Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy.
OBJECTIVE
Defects in glycosylation of alpha-dystroglycan are associated with several forms of muscular dystrophy, often characterized by congenital onset and severe structural brain involvement, collectively known as dystroglycanopathies. Six causative genes have been identified in these disorders including fukutin. Mutations in fukutin cause Fukuyama congenital muscular dystrophy. This is the second most common form of muscular dystrophy in Japan and is invariably associated with mental retardation and structural brain defects. The aim of this study was to determine the genetic defect in two white families with a dystroglycanopathy.


METHODS
The six genes responsible for dystroglycanopathies were studied in three children with a severe reduction of alpha-dystroglycan in skeletal muscle.


RESULTS
We identified pathogenic fukutin mutations in these two families. Affected children had normal intelligence and brain structure and shared a limb girdle muscular dystrophy (LGMD) phenotype, had marked elevation of serum creatine kinase, and were all ambulant with remarkable steroid responsiveness.


CONCLUSIONS
Our data suggest that fukutin mutations occur outside Japan and can be associated with much milder phenotypes than Fukuyama congenital muscular dystrophy. These findings significantly expand the spectrum of phenotypes associated with fukutin mutations to include this novel form of limb girdle muscular dystrophy that we propose to name LGMD2L.
Godfrey
Caroline
C
DNA Laboratory, Genetics Centre, Guy's Hospital, London, United Kingdom.
Escolar
Diana
D
Research Center for Genetic Medicine, Children's National Medical Center, George Washington University, Washington, DC.
Brockington
Martin
M
Dubowitz Neuromuscular Centre, Department of Paediatrics, Hammersmith Campus, Imperial College London, London.
Clement
Emma M
EM
Dubowitz Neuromuscular Centre, Department of Paediatrics, Hammersmith Campus, Imperial College London, London.
Mein
Rachael
R
DNA Laboratory, Genetics Centre, Guy's Hospital, London, United Kingdom.
Jimenez-Mallebrera
Cecilia
C
Dubowitz Neuromuscular Centre, Department of Paediatrics, Hammersmith Campus, Imperial College London, London.
Torelli
Silvia
S
Dubowitz Neuromuscular Centre, Department of Paediatrics, Hammersmith Campus, Imperial College London, London.
Feng
Lucy
L
Dubowitz Neuromuscular Centre, Department of Paediatrics, Hammersmith Campus, Imperial College London, London.
Brown
Susan C
SC
Dubowitz Neuromuscular Centre, Department of Paediatrics, Hammersmith Campus, Imperial College London, London.
Sewry
Caroline A
CA
Dubowitz Neuromuscular Centre, Department of Paediatrics, Hammersmith Campus, Imperial College London, London.|Centre for Inherited Neuromuscular Disorders, Robert Jones & Agnes Hunt Orthopaedic Hospital, Oswestry, London, United Kingdom.
Rutherford
Mary
M
Robert Steiner Magnetic Resonance Unit, Clinical Sciences Centre, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Shapira
Yehuda
Y
Division of Child Neurology, Hadassah University Hospital, Jerusalem, Israel.
Abbs
Stephen
S
DNA Laboratory, Genetics Centre, Guy's Hospital, London, United Kingdom.
Muntoni
Francesco
F
Dubowitz Neuromuscular Centre, Department of Paediatrics, Hammersmith Campus, Imperial College London, London.
D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D049030:Dystroglycans / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005260:Female; D006031:Glycosylation; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism; D049288:Muscular Dystrophies, Limb-Girdle / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics*; D011241:Prednisone / Q000627:therapeutic use; D035781:Siblings
D000893:Anti-Inflammatory Agents; C113587:FKTN protein, human; D008565:Membrane Proteins; D049030:Dystroglycans; D011241:Prednisone