An NEFH founder mutation causes broad phenotypic spectrum in multiple Japanese families.

BACKGROUND AND AIMS: Mutations in neurofilament genes have been linked to several neuromuscular disorders. The neurofilament heavy (NEFH) gene was identified as the causative gene of Charcot-Marie-Tooth disease type 2CC (CMT2CC) in 2016, with a toxic gain of function mechanism caused by the translation and aggregation of cryptic amyloidogenic element (CAE) in the 3' untranslated region (UTR). But the NEFH-related clinical and genetic spectrums are still unclear in Japan. METHODS: We analyzed all variants in the NEFH gene from our in-house whole-exome sequencing data, established from Japanese nationwide patients with neuromuscular disorders, including Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA). RESULTS: We identified a c.3017dup (p.Pro1007Alafs*56) variant in NEFH from three families clinically diagnosed with CMT, and one family with SMA. In addition to the patients presented with typical peripheral neuropathies, pyramidal signs were observed from one CMT patient. Whereas the SMA patients showed severe characteristic weakness of triceps brachii and quadriceps femoris. All of these four families reside in Kagoshima Prefecture of Japan, and a following haplotype analysis strongly suggests a founder effect. INTERPRETATION: This is the original report referring to a founder mutation in NEFH. The clinical diversity in our study, comprising CMT, with or without pyramidal signs, and SMA, suggest an extensive involvement of peripheral nerve, anterior horn cells, or both. Our findings broaden the phenotypic spectrum of NEFH-related disorders.

Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan.

BACKGROUND AND OBJECTIVES: The GAA repeat expansion within the fibroblast growth factor 14 (FGF14) gene has been found to be associated with late-onset cerebellar ataxia. This study aimed to investigate the genetic causes of cerebellar ataxia in patients in Japan. METHODS: We collected a case series of 940 index patients who presented with chronic cerebellar ataxia and remained genetically undiagnosed after our preliminary genetic screening. To investigate the FGF14 repeat locus, we employed an integrated diagnostic strategy that involved fluorescence amplicon length analysis polymerase chain reaction (PCR), repeat-primed PCR, and long-read sequencing. RESULTS: Pathogenic FGF14 GAA repeat expansions were detected in 12 patients from 11 unrelated families. The median size of the pathogenic GAA repeat was 309 repeats (range: 270-316 repeats). In these patients, the mean age of onset was 66.9 ± 9.6 years, with episodic symptoms observed in 56% of patients and parkinsonism in 30% of patients. We also detected FGF14 repeat expansions in a patient with a phenotype of multiple system atrophy, including cerebellar ataxia, parkinsonism, autonomic ataxia, and bilateral vocal cord paralysis. Brain magnetic resonance imaging (MRI) showed normal to mild cerebellar atrophy, and a follow-up study conducted after a mean period of 6 years did not reveal any significant progression. DISCUSSION: This study highlights the importance of FGF14 GAA repeat analysis in patients with late-onset cerebellar ataxia, particularly when they exhibit episodic symptoms, or their brain MRI shows no apparent cerebellar atrophy. Our findings contribute to a better understanding of the clinical variability of GAA-FGF14-related diseases.

Prodromal headache in anti-NMDAR encephalitis: An epiphenomenon of NMDAR autoimmunity.

OBJECTIVE: To investigate the nature of prodromal headache in anti-NMDA receptor (NMDAR) encephalitis. METHODS: Retrospective review of the clinical information of 39 patients with anti-NMDAR encephalitis admitted between January 1999 and September 2017. Five patients with an atypical presentation were excluded. Thus, in 34 patients (median 27 years [range, 12-47 years]; 28 [82%] female), the clinical features were compared between patients who initially reported headache and those who did not report. RESULTS: Twenty-two patients (65%) reported headache either transiently (n = 5) or continuously (n = 17). Encephalitic symptoms (psychobehavioral memory alterations, seizure, dyskinesias, or altered level of consciousness) developed in 20 patients with median 5.5 days (range, 1-29 days) after headache onset. In one patient, NMDAR antibodies were detected in CSF 3 days after headache onset. Patients with headache had more frequently fever (14/22 [64%] vs. 2/12 [17%] p = 0.013) and higher CSF pleocytosis (median white blood cells 79/µl [range, 6-311/µl] vs. 30/µl [range, 2-69/µl], p = 0.035) than those without headache, but there was no difference in gender, age at onset, seizure, migraine, CSF oligoclonal band detection, elevated IgG index, tumor association, or brain MRI abnormalities between them. CONCLUSIONS: Headache often developed with fever and pleocytosis, but it was rapidly replaced by psychiatric symptoms. Based on current knowledge on the antibody-mediated mechanisms that cause a decrease of synaptic NMDAR through crosslinking and internalization leading to a state mimicking "dissociative anesthesia," we speculated that prodromal headache is not likely caused by direct effect of the autoantibodies but rather meningeal inflammation (noninfectious aseptic meningitis) that occurs in parallel to intrathecal antibody synthesis as an epiphenomenon of NMDAR autoimmunity. Psychobehavioral alterations following headache is an important clue to the diagnosis.

[Case of oromandibular dystonia presenting with severe impairment of mouth-opening, and a marked effect by administration of baclofen].

We report a 67-year-old woman with idiopathic oromandibular dystonia (OMD). She could neither open the mouth nor take meals due to involuntarily strong mouth-closing. The movement of face, pharynx and tongue were normal, and she could open the mouth slightly when jaw and cheek were touched (sensory trick). Chvostek sign and Trousseau sign were negative, and opisthotonus was not recognized. The laboratory data including calcium, phosphorous and cerebrospinal fluid were within normal limits, head and cervical MRI, temporomandibular joints-Xp and needle electromyography were normal. The surface electromyography revealed that masseter and chin muscles contracted synchronously. This result meant dystonia around the mouth. The clinical course and physical examination did not support the diagnosis of tetanus, tetany or bulldog response. She was diagnosed as OMD. She had peroral administration of baclofen, because this drug is a GABA-derivative and acts as a muscular relaxant. Her clinical symptoms and dystonic pattern on the surface electromyography improved markedly after the administration. Baclofen is an effective drug for treatment of oromandibular dystonia.

[A steroid-responsive case of severe rhabdomyolysis associated with cytomegalovirus infection].

A 31-year-old man was admitted to our hospital, complaining of muscular weakness and pain in the legs one month after a common cold. On admission, neurological examinations demonstrated moderate weakness in the arms and mild weakness in the legs with decreased or diminished deep tendon reflexes, and mild dysphagia. Weakness was gradually extended to the arm, throat and respiratory muscles, requiring artificial ventilation. Laboratory examinations demonstrated increased levels of CK (upto 24,380 IU/L) and positive anti-cytomegalovirus (CMV) -IgM antibodies in the serum, and myogloburinuria. CMV was not detected in either the blood cells or muscles by PCR. There were no antibodies against viruses including Ebstein-Barr virus and HIV, in the serum. There were no autoantibodies related to collagen diseases in the serum. Systemic PET scan did not show any evidence of malignancy. Bone marrow biopsy did not show any atypical cells. Muscle MRI demonstrated mild atrophy with high intensity signals in part. Muscle biopsy demonstrated scattered necrotic and regenerated muscle fibers without inflammatory cell infiltration. The patient was therefore diagnosed as having rhabdomyolysis associated with CMV infection. After three courses of intravenously administered high dose methylprednislone over three days, muscle weakness improved gradually, and the serum CK level was normalized in two months. The patient recovered and was removed from artificial ventilation three months after the therapy. There were no sign of renal failure. Steroid therapy should be considered for the treatment of rhabdomyolysis or myopathy associated with CMV infection in order to prevent renal failure or fatal progression of the disease.

[Measurement of patient skin dose in interventional radiology using passive integrating dosimeter].

To avoid radiation injury from interventional radiology (IVR), quality assurance (QA) of IVR equipment based on dosimetry is important. In this study, we investigated the usefulness of measuring patient skin dose with a passive integrating dosimeter and water phantom. The optically stimulated luminescence dosimeter (OSLD) was chosen from among various passive integrating dosimeters. The characteristics of the OSLD were compared with a reference ionization dosimeter. The effective energy obtained from the OSLD was compared with that found by the aluminum attenuation method for using the reference ionization dosimeter. Doses and effective energies measured by OSLD correlated well with those of the reference ionization dosimeter. (dose: y=0.971x, r=0.999, effective energy: y=0.990x, r=0.994). It was suggested that OSLD could simultaneously and correctly measure both patient skin dose and effective energy. Patient skin dose rate and effective energy for 15 IVR units of 10 hospitals were investigated using OSLD and a water phantom for automatic brightness control fluoroscopy. The measurement was performed at the surface of a water phantom that was located on the interventional reference point, and source image intensifier distance was fixed to 100 cm. When the 9-inch field size was selected, the average patient skin dose rate was 16.3+/-8.1 mGy/min (3.6-32.0 mGy/min), the average effective energy was 34.6+/-4.1 keV (30.5-42.5 keV). As a result, it was suggested that QA should be performed not only for patient dose but also for effective energy. QA of equipment is integral to maintaining consistently appropriate doses. Consequently, the dosimetry of each IVR unit should be regularly executed to estimate the outline of patient skin dose. It was useful to investigate patient skin dose/effective energy with the passive integrating dosimeter for IVR equipment.

[Estimation of the effective dose of patient in interventional radiology: study of coronary angiography].

The applications of interventional radiology (IVR) increasingly are being used in clinical examinations, where they tend to extend examination time. In addition, the risk of occupational exposure necessarily is increasing with this technology. In this study, the dose distributions in a sliced acrylic-acid phantom involving the bore for each irradiation condition were measured using a thermoluminescence dosimeter (TLD). Four patterns of set-up for the fluoroscopy unit were chosen as references for the conditions generally used clinically. Exposure also was measured with dose area product (DAP), and we then calculated the entrance skin dose and effective dose for the patient. The results showed that the effective dose was 7.0 mSv to 8.0 mSv at LAO45 degrees and RAO30 degrees; 100 kV, 2.3 mSv to 3.3 mSv at LAO45 degrees and RAO30 degrees; 80 kV. The effective dose is greatly influenced by the setup of fluoroscopy in IVR. The change in DAP is especially influenced. We found that the relation between DAP and effective dose was corrected with the exponential function. The effective doses were not necessarily less than those of other radiation examinations, and increase. When PCI and TAE are repeated many times in IVR, we propose that the effective dose should be taken into consideration together with the skin dose for dose control management.

[Estimation of X-radiation protective coats in abdominal angiography].

Medical personnel involved in abdominal angiography are exposed not only to direct radiation but also scattered radiation from inspection tables, patients, image intensifiers, and the beam-limiting system (collimator), among others. Japanese standard JISZ4831 prescribes protective coats of at least 0.25 mm lead equivalent, which is the uniform thickness of lead equivalent. The most commonly used protective coats are 0.25 mm Pb, 0.35 mm Pb, or 0.5 mm Pb in thickness. The weight of a typical protective coat is about 3 kg. While some coats weigh up to 6 kg, wearing such heavy coats becomes physically burdensome as inspection time increases. The trade-off between physical burden and protection was considered by analyzing the X-ray intensity distribution and attenuation rate of scattered radiation in each position assumed by the medical staff. In the case of inspections performed at an x-ray tube voltage of 80 kV, it may be possible to reduce the weight of the lead rubber apron by about 33%. Namely, the lead thickness can be reduced uniformly by 0.20 mm Pb at 70 cm and 0.05 mm Pb at 100 cm, when the shielding capability of a 0.25 mm thick Pb layer is accepted as the standard at 40 cm above the gonad position. The same range of permeated X-ray dose for the gonad position may be reduced as well. In the case of 110 kV, when the lead thicknesses are 0.30 mm Pb at 40 cm and 70 cm, and 0.10 mm Pb at 100 cm, it is possible to reduce the weight of the lead rubber apron by about 28%.

Gastric dysmotility associated with accumulation of mitochondrial A3243G mutation in the stomach.

OBJECTIVE: We analyzed the accumulation of a mitochondrial A-to-G mutation at nucleotide position 3243 (A3243G) in the stomach and gastric motility in patients with gastric symptoms, post-prandial nausea/vomiting and epigastralgia. METHODS: Detection and quantification of A3243G mutation in mtDNA in the gastric mucosa, oral mucosa, leukocyte, and skeletal muscle were performed. Gastric motility was evaluated by gastric myoelectrical activity on electrogastrography (EGG), and gastric emptying was evaluated by measurement of plasma paracetamol concentration before and after meals. PATIENTS OR MATERIALS: Four patients with A3243G mutation in the leukocyte mtDNA and gastric symptoms were examined. RESULTS: The A3243G mutation was detected at higher percentages in the gastric body (69-94% for mutation; mean, 83%) than in the angle portion (37-82%; mean, 52%), the antrum (40-84%; mean, 57%) or leukocytes (28-52%; mean, 39%), and at slightly higher percentages than in the skeletal muscles (45-87%; mean, 70%) or oral mucosae (52-86%; mean, 69%) in the four patients examined. Abnormal EGGs were observed in the three patients examined. The pre-prandial myoelectrical activities were low in these patients (49% in patient 1, 54% in patient 2, 63% in patient 3; normal >70%). The plasma concentrations of paracetamol were low (3.6 microg/ml in patient 1, 2.4 microg/ml in patient 2, <2.0 microg/ml in patient 3; normal, 7-12 microg/ml). CONCLUSION: Accumulation of mitochondrial A3243G mutation in the stomach is a contributory factor in gastric dysmotility and gastric symptoms in patients with the mutation in their leukocytes.

[Thiamine deficiency polyneuropathy after gastrectomy associated with high level of serum vascular endothelial growth factor (VEGF). A case report].

We report a 66-year-old man who developed vitamin B1 deficiency polyneuropathy long after a gastrectomy. After a preceding bronchial infection, the patient noticed numbness and weakness in his extremities, followed by generalized edema and exertional dyspnea. He had undergone subtotal gastrectomy due to duodenal ulcer at age 19. His daily oral intake of food was normal without any alcoholic abuse. He was admitted to our hospital with rapidly progressive gait disturbance due to muscle weakness, and sensory disturbance. Neurological examination showed peripheral polyneuropathy with distal dominant muscular weakness and sensory disturbance. Chest X-ray film showed marked cardiomegaly and pleural effusion. Nerve conduction studies showed decreases in the action potentials of both the motor and sensory nerves, with the sensory nerves being more severely affected than the motor nerves. Sural nerve biopsy demonstrated severe axonal degeneration without any inflammatory change. The blood concentration of thiamine (vitamin B1) was slightly decreased below the normal range (19 ng/ml; normal, 20-50), and the serum vascular endothelial growth factor (VEGF) was high (890 pg/ml; normal < 200 pg/ml). Intravenous administration of vitamin B1 (50 mg per day) dramatically improved his symptoms in a few days and the level of VEGF returned to nearly normal. In this gastrectomized patient many years ago, vitamin B1 deficiency neuropathy is warranted in view of a prompt response to thiamine administration. This case suggests that VEGF is involved in the pathogenesis of vitamin B1 deficiency polyneuropathy.

[Adult cases of viral meningitis caused by echovirus type 13].

Adult cases of viral meningitis caused by echovirus type 13 (E13) were studied. E13 was isolated from 8 of 11 adult patients (73%) with viral meningitis between April and September 2002 in Fukui Prefecture. The mean age was 27.4 +/- 6.4 years (4 males and 4 females). The disease was prevalent among adults, especially younger adults as well as children. The symptoms and signs were as follows; headache (100%), fever (100%), nausea and/or vomiting (88%), Kernig's sign (88%), and increased deep tendon reflexes (50%). The average cell counts in cerebrospinal fluid (CSF) were 118 +/- 111/mm3. Of the 2 patients, polynuclear cells were dominant during the early phase of the disease. The prognosis was good. Since May 2002, the number of patients with viral meningitis caused by E13 has rapidly increased. Most of the reported patients were children. We should consider the possibility of E13 infection as a cause of adult viral meningitis.

[Shielding effect of clinical X-ray protector and lead glass against annihilation radiation and gamma rays of 99mTc].

Various pharmaceutical companies in Japan are making radioactive drugs available for positron emission tomography (PET) in hospitals without a cyclotron. With the distribution of these drugs to hospitals, medical check-ups and examinations using PET are expected to increase. However, the safety guidelines for radiation in the new deployment of PET have not been adequately improved. Therefore, we measured the shielding effect of a clinical X-ray protector and lead glass against annihilation radiation and gamma rays of (99m)Tc. We then calculated the shielding effect of a 0.25 mm lead protector, 1 mm lead, and lead glass using the EGS4 (Electron Gamma Shower Version 4) code. The shielding effects of 22-mm lead glass against annihilation radiation and gamma rays of (99m)Tc were approximately 31.5% and 93.3%, respectively. The clinical X-ray protector against annihilation radiation approximately doubled the skin-absorbed dose.

Unique clinicopathological features and PrP profiles in the first autopsied case of dura mater graft-associated Creutzfeldt-Jakob disease with codon 219 lysine allele observed in Japanese population.

Polymorphism at codon 219 lysine in prion protein (PrP) is considered to affect the clinicopathological features of prion diseases including Creutzfeldt-Jakob disease (CJD) and to have an inhibiting effect on the pathogenesis of these diseases. We describe the first autopsied case of dura mater graft-associated CJD (dCJD) with heterozygosity of lysine at codon 219 in PrP observed in a Japanese subject. Although this case demonstrated the non-plaque type of dCJD and MM1 subgroup of CJD pathologically and biochemically, the patient demonstrated a long incubation period (19.3 years), atypical periodic sharp-wave complexes with a dominant rhythm on EEG, partially scattered small deposits of plaque-like PrP along with synaptic type deposits of PrP on immunohistochemistry and an atypical MM1 glycosylation pattern with a relatively increased diglycosylated isoform of proteinase-resistant PrP on western blot analysis (i.e. "MM1 variant" pattern). These findings in this case were atypical of the non-plaque type of dCJD and MM1 subgroup of CJD. Thus, these findings can be unique to dCJD with codon 219 lysine allele, and this allele may influence the clinicopathological features and PrP profiles in dCJD.