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Published online before print March 18, 2009, doi:10.1212/01.wnl.0000346518.68110.60)
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NEUROLOGY 2009;72:1802-1809
© 2009 American Academy of Neurology

Congenital muscular dystrophies with defective glycosylation of dystroglycan

A population study

E. Mercuri, MD, PhD, S. Messina, MD, PhD, C. Bruno, MD, PhD, M. Mora, PhD, E. Pegoraro, MD, PhD, G. P. Comi, MD, PhD, A. D'Amico, MD, C. Aiello, PhD, R. Biancheri, MD, A. Berardinelli, MD, PhD, P. Boffi, MD, D. Cassandrini, PhD, A. Laverda, PhD, M. Moggio, MD, PhD, L. Morandi, MD, PhD, I. Moroni, MD, M. Pane, MD, R. Pezzani, PhD, A. Pichiecchio, MD, PhD, A. Pini, MD, PhD, C. Minetti, MD, PhD, T. Mongini, MD, PhD, E. Mottarelli, PhD, E. Ricci, MD, PhD, A. Ruggieri, PhD, S. Saredi, PhD, C. Scuderi, MD, A. Tessa, PhD, A. Toscano, MD, PhD, G. Tortorella, MD, PhD, C. P. Trevisan, MD, PhD, C. Uggetti, MD, PhD, G. Vasco, MD, F. M. Santorelli, PhD and E. Bertini, MD, PhD

Authors' affiliations are listed at the end of the article.

Address correspondence and reprint requests to Dr. Eugenio Mercuri, Department of Child Neurology, Policlinico Gemelli, Largo Gemelli 00168, Rome, Italy mercuri{at}rm.unicatt.it

Background: Congenital muscular dystrophies (CMD) with reduced glycosylation of alpha-dystroglycan ({alpha}-DG) are a heterogeneous group of conditions associated with mutations in six genes encoding proven or putative glycosyltransferases.

Objectives: The aim of the study was to establish the prevalence of mutations in the six genes in the Italian population and the spectrum of clinical and brain MRI findings.

Methods: As part of a multicentric study involving all the tertiary neuromuscular centers in Italy, FKRP, POMT1, POMT2, POMGnT1, fukutin, and LARGE were screened in 81 patients with CMD and {alpha}-DG reduction on muscle biopsy (n = 76) or with a phenotype suggestive of {alpha}-dystroglycanopathy but in whom a muscle biopsy was not available for {alpha}-DG immunostaining (n = 5).

Results: Homozygous and compound heterozygous mutations were detected in a total of 43/81 patients (53%), and included seven novel variants. Mutations in POMT1 were the most prevalent in our cohort (21%), followed by POMT2 (11%), POMGnT1 (10%), and FKRP (9%). One patient carried two heterozygous mutations in fukutin and one case harbored a new homozygous variant in LARGE. No clear-cut genotype-phenotype correlation could be observed with each gene, resulting in a wide spectrum of clinical phenotypes. The more severe phenotypes, however, appeared to be consistently associated with mutations predicted to result in a severe disruption of the respective genes.

Conclusions: Our data broaden the clinical spectrum associated with mutations in glycosyltransferases and provide data on their prevalence in the Italian population.

Abbreviations: {alpha}-DG = alpha-dystroglycan; CMD = congenital muscular dystrophy; CMD-CRB = congenital muscular dystrophy with cerebellar involvement; LGMD = limb-girdle muscular dystrophy; MEB = muscle-eye-brain; WWS = Walker-Walburg syndrome.

Supplemental data at www.neurology.org

Editorial, page 1798

e-Pub ahead of print on March 18, 2009, at www.neurology.org.

*These authors contributed equally.

Supported by the Italian Telethon Foundation GUP3558, GUP6004, GTF05008, and TGB07001 (G.P. Comi, M. Moggio, M. Mora); Ministry of Health-Ricerca Finalizzata (C. Bruno); Italian Telethon project GTB07001E; and the Eurobiobank project QLTR-2001-02769 (M. Mora).

Medical Device: BigDye 3.1 (Applied Biosystems, Foster City, CA).

Disclosure: The authors report no disclosures.

Received November 25, 2008. Accepted in final form January 14, 2009.


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