Abstract
Autosomal dominant myopathy, Paget disease of bone, and dementia constitute a unique disorder (MIM 605382). Here we describe the clinical, biochemical, radiological, and pathological characteristics of 49 affected (23 male, 26 female) individuals from four unrelated United States families. Among these affected individuals 90% have myopathy, 43% have Paget disease of bone, and 37% have premature frontotemporal dementia. EMG shows myopathic changes and muscle biopsy reveals nonspecific myopathic changes or blue-rimmed vacuoles. After candidate loci were excluded, a genome-wide screen in the large Illinois family showed linkage to chromosome 9 (maximum LOD score 3.64 with marker D9S301). Linkage analysis with a high density of chromosome 9 markers generated a maximum two-point LOD score of 9.29 for D9S1791, with a maximum multipoint LOD score of 12.24 between D9S304 and D9S1788. Subsequent evaluation of three additional families demonstrating similar clinical characteristics confirmed this locus, refined the critical region, and further delineated clinical features of this unique disorder. Hence, autosomal dominant inclusion body myopathy (HIBM), Paget disease of bone (PDB), and frontotemporal dementia (FTD) localizes to a 1.08–6.46 cM critical interval on 9p13.3–12 in the region of autosomal recessive IBM2.
Highlights
Hereditary inclusion body myopathy with early-onset PDB and FTD is distinct among the clinically and genetically heterogeneous family of hereditary myopathies
A progressive frontal dementia with bone cysts associated with signs of upper motor neuron involvement has been reported in Nasu-Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy [38,39], a recessively inherited disorder (MIM 221770)
There is no evidence that Nasu-Hakola disease causes a myopathy, the bone cysts do not resemble PDB, and the dementia is associated with white matter rather than gray matter changes
Summary
Consent was obtained from each subject prior to participation. Clinical studies were approved by the Springfield Committee for Research Involving Human Subjects. Individuals included in the analysis were over age 18 years Members of these families were examined for muscular weakness, PDB, and dementia through clinical, biochemical, and radiological studies. For individuals VI: and VI: of pedigree 1, archival histology specimens or autopsy tissue provided the source of DNA used in genetic analysis. DNA from 39 individuals in Family 1 (9 affected, 24 unaffected, 6 spouses) was submitted for a genome-wide search to the National Heart, Lung, and Blood Institute Mammalian Genotyping Service (Marshfield, WI). All individuals included in the analysis were above 18 years of age. The marker-allele frequencies were estimated from the data by means of both observed and reconstructed genotypes of founders within the pedigrees. Linkage was considered established to a locus if a positive LOD score of 3 was obtained and was considered excluded if a LOD score of −2 was obtained
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