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Open Access Research article

Variable disease severity in Saudi Arabian and Sudanese families with c.3924 + 2 T > C mutation of LAMA2

Claudia Di Blasi1, Emanuela Bellafiore1, Mustafa AM Salih2, M Chiara Manzini3, Steven A Moore4, Mohammed Z Seidahmed5, Maowia M Mukhtar6, Zein A Karrar7, Christopher A Walsh3, Kevin P Campbell8, Renato Mantegazza1, Lucia Morandi1 and Marina Mora1*

Author Affiliations

1 Division of Neuromuscular Diseases and Neuroimmunology, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy

2 Division of Pediatric Neurology, Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia

3 Howard Hughes Medical Institute, Division of Genetics and Manton Center for Orphan Disease Research, Children's Hospital, Boston, MA 02115, USA

4 Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA

5 Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia

6 Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan

7 Department of Pediatrics and Child Health, College of Medicine, University of Khartoum, Khartoum, Sudan

8 Howard Hughes Medical Institute and Department of Molecular Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA

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BMC Research Notes 2011, 4:534  doi:10.1186/1756-0500-4-534

Published: 13 December 2011

Abstract

Background

Congenital muscular dystrophy type 1A is caused by mutations in the LAMA2 gene that encodes the laminin α2 chain, a component of the skeletal muscle extracellular matrix protein laminin-211. The clinical spectrum of the disease is more heterogeneous than previously thought, particularly in terms of motor achievement and disease progression. We investigated clinical findings and performed molecular genetic analysis in 3 families from Saudi Arabia and 1 from Sudan in whom congenital muscular dystrophy 1A was suspected based on homozygosity mapping and laminin α2 chain deficiency.

Methods

We investigated 9 affected individuals from 1 Sudanese and 3 Saudi families in whom MDC1A was suggested by clinical, neuroimaging and/or pathological findings and by homozygosity mapping at the LAMA2 locus. Morphological and immunohistochemical analysis were performed in 3 patients from the 3 Saudi families. SSCP analysis, DNA sequencing and microsatellite analysis were carried out in the 4 index cases.

Results

A previously described mutation in the LAMA2 gene, a homozygous T > C substitution at position +2 of the consensus donor splice site of exon 26, was found in the 4 index patients. Clinical evaluation of 9 patients from the 4 families revealed variable disease severity particularly as regards motor achievement and disease progression. Microsatellite analysis showed an identical mutation-associated haplotype in the 4 index cases indicating a founder effect of the mutation in all 4 families.

Conclusions

Our data provide further evidence that the clinical spectrum of MDC1A due to a single mutation is heterogeneous, particularly in terms of motor achievement and disease progression, making it difficult to give a reliable prognosis even in patients with identical LAMA2-associated haplotype. The c.3924 + 2 T > C mutation to date has been found only in patients originating from the Middle East or Sudan; therefore laminin 2 chain deficiency in patients from those regions should initially prompt a search for this mutation.

Keywords:
MDC1A; LAMA2; gene; Laminin α2 chain; Merosin