Clinical delineation and localization to chromosome 9p13.3-p12 of a unique dominant disorder in four families: hereditary inclusion body myopathy, Paget disease of bone, and frontotemporal dementia

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.

FIG. 1.

Partial pedigree of Family 1 affected with autosomal dominant HIBM and PDB showing genotype and haplotype analysis for markers on chromosome 9. , IBM; , PDB; , dementia. The proband is indicated with an arrow on the left.

FIG. 2.

Partial pedigree of Family 2 affected with autosomal dominant HIBM and PDB showing genotype and haplotype analysis for markers on chromosome 9. , IBM; , PDB; , dementia. The proband is indicated with an arrow on the left.

FIG. 3.

Partial pedigree of Family 3 affected with autosomal dominant HIBM and PDB showing genotype and haplotype analysis for markers on chromosome 9. , IBM; , PDB; , dementia. The proband is indicated with an arrow on the left.

FIG. 4.

Partial pedigree of Family 4 affected with autosomal dominant HIBM and PDB showing genotype and haplotype analysis for markers on chromosome 9. , IBM; , PDB; , dementia. The proband is indicated with an arrow on the left.

FIG. 5.

Figure of a 55-year-old male with proximal myopathy showing atrophy of the deltoid and striking winging of the scapulae while attempting to raise his arms.

FIG. 6.

Muscle biopsy analysis. Figure 5A is an H&E stain which illustrates the myopathic features with variation in fiber size and grouped regions of muscle fiber atrophy. Figure 5B is also an H&E stain which shows blue-rimmed vacuoles in small and large muscle fibers. Figure 5C is stained with Congo red and illustrates blue rimmed vacuoles with punctate, blue staining debris.

FIG. 7.

Multipoint linkage analysis of markers mapped to the chromosome 9. The markers and cytogenetic localization are designated on the X axis with relative marker distances (cM).

FIG. 8.

Summary of haplotype analysis. Microsatellite markers used in molecular analysis are listed in order from p-arm to q-arm (top to bottom) on the backbone of chromosome 9. Relative marker positions are based on assignments from the Human Genome draft sequence and intermarker distances (cM) were obtained from the chromosome 9 sex-averaged genetic linkage map (Marshfield). The critical region for HIBM/PDB/FTD is represented by a solid black bar. The genetic loci for autosomal recessive IBM2 and ALS presenting with FTD are indicated with diagonally striped bars. The double recombination event affecting markers D9S234, D9S1844, D9S1862, D9S1879, and D9S1800 is indicated with a gray box surrounding these markers.