ABSTRACT
Inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia is a rare but highly penetrant autosomal dominant progressive disorder linked to mutations in valosin containing protein (VCP). Here, we characterize a novel mutation in the linker 1 domain of VCP leading to inclusion body myopathy and/or frontotemporal dementia in 3 generations of a Swiss family. A detailed history of several years of clinical follow-up and electrophysiological, radiological and pathological findings are presented. Five out of 6 individuals suffered from progressive myopathy and 2 out of 6 from frontotemporal dementia, respectively. A radiologically suspected Paget's disease of the bone could not been confirmed at autopsy. This case study illustrates that only a subset of individuals shows the full triad of the disease complex and that clinicopathological findings are - when interpreted apart from familial history - hard to distinguish from sporadic inclusion body myositis.
Subject(s)
Adenosine Triphosphatases/genetics , Cell Cycle Proteins/genetics , Frontotemporal Dementia/genetics , Muscular Dystrophies, Limb-Girdle/genetics , Mutation/genetics , Myositis, Inclusion Body/genetics , Osteitis Deformans/genetics , Biopsy , Female , Frontotemporal Dementia/ethnology , Frontotemporal Dementia/pathology , Humans , Male , Middle Aged , Muscle, Skeletal/pathology , Muscular Dystrophies, Limb-Girdle/ethnology , Muscular Dystrophies, Limb-Girdle/pathology , Myositis, Inclusion Body/ethnology , Myositis, Inclusion Body/pathology , Osteitis Deformans/ethnology , Osteitis Deformans/pathology , Pedigree , Switzerland , Valosin Containing ProteinABSTRACT
Anti-myelin-associated glycoprotein (MAG) neuropathy is an antibody-mediated polyneuropathy. We correlated clinical features, immunoglobulin (Ig) M blood levels, IgM deposition and axonal degeneration in skin biopsies of anti-MAG neuropathy patients. By confocal microscopy, IgM deposits were found exclusively within perineurium-enclosed nerves; they were not found on single, non-perineurium-ensheathed myelinated axons. There was a linear correlation between IgM accumulation in nerve fascicles with IgM blood levels but not with anti-MAG antibody titer or disease duration. Axons with specific IgM deposits had signs of axonal damage, including neurofilament disintegration. Nodal structures were intact even at sites where the axons showed pathologic changes. Ultrastructural analysis revealed degeneration of myelinating Schwann cells. Taken together, these findings suggest that in anti-MAG neuropathy patients, IgM deposits are entrapped within cutaneous perineurium-ensheathed nerve bundles where they accumulate in the endoneurial space. High local IgM levels in the endoneurium may be required for IgM deposition on myelin and subsequent axonal injury and degeneration. This study underlines the importance of early, effective anti-B-cell treatments for preventing progression of this neuropathy.
