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From the Institute of Human Genetics (Drs. Poppe, Buddles, and Bushby, and L. Cree and M. Eagle), Department of Cardiology (J. Bourke), Department of Neurobiology (Dr. Anderson), and Department of Radiology (Dr. Birchall), the University Newcastle upon Tyne; Neuromuscular Unit (M. Brockington and Dr. Muntoni), Hammersmith Hospital, London; Department of Neurology (Dr. Busby), St Lukes Hospital, Bradford; and Department of Neurology (Dr. Wills), University Hospital, Nottingham, UK.
Address correspondence and reprint requests to Professor Kate Bushby, Professor of Neuromuscular Genetics, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK; e-mail: kate.bushby{at}ncl.ac.uk
Background: Mutations in the fukutin-related protein gene FKRP cause limb-girdle muscular dystrophy (LGMD2I) as well as a form of congenital muscular dystrophy (MDC1C).
Objective: To define the phenotype in LGMD2I.
Methods: The authors assessed 16 patients from 14 families with FKRP gene mutations and LGMD and collected the results of mutation analysis, protein studies, and respiratory and cardiac investigations.
Results: Thirteen patients, most with adult presentation, were homozygous for the common C826A mutation in FKRP. The three other cases were compound heterozygotes for C826A and two of them presented in childhood, with more progressive disease. The pattern of muscle involvement, frequently including calf hypertrophy, was similar to dystrophinopathy. Complications in patients with LGMD2I were common and sometimes out of proportion to the skeletal muscle involvement. Six patients had cardiac involvement, and 10 had respiratory impairment: five required nocturnal respiratory support. All patients had serum creatine kinase at least 5 to 70 times normal. The most consistent protein abnormality found on muscle biopsy was a reduction of laminin 
2 immunolabeling, either on muscle sections or immunoblotting alone.
Conclusions: LGMD2I due to FKRP mutations appears to be a relatively common cause of LGMD, with respiratory and cardiac failure as prominent complications.
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