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May 23 Highlight and Commentary

Congenital muscular dystrophies

D’Amico et al. report three children with POMP1 mutations who had congenital muscular dystrophy, microcephaly, and mental retardation but neither the brain nor ocular malformations characteristic of Walker-Warburg syndrome.

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Congenital muscular dystrophies

Commentary by Hanns Lochmüller, MD

Muscular dystrophies characteristically affect skeletal and cardiac muscle, leaving other organs and functions intact. Therefore, patients with muscular dystrophy take part in social, academic, and occupational life as long as motor disabilities allow. However, a subgroup of congenital muscular dystrophies presents with mental retardation and blindness due to brain and eye malformation. The molecular pathway relevant for both skeletal muscle and the CNS was unknown until recently. A first clue came from the identification of a gene defect in patients with Fukuyama congenital muscular dystrophy (FCMD), but the exact function of this gene remained obscure. Only within the last 5 years, it was recognized that alpha-dystroglycan in its glycosylated form plays a pivotal role both for brain development and for skeletal muscle integrity. Glycosylation is a post-translational modification of proteins, and for alpha-dystroglycan, appears to involve various enzymes (glycosyltransferases) and additional factors. Several congenital and limb girdle muscular dystrophies are now associated with mutations in genes encoding for proteins that are either putative or established glycosyltransferases.¹ Muscle biopsies frequently show reduced or absent immunolabeling of alpha-dystroglycan along with possible reduction of merosin staining. Mutations of the POMT1 gene have been linked to the most severe form of congenital muscular dystrophy associated with brain abnormalities,² the so-called Walker-Warburg syndrome (WWS), while other gene defects such as FKRP (fukutin-related protein) were thought to result in milder disease.³ However, genotype-phenotype correlations are not straightforward, as exemplified in the study by D’Amico et al. Additional genetic or environmental factors must modify disease severity in this new group of disorders. Identifying these factors is a formidable challenge, but may open the way for new therapeutic approaches.

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References

1. Muntoni F, Brockington M, Torelli S, Brown SC. Defective glycosylation in congenital muscular dystrophies. Curr Opin Neurol 2004;17:205–209.[Medline]
2. Beltran-Valero de Bernabe D, Currier S, Steinbrecher A, et al. Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am J Hum Genet 2002;71:1033–1043.[Medline]
3. Walter MC, Petersen JA, Stucka R, et al. FKRP (826C>A) frequently causes limb-girdle muscular dystrophy in German patients. J Med Genet 2004;41:e50.[Free Full Text]

This Article Full Text (PDF) Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Search for Related Content Related Collections Related Article