Therapeutic advances in muscular dystrophy

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Abstract

The muscular dystrophies comprise a heterogeneous group of genetic disorders that produce progressive skeletal muscle weakness and wasting. There has been rapid growth and change in our understanding of these disorders in recent years, and advances in basic science are being translated into increasing numbers of clinical trials. This review will discuss therapeutic developments in 3 of the most common forms of muscular dystrophy: Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. Each of these disorders represents a different class of genetic disease (monogenic, epigenetic, and repeat expansion disorders), and the approach to therapy addresses the diverse and complex molecular mechanisms involved in these diseases. The large number of novel pharmacologic agents in development with good biologic rationale and strong proof of concept suggests there will be an improved quality of life for individuals with muscular dystrophy.

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Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member.

J. D. Brook, M. McCurrach, H Harley … (1992)

Using positional cloning strategies, we have identified a CTG triplet repeat that undergoes expansion in myotonic dystrophy patients. This sequence is highly variable in the normal population. PCR analysis of the interval containing this repeat indicates that unaffected individuals have been 5 and 27 copies. Myotonic dystrophy patients who are minimally affected have at least 50 repeats, while more severely affected patients have expansion of the repeat containing segment up to several kilobase pairs. The CTG repeat is transcribed and is located in the 3' untranslated region of an mRNA that is expressed in tissues affected by myotonic dystrophy. This mRNA encodes a polypeptide that is a member of the protein kinase family.

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Evidence-based path to newborn screening for Duchenne muscular dystrophy.

Jerry R Mendell, Chris Shilling, Nancy D Leslie … (2012)

Creatine kinase (CK) levels are increased on dried blood spots in newborns related to the birthing process. As a marker for newborn screening, CK in Duchenne muscular dystrophy (DMD) results in false-positive testing. In this report, we introduce a 2-tier system using the dried blood spot to first assess CK with follow-up DMD gene testing. A fluorometric assay based upon the enzymatic transphosphorylation of adenosine diphosphate to adenosine triphosphate was used to measure CK activity. Preliminary studies established a population-based range of CK in newborns using 30,547 deidentified anonymous dried blood spot samples. Mutation analysis used genomic DNA extracted from the dried blood spot followed by whole genome amplification with assessment of single-/multiexon deletions/duplications in the DMD gene using multiplex ligation-dependent probe amplification. DMD gene mutations (all exonic deletions) were found in 6 of 37,649 newborn male subjects, all of whom had CK levels>2,000U/l. In 3 newborns with CK>2,000U/l in whom DMD gene abnormalities were not found, we identified limb-girdle muscular dystrophy gene mutations affecting DYSF, SGCB, and FKRP. A 2-tier system of analysis for newborn screening for DMD has been established. This path for newborn screening fits our health care system, minimizes false-positive testing, and uses predetermined levels of CK on dried blood spots to predict DMD gene mutations. Copyright © 2012 American Neurological Association.

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A unifying genetic model for facioscapulohumeral muscular dystrophy.

Richard J. L. F. Lemmers, Patrick J. van der Vliet, Rinse Klooster … (2010)

Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy in adults that is foremost characterized by progressive wasting of muscles in the upper body. FSHD is associated with contraction of D4Z4 macrosatellite repeats on chromosome 4q35, but this contraction is pathogenic only in certain "permissive" chromosomal backgrounds. Here, we show that FSHD patients carry specific single-nucleotide polymorphisms in the chromosomal region distal to the last D4Z4 repeat. This FSHD-predisposing configuration creates a canonical polyadenylation signal for transcripts derived from DUX4, a double homeobox gene of unknown function that straddles the last repeat unit and the adjacent sequence. Transfection studies revealed that DUX4 transcripts are efficiently polyadenylated and are more stable when expressed from permissive chromosomes. These findings suggest that FSHD arises through a toxic gain of function attributable to the stabilized distal DUX4 transcript.

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Author and article information

Journal

Journal ID (nlm-ta): Ann Neurol

Journal ID (iso-abbrev): Ann. Neurol

Journal ID (publisher-id): ana

Title: Annals of Neurology

Publisher: Blackwell Publishing Ltd

ISSN (Print): 0364-5134

ISSN (Electronic): 1531-8249

Publication date (Print): September 2013

Publication date (Electronic): 09 October 2013

Volume: 74

Issue: 3

Pages: 404-411

Affiliations

[1 ]Center for Genetic Muscle Disorders, Kennedy Krieger Institute Baltimore, MD

[2 ]Departments of Neurology, Johns Hopkins School of Medicine Baltimore, MD

[3 ]Neuroscience, Johns Hopkins School of Medicine Baltimore, MD

Author notes

Address correspondence to Dr Wagner, Center for Genetic Muscle Disorders, Kennedy Krieger Institute, 707 North Broadway, Baltimore, MD 21205. E-mail: wagnerk@ 123456kennedykrieger.org

Article

DOI: 10.1002/ana.23989

PMC ID: 3886293

PubMed ID: 23939629

SO-VID: 23775886-e1dc-4878-85e5-d364c32e828a

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Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

History

Date received : 18 June 2013

Date revision received : 29 July 2013

Date accepted : 13 August 2013

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Therapeutic advances in muscular dystrophy

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Karger: Neurology and Neuroscience

Most cited references 78

Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member.

Evidence-based path to newborn screening for Duchenne muscular dystrophy.

A unifying genetic model for facioscapulohumeral muscular dystrophy.

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Cited by 30

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