Abstract:

BACKGROUND AND PURPOSE: Mutations in the valosin-containing protein (VCP) gene are known to cause inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) and familial amyotrophic lateral sclerosis (ALS). Despite an increasing number of clinical reports, only one Asian family with IBMPFD has been described.
METHODS: To characterize patients with VCP mutations, we screened a total of 152 unrelated Asian families who were suspected to have rimmed vacuolar myopathy.
RESULTS: We identified VCP mutations in seven patients from six unrelated Asian families. Five different missense mutations were found, including a novel p.Ala439Pro substitution. All patients had adult-onset progressive muscle wasting with variable involvement of axial, proximal, and distal muscles. Two of seven patients were suggested to have mild brain involvement including cerebellar ataxia, and only one showed radiological findings indicating a change in bone. Findings from skeletal muscle indicated mixed neurogenic and myogenic changes, fibers with rimmed vacuoles, and the presence of cytoplasmic and nuclear inclusions. These inclusions were immunopositive for VCP, ubiquitin, transactivation response DNA-binding protein 43, and also histone deacetylase 6 (HDAC6), of which function is regulated by VCP. Evidence of early nuclear and mitochondrial damage was also characteristic.
CONCLUSIONS:   Valosin-containing protein mutations are not rare in Asian patients, and gene analysis should be considered for patients with adult-onset rimmed vacuolar myopathy with neurogenic changes. A wide variety of central and peripheral nervous system symptoms coupled with rare bone abnormalities may complicate diagnosis.

日本語要旨:

VCP変異はIBMPFDの他、家族性ALSの原因でもある。これまでに報告されているアジア人VCP変異は1例のみでありまれな疾患と考えられていた。我々は縁取り空胞を伴うアジア人ミオパチー154家系についてVCP変異をスクリーニングし、6家系7人(4％)に変異を認めた。神経筋症状はこれまでに報告されているものより多彩である一方、骨病変の合併はまれであったことから、報告例が少なかった者と考えられた。筋病理学的には、筋原性変化とともに神経原性変化を認め、早期の核およびミトコンドリア異常が重要所見であることを新たに明らかにした。