Titinopathies and extension of the M-line mutation phenotype beyond distal myopathy and LGMD2J
B. Udd, MD, PhD,
A. Vihola, MSc,
J. Sarparanta,
I. Richard, PhD and
P. Hackman, PhD
From the Neurological Department (Dr. Udd, A. Vihola), Vaasa Central Hospital, Department of Neurology (Dr. Udd), Tampere University Hospital, and Folkhälsan Institute of Genetics and Department of Medical Genetics (Dr. Hackman, A. Vihola and J. Sarparanta), University of Helsinki, Finland; and Généthon-CNRS8115 (Dr. Richard), Evry, France.
Address correspondence and reprint requests to Dr. B. Udd, Department of Neurology, Vaasa Central Hospital, FIN-65130 Vaasa, Finland; e-mail: Bjarne.Udd{at}vshp.fi
Objective: To determine the phenotype variability associatedwith the specific C-terminal M-line titin mutation known tocause autosomal dominant distal myopathy, tibial muscular dystrophy(TMD; MIM 600334), and limb girdle muscular dystrophy 2J (LGMD2J).
Methods: Three hundred eighty-six individuals were genotypedfor the Finnish founder mutation in titin (FINmaj) causing TMD/LGMD2J.
Results: Two hundred seven patients were heterozygous for themutation. Among these patients, 189 (91%) had a more commonphenotype compatible with the classic description of TMD. However,18 (9%) had unusual phenotypes such as proximal leg or posteriorlower leg muscle weakness and atrophy even at onset. Four patientswere confirmed homozygotes representing the LGMD2J phenotype.These homozygotes were half of the eight LGMD patients previouslydescribed in the original large consanguineous kindred.
Conclusions: Large variability of phenotypic expression causedby just one mutation, the Finnish FINmaj, suggests that no certainphenotype of myopathy/dystrophy can be excluded from being causedby mutated titin. Yet unknown homozygous or compound heterozygoustitin mutations without phenotype in the heterozygote carriersmay be responsible for undetermined recessive MD and LGMD.
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