Tomoya Asaka

A novel mutation in the GNE gene and a linkage disequilibrium in Japanese pedigrees

Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive muscular disorder characterized by weakness of the anterior compartment of the lower limbs with onset in early adulthood and sparing of the quadricep muscles. The UDP‐N‐acetylglucosamine‐2‐epimerase/N‐acetylmannosamine kinase (GNE) gene was recently identified as the causative gene for hereditary inclusion body myopathy (HIBM). To investigate whether DMRV and HIBM are allelic diseases, we conducted mutational analysis of the GNE gene of six Japanese DMRV pedigrees and found that all the pedigrees share a homozygous mutation (V572L) associated with a strong linkage disequilibrium, suggesting a strong founder effect in Japanese DMRV pedigrees.

Hereditary inclusion body myopathy with a novel mutation in the GNE gene associated with proximal leg weakness and necrotizing myopathy

Sir, Autosomal recessive hereditary inclusion body myopathy (HIBM) is a muscular disorder characterized by early adult-onset weakness beginning in the distal muscles of the lower limbs with relative sparing of the quadriceps [1], and is frequently associated with mutations in the UDP-N-acetylglucosamine 2-epimerase/ N-acetylmannosamine kinase gene (GNE) on chromosome 9p12-p13 [2]. The presence of rimmed vacuoles on muscle biopsy is the most important finding for diagnosis of this disorder. A 28-year-old man developed progressive muscle weakness of the legs. He had no myalgia, but often complained of muscle cramp. At age 29, neurological examination demonstrated weakness of the bilateral iliopsoas and hamstrings with sparing of the quadriceps. The serum creatine kinase level was elevated [2224 (normal <306) IU/l]. Biopsy of the biceps femoris muscle showed many necrotic and regenerating fibers (Fig. 1a). Treatment with methyl prednisolone pulse therapy, oral prednisolone (60 mg/day), oral cyclophosphamide, or oral cyclosporin did not improve muscle weakness. At age 31, fat-suppressed MRI demonstrated increased signals in the thighs suggesting muscle inflammation [3]. The second biopsy from the right quadriceps femoris muscle showed some necrotic and regenerating fibers. Despite intravenous immunoglobulin therapy (0.4 g/ kg · 5 days) under a diagnosis of steroidrefractory chronic polymyositis, the lower limb weakness progressed. The third biopsy from the tibialis anterior muscle demonstrated numerous rimmed vacuoles with some necrotic fibers and sparse regenerating fibers (Fig. 1b); immunohistochemically, the muscle fibers showed partial expression of major histocompatibility complex class Imoleculewith infiltration of a few CD8+ T cells. After obtaining informed consent, we isolated genomic DNA from the whole blood sample of the patient and his parents. Analysis of eleven coding exons (exons 2– 12) of GNE [4] demonstrated compound heterozygous mutations changing GAT (aspartic acid) to GTT (valine) at codon 176 (D176V) on exon 3, and CCT (proline) to CAT (histidine) at codon 511 (P511H) on exon 9. The patient’s father carried a D176V mutation, and his mother had a P511H mutation. Although the D176V mutation was previously reported [5], the P511H mutation was novel. Several aspects of the clinicopathological features in our patient were similar to acquired inflammatory myopathy. A variety of mutations in the GNE gene showing atypical phenotypes have been identified, including sporadic occurrence [6], muscle inflammation [7], and absence of distal weakness [5]. Although theGNEmutations would lead to changes in the activities of UDP-N-acetylglucosamine 2-epimerase or N-acetylmannosamine kinase and to a decrease in sialylation in muscle [8], pathomechanisms underlying the muscle involvement remain unclear, and the variations in myopathic features of HIBM can not be explained simply by the sites of the GNEmutations.Mutations associatedwith proximal leg weakness included V572L/ V572L, C303V/V572L, and C13S/D176V [5,6]; however, distal myopathy was also reported in HIBM with the V572L/V572L mutation [6]. Our patient with HIBM presented with atypical features including muscle fiber necrosis, although a characteristic feature ofHIBM, i.e., sparing of the quadriceps [1], was still present. It is suggested that a subset of HIBM patients present with a clinical phenotype similar to acquired inflammatory myopathy, although the phenotype–genotype relationship remains to be determined.

Germanium intoxication with sensory ataxia

Sensory ataxia in inorganic germanium intoxication is rare. A 63-year-old housewife had taken inorganic germanium preparations at a dosage of 36 mg a day for about 6 years (total dose about 80 g). She subsequently developed difficulty in writing and gait disturbance with peripheral neuropathy and renal involvement. Germanium, which is not usually detected in the non-germanium user, was accumulated in her hair and nails, permitting a diagnosis of inorganic germanium intoxication. The peripheral neuropathy and renal injury were not reversible after discontinuing the preparation. Pneumonia and sepsis then supervened and the patient died. Autopsy findings showed degeneration and loss of the dorsal root ganglion cells and degeneration of the dorsal column of the spinal cord. Two previously reported cases presented with ataxia. These patients took germanium for long periods and/or large quantities like our case. It was supposed that sensory ataxia was induced by chronic and dose dependent toxicity of inorganic germanium.

Homozygosity and linkage disequilibrium mapping of autosomal recessive distal myopathy (Nonaka distal myopathy)

AbstractAutosomal recessive distal myopathy or Nonaka distal myopathy (NM) is characterized by its unique distribution of muscular weakness and wasting. The patients present with spared quadriceps muscles even in a late stage of the disease. The hamstring and tibialis anterior muscles are affected severely in early adulthood. We have localized the NM gene to the region between markers D9S319 and D9S276 on chromosome 9 by linkage analysis. To further refine the localization of the NM gene, we conducted homozygosity and linkage disequilibrium analysis for 14 patients from 11 NM families using 18 polymorphic markers. All of the patients from consanguineous NM families were found to be homozygous for six markers located within the region between markers D9S2178 and D9S1859. We also provided evidence for significant allelic associations between the NM region and five marker loci. Examination of the haplotype analysis identified a predominant ancestral haplotype comprising the associated alleles 199-160-154-109 (marker order: D9S2179-D9S2180-D9S2181-D9S1804), present in 60% of NM chromosomes and in 0% of parent chromosomes. On the basis of the data obtained in this study, the majority of NM chromosomes were derived from a single ancestral founder, and the NM gene is probably located within the 1.5-Mb region between markers D9S2178 and D9S1791.

Hereditary rimmed vacuole myopathy showing interstitial amyloid deposition in muscle tissue

We describe a consanguineous family that had progressive myopathy with rimmed vacuole (RV) formation and amyloid deposition. Patient 1 is a 71‐year‐old woman with muscle atrophy in the lumbar girdle and lower extremities. Patient 2 is a 40‐year‐old man (the son of Patient 1) with fatty changes in the biceps femoris muscles. Muscle biopsies revealed myopathic and neurogenic degeneration with RV, necrotic fibers, and interstitial amyloid deposition. Amyloid deposition was detected only in the muscle tissue. Muscle Nerve, 2009