Genotype-phenotype characteristics and baseline natural history of Chinese myelin protein zero gene related neuropathy patients.

BACKGROUND AND PURPOSE: The aim was to characterize the phenotypic and genotypic features of myelin protein zero (MPZ) related neuropathy and provide baseline data for longitudinal natural history studies or drug clinical trials. METHOD: Clinical, neurophysiological and genetic data of 37 neuropathy patients with MPZ mutations were retrospectively collected. RESULTS: Nineteen different MPZ mutations in 23 unrelated neuropathy families were detected, and the frequency of MPZ mutations was 5.84% in total. Mutations c.103_104InsTGGTTTACACCG, c.513dupG, c.521_557del and c.696_699delCAGT had not been reported previously. Hot spot mutation p.Thr124Met was detected in four unrelated families, and seven patients carried de novo mutations. The onset age indicated a bimodal distribution: prominent clustering in the first and fourth decades. The infantile-onset group included 12 families, the childhood-onset group consisted of two families and the adult-onset group included nine families. The Charcot-Marie-Tooth Disease Neuropathy Score ranged from 3 to 25 with a mean value of 15.85 ± 5.88. Mutations that changed the cysteine residue (p.Arg98Cys, p.Cys127Trp, p.Ser140Cys and p.Cys127Arg) in the extracellular region were more likely to cause severe early-onset Charcot-Marie-Tooth disease type 1B (CMT1B) or Dejerine-Sottas syndrome. Nonsense-mediated mRNA decay mutations p.Asp35delInsVVYTD, p.Leu174Argfs*66 and p.Leu172Alafs*63 were related to severe infantile-onset CMT1B or Dejerine-Sottas syndrome; however, mutation p.Val232Valfs*19 was associated with a relatively milder childhood-onset CMT1 phenotype. CONCLUSION: Four novel MPZ mutations are reported that expand the genetic spectrum. De novo mutations accounted for 30.4% and were most related to a severe infantile-onset phenotype. Genetic and clinical data from this cohort will provide the baseline data necessary for clinical trials and natural history studies.

Clinical and genetic features of Charcot-Marie-Tooth disease patients with IGHMBP2 mutations.

Autosomal recessive Charcot-Marie-Tooth disease Type 2S (AR-CMT2S) caused by IGHMBP2 mutation was first reported in 2014, and an increasing number of cases have been reported in the past eight years. We detected 15 distinct IGHMBP2 mutations among 8 typical AR-CMT2S families in our cohort of 178 Chinese CMT2 families using Sanger sequencing and next-generation sequencing (NGS), making IGHMBP2 mutations the most frequent cause of AR-CMT2 in our cohort. From 2014 to 2022, 34 AR-CMT2S families, including 45 patients and 47 different mutations, were reported. One third of identified mutations represented presumed loss-of-function variants (nonsense, frameshift and splicing), while two-thirds were missense changes which clustered in the helicase and ATPase domains. The age at onset ranged from 0.11 years to 20 years (mean±SD: 3.76±3.93 years) and the infantile (0-2 years) onset group accounted for the most patients (51.1%). The initial symptoms included muscle weakness (15, 33.3%), delayed milestones (9, 20%), feet deformity (8, 17.8%), gait disturbance (8, 17.8%), feet drop (7, 15.6%), frequent falls (3, 6.7%), hypotonia (2, 4.4%) and thenar atrophy (1, 2.2%). Molecular structural model analysis of 26 missense IGHMBP2 mutations using PyMOL software revealed that six mutations were close to the RNA-binding channel, eight mutations were in or close to the nucleotide-binding pocket. Based on available limited clinical information, it seems possible that missense changes located in or close to these motifs might be linked to a more severe clinical outcome. In conclusion, IGHMBP2 mutation screening should recommended for early-onset, moderately or severely affected, and sporadic or AR-CMT2 patients. A tiny minority of patients were relatively late onset and mild affected, which should be given more attention in genetic diagnosis and treatment. While our preliminary analysis suggests a potential link between the localization of missense mutations and clinical presentation, definition of genotype-phenotype relationships will require harmonized clinical information from a larger series of patients.

Transmission Dynamics of Coronavirus Disease 2019 (COVID-19) in the World: The Roles of Intervention and Seasonality

The coronavirus disease 2019 (COVID-19) is spreading rapidly all over the world. The transmission dynamics of the COVID-19 pandemic is still unclear, but developing strategies for mitigating the severity of the pandemic is yet a top priority for global public health. In this study, we developed a novel compartmental model, SEIR-CV(susceptible-exposed-infectious-removed with control variables), which not only considers the key characteristics of asymptomatic infection and the effects of seasonal variations, but also incorporates different control measures for multiple transmission routes, so as to accurately predict and effectively control the spread of COVID-19. Based on SEIR-CV, we predicted the COVID-19 epidemic situation in China out of Hubei province and proposed corresponding control strategies. The results showed that the prediction results are highly consistent with the outbreak surveillance data, which proved that the proposed control strategies have achieved sound consequent in the actual epidemic control. Subsequently, we have conducted a rolling prediction for the United States, Brazil, India, five European countries (the United Kingdom, Italy, Spain, Germany, and France), southern hemisphere, northern hemisphere, and the world out of China. The results indicate that control measures and seasonal variations have a great impact on the progress of the COVID-19 pandemic. Our prediction results show that the COVID-19 pandemic is developing more rapidly due to the impact of the cold season in the southern hemisphere countries such as Brazil. While the development of the pandemic should have gradually weakened in the northern hemisphere countries with the arrival of the warm season, instead of still developing rapidly due to the relative loose control measures such as the United States and India. Furthermore, the prediction results illustrate that if keeping the current control measures in the main COVID-19 epidemic countries, the pandemic will not be contained and the situation may eventually turn to group immunization, which would lead to the extremely severe disaster of about 5 billion infections and 300 million deaths globally. However, if Chinas super stringent control measures were implemented from 15 July, 15 August or 15 September 2020, the total infections would be contained about 15 million, 32 million or 370 million respectively, which indicates that the stringent and timely control measures is critical, and the best window period is before September for eventually overcoming COVID-19. SignificanceCOVID-19 is now posing a huge threat to global public health. The key features such as asymptomatic infection and droplet or airborne transmission make COVID-19 more easily spread and more widely distributed around the world. It is an urgent need to explore the optimal intervention strategies and measures to contain the pandemic. Our novel SEIR-CV compartmental model considers the new features of COVID-19, exhibits the impact of the intervention strategies and seasonal variations, and thus can accurately predicts its trajectory in China and the rest of the world. Our research results suggest that control measures and seasonal variations have a great impact on the development of the COVID-19 pandemic, which can only be contained by stringent strategies during the best window period before September 2020 for eventually overcoming COVID-19, otherwise it would cause a severer global catastrophe.

Genetic and clinical features of sorbitol dehydrogenase gene-related Charcot-Marie-Tooth disease in Chinese population / 中华神经科杂志

Objective:To report the genetic and clinical features of sorbitol dehydrogenase (SORD) gene-related Charcot-Marie-Tooth disease (CMT) in Chinese population.Methods:Fifty-seven undiagnosed sporadic or autosomal recessive (AR) inherited CMT2 families were collected from the Department of Neurology of the Third Xiangya Hospital from 2009 through 2018 .Polymerase chain reaction combined with Sanger sequencing were used to detect the mutations of SORD gene, and the relative clinical features were summarized. Results:The homozygous SORD gene hot spot mutation c.757delG (p. Ala253GlnfsTer27) was detected in four sporadic patients, accounting for about 7% of the total. Two patients with CMT2 phenotype were characterized by progressive lower limb weakness and atrophy with electromyogram changes of axonal degeneration in both motor and sensory nerves. Two patients with distal hereditary motor neuropathy (dHMN) phenotype exhibited progressive lower limb weakness and atrophy with electromyogram changes of axonal degeneration in motor nerves only. The age of onset was between five and 16 years, and the CMT neuropathy score was 2-9.Conclusions:The homozygous hot spot mutation of SORD gene (c.757delG, p.Ala253GlnfsTer27), and related childhood or adolescence onset, mildly affected CMT2/dHMN phenotypes are firstly reported in Chinese population. SORD gene-related CMT might be the most common subtype of AR-CMT2.

The electrophysiological characteristics of the four most common genotypes of Charcot-Marie-Tooth disease / 中华神经科杂志

Objective To analyze the electrophysiological characteristics of Charcot-Marie-Tooth (CMT) disease 1A,1X,2A and myelin protein zero (MPZ)-related CMT in Chinese patients.Methods Baseline electrophysiological data from 36 CMT1A patients,78 CMT1X patients,31 CMT2A patients and 10 MPZ-related CMT patients in the Third Xiangya Hospital and Xiangya Hospital of Central South University during 2004-2018 were analyzed.Electrophysiological recordings were taken from the upper limbs (median nerve,ulnar nerve) and lower limbs (tibial nerve,peroneal nerve).Demyelination in different nerve segments was assessed by measurement of distal motor latency,motor nerve conduction velocity (MNCV),sensory nerve conduction velocity and F-wave latency,and calculation of conduction block,terminal latency index (TLI) and modified F ratio (MFR);Axonal degeneration was assessed by measuring compound motor action potential (CMAP) and sensory nerve action potential.The relationship between the gender,age at onset,duration,Overall Neuropathy Limitation Scale (ONLS) score and indexes of peripheral nerve electrophysiology was statistically analyzed.Results The peripheral nerves of CMT1A patients were characterized by uniform demyelination and axonal degeneration.MNCV ((21.39± 6.72) m/s) and CMAP amplitude (2.40 (3.50) mY) of median nerve of CMT1A patients were decreased.The peripheral nerves of CMT1X patients were also characterized by uniform demyelination and axonal degeneration.MNCV (35.20 (6.77) m/s) and CMAP amplitude (2.60 (3.79) mY) of median nerve of CMT1X patients were decreased.CMT2A patients showed axonal degeneration of the peripheral nerves and CMAP amplitude ((4.75 ±2.38) mV) of median nerve of CMT2A patients was decreased.The electrophysiological data in MPZ-related CMT patients demonstrated variability.The TLI and MFR for the median and ulnar nerves in these four subtypes were normal.MNCV (r=0.423,P=0.025) of median nerve in CMT1A patients was positively correlated with age at onset.MNCV (r=0.782,P=-0.013) of median nerve in MPZ-related CMT patients was positively correlated with age at onset.CMAP amplitude (r=0.652,P＜0.01) of median nerve in CMT2A patients was positively correlated with age at onset.Demyelination and axonal degeneration in male CMT1X patients were relatively more severe than those in female patients,and MNCV (Z=-3.300,P＜0.01) and CMAP amplitude (Z=-3.960,P＜0.01) of median nerve,MNCV (Z=-2.56,P=0.011) and CMAP amplitude (Z=-2.311,P=0.048) of ulnar nerve of male patients were lower than those of female patients.The ONLS score of CMT1A (r=-0.494,P＜0.01),CMT1X (r=-0.596,P＜0.01) and CMT2A patients (r=-0.494,P=0.012) was inversely associated with CMAP amplitude.Conclusions The electrophysiological characteristics of CMT1A,CMT1X,CMT2A and MPZ-related CMT are different.Electrophysiological examinations are the basis of clinical classification and could provide guidance for further genetic testing and diagnosis.CMAP amplitude may serve as an objective index to assess the severity of functional disability in CMT patients.