Yuko Motozaki

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.

Autoantibody to dihydropyridine receptor in myasthenia gravis.

To investigate autoantibodies related to excitation-contraction (E-C) coupling in patients with myasthenia gravis (MG), we developed a novel method to detect autoantibodies against dihydropyridine receptor (DHPR). Using this method, we detected DHPR antibody in 37% (11 out of 30) of MG patients with thymoma. Antibodies were not detected in normal nor disease controls. The titer of DHPR antibodies showed no significant correlation with autoantibodies to acetylcholine nor ryanodine receptors. The DHPR antibody is another marker for thymoma in MG, and it might have some role in clinical symptoms related to E-C coupling.

Cause of Death in Japanese Patients with Amyotrophic Lateral Sclerosis on Tracheostomy-Positive Pressure Ventilation

uated from the medical records and autopsy findings if available. Differences between the two groups were assessed by nonparametric analysis. The characteristics of the patients are shown in table 1 . There were no significant differences in gender, age at onset and age at death between the two groups; however, disease duration was significantly longer in patients with TPPV than without TPPV (Wilcoxon’s test, p ! 0.05). The hospitalization period until death was also significantly longer in patients with TPPV (Wilcoxon’s test, p ! 0.05). All patients with TPPV died in hospital, whereas a few patients without TPPV died at home. Twenty-two patients underwent autopsy and the diagnosis of ALS was confirmed in all patients by pathologic study. The causes of death in this study are shown in table 2 . The most frequent cause of death in patients with TPPV was respiratory failure (46.2%), as well as in patients without TPPV (89.6%). It was previously reported that 81.3% of ALS patients without TPPV died of respiratory failure [4] . Taken together with a previous report [4] and our study, the frequency of respiratory failure as a cause of death in patients with TPPV seems to be lower than in patients without TPPV. In addition, it is notable that all patients with TPPV developed reDear Sirs, Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by loss of upper and lower motor neurons, leading to weakness and wasting of the affected muscles [1] . Previous reports have shown that the most common cause of death in patients with ALS is respiratory failure followed by other causes, including cardiac problems (myocardial infarction, arrhythmia), sepsis and malignancies [2– 5] ; however, knowledge about the causes of death in patients treated with tracheostomy-positive pressure ventilation (TPPV) is very limited. In this study, we investigated the causes of death of ALS patients on TPPV. We retrospectively reviewed the medical records of 112 consecutive patients with ALS referred to our hospital between April 2006 and September 2011. Diagnosis of ALS was made according to El Escorial diagnostic criteria [6] and clinically probable or definite patients were evaluated in this study. We identified 51 patients who died in this period and divided them into two groups: 13 patients who had been assisted with TPPV at the time of death and 38 patients who had not (9 patients had been assisted with noninvasive positive pressure ventilation, and 29 patients had not received any mechanically assisted ventilation). The causes of death were evalReceived: March 14, 2012 Accepted: June 24, 2012 Published online: September 21, 2012

Increased skeletal muscle expression of the endoplasmic reticulum chaperone GRP78 in patients with myasthenia gravis

In myasthenia gravis (MG), damage to neuromuscular junctions may induce endoplasmic reticulum (ER) stress in skeletal muscles. In the current study, skeletal muscles obtained from patients with MG exhibited upregulation of glucose-regulated protein 78 (GRP78) mRNA that was activated by ER stress. Furthermore, GRP78 mRNA expression was higher in patients with MG and myositis than in patients with non-myopathy. We also observed a significant positive correlation between GRP78 mRNA expression and GRP78 protein levels and between GRP78 mRNA expression and age of MG onset. Our findings suggest that muscle weakness in MG might be caused by both neuromuscular junction disruption and ER stress.

Phenotypic heterogeneity in a family with FAP due to a TTR Leu58Arg mutation: A clinicopathologic study

A family with familial amyloid polyneuropathy (FAP) due to a transthyretin (TTR) Leu58Arg mutation was investigated clinicopathologically. The proband presented with sensorimotor-autonomic polyneuropathy and autopsy demonstrated massive amyloid deposition in the peripheral nerves and heart. However, the mother was characterized by carpal tunnel syndrome and ocular vitreous opacities. Thus, there was considerable phenotypic heterogeneity among family members despite the identical TTR genotype.

Antiphospholipid antibodies in patients with multiple sclerosis or neuromyelitis optica

Introduction:Multiple sclerosis (MS) is an autoimmune-mediated disease of unknown etiology. There are two generally accepted options for treating MS. First, preventing the damage and second, to repair the already damaged in the Central Nervous System (CNS). Endogenous adult human stem cells can remyelinate the human CNS; however generally, this process often fails or is inhibited, resulting in chronic demyelination and progressive axonal death. In contrast, stem cells (SC) emerge as a potential new hope for treatment of MS. There is a growing body of literature that supports SCs potential contribution to immunomodulation and remyelination. We are going to examine the efficacy of MSC in treatment of the patients with MS and compare it with Mitoxantrone. Methods and materials: This is a double blind clinical trial study. In this study, 150 patients with MS were selected. The MS patients were aggressive type of MS who did not have any response to conventional DMDs. They have EDSS more than 4 and less than 7. These group of the patients were divided into 2 groups: 50 will be received autologous mesenchymal stem cells (A-MSC) the second group will be infused Mitoxantrone. In the first group, after harvesting of the bone marrow, we have purified MSC and cultured them. The first injection of cells was done after the MSC number reached to 30 million cells. In fact, we are going to inject 4 times MSCs. Except for the first dose; all injections will be done from L4 to L5 space intra-techally. For the other arm, Mitoxantrone have been infused in 0, 1 and 2 months and then every 3 months up to 140 mg/body m. Clinical assessments, radiological findings and immunological markers will be evaluated before and after MSC and Mitoxantrone infusions as double blind evaluation. Results: In the paper, we will discuss the preliminary results of clinical, radiological and immunological assessments of the patients.