Brain Advance Access published online on January 29, 2009
Brain, doi:10.1093/brain/awn325
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Clinical, histological and genetic characterization of reducing body myopathy caused by mutations in FHL1
1 Division of Neurology, The Children's Hospital of Philadelphia, Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA 2 Department of Neuropathology, Institute for Neurological Research/FLENI, Buenos Aires, Argentina 3 Dubowitz Neuromuscular Centre, UCL-Institute of Child Health, Guilford Street, London WC1N 1EH, UK 4 Wolfson Centre for Inherited Neuromuscular Disorders, Department of Musculoskeletal Pathology, Robert Jones & Agnes Hunt Orthopedic Hospital, Oswestry, SY10 7AG, UK 5 Department of Developmental Neuroscience, Stella Maris Scientific Institute, Pisa, Italy 6 Department of Pathology, University of Utah, Salt Lake City, UT, USA 7 Department of Human Genetics, University of Utah, Salt Lake City, UT, USA 8 French Hospital and Favaloro Foundation, Buenos Aires, Argentina 9 R. Gutierrez Children's Hospital, Buenos Aires, Argentina 10 Department of Neuropediatrics, Churruca Visca Hospital, Buenos Aires, Argentina 11 Division of Neurosciences, Department of Neuropathology, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK 12 Department of Pediatrics, Princess Elizabeth Hospital, St. Peter Port, Guernsey 13 Department of Neurology, University of Utah, Salt Lake City, UT, USA 14 Department of Pediatrics, University of Utah, Salt Lake City, UT, USA 15 Alfred I. duPont Hospital for Children, Wilmington, DE, USA 16 Department of Neuropathology, Johannes Gutenberg University, Mainz, Germany 17 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
Correspondence to:
Carsten G. Bönnemann, MD, The Children's Hospital of Philadelphia, Division of Neurology, Abramson Research Center 516 I, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104, USA E-mail: bonnemann{at}email.chop.edu
We recently identified the X-chromosomal four and a half LIM domain gene FHL1 as the causative gene for reducing body myopathy, a disorder characterized by progressive weakness and intracytoplasmic aggregates in muscle that exert reducing activity on menadione nitro-blue-tetrazolium (NBT). The mutations detected in FHL1 affected highly conserved zinc coordinating residues within the second LIM domain and lead to the formation of aggregates when transfected into cells. Our aim was to define the clinical and morphological phenotype of this myopathy and to assess the mutational spectrum of FHL1 mutations in reducing body myopathy in a larger cohort of patients. Patients were ascertained via the detection of reducing bodies in muscle biopsy sections stained with menadione-NBT followed by clinical, histological, ultrastructural and molecular genetic analysis. A total of 11 patients from nine families were included in this study, including seven sporadic patients with early childhood onset disease and four familial cases with later onset. Weakness in all patients was progressive, sometimes rapidly so. Respiratory failure was common and scoliosis and spinal rigidity were significant in some of the patients. Analysis of muscle biopsies confirmed the presence of aggregates of FHL1 positive material in all biopsies. In two patients in whom sequential biopsies were available the aggregate load in muscle sections appeared to increase over time. Ultrastructural analysis revealed that cytoplasmic bodies were regularly seen in conjunction with the reducing bodies. The mutations detected were exclusive to the second LIM domain of FHL1 and were found in both sporadic as well as familial cases of reducing body myopathy. Six of the nine mutations affected the crucial zinc coordinating residue histidine 123. All mutations in this residue were de novo and were associated with a severe clinical course, in particular in one male patient (H123Q). Mutations in the zinc coordinating residue cysteine 153 were associated with a milder phenotype and were seen in the familial cases in which the boys were still more severely affected compared to their mothers. We expect the mild end of the spectrum to significantly expand in the future. On the severe end of the spectrum we define reducing body myopathy as a progressive disease with early, but not necessarily congenital onset, distinguishing this condition from the classic essentially non-progressive congenital myopathies.
Key Words: reducing body myopathy; FHL1; aggresomes; LIM; X-linked
Abbreviations: BiPAP, bilevel positive airways pressure; CK, creatine kinase; EM, electron microscopy; FHL1, four and a half LIM domain 1; LIM, Lin-11, Isl-1, Mec-3; NADH-TR, nicotinamide adenine dinucleotide tetrazolium reductase; NBT, nitro-blue-tetrazolium; RBM, reducing body myopathy
Received July 31, 2008. Revised October 15, 2008. Accepted November 6, 2008.
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