnosed after 18 months, are able to walk, can have children, and often live at least into the second or third decade. 39 This study presents the clinical experience of 6 years of SMA testing in the Molecular Pathology Laboratory at The Ohio State University. Despite the fact that more than 95% of 5q-linked SMA patients lack any intact SMN1, it has been our experience that Ͻ43% of patients referred for diagnostic testing have the common SMN1 deletion.…”

mentioning

confidence: 99%

Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2

Mailman

Heinz

Papp

et al. 2002

Genetics in Medicine

324

220

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Purpose: This study describes SMN1 deletion frequency, carrier studies, and the effect of the modifying SMN2 gene on the spinal muscular atrophy (SMA) phenotype. A novel allele-specific intragenic mutation panel increases the sensitivity of SMN1 testing. Methods: From 1995 to 2001, 610 patients were tested for SMN1 deletions and 399 relatives of probands have been tested for carrier status. SMN2 copy number was compared between 52 type I and 90 type III patients, and between type I and type III patients with chimeric SMN genes. A fluorescent allele-specific polymerase chain reaction (PCR) -based strategy detected intragenic mutations in potential compound heterozygotes and was used on 366 patients. Results: Less than half of the patients tested were homozygously deleted for SMN1. A PCR-based panel detected the seven most common intragenic mutations. SMN2 copy number was significantly different between mild and severely affected patients. Conclusions: SMN1 molecular testing is essential for the diagnosis of SMA and allows for accurate carrier testing.Screening for intragenic mutations in SMN1 increases the sensitivity of diagnostic testing. Finally, SMN2 copy number is conclusively shown to ameliorate the phenotype and provide valuable prognostic information. Genet Key Words: spinal muscular atrophy, SMN, polymerase chain reactionSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease caused by homozygous mutation of the SMN1 gene 1 on chromosome 5q13. 2-12 5q-SMA has an incidence of 1/10,000 with an estimated carrier frequency of 1/50. [13][14][15][16][17] Deletion and gene conversion events result in a 95% to 98% rate of homozygous loss of the SMN1 gene in patients with classic SMA. 1,18 -31 A further 1% to 3% of well-characterized SMA cases are the result of compound heterozygosity with an intragenic mutation and a deletion. 31,32 Clinically, SMA patients are classified as type I, II, or III, based on the severity of the disease and the age of onset. 33,34 SMA type I, also known as Werdnig-Hoffmann disease, 35,36 is the most severe presentation. Type I infants are hypotonic and have severe proximal muscle wasting due to a lack of ␣-motor neurons in the anterior horn of the spinal cord. These patients are diagnosed prenatally or within 6 months after birth. They never sit unaided and usually die within the first 2 years, most often due to respiratory muscle weakness. Patients with intermediate SMA type II develop the disease before 18 months of age. They are able to sit unaided, but do not stand or walk. SMA type III, also called Kugelberg-Welander disease, is less severe. 37,38 Type III patients are diagnosed after 18 months, are able to walk, can have children, and often live at least into the second or third decade. 39 This study presents the clinical experience of 6 years of SMA testing in the Molecular Pathology Laboratory at The Ohio State University. Despite the fact that more than 95% of 5q-linked SMA patients lack any intact SMN1, it has been our experience that Ͻ43% of patients ...

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Function changes in spinal muscular atrophy II and III

Cited by 99 publications

References 5 publications

Therapeutic developments in spinal muscular atrophy

Therapeutic developments in spinal muscular atrophy

A modified Hammersmith functional motor scale for use in multi-center research on spinal muscular atrophy

Molecular analysis of spinal muscular atrophy and modification of the phenotype by SMN2

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