In a 3-year-old Algerian boy with a severe form of congenital muscular dystrophy and mental retardation, Louhichi et al. (2004) identified a new homozygous mutation in the fukutin-related protein (FKRP) gene, a transversion 1213G-T, resulting in a val405-to-leu (V405L) substitution. This mutation could not be found by direct sequencing in 150 healthy control subjects (50 Algerian and 100 French). EMG showed myopathic features and muscle biopsy of the tibialis muscle showed severe dystrophic features. The boy also presented cerebellar cysts, megacisterna with hypoplasia of the vermis, microcephaly and abnormally high periventricular intensity.

In a consanguineous family from Libya with a severe form of CMD, Brockington et al. (2001) found that the one affected child was homozygous for a pro448-to-leu (P448L) missense mutation in the FKRP gene. The patient presented in the first few weeks of life with hypotonia and feeding difficulties, followed by motor delay. On examination at age 16 months, she could not walk and was weaker in her arms than in her legs. She had calf hypertrophy and facial weakness. Serum creatine kinase was very high and she had a myopathic EMG. Her intelligence was normal.

In a consanguineous Tunisian family in which 13 members had limb-girdle muscular dystrophy type 2I, Driss et al. (2003) identified a homozygous 1486T-A change in the FKRP gene, which abolishes a stop codon and is predicted to add 21 amino acids to the C-terminal end of the protein. The patients had symmetric proximal muscle weakness and wasting in all four limbs. No heart involvement was found. Immunohistochemical and immunoblot analysis showed abnormal expression of alpha-dystroglycan and alpha-2 laminin, supporting the hypothesis that FKRP has a role in the interaction between components of the extracellular matrix.

Louhichi et al. (2004) found a new homozygous missense mutation 1364C-A of the fukutin-related protein (FKRP) gene on chromosome 19 in six patients, all from consanguineous Tunisian families, with hypotonia, weakness, increased serum CK and dystrophic changes in muscle samples. The mutation is expected to result in an ala455-to-asp (A455D) substitution in the protein. Linkage to CMD loci FCMD, MEB, MDC1A and MDC1B was excluded. Three patients presented a severe form of CMD with mental retardation and cerebellar cysts. After immunocytochemistry, the patients showed reduced immunohistochemical staining of laminin alpha2 chain and the decrease in the alpha-Dystroglycan expression in the available samples. Sequencing revealed the same mutation within the six patients. The inheritance of the mutation followed an autosomal recessive pattern of inheritance. The patients were homozygous for the markers D19S219, D19S412 and D19S606, 1,255 kb and 238 kb proximal and 722 kb distal to FKRP on chromosome 19q13.3; suggesting a founder effect for the 1364C-A transversion in the Tunisian population.