title: Variable disease severity in Saudi Arabian and Sudanese families with c.3924 + 2 T > C mutation of LAMA2.
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.
authors.affiliation: Division of Neuromuscular Diseases and Neuroimmunology, Fondazione IRCCS Istituto Neurologico C, Besta, Milan, Italy. mmora@istituto-besta.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Di Blasi
authors.forename: Emanuela
authors.initials: E
authors.lastname: Bellafiore
authors.forename: Mustafa Am
authors.initials: MA
authors.lastname: Salih
authors.forename: M Chiara
authors.initials: MC
authors.lastname: Manzini
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.forename: Mohammed Z
authors.initials: MZ
authors.lastname: Seidahmed
authors.forename: Maowia M
authors.initials: MM
authors.lastname: Mukhtar
authors.forename: Zein A
authors.initials: ZA
authors.lastname: Karrar
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Walsh
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
authors.forename: Renato
authors.initials: R
authors.lastname: Mantegazza
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.forename: Marina
authors.initials: M
authors.lastname: Mora