Satoshi Nozuma

Mutations in MME cause an autosomal-recessive Charcot–Marie–Tooth disease type 2

The objective of this study was to identify new causes of Charcot–Marie–Tooth (CMT) disease in patients with autosomal‐recessive (AR) CMT.

Hereditary sensory and autonomic neuropathy type IID caused by an SCN9A mutation

Objective: To identify the clinical features of Japanese patients with suspected hereditary sensory and autonomic neuropathy (HSAN) on the basis of genetic diagnoses. Methods: On the basis of clinical, in vivo electrophysiologic, and pathologic findings, 9 Japanese patients with sensory and autonomic nervous dysfunctions were selected. Eleven known HSAN disease–causing genes and 5 related genes were screened using a next-generation sequencer. Results: A homozygous mutation, c.3993delGinsTT, was identified in exon 22 of SCN9A from 2 patients/families. The clinical phenotype was characterized by adolescent or congenital onset with loss of pain and temperature sensation, autonomic nervous dysfunctions, hearing loss, and hyposmia. Subsequently, this mutation was discovered in one of patient 1s sisters, who also exhibited sensory and autonomic nervous system dysfunctions, with recurrent fractures being the most predominant feature. Nerve conduction studies revealed definite asymmetric sensory nerve involvement in patient 1. In addition, sural nerve pathologic findings showed loss of large myelinated fibers in patient 1, whereas the younger patient showed normal sural nerve pathology. Conclusions: We identified a novel homozygous mutation in SCN9A from 2 Japanese families with autosomal recessive HSAN. This loss-of-function SCN9A mutation results in disturbances in the sensory, olfactory, and autonomic nervous systems. We propose that SCN9A mutation results in the new entity of HSAN type IID, with additional symptoms including hyposmia, hearing loss, bone dysplasia, and hypogeusia.

Novel mutation in the replication focus targeting sequence domain of DNMT1 causes hereditary sensory and autonomic neuropathy IE

DNMT1, encoding DNA methyltransferase 1 (Dnmt1), is a critical enzyme which is mainly responsible for conversion of unmethylated DNA into hemimethylated DNA. To date, two phenotypes produced by DNMT1 mutations have been reported, including hereditary sensory and autonomic neuropathy (HSAN) type IE with mutations in exon 20, and autosomal dominant cerebellar ataxia, deafness, and narcolepsy caused by mutations in exon 21. We report a sporadic case in a Japanese patient with loss of pain and vibration sense, chronic osteomyelitis, autonomic system dysfunctions, hearing loss, and mild dementia, but without definite cerebellar ataxia. Electrophysiological studies revealed absent sensory nerve action potential with nearly normal motor nerve conduction studies. Brain magnetic resonance imaging revealed mild diffuse cerebral and cerebellar atrophy. Using a next‐generation sequencing system, 16 candidate genes were analyzed and a novel missense mutation, c.1706A>G (p.His569Arg), was identified in exon 21 of DNMT1. Our findings suggest that mutation in exon 21 of DNMT1 may also produce a HSAN phenotype. Because all reported mutations of DNMT1 are concentrated in exons 20 and 21, which encode the replication focus targeting sequence (RFTS) domain of Dnmt1, the RFTS domain could be a mutation hot spot.

Familial clusters of HTLV-1-associated myelopathy/tropical spastic paraparesis.

Objective HTLV-1 proviral loads (PVLs) and some genetic factors are reported to be associated with the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, there are very few reports on HAM/TSP having family history. We aimed to define the clinical features and laboratory indications associated with HAM/TSP having family history. Methods Records of 784 HAM/TSP patients who were hospitalized in Kagoshima University Hospital and related hospitals from 1987 to 2012 were reviewed. Using an unmatched case-control design, 40 patients of HAM/TSP having family history (f-HAM/TSP) were compared with 124 patients suffering from sporadic HAM/TSP, who were admitted in series over the last 10 years for associated clinical features. Results Of the 784 patients, 40 (5.1%) were f-HAM/TSP cases. Compared with sporadic cases, the age of onset was earlier (41.3 vs. 51.6 years, p<0.001), motor disability grades were lower (4.0 vs. 4.9, p = 0.043) despite longer duration of illness (14.3 vs. 10.2 years, p = 0.026), time elapsed between onset and wheelchair use in daily life was longer (18.3 vs. 10.0 years, p = 0.025), cases with rapid disease progression were fewer (10.0% vs. 28.2%, p = 0.019), and protein levels in cerebrospinal fluid (CSF) were significantly lower in f-HAM/TSP cases (29.9 vs. 42.5 mg, p<0.001). There was no difference in HTLV-1 PVLs, anti-HTLV-1 antibody titers in serum and CSF, or cell number and neopterin levels in CSF. Furthermore, HTLV-1 PVLs were lower in cases with rapid disease progression than in those with slow progression in both f-HAM/TSP and sporadic cases. Conclusions We demonstrated that HAM/TSP aggregates in the family, with a younger age of onset and a slow rate of progression in f-HAM/TSP cases compared with sporadic cases. These data also suggested that factors other than HTLV-1 PVLs contribute to the disease course of HAM/TSP.

HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP): A comparative study to identify factors that influence disease progression

OBJECTIVE HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) can progress slowly or rapidly even though a set of symptoms such as spastic paraparesis with pathological reflexes and sweating loss of the lower extremities are commonly observed in patients. Although most of the patients are thought to be infected to HTLV-1 from their mothers by breast feeding, symptoms of HAM/TSP typically manifest in patients later in life (50-60years old in age) and also with a higher prevalence of women to men at a ratio of approximately 3:1. Probability of developing HAM/TSP and how fast an individuals disease may progress from the time of diagnosis could be multifactorial. METHODS We reviewed the records of 150 patients with HAM/TSP admitted to Kagoshima University Hospital between 2002 and 2014. Laboratory data of cerebrospinal fluid and serum and the clinical measurements including age, age of disease onset, progression rate, duration of illness, initial symptoms, Osames Motor Disability Score were evaluated. Rapid disease progression of the disease was defined by deterioration of motor disability by >3 grades within 2years. RESULTS Of 150 HAM/TSP patients in our cohort, 114 cases (76%) were females. Patients presenting with rapid disease progression are approximately 15years older at the age of onset than those with a protracted disease course, and have increased number of cell, and elevated levels of protein as well as anti-HTLV-1 antibody titer in the CSF, suggesting a more active inflammatory process. There is no significant difference in the average values of clinical and laboratory parameters between the sexes. Furthermore, there is no apparent correlation between rate of disease progression and gender. CONCLUSIONS Our results suggest that age and virus mediated inflammation are correlated with disease phenotypes while additional factors such as host or HTLV-1 genetics and gender may influence disease susceptibility.

New type of encephalomyelitis responsive to trimethoprim/sulfamethoxazole treatment in Japan

Objective: To determine the causative pathogen and investigate the effective treatment of a new type of encephalomyelitis with an unknown pathogen in Japan and report the preliminary ultrastructural and genomic characterization of the causative agent. Methods: From 2005 to 2012, we treated 4 Japanese patients with geographic clustering and comparable clinical features, serum/CSF cytology, and radiologic findings. Brain biopsy was conducted in all patients to analyze neuropathologic changes by histology, and electron microscopy was applied to reveal the features of the putative pathogen. Genomic DNA was obtained from the affected brain tissues and CSF, and an unbiased high-throughput sequencing approach was used to screen for specific genomic sequences indicative of the pathogen origin. Results: All patients exhibited progressive dementia with involuntary tongue movements. Cytologic examination of CSF revealed elevated mononuclear cells. Abnormal MRI signals were observed in temporal lobes, subcortical white matter, and spinal cord. Biopsied brain tissue exhibited aggregated periodic acid-Schiff–positive macrophages and 2–7 μm diameter round/oval bodies without nuclei or cell walls scattered around the vessels. Unbiased high-throughput sequencing identified more than 100 archaea-specific DNA fragments. All patients were responsive to trimethoprim/sulfamethoxazole (TMP-SMX) plus corticosteroid therapy. Conclusions: We report 4 cases of encephalomyelitis due to an unknown pathogen. On the basis of ultrastructural and genomic studies, we propose a new disease entity resulting from a causative pathogen having archaeal features. TMP-SMX therapy was effective against this new type of encephalomyelitis.

Clinical and genetic features of Charcot-Marie-Tooth disease 2F and hereditary motor neuropathy 2B in Japan: Tanabe et al

Mutations in small heat shock protein beta‐1 (HspB1) have been linked to Charcot‐Marie‐Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole‐exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1‐related disorders.

Clinical and Electron Microscopic Findings in Two Patients with Mitochondrial Myopathy Associated with Episodic Hyper-creatine Kinase-emia

Mitochondrial myopathy with episodic hyper-creatine kinase (CK)-emia (MIMECK) is a new disease entity characterized by episodic or persistent muscle weakness and elevated CK levels. We herein report two cases of MIMECK with the findings of histopathological studies. Histopathological examinations revealed strongly succinate dehydrogenase-reactive vessels. Electron microscopy showed abnormal mitochondria in the vessels and proliferating and vacuolated mitochondria under the sarcolemma. Both patients exhibited recurrent severe myalgia, weakness and increased CK levels. L-arginine treatment significantly ameliorated their muscle symptoms. These findings indicate that mitochondrial angiopathy plays an important role in the pathophysiology of MIMECK. L-arginine may be a potential therapeutic agent for this disorder.

Clinical presentation of axial myopathy in two siblings with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP)

BackgroundThe clinical features of myositis related with Human T-cell leukemia virus type 1 (HTLV-1) remains unclear despite epidemiological studies suggesting inflammatory myopathy associated with the virus.Case presentationHere, we described the clinical presentations, muscle biopsy studies and laboratory results of two siblings with HTLV-1-associated myelopathy / tropical spastic paraparesis (HAM/TSP) who were affected with lumbar lordosis. Computed tomography (CT) scans demonstrated marked paraspinal muscle atrophy in both patients. Immunohistochemical studies of biopsy tissue obtained from one of the patients revealed inflammatory change of the muscle. Upon oral prednisolone therapy, the patient showed improvement in muscle strength and serum creatine kinase (CK) level.ConclusionMyopathy or specifically axial myopathy should be considered as clinical symptom when treating the patients with HTLV-1 infection.

Clinical features of familial HAM/TSP

Some genetic factors are associated with the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). So far, there is a very few report about familial HAM/TSP. This study aimed to clarify the clinical features of familial HAM/TSP. We reviewed all patients with HAM/TSP, 784 in number, hospitalized to Kagoshima University Hospital from 1987 to 2012. Familial HAM/TSP cases (patients with one or more HAM/TSP patients in their family) were compared with 124 sporadic HAM/TSP cases (patients with no other HAM/TSP patient in their family) admitted in series for association of clinical features in an unmatched case-control design. As a result, 40 patients (5.1%) in total 784 were familial cases. In familial cases compared to sporadic cases, age of onset was earlier (41.3 year old vs. 51.6 year old, P<0.001), the number of acute progression cases was smaller (10.0 percent vs. 28.2 percent, p=0.019), motor disability grade was lower (4.0 vs. 4.9, p=0.043) in spite of longer duration of illness (14.3 years vs. 10.2 years, P=0.026), and duration between onset and time to use a wheelchair in daily life was longer (18.3 years vs. 10.0 years, P=0.025) significantly. Protein in cerebrospinal fluid (CSF) was significantly lower in familial cases (29.9 mg vs. 42.5 mg, p<0.001). HTLV-1 provirus load, anti-HTLV-1 antibody in serum and CSF, cells in CSF was not significantly different. Thus, we demonstrate familial HAM/TSP showing younger onset and slower progress than in sporadic cases. Our results suggest that some genetic factors might influence the incidence of familial HAM/TSP.