Congenital muscular dystrophy with muscle inflammation alpha dystroglycan glycosylation defect and no mutation in FKRP gene
Introduction
Congenital muscular dystrophies are a heterogeneous group of autosomal recessive disorders in infancy with symptoms of muscle weakness, contractures and dystrophic changes at the skeletal muscle biopsy. The association of mental retardation with major central nervous system (CNS) abnormalities, such as alterations of neuronal migration and eye abnormalities, are present in muscle–eye–brain (MEB) disease, Walker–Warburg Syndrome (WWS) and in Fukuyama congenital muscular dystrophy [1]. These syndromes result from mutations of POMGnT1, POMT1 and Fukutin genes, respectively. Recently only one case presenting as a WWS has been described associated with a POMT2 gene mutation [2]. Finally, mutations in the human homologue of the murine LARGE gene have been described, associated with a new form of CMD with severe brain involvement named CMD1D [3]. Common to all these conditions is the hypoglycosylation of α-dystroglycan (α-DG) in muscle.
A CMD form without brain involvement and a mild limb girdle muscular dystrophy is caused by homozygous and compound heterozygous mutations in the Fukutin-Related Protein (FKRP) gene [4]. The FKRP gene encodes a protein of unknown function. However, the marked reduction of muscle α-DG immunostaining and the decreased molecular weight of FKRP protein at Western Blot analysis in patients carrying FKRP mutations suggest that fukutin-related protein is involved in α-DG glycosylation pathway [4], [5].
Here we describe a case of congenital muscular dystrophy characterized by muscle weakness, psychomotor developmental delay and normal brain MRI. Muscle biopsy showed dystrophic alterations, α-dystroglycan glycosylation defect with partial α2-laminin deficiency and severe inflammation with large cellular infiltrates. Genetic studies did not show any pathogenic mutation in the genes associated with α-DG glycosylation defects, namely FKRP, LARGE, POMT1 and POMGnT1.
Section snippets
Case report
A 3-year-old boy was born at term after an uncomplicated delivery, from unrelated healthy parents. The child's father has a history of drug abuse, and the boy's 4-year-old sister is healthy. During pregnancy, the mother did not perceive any fetal movement. The newborn had always presented severe hypotonia and microcephalia. At 6 months of age, motor and psychic milestone delay and weakness were noticed. Marked hypotonia was still present. Serum creatine chinase CK level was 5000 IU
Muscle biopsy
The muscle biopsy performed at 6 months of age revealed dystrophic changes with muscle necrosis and increase of connective tissue (Fig. 1A, B). Huge inflammatory infiltrates (Fig. 1A), predominantly consisting of macrophages and CD4–CD8 lymphocytes, were also seen (Fig. 1C, D). MHC I was slightly expressed at the muscle membrane level in non-necrotic muscle fibers.
Complete absence of α-dystroglycan using the antibody against the glycosylated epitope was observed (Fig. 2E).
Normal staining for
Discussion
We describe a case of CMD characterized by severe muscle weakness, high CK levels, moderate mental retardation and normal brain MRI associated with a partial deficiency of α2-laminin and with the absence of the glycosylated epitope of α-DG. Congenital muscular dystrophies are a group of disorders often characterized by the association of muscle dystrophic changes with major CNS alterations depending on defects of neuronal migration, such as microgyria, pachigyria, heterotopia. Also, eye
Acknowledgments
The financial support of Associazione Amici del Centro Dino Ferrari-University of Milan, the Telethon project GTF02008, the Eurobiobank project QLTR-2001-02769 and R.F. 2002 Criobanca Automatizzata di Materiale Biologico are gratefully acknowledged.
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