TY - JOUR
T1 - Reducing bodies and myofibrillar myopathy features in FHL1 muscular dystrophy
AU - Selcen, Duygu
AU - Bromberg, Mark B.
AU - Chin, Steven S.
AU - Engel, Andrew G.
N1 - Funding Information:
Dr. Selcen has received research support from the NIH. Dr. Bromberg is a medical advisor for Accordant Health Care; has received funding from Rx Solutions and Talecris; is an Assistant Editor for Muscle & Nerve, Clinical Neurophysiology , and the Journal of Neuromuscular Diseases ; receives royalties from Handbook of Peripheral Neuropathy and UpToDate ; and is on the speaker's bureau of Talecris Biotherapeutics. Dr. Chin holds stock in Myriad Genetics, Inc. Dr. Engel serves as an Associate Editor of Neurology ® ; receives publishing royalties for Myology, 3rd ed. (McGraw-Hill, 2004); and has received research support from the NIH and the Muscular Dystrophy Association. Dr. Bromberg serves on a scientific advisory board for Accordant Health Services, Inc.; has received funding for travel and speaker honoraria from Rx Solutions and Talecris Biotherapeutics; serves as an Assistant Editor for Muscle & Nerve and the Journal of Neuromuscular Diseases and as Editor of Clinical Neurophysiology ; receives publishing royalties for Handbook of Peripheral Neuropathy (Taylor & Francis, 2005) and Quality of Life Measurement in Neurodegenerative and Related Conditions (Cambridge, 2010); serves on the speakers' bureau for Talecris Biotherapeutics; and receives research support from Knopp Neurosciences Inc. and the NIH.
PY - 2011/11/29
Y1 - 2011/11/29
N2 - Objective: Some pathologic features of the FHL1 myopathies and the myofibrillar myopathies (MFMs) overlap; we therefore searched for mutations in FHL1 in our cohort of 50 patients with genetically undiagnosed MFM. Methods: Mutations in FHL1 were identified by direct sequencing. Polymorphisms were excluded by using allele-specific PCR in 200 control subjects. Structural changes in muscle were analyzed by histochemistry, immunocytochemistry, and electron microscopy. Results: We detected 2 novel and 1 previously identified missense mutation in 5 patients. Patients 1-4 presented before age 30, display menadione-nitro blue tetrazolium-positive reducing bodies, and harbor mutations in the FHL1 LIM2 domain. Patient 5 presented at age 75 and has no reducing bodies, and his mutation is not in a LIM domain. The clinical features include progressive muscle weakness, hypertrophied muscles, rigid spine, and joint contractures, and 1 patient also has peripheral neuropathy. High-resolution electron microscopy reveals the reducing bodies composed of 13-nm tubulofilaments initially emanating from Z-disks. At a more advanced stage, abundant reducing bodies appear in the cytoplasm and nuclei with concomitant myofibrillar disintegration, accumulation of cytoplasmic degradation products, and aggregation of endoplasmic reticulum and sarcotubular profiles. Conclusions: FHL1 dystrophies can be associated with MFM pathology. Mutations in the LIM2 domain are associated with reducing bodies composed of distinct tubulofilaments. A mutation extraneous to LIM domains resulted in a mild late-onset phenotype with MFM pathology but no reducing bodies.
AB - Objective: Some pathologic features of the FHL1 myopathies and the myofibrillar myopathies (MFMs) overlap; we therefore searched for mutations in FHL1 in our cohort of 50 patients with genetically undiagnosed MFM. Methods: Mutations in FHL1 were identified by direct sequencing. Polymorphisms were excluded by using allele-specific PCR in 200 control subjects. Structural changes in muscle were analyzed by histochemistry, immunocytochemistry, and electron microscopy. Results: We detected 2 novel and 1 previously identified missense mutation in 5 patients. Patients 1-4 presented before age 30, display menadione-nitro blue tetrazolium-positive reducing bodies, and harbor mutations in the FHL1 LIM2 domain. Patient 5 presented at age 75 and has no reducing bodies, and his mutation is not in a LIM domain. The clinical features include progressive muscle weakness, hypertrophied muscles, rigid spine, and joint contractures, and 1 patient also has peripheral neuropathy. High-resolution electron microscopy reveals the reducing bodies composed of 13-nm tubulofilaments initially emanating from Z-disks. At a more advanced stage, abundant reducing bodies appear in the cytoplasm and nuclei with concomitant myofibrillar disintegration, accumulation of cytoplasmic degradation products, and aggregation of endoplasmic reticulum and sarcotubular profiles. Conclusions: FHL1 dystrophies can be associated with MFM pathology. Mutations in the LIM2 domain are associated with reducing bodies composed of distinct tubulofilaments. A mutation extraneous to LIM domains resulted in a mild late-onset phenotype with MFM pathology but no reducing bodies.
UR - http://www.scopus.com/inward/record.url?scp=82955228817&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=82955228817&partnerID=8YFLogxK
U2 - 10.1212/WNL.0b013e31823a0ebe
DO - 10.1212/WNL.0b013e31823a0ebe
M3 - Article
C2 - 22094483
AN - SCOPUS:82955228817
SN - 0028-3878
VL - 77
SP - 1951
EP - 1959
JO - Neurology
JF - Neurology
IS - 22
ER -