ObjectiveThe objective of this study was to identify new causes of Charcot–Marie–Tooth (CMT) disease in patients with autosomal‐recessive (AR) CMT.MethodsTo efficiently identify novel causative genes for AR‐CMT, we analyzed 303 unrelated Japanese patients with CMT using whole‐exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation.ResultsWe identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta‐amyloid (Aβ)‐degrading enzymes. All patients had a similar phenotype consistent with late‐onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the MME mutations could be loss‐of‐function mutations, and we confirmed a lack/decrease of NEP protein expression in a peripheral nerve. No patients showed symptoms of dementia, and 1 patient showed no excess Aβ in Pittsburgh compound‐B positron emission tomography imaging.InterpretationOur results indicate that loss‐of‐function MME mutations are the most frequent cause of adult‐onset AR‐CMT2 in Japan, and we propose that this new disease should be termed AR‐CMT2T. A loss‐of‐function MME mutation did not cause early‐onset Alzheimer's disease. Identifying the MME mutation responsible for AR‐CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT. Ann Neurol 2016;79:659–672

Key features for early diagnosis of Gerstmann-Sträussler-Scheinker syndrome caused by Pro102Leu mutation in PRNP (GSS102) are truncal ataxia, dysesthesia and hyporeflexia of the lower legs, and mild dysarthria. Normal cerebellar MRI and abnormal cerebral SPECT findings are characters of early GSS102.

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Highlights d Sense poly(GP) and antisense poly(PR) DPRs are produced in SCA36 d Unlike in c9ALS/FTD, poly(GP) is soluble and does not aggregate in SCA36 d Poly(GA:GP) chimeric DPRs underlie observed poly(GP) aggregation in c9ALS/FTD d Repeat-targeting ASOs robustly reduce poly(GP) DPRs in SCA36

Usefulness of transcutaneous Doppler jugular venous echo to predict pulmonary hypertension in COPD patients. W. Matsuyama, R. Ohkubo, K. Michizono, M. Abe, Y. Nakamura, M. Kawabata, M. Osame. #ERS Journals Ltd 2001. ABSTRACT: Pulmonary hypertension is an important factor that determines the prognosis of chronic obstructive pulmonary disease (COPD) patients. Echocardiography is a noninvasive and useful bedside method for measurement of pulmonary artery pressure. However, this method is sometimes difficult because of the overinflated lungs in COPD patients. This study attempted to estimate pulmonary hypertension in COPD patients using transcutaneous Doppler jugular vein flow velocity recording.The mean pulmonary artery pressure (MPAP) of 64 COPD patients was examined using cardiac catheterization. The right jugular vein flow velocity was measured within 24 h using transcutaneous Doppler echo, after which the ratio of diastolic flow (Df) and systemic flow (Sf) velocity was calculated. Subsequently, the statistical correlation of MPAP and the Df/Sf ratio was examined. MPAP was also measured using standard cardiac echo methods and the results were compared.The Df/Sf velocity ratio showed significant correlation with MPAP in COPD patients (r~0.844, pv0.0001). The sensitivity was 71.4%, and the specificity 95.3% (cut-off ratio~1.0). Jugular venous Doppler echo could be performed in all patients while other cardiac echo methods could not be performed in all patients. The specificity of the methods used was higher than other cardiac echo methods.Transcutaneous jugular vein flow velocity measurement may be applicable to bedside prediction of pulmonary hypertension in chronic obstructive pulmonary disease patients. [6,7]. However, these methods have some disadvantages, namely: 1) right-sided cardiac catheterization is invasive; 2) echocardiography is sometimes difficult in COPD patients because of the overinflated lungs; 3) the specificity and sensitivity of electrocardiography is low [8]; and 4) myocardial scintigraphy is expensive. In 1989, RANGANATHAN and SIVACIYAN [9] reported the usefulness of transcutaneous Doppler jugular venous flow velocity recording to estimate pulmonary artery pressure in patients with cardiac disorders but this method was not investigated in COPD patients. This study measured mean pulmonary artery pressure (MPAP) in COPD patients using the previous methods and investigated the predicted value of transcutaneous Doppler jugular venous flow velocity recording. This method was found to be applicable for bedside prediction of pulmonary hypertension in COPD patients. Patients and methodsThis study investigated 64 COPD patients (60 males) who were admitted to the Third Dept of Internal Medicine (Kagoshima University School of Medicine) and the Dept of Cardiology (NakamuraOnsen Hospital). Fifty-nine patients were suffering from emphysema while others had chronic bronchitis. All patients gave their written consent to participate in this study. All patients with tachycardia, arrythmia, infectious disor...