Genetic analysis of a child with restricted cardiomyopathy and phenylketonuria and a literature review / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical and genetic characteristics of a child with restricted cardiomyopathy (RCM) and phenylketonuria (PKU), and summarize the clinical characteristics and genetic diversity of RCM in children through a literature review.@*METHODS@#A child with RCM in conjunct with PKU who was admitted to the Children's Hospital Affiliated to Zhengzhou University in June 2020 due to edema of eyelids and lower limbs for 1 year and aggravation for over 1 month was selected as the study subject. Relevant clinical data were collected. Peripheral blood samples of the child and his parents were collected for whole exome sequencing (WES). Candidate variants were validated by Sanger sequencing and bioinformatic analysis. Childhood, TNNI3 gene and restricted cardiomyopathy were used as the keywords to search the Wanfang data knowledge service platform, Chinese Journal Full-text database and PubMed database, and the search period was limited to from the time of establishment till August 2022. Clinical manifestations and characteristics of the TNNI3 gene variants were summarized.@*RESULTS@#The child, a 2-year-old-and-4-month-old male, had normal intelligence, facial features and normal hair and skin color, but his motor and physical development was delayed, in addition with edema of bilateral eyelids and lower limbs. The results of WES and Sanger sequencing revealed that he has harbored compound heterozygous variants of the PAH gene, namely c.331C>T (p.R111X) and c.940C>A (p.P341T), which were inherited from his father and mother, respectively. In addition, he has also harbored a de novo heterozygous variant of c.508C>T (p.R170W) of the TNNI3 gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the TNNI3: c.508C>T (p.R170W) was classified as a pathogenic variant (PS2+PS4+PM2_Supporting+PM5), PAH: c.331C>T (p.R111X) as a pathogenic variant (PVS1+PM2_Supporting+PM3+PP4), and c.940C>A (p.P341T) as a likely pathogenic variant (PM2_Supporting+PM3+PM5+PP4). In total 30 children with RCM caused by TNNI3 gene variants were retrieved, with a male-to-female ratio of 1 : 1.55 and manifestations including heart failure, sinus rhythm, bi-atrial enlargement, ST-T wave change, ventricular restricted filling, and decreased ventricular diastolic function. In total 16 variants of the TNNI3 gene were identified, among which c.575G>A was the most common, and all cases had conformed to an autosomal dominant inheritance.@*CONCLUSION@#Phenylalanine hydroxylase deficiency and RCM are rare diseases with complex clinical manifestations. The PAH: c.331C>T (p.R111X)/c.940C>A (p.P341T) and TNNI3: c.508C>T (p.R170W) variants probably underlay the RCM and PKU in this child.

Emerging therapeutic approaches of neurogenetic diseases / 中华神经科杂志

Neurogenetic diseases are a group of hereditary diseases that predominantly affect the nervous system, including the central nervous system, peripheral nerves, and muscles. The clinical manifestations are complex, and the treatments are rather difficult. In recent years, with the in-depth study of the etiology and pathogenesis of neurogenetic diseases, gene therapeutic approaches developed for mutant genes, such as antisense oligonucleotides, RNA interference, adeno-associated virus-mediated gene transduction, small molecule compounds with gene modification effects, and clustered regularly interspaced short palindromic repeats/Cas9 gene editing strategies are gradually transformed into clinical applications. The drugs with potential therapeutic effects are developed in according to the promising targets within the pathogenic mechanism of diseases. These emerging therapeutic approaches provide innovative prospects for patients with neurogenetic diseases.

Analysis of a case of corticobasal degeneration started with primary progressive aphasia / 中华神经科杂志

Objective:Through a typical case of corticobasal degeneration (CBD) with primary progressive aphasia (PPA) to analyze the clinical characteristics of CBD and the special manifestations of aphasia with that disease.Methods:Retrospective analysis was performed on a patient with PPA based CBD who was admitted to the First Affiliated Hospital, Sun Yat-sen University in July 2020 to summarize the clinical features and diagnostic thinking of CBD.Results:The patient was a 59-year-old male, manifested rapidly progressive dysfunction of language and memory function. The aphasia was mainly featured as slow speech, reduced content and grammatical errors, and diagnosed as PPA, non-fluent grammatical variation. The imaging results showed the atrophy of the left frontal lobe, parietal lobe, basal ganglia and thalamus, coupled with the reduction in 18F-fluorodeoxyglucose radioactive uptake. The patient was finally diagnosed as possible CBD. Conclusions:PPA as the initial manifestation of CBD is very rare in clinical practice. The high non-specificity of clinical features and the lack of typical motor symptoms result in the difficulty of correct diagnosis of CBD. Timely functional imaging in nuclear medicine and reliable biomarkers help to facilitate early diagnosis of atypical CBD.

Clinical features and genetic analysis of a Welander distal myopathy family with a mutation in T-cell intracellular antigen 1 gene / 中华神经科杂志

Objective:To discuss the clinical features of a family with Welander distal myopathy and analyze the genetic characteristics of the T-cell intracellular antigen 1 (TIA1) gene mutation in this family.Methods:The clinical data, electrophysiological and pathological examination results of some family members were collected, and the proband was tested by next generation sequencing techniques to detect possible pathogenic mutations. Sanger sequencing was performed in some family members for the gene mutations closely related to the clinical phenotype.Results:The proband, a 30-year-old man, manifested progressive weakness and muscle atrophy in distal limbs, followed by the involvement of muscles in proximal limbs. A gene mutation of c.91G>A was detected by genetic testing in the TIA1 gene, which was associated with Welander distal myopathy. The further Sanger sequencing revealed the same mutation site in the proband′s mother, one younger brother and his youngest uncle, who showed similar symptoms as the proband including muscle weakness and atrophy. The youngest brother of the proband was a mutation carrier without obvious symptoms, and his electromyography test showed myogenic injuries.Conclusions:Welander′s distal myopathy is a slowly progressing autosomal dominant disorder, characterized by weakness and muscle atrophy mainly in the extremities. In this family, the patients showed the onset in the extremities of the lower limbs and presented weakness and atrophy in distal and proximal limbs, with disease heterogeneity among patients. Genetic testing and the analysis of the family members confirmed the diagnosis of Welander′s distal myopathy and the pathogenic mutation c.91G>A in the TIA1 gene.

Summary of the 30th International Symposium on Amyotrophic Lateral Sclerosis-Motor Neuron Disease / 中华神经科杂志

The 30th International Symposium on Amyotrophic Lateral Sclerosis-Motor Neuron Disease was held in Perth, Australia from December 4 to 6, 2019. This article mainly introduces the clinical research of this meeting, including epidemiology, non-motor symptoms, auxiliary examinations and biomarkers, etc., while the basic research includes genomics and genetics, protein metabolism abnormalities, neuroimmunity and inflammation, synapse pathology and preclinical treatment strategies,

Summary of the Twenty-ninth International Symposium on Amyotrophic Lateral Sclerosis-Motor Neuron Disease / 中华神经科杂志

The 29th International Symposium on Amyotrophic Lateral Sclerosis (ALS)-Motor Neuron Disease was held in Glasgow from December 7 to 9, 2018. The symposium was divided into 23 topics, with 109 special reports and paper′s exchange and 515 posters exchange. This article briefly introduces some topics of the symposium, involving basic researches, clinical researches and clinical trials. Among these, basic researches include genetics and genomics, axonal degeneration, disease models, and preclinical therapeutic strategies; Clinical researches include epidemiology, clinical progression, cognitive and psychological change, neuropathology, neurophysiology, neuroimaging and biomarkers.

Differential diagnosis of motor neuron disease / 中华神经科杂志

Motor neuron disease (MND) is a type of chronic progressive neurodegenerative disease involving upper and/or lower motor neurons, including amyotrophic lateral sclerosis, progressive bulbar palsy, primary lateral sclerosis, progressive muscular atrophy, and spinal muscular atrophy. Different types of motor neuron diseases have distinct characteristics. Therefore, the diagnosis mainly depends on clinical manifestations, physical examination and electrophysiological examination, and is made by exclusion of other diseases. Atypical cases are sometimes difficult for clinical physicians to distinguish from other diseases involving upper and/or lower motor neurons. This article is going to introduce various types of MND and their differential diagnosis according to site of lesion of motor neuron disease.

Summary of the Twenty?ninth International Symposium on Amyotrophic Lateral Sclerosis?Motor Neuron Disease / 中华神经科杂志

The 29th International Symposium on Amyotrophic Lateral Sclerosis (ALS)?Motor Neuron Disease was held in Glasgow from December 7 to 9, 2018. The symposium was divided into 23 topics, with 109 special reports and paper′s exchange and 515 posters exchange. This article briefly introduces some topics of the symposium, involving basic researches, clinical researches and clinical trials. Among these, basic researches include genetics and genomics, axonal degeneration, disease models, and preclinical therapeutic strategies; Clinical researches include epidemiology, clinical progression, cognitive and psychological change, neuropathology, neurophysiology, neuroimaging and biomarkers.

Differential diagnosis of motor neuron disease / 中华神经科杂志

Motor neuron disease (MND) is a type of chronic progressive neurodegenerative disease involving upper and/or lower motor neurons, including amyotrophic lateral sclerosis, progressive bulbar palsy, primary lateral sclerosis, progressive muscular atrophy, and spinal muscular atrophy. Different types of motor neuron diseases have distinct characteristics. Therefore, the diagnosis mainly depends on clinical manifestations, physical examination and electrophysiological examination, and is made by exclusion of other diseases. Atypical cases are sometimes difficult for clinical physicians to distinguish from other diseases involving upper and/or lower motor neurons. This article is going to introduce various types of MND and their differential diagnosis according to site of lesion of motor neuron disease.

The clinical and electrophysiological features of non-inflammatory myopathy with neurogenic lesions / 中国神经精神疾病杂志

Objective To investigate the clinical and electrophysiological features of patients with non-inflammatory myopathy with neurogenic lesions. Method The clinical and electromyography data was retrospectively collected from 110 patients who were diagnosed with myopathy and completed routine electromyography examination from 2015 to 2017. A retrospective analysis of clinical and electrophysiological features was conducted on 4 patients with non-inflammatory myopathy with neurogenic lesions. Result Of the 110 patients, 10 patients with neurogenic lesions and 4 of them were diagnosed to have non-inflammatory myopathy. These 4 patients had limb and trunk weakness with muscle atrophy and the electromyography showed neurogenic lesion with or without peripheral nerve lesion. Conclusion This study has revealed neurogenic lesions in a small number of non-inflammatory myopathy on the electromyography, suggesting that the electromyography alone may not be sufficient for diagnosis of myopathy.

Clinical study and literature review of mifepristone in the treatment of the occult ectopic adrenocorticotropin syndrome / 中华内分泌代谢杂志

This is a follow-up study in two patients who were diagnosed with the occult ectopic adrenocorticotropin syndrome ( EAS) and treated with mifepristone in our hospital. The efficacy and adverse reactions of mifepristone in these two patients with EAS were investigated. The patients had significant improvement in clinical manifestations, the plasma adrenocorticotropic hormone ( ACTH) and cortisol levels decreased in patient 1, while patient 2 remained stable during the treatment. Patient 1 with diabetes mellitus stopped hypoglycemic agents, while the dose of antihypertensive drugs decreased in patient 2 with hypertension, and she was treated with surgery and suffered from transient adrenocortical insufficiency after surgical excision of the lesion. Mifepristone is effective and safe in treating EAS. Surgical treatment should be performed once the lesion is found during the follow-up.

Effects and Safety of Metformin Combined with Vildagliptin on the Glycemic Control for Patients with Newly Diagnosed Type 2 Diabetes Mellitus / 现代生物医学进展

Objective:To study the effects and safety of metformin combined with vildagliptin on the glycemic control for patients with newly diagnosed type 2 diabetes mellitus.Methods:60 patients with type 2 diabetes mellitus who were treated from February 2015 to April 2016 were selected and divided into the control group and the observation group according to different treatment methods.The control group was treated with routine treatment.The observation group was treated with vildagliptin based on the control group.The blood glucose,glycosylated hemoglobin,two-hour postprandial blood glucose and serum as well as urinal amylase were measured before and after treatment,and the clinical curative effect of the two groups and the levels of interleukin-6,tumor necrosis factor and C-reactive protein were compared.Results:After treatment,the total effective rate of observation group was 90％,which was significantly higher than that of the control group(66.7％,P＜0.05).After treatment,the serum interleukin-6,tumor necrosis factor,C-reactive protein and fasting blood glucose,glycosylated hemoglobin and postprandial blood glucose levels were significantly lower than those of the control group[(7.63± 1.12)dvs(8.68± 1.30)d;(7.23± 0.95)d vs(7.89± 1.20)d;(11.14± 1.56)d vs(12.12± 1.89)d];[(12.12± 1.89)d vs(ll.20± 1.34)d;(6.89± 0.96)d vs(8.23± 1.10)d;(1.65± 0.23)d vs(3.65± 0.48)d] (P＜0.05).After treatment,the INS level of observation group was significantly lower than that of the control group (P＜0.05) and the GLP-1 level was significantly higher than that of the control group (P＜0.05).Conclusion:Metformin combined with vildagliptin could effectively control the blood glucose of patients with newly diagnosed type 2 diabetes and enhance the safety.

The clinical features of Kennedy disease and the correlation between clinical features and length of CAG re-peats / 中国神经精神疾病杂志

Objective To analyze the clinical features of 35 cases of Kennedy's disease and the correlation be?tween clinical features and CAG repeat size to strengthen the understanding of KD and to avoid misdiagnosis and delayed diagnosis.Methods Clinical data, including clinical signs and symptoms ,serum lipid, serum sex hormone level, electro?myography, the number of CAGs and (amyotrophic lateral sclerosis muscular atrophy,ALS) rating scale were collected from 35 patients genetically diagnosed of Kennedy disease and proceed system analysis. Results Patients with KD were adult onset with the average age of (40.77 ± 8.57) years and the average confirmed course were (8.32 ± 4.17) years. Forty-two point nine percent of the patients had family history. Clinical features included medulla oblongata and spinal muscular atrophy and weakness, limbs tremor, perioral muscles twitch and endocrine function and metabolic disorders in some cases. Creatine kinase, triglyceride, low density lipoprotein, follicle estrogen and prolactin were significantly in?creased compared to healthy adults (P:0.000,0.018,0.000,0.000,0.003). The number of CAG repeat was negatively correlated with the onset age (r=-0.549, P=0.001) but not associated with the illness severity (ALS rating scale) (r=0.001, P=0.998). ALS score was negatively correlated with course of disease(r=-0.540, P=0.001).Conclusions Chinese KD pa? tients share similar clinical phenotypes with those of other races but exhibit slightly different clinical characteristics. The length of the CAG repeat influences age at onset but not the severity of disease. Severity of disease is related to the course of disease.

A clinical study on mild cognitive impairment in amyotrophic lateral sclerosis / 中华神经科杂志

Objective To explore the cognitive status of amyotrophic lateral sclerosis (ALS) patients, and to explore the involved cognitive domains, subtypes and risk factors of mild cognitive impairment in ALS ( ALS-MCI).Methods Twenty-nine cases of ALS and 58 healthy volunteers were included.The severity of the bulbar and spinal functions of the patients was evaluated by the Improved Norris Scale.According to the Diagnostic and Statistical Manual of Mental Disorders 4th Edition-Revised( DSM-Ⅳ-R) criteria of dementia, ALS cases were classified as demented and non-demented.For non-demented ALS cases, the common cognitive batteries evaluating mental state, verbal memory, executive, attentional and visuospatial abilities were performed.Hamilton Anxiety Scale ( HAMA) and Hamilton Depression Scale (HAMD) were evaluated too.They were further classified into ALS-cognitively normal (ALS-CogNL) and ALS-MCI groups according to Petersen criteria of MCI.Risk factors possibly correlated with ALS-MCI were analyzed by comparing the differences in age, age of onset, duration of the disease, sites of onset, symptoms of bulbar and limb function between ALS-CogNL and ALS-MCI groups.Results Among 29 ALS cases, 14 (48.3% ) cases with cognitively normal( ALS-CogNL), 15 cases (51.7% ) with ALS-MCI,and none with dementia were identified.Among 15 ALS-MCI cases, 12 cases with executive dysfunction, 8 cases with memory deficits,9 cases with attention impairment and none with visuospatial impairment were found.ALSMCI cases could be further classified into three subtypes; 1 case with amnestic MCI (aMCI) ,6 cases with single domain non-memory MCI ( sdMCI), and 8 cases with multiple domains slightly impaired MCI (mdMCI).Between ALS-MCI and ALS-CogNL groups, there were significant differences (t = -2.435,- 2.576, both P ＜ 0.05) in education ((8.7 ± 2.8) years vs (11.3 ± 3.0) years) and Improved Norrisscale (bulbar score: (28.4 ± 7.7) scores vs ( 34.0 ± 3.4) scores) , however, no significant differences in sex, age, age of onset, duration,site of onset,HAMA or HAMD scores,and Improved Norris scale( spinal score) were found.Conclusions Cognitive deficits commonly exist in ALS patients.For the involved domains, executive dysfunction is the most common, deficits of attention and memory are also common, and deficit in visuospatial function is not found.The most common subtype of ALS-MCI is mdMCI.Severe bulbar symptoms and lower education may be the risk factors of ALS-MCI.

Effects of lentivirus-mediated CC chemokine ligand 5 (CCL5)-RNAi on biological behaviors of human breast cancer cells (MDA-MB-231) / 中华普通外科杂志

Objective To study the effect of lentivirus-mediated CCL5-RNAi on the biological behaviors of human breast cancer cells. Methods CCL5-specific siRNA gene was synthesized and cloned into the recombinant lentiviral vector, pGCSIL-GFP. Human high-metastatic breast cancer cells, MDA-MB-231, were infected by CCL5-siRNA recombinant lentivirus, which was set as KD group. Cells infected with CCL5-NC was as NC group, and cells cultured was as CON group. The expression of CCL5 mRNA and protein in MDA-MB-231 cells was detected by RT-PCR and western blot, respectively. Cell growth suppression and cell cycle was observed by MTT assay and fluorescence activated cell sorting (FACS). Colony formation and migration ability were determined by colony-rorming assay and Boyden chamber method. Results After infection of CCL5-siRNA recombinant lentivirus, the expression level of CCL5 mRNA and protein in MDA-MB-231 cells as well as the colony formation and migration ability decreased significantly, but cell's proliferation was not affected obviously. Compared with MDA-MB-231 (0.88± 0.15) and MDA-MB-231/CCL5-NC (1.00±0.07) cells, the expression of CCL5 mRNA in MDA-MB-231/ CCL5-siRNA decreased to 0.18±0.03, P<0.01. Compared with MDA-MB-231/CCL5-NC (1.82±0.18) cells, the expression of CCL5 protein in MDA-MB-231/CCL5-siRNA decreased to 0.33±0.13, P <0.01. Colony-forming assay and Boyden chamber method showed that the colony formation and migration ability of MDA-MB-231/CCL5-siRNA decreased markedly (P<0.05). The clone count in KD group was (0.33± 0.10), which was a significant decrease from (0.97±0.09) (NC group) and (1.04±0.07) (CON group), P<0.05. The number of cells that migrated through the chamber membrane of KD group (38± 15) was less than that of NC group (77±11, P <0.05) and CON group (69±9, P <0.05). However, MTT assay and FACS revealed that the proliferation of MDA-MB-231/CCL5-siRNA was not different from MDA-MB-231/CCL5-NC and MDA-MB-231 (P>0.05), the proliferation index (PI) of group KD, NC and CON were (0.48±0.02), (0.44±0.05) and (0.47±0.02) respectively. The difference was not statistically significant by multiple comparison (P>0.05). Conclusion CCL5-specific siRNA can specifically suppress the colony formation and migration of human high-matastatic breast cancer cells.

Association of adiponectin receptor 1(Adipo R1)gene polymorphism with type 2 diabetes / 中国糖尿病杂志

Objective To study the association of SNP of the AdipoR1 gene with T2DM in Xi’an population. Methods The amplification refractory mutation system(ARMS) analysis and gene sequencing were used to investigate the AdipoR1 gene polymorphism in 100 type 2 diabetics and 84 normal control subjects. Results (1) The genotype and allele frequencies of -106A/G, 5843A/G were not significantly different between type 2 diabetics and normal control subjects. (2) The diagnosis age of diabetics was significantly younger in AdipoR1 5843GG genotype group than in other genotype groups. Conclusions The data implicate that the AdipoR1 gene -106A/G and 5843A/G polymorphism may be not associated with pathogenesis of T2DM. AdipoR1 5843 GG genotype may be associated with the earlier diagnosis of T2DM

Immunoblot changes of dystrophin expression in mice after bone marrow stem cells transplantation / 中国组织工程研究

AIM: To investigate the immunoblot changeS of dystrophin expression in mdx mice after bone marrow stem cells transplantation. METHODS: The experiment was conducted in the laboratory of Department of Neurology, the First Affiliated Hospital, Sun Yat-sen University from September to December 2004. ①Twenty-five mdx mice of 7-8 weeks old were selected and randomly divided into transplantation 4, 8, 12 and 16 weeks groups and blank control group with 5 mice in each group. Meanwhile, 20 C57 mice of 4 to 6 weeks old were selected as donor mice, and 5 C57 mice aged 10 weeks served as positive control mice. ②All mice were preconditioned with 7 Gy ?-ray. After radiotherapy, 2?107 marrow stem cells per mouse (about 0.3-0.5 mL) were injected into the vena caudalis of mice; 0.3 mL PBS was injected into the blank control group and positive control group. ③The mice in 4 transplantation groups were killed at each time point, and the gastrocnemius was harvested to prepare dystrophin samples. The amount of dystrophin expression was detected by Western blot with GAPDH as control. RESULTS: All 25 mdx mice and 5 C57 mice were involved in the result analysis. Western Blot analysis of dystrophin after transplantation: No dystrophin was detected in the blank control group; in the 4 weeks after transplantation group, only few dystrophin expressions were detected, and the dystrophin/GAPDH was about 0.095?0.267; in the 12 weeks after transplantation group, dystrophin/GAPDH was about 0.218?0.338; dystrophin expressions were increased with time, at 16 weeks after transplantation, the expressions were much more than those at 8 weeks (dystrophin/GAPDH: 0.393?0.385, 0.173?0.284, t =6.062, P

Research progress in stem cell transplantation for treating amyotrophic lateral sclerosis / 中国组织工程研究

Amyotrophic lateral sclerosis is a progressive neurodegenerative disease that targets motor neurons without efficient treatment. Stem cell receives the enormous attention because it from specific tissues can differentiate into motor neuron. Stem cells from specific tissues could be used for amyotrophic lateral sclerosis, such as embryonic stem cells, neural stem cells, bone marrow mesenchymal stem cells, umbilical cord blood-derived stem cells and induced pluripotent stem cells. The mechanism of stem-cell therapy includes cell-replacement, delivery neurotrophic factors and immunomodulation. Animal researches and some clinical trails have confirmed that stem cells have great potential to treat neurodegenerative diseases. Till now, people are still unknown some aspects of stem cells, and many problems still need to be resolved.

On the relationship between E-selectin and diabetic retinopathy / 中华内分泌代谢杂志

The patients with diabetic retinopathy (DR) had higher plasma level of soluble E-selectin than those without DR, and the level of soluble E-selectin showed a positive relationship with the extent of DR, suggesting that E-selectin might play a role in the development of DR.

Myoblast transplantation in mdx mice prevents muscle damage by exercise / 中国病理生理杂志

AIM: To observe skeletal muscle damage of mdx mice after overload exercise, and protection to muscle damage induced by exercise due to myoblast transplantation (MTT). METHODS: Muscle samples of C 57 mice were minced and digested with trypsin, and myoblasts were cultured ex vivo , purified and detected by immunohistochemistry stains. The myoblasts were injected into muscle of left limb of mdx mice, whereas the right limb was injected with DMEM liquid as control. Mice were submitted to exercise for 3 days starting 1 month after MTT, and then Evans blue was injected intravenously through the tail vein. The muscle cryostat sections of mdx mice were made, and then detected the immunofluorescence of dystrophin. Under a fluorescence microscope, the number of fiber stained with Evans blue and dystrophin was counted, analyzed quantitatively with image software. RESULTS: Under a fluorescence microscope, only 10 37%?2 87% muscle fibers in the myoblast grafted muscles were stained with Evans blue. In contrast, 26 82%?14 85% muscle fibers in right control muscles were stained. Significant differences between these two groups were showed ( P