Abstract

We describe a novel autosomal dominant hereditary inclusion body myopathy (HIBM) that clinically mimics limb girdle muscular dystrophy in a Chinese family. We performed a detailed clinical assessment of 36 individuals spanning four generations. The age of onset ranged from the 30s to the 50s. Hip girdle, neck flexion and axial muscle weakness were involved at an early stage. This disease progressed slowly, and a shoulder girdle weakness appeared later in the disease course. Muscle biopsies showed necrotic, regenerating, and rimmed vacuolated fibers as well as congophilic inclusions in some of the fibers. Electron micrograph revealed cytoplasmic inclusions of 15–21 nm filaments. A genomewide scan and haplotype analyses were performed using an Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM), which traced the disease to a new locus on chromosome 7q22.1–31.1 with a maximum multi-point LOD score of 3.65. The critical locus for this unique disorder, which is currently referred to as hereditary inclusion body myopathy 4 (HIBM4), spans 8.78 Mb and contains 65 genes. This localization raises the possibility that one of the genes clustered within this region may be involved in this disorder.

Highlights

  • Hereditary inclusion body myopathy (HIBM) constitutes a heterogeneous group of disorders,histologically characterized by muscle fibers with rimmed vacuoles and inclusions consisting of filaments with a diameter of 15–21 nm

  • Five different HIBMs have been reported: one for the autosomal recessive (AR) IBM, which is known as HIBM2 (MIM #600737), Distal Myopathy with Rimmed Vacuoles (DMRV) or Nonaka Myopathy (MIM #605820) [1,2], and four for the autosomal dominant (AD) IBMs

  • The AD IBM includes HIBM1 (MIM #601419), HIBM3 (MIM #605637), HIBM associated with Paget disease of the bone and/or frontotemporal dementia (HIBM-PFD, MIM #167320) and HIBM with early respiratory failure (HIBM-ERF, MIM #607569)

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Summary

Introduction

Hereditary inclusion body myopathy (HIBM) constitutes a heterogeneous group of disorders,histologically characterized by muscle fibers with rimmed vacuoles and inclusions consisting of filaments with a diameter of 15–21 nm. HIBM2 is characterized by muscle weakness that initiates within the distal muscles of the lower limbs with relative sparing of the quadriceps [6,7]. HIBM3 (MIM #605637) is characterized by congenital joint contractions, external ophthalmoplegia, and a predominant proximal muscle weakness and is caused by a defect in the myosin heavy chain IIa gene located at 17p13.1[10,11,12]. HIBM-PFD, which is located at 9p13, is caused by a defect in the valosin-containing protein gene [13,14,15]. The locus of HIBM-ERF has not yet been identified

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