Background and aims: Fatty acid oxidation disorders (FAODs) are a group of autosomal recessive metabolic diseases included in many newborn screening (NBS) programs, but the incidence and disease spectrum vary widely between ethnic groups. We aimed to elucidate the incidence, disease spectrum, and genetic features of FAODs in a southern Chinese population. Materials and methods: The FAODs screening results of 643,606 newborns from 2014 to 2022 were analyzed. Results: Ninety-two patients were eventually diagnosed with FAODs, of which 61 were PCD, 20 were MADD, 5 were SCADD, 4 were VLCADD, and 2 were CPT-IAD. The overall incidence of FAODs was 1:6996 (95 % CI: 1:5814-1:8772) newborns. All PCD patients had low C0 levels during NBS, while nine patients (14.8 %) had normal C0 levels during the recall review. All but one MADD patients had elevated C8, C10, and C12 levels during NBS, while eight patients (40 %) had normal acylcarnitine levels during the recall review. The most frequent SLC22A5 variant was c.760C > T (p.R254*) with an allele frequency of 29.51 %, followed by c.51C > G (p.F17L) (17.21 %) and c.1400C > G (p.S467C) (16.39 %). The most frequent ETFDH variant was c.250G > A (p.A84T) with an allelic frequency of 47.5 %, followed by c.524G > A (R175H) (12.5 %), c.998A > G (p.Y333C) (12.5 %), and c.1657T > C (p.Y553H) (7.5 %). Conclusion: The prevalence, disease spectrum, and genetic characteristics of FAODs in a southern Chinese population were clarified. PCD was the most common FAOD, followed by MADD. Hotspot variants were found in SLC22A5 and ETFDH genes, while the remaining FAODs showed great molecular heterogeneity. Incorporating second-tier genetic screening is critical for FAODs.
OBJECTIVES: Newborn screening (NBS) for primary carnitine deficiency (PCD) exhibits suboptimal performance. This study proposes a strategy to enhance the efficacy of second-tier genetic screening by adjusting the cutoff value for free carnitine (C0). METHODS: Between January 2021 and December 2022, we screened 119,898 neonates for inborn metabolic disorders. Neonates with C0 levels below 12⯵mol/L were randomly selected for second-tier genetic screening, employing a novel matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) assay. RESULTS: In total, 2,515 neonates with C0 <12⯵mol/L underwent further screening, including 206 neonates with C0 <8.5⯵mol/L and 320 neonates with 8.5
Cardiomyopathies , Carnitine/deficiency , Genetic Testing , Hyperammonemia , Muscular Diseases , Neonatal Screening , Infant, Newborn , Humans , Neonatal Screening/methods , Solute Carrier Family 22 Member 5/genetics , Mutation , Tandem Mass Spectrometry
Background: Transnasal humidified rapid-insufflation ventilator exchange (THRIVE) has the characteristics of operating easily and maintaining oxygenation and eliminating CO2, which makes it possible to be used in endoscopic thoracic sympathectomy (ETS). The application of THRIVE in ETS remains undefined. The purpose of this randomized controlled study is to assess the efficacy between THRIVE and laryngeal mask airway (LMA) for ETS. Methods: In total, 34 patients from May 2022 to May 2023 in Huazhong University of Science and Technology Union Shenzhen Hospital undergoing ETS were randomly divided into a THRIVE group (n = 17) and an LMA group (n = 17). A serial arterial blood gas analysis was conducted during the perioperative period. The primary outcome was the arterial partial pressure of carbon dioxide (PaCO2) during the perioperative period. The secondary outcome was arterial partial pressure of oxygen (PaO2) during the perioperative period. Results: The mean (SD) highest PaCO2 in the THRIVE group and LMA group were 99.0 (9.0) mmHg and 51.7 (5.2) mmHg, respectively (p < 0.001). The median (inter-quartile range) time to PaCO2 ≥ 60 mmHg in the THRIVE group was 26.0 min (23.2-28.8). The mean (SD) PaO2 was 268.8 (89.0) mmHg in the THRIVE group and 209.8 (55.8) mmHg in the LMA group during surgery (p = 0.027). Conclusion: CO2 accumulation in the THRIVE group was higher than that of the LMA group during ETS, but THRIVE exhibited greater oxygenation capability compared to LMA. We preliminarily testified that THRIVE would be a feasible non-intubated ventilation technique during ETS under monitoring PaCO2.
To evaluate the prevalence, influencing factors, and behavior rules of self-medication in children. Articles on self-medication in children from various electronic databases (PubMed, Cochrane Library, Web of Science, the WHO website (https://www.who.int/), ABI, CNKI, and Wanfang), were searched to August 2022. The single-group meta-analyses of the prevalence, influencing factors, and behavior rules of self-medication in children were performed using Revman 5.3 and Stata 16.0. The overall pooled prevalence of self-medication in children was 57% (95% CI: 0.39-0.75, I² = 100%, P < .00001 Z = 6.22). The pooled prevalence for main influencing factors, in terms of caregivers, was: 73% (95% CI: 0.72-0.75, I² = 100%, P < .00001, Z = 111.18) for those in rural areas; 55% (95% CI: 0.51-0.59, P = .04, Z = 26.92, I² = 68%, P < .00001) for females; 75% (95% CI: 0.74-0.76, I² = 68%, P < .00001, Z = 106.66) for those whose income was less than 716 dollars; 77% (95% CI: 0.75-0.79, I² = 99%, P < .000001, Z = 92.59) for the middle-aged and elderly; and 72% (95% CI: 0.58-87, I² = 99%, P < .00001, Z = 9.82) for those with a degree below bachelor. In the process of self-medication for children, 19% (95% CI: 0.06-0.32, I² = 99%, P < .00001, Z = 2.82) of the caregivers did not read the instructions, 28% (95% CI: -0.03-0.60, I² = 100%, P < .000001, Z = 1.77) neglected adverse effects, 49% (95% CI: 0.11-0.87, I² = 100%, P = .01, Z = 2.51) spontaneously increased or decreased the dosages, 49% (95% CI: 0.48-0.55, I² = 65%, P < .00001, Z = 16.51) had an awareness of over-the-counter (OTC) drugs, and 41% (95% CI: 0.18-0.64, I² = 99%, P < .00001, Z = 3.49) misrecognized the antibiotics. Self-medication for children was common, although the overall prevalence was not very high. The prevalence of self-medication in children was relatively higher among those caregivers who were female, rural, had low-income, were elder, or had a degree below bachelor. Common behaviors during self-medication in children included spontaneous dose increase or decrease, a lack of awareness of OTC drugs, and misconception of antibiotics. Government departments should formulate corresponding policies to provide quality health education resources for the caregivers of children.
Nonprescription Drugs , Self Medication , Aged , Middle Aged , Humans , Female , Child , Male , Self Medication/adverse effects , Anti-Bacterial Agents , Prevalence , Poverty
PURPOSE: Pediatric diffuse malignant glioma located in the brainstem was officially named "diffuse midline glioma" (DMG) by the World Health Organization in 2016. For this disease, radical surgery is not beneficial, and the only major treatment strategy is radiotherapy. However, the dose limitations to brainstem tissue mean that treatment by radiotherapy can only control and not eradicate the tumors, and there is no effective treatment for recurrence, resulting in short overall survival of 6-12 months. This paper reports our experience with boron neutron capture therapy (BNCT), a new treatment process, and its efficacy in treating children with recurrent DMG. METHODS: From September 2019 to July 2022, we treated 6 children affected by recurrent DMG. With the collaboration of Taipei Veteran General Hospital (TVGH) and National Tsing-Hua University (NTHU), each patient received two sessions of BNCT within 1 month. RESULTS: Among the six patients, three showed partial response and the rest had stable disease after the treatment. The overall survival and recurrence-free survival duration after treatment were 6.39 and 4.35 months, respectively. None of the patients developed severe side effects, and only one patient developed brain necrosis, which was most likely resulted from previous hypofractionated radiotherapy received. CONCLUSION: BNCT elicited sufficient tumor response with low normal tissue toxicity; it may benefit vulnerable pediatric patients with DMG.
Boron Neutron Capture Therapy , Brain Neoplasms , Glioma , Humans , Child , Brain Neoplasms/radiotherapy , Boron Neutron Capture Therapy/adverse effects , Boron Neutron Capture Therapy/methods , Glioma/radiotherapy , Treatment Outcome , Neoplasm Recurrence, Local/pathology
Carnitine palmitoyltransferase 1A (CPT1A) deficiency is an inherited disorder of mitochondrial fatty acid ß-oxidation that impairs fasting ketogenesis and gluconeogenesis in the liver. Few studies implementing newborn screening (NBS) for CPT1A deficiency in the Chinese population have been reported. This study aimed to determine the biochemical, clinical, and genetic characteristics of patients with CPT1A deficiency in China. A total of 204,777 newborns were screened using tandem mass spectrometry at Quanzhou Maternity and Children's Hospital between January 2017 and December 2018. Newborns with elevated C0 levels were recruited, and suspected patients were subjected to further genetic analysis. Additionally, all Chinese patients genetically diagnosed with CPT1A deficiency were reviewed and included in the study. Among the 204,777 screened newborns, two patients were diagnosed with CPT1A deficiency; thus, the estimated incidence in the selected population was 1:102,388. In addition to the two patients newly diagnosed with CPT1A deficiency, we included in our cohort 10 Chinese patients who were previously diagnosed. Five of these 12 patients were diagnosed via NBS. All patients exhibited elevated C0 and/or C0/(C16+C18) ratios. No clinical symptoms were observed in the five patients diagnosed via NBS, while all seven patients presented with clinical symptoms, including fever, cough, vomiting, diarrhea, and seizures. Eighteen distinct CPT1A variants were identified, 15 of which have been previously reported. The three novel variants were c.272T>C (p.L91P), c.734G>A (p.R245Q), and c.1336G>A (p.G446S). in silico analysis suggested that all three novel variants were potentially pathogenic. The most common variant was c.2201T>C (p.F734S), with an allelic frequency of 16.67% (4/24). Our findings demonstrated that NBS for CPT1A deficiency is beneficial. The three novel variants expand the mutational spectrum of CPT1A in the Chinese population, and c.2201T>C (p.F734S) may be a potential hotspot CPT1A mutation.
BACKGROUND: Glutaric acidemia type 1 (GA1) is a treatable disorder affecting cerebral organic acid metabolism caused by a defective glutaryl-CoA dehydrogenase (GCDH) gene. GA1 diagnosis reports following newborn screening (NBS) are scarce in the Chinese population. This study aimed to assess the acylcarnitine profiles and genetic characteristics of patients with GA1 identified through NBS. RESULTS: From January 2014 to September 2020, 517,484 newborns were screened by tandem mass spectrometry, 102 newborns with elevated glutarylcarnitine (C5DC) levels were called back. Thirteen patients were diagnosed with GA1, including 11 neonatal GA1 and two maternal GA1 patients. The incidence of GA1 in the Quanzhou region was estimated at 1 in 47,044 newborns. The initial NBS results showed that all but one of the patients had moderate to markedly increased C5DC levels. Notably, one neonatal patient with low free carnitine (C0) level suggest primary carnitine deficiency (PCD) but was ultimately diagnosed as GA1. Nine neonatal GA1 patients underwent urinary organic acid analyses: eight had elevated GA and 3HGA levels, and one was reported to be within the normal range. Ten distinct GCDH variants were identified. Eight were previously reported, and two were newly identified. In silico prediction tools and protein modeling analyses suggested that the newly identified variants were potentially pathogenic. The most common variant was c.1244-2 A>C, which had an allelic frequency of 54.55% (12/22), followed by c.1261G>A (p.Ala421Thr) at 9.09% (2/22). CONCLUSIONS: Neonatal GA1 patients with increased C5DC levels can be identified through NBS. Maternal GA1 patients can also be detected using NBS due to the low C0 levels in their infants. Few neonatal GA1 patients may have atypical acylcarnitine profiles that are easy to miss during NBS; therefore, multigene panel testing should be performed in newborns with low C0 levels. This study indicates that the GCDH variant spectra were heterogeneous in this southern Chinese cohort.
Amino Acid Metabolism, Inborn Errors , Brain Diseases, Metabolic , Amino Acid Metabolism, Inborn Errors/diagnosis , Amino Acid Metabolism, Inborn Errors/genetics , Brain Diseases, Metabolic/diagnosis , Brain Diseases, Metabolic/genetics , China , Glutaryl-CoA Dehydrogenase/deficiency , Glutaryl-CoA Dehydrogenase/genetics , Humans , Infant , Infant, Newborn , Neonatal Screening
OBJECTIVES: Non-communicable diseases (NCDs) have become the main cause of mortality in China. In 2009, the Chinese government introduced the Basic Public Health Service (BPHS) program to relieve the rising burden of NCDs through public health measures and delivery of essential medical care. The primary aim of this study was to evaluate the impact of the BPHS program on hypertension control. METHODS: The China National Health Development Research Center (CNHDRC) undertook a Cross-sectional Health Service Interview Survey (CHSIS) of 62,097 people from primary healthcare reform pilot areas across 17 provinces from eastern, central, and western parts of China in 2014. The current study is based on responses to the CHSIS survey from 7,867 participants, who had been diagnosed with hypertension. Multi-variable mixed logit regression analysis was used to estimate the association between BPHS management and uncontrolled hypertension. In a follow-up analysis, generalized structural equation modelling (GSEM) was used to test for mediation of the BPHS program effect through patient compliance with medication. FINDINGS: The estimated proportion of patients with uncontrolled hypertension was 30% lower (23.2% vs 31.5%) in those participants who were adequately managed under the BPHS program. Other predictors of hypertension control included compliance with medication, self-reported wellbeing, income, educational attainment and exercise; smoking was associated with reduced hypertension control. The significant inverse association between uncontrolled hypertension and age indicates poor outcomes for younger patients. Additional testing suggested that nearly 40% of the effect of BPHS management (95% CI: 28.2 to 51.7) could be mediated by improved compliance with medication; there was also an indication that the effect of management was 30% stronger in districts/counties with established digital information management systems (IMS). CONCLUSION: Hypertension control improved markedly following active management through the BPHS program. Some of that improvement could be explained by greater compliance with medication among program participants. This study also identified the need to tailor the BPHS program to the needs of younger patients to achieve higher levels of control in this population. Future investigations should explore ways in which existing healthcare management influences the success of the BPHS program.
Community Health Services/statistics & numerical data , Health Care Reform/legislation & jurisprudence , Hypertension/prevention & control , Public Health/standards , Aged , China/epidemiology , Cross-Sectional Studies , Female , Humans , Hypertension/epidemiology , Male , Middle Aged , Public Health/statistics & numerical data , Surveys and Questionnaires
OBJECTIVES: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid, amino acid and choline metabolism. Late-onset MADD is caused by ETFDH mutations and is the most common lipid storage myopathy in China. However, few patients with MADD have been identified through newborn screening (NBS). This study assessed the acylcarnitine profiles and molecular features of patients with MADD identified through NBS. METHODS: From January 2014 to June 2020, 479,786 newborns screened via tandem mass spectrometry were recruited for this study. Newborns with elevated levels of multiple acylcarnitines were recalled, those who tested positive in the reassessment were referred for genetic analysis. RESULTS: Of 479,786 newborns screened, six were diagnosed with MADD. The MADD incidence in the Chinese population was estimated to be 1:79,964. Initial NBS revealed five patients with typical elevations in the levels of multiple acylcarnitines; however, in one patient, acylcarnitine levels were in the normal reference range during recall. Notably, one patient only exhibited a mildly increased isovalerylcarnitine (C5) level at NBS. The patient with an atypical acylcarnitine profile was diagnosed with MADD by targeted gene sequencing. Six distinct ETFDH missense variants were identified, with the most common variant being c.250G>A (p.A84T), with an allelic frequency of 58.35 (7/12). CONCLUSIONS: These findings revealed that it is easy for patients with MADD to go unidentified, as they may have atypical acylcarnitine profiles at NBS and the recall stage, indicating the value of genetic analysis for confirming suspected inherited metabolic disorders in the NBS program. Therefore, false-negative (FN) results may be reduced by combining tandem mass spectrometry (MS/MS) with genetic testing in NBS for MADD.
Acyl-CoA Dehydrogenase/deficiency , Acyl-CoA Dehydrogenase/genetics , Asian People/genetics , Carnitine/analogs & derivatives , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/diagnosis , Mutation , Neonatal Screening/methods , Carnitine/blood , China/epidemiology , Female , Follow-Up Studies , Genetic Testing , Genotype , Humans , Infant, Newborn , Male , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/blood , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/epidemiology , Multiple Acyl Coenzyme A Dehydrogenase Deficiency/genetics , Prognosis
BACKGROUND: Newborn screening for primary carnitine deficiency (NBS) is commonly implemented worldwide; however, it has poor sensitivity. This study aimed to evaluate the feasibility of improving screening by including a second-tier genetic assay. RESULTS: An Agena iPLEX assay was developed to identify 17 common SLC22A5 mutations in Chinese populations and was applied in NBS as a second-tier screening. From January 2017 to December 2018, 204,777 newborns were screened for PCD using tandem mass spectrometry. A total of 316 (0.15%) residual NBS-positive specimens with low free carnitine (C0) levels were subjected to this second-tier screening. The screening identified 20 screen-positive newborns who harboured biallelic mutations in theSLC22A5 gene, 99 carriers with one mutation, and 197 screen-negative newborns with no mutations. Among the 99 carriers, four newborns were found to have a second disease-causing SLC22A5mutation by further genetic analysis. Among the 197 screen-negatives were four newborns with persistently low C0 levels, and further genetic analysis revealed that one newborn had two novel SLC22A5 pathogenic variants. In total, 25 newborns were diagnosed with PCD, for a positive predictive value of 7.91% (25/316). Based on these data, we estimate the incidence of PCD in Quanzhou is estimated to be 1:8191.Thirteen distinct SLC22A5 variants were identified, and the most common was c.760C > T, with an allelic frequency of 32% (16/50), followed by c.1400C > G (7/50, 14%), and c.51C > G (7/50, 14%). CONCLUSION: Data from this study revealed that 24% (6/25) of PCD cases would have been missed by conventional NBS. This high-throughput iPLEX assay is a powerful tool for PCD genotyping. The addition of this second-tier genetic screening to the current NBS program could identify missed PCD cases, thereby increasing PCD detection. However, further studies are needed to optimise the workflow of the new screening algorithm and to evaluate the cost-effectiveness of this screening approach.
Carnitine , Neonatal Screening , Cardiomyopathies , Carnitine/deficiency , Genetic Testing , Humans , Hyperammonemia , Infant, Newborn , Muscular Diseases , Solute Carrier Family 22 Member 5/genetics
OBJECTIVE: The purpose of this meta-analysis is to assess the effect of dexmedetomidine on delirium in elderly surgical patients. DATA SOURCES: The Cochrane Library, Web of Science, PubMed, EMBASE, and Google Scholar were searched (January 1, 2000, to February 4, 2020) for randomized controlled trials (RCTs). STUDY SELECTION AND DATA EXTRACTION: RCTs without language restrictions were included if delirium incidence was assessed in elderly surgical patients receiving dexmedetomidine. Intervention and basic information were extracted. DATA SYNTHESIS: 21 studies were included. Dexmedetomidine reduced delirium occurrence (risk ratio [RR] = 0.55; 95% CI = 0.45 to 0.67) in elderly surgical patients with sufficient evidence from trial sequential analysis. Dexmedetomidine did not prevent delirium incidence for cardiac surgery (RR = 0.71; 95% CI = 0.44 to 1.15) with insufficient evidence. Dexmedetomidine decreased mortality incidence (RR = 0.47; 95% CI = 0.25 to 0.89), shortened the length of intensive care unit (ICU; standard mean difference [SMD] = -0.46) and hospital stays (SMD = -0.41), and increased bradycardia incidence (RR = 1.60). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review revealed that dexmedetomidine could reduce delirium incidence for elderly noncardiac surgical patients, and the effect of dexmedetomidine on delirium for elderly cardiac surgical patients needs further studies to guide clinicians. CONCLUSION: Dexmedetomidine reduced delirium incidence in elderly surgical patients. The efficacy of dexmedetomidine on delirium for elderly cardiac surgical patients warrants further studies. Furthermore, dexmedetomidine was associated with an increased bradycardia incidence, shorter length of ICU/hospital stays, and a lower incidence of mortality.
Adrenergic alpha-2 Receptor Agonists/therapeutic use , Delirium/drug therapy , Dexmedetomidine/therapeutic use , Postoperative Cognitive Complications/prevention & control , Randomized Controlled Trials as Topic/methods , Adrenergic alpha-2 Receptor Agonists/adverse effects , Aged , Bradycardia/chemically induced , Bradycardia/diagnosis , Bradycardia/epidemiology , Delirium/diagnosis , Delirium/epidemiology , Dexmedetomidine/adverse effects , Humans , Intensive Care Units/trends , Length of Stay/trends , Postoperative Cognitive Complications/diagnosis , Postoperative Cognitive Complications/epidemiology
BACKGROUND: Primary carnitine deficiency (PCD) is an autosomal recessive disorder affecting the carnitine cycle and resulting in defective fatty acid oxidation. Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is an autosomal recessive disorder and one of the main causes of inherited neonatal cholestasis. Both PCD and NICCD are included in the current expanded newborn screening (NBS) targets. CASE PRESENTATION: Targeted exome sequencing was performed on a Chinese proband, and Sanger sequencing was utilised to validate the detected mutations. The patient who was initially suspected to have PCD based on the NBS results presented with neonatal intrahepatic cholestasis and ventricular septal defect. Further investigations not only confirmed PCD but also revealed the presence of NICCD. Four distinct mutations were detected, including c.51C > G (p.F17L) and c.760C > T (p.R254X) in SLC22A5 as well as c.615 + 5G > A and IVS16ins3kb in SLC25A13. CONCLUSIONS: This is the first reported case of PCD and NICCD occurring in the same patient. The dual disorders in a newborn broaden our understanding of inherited metabolic diseases. Thus, this study highlighted the importance of further genetic testing in patients presenting with unusual metabolic screening findings.
Carnitine , Cholestasis, Intrahepatic , Citrullinemia , Cardiomyopathies , Carnitine/deficiency , China , Cholestasis, Intrahepatic/etiology , Cholestasis, Intrahepatic/genetics , Citrullinemia/complications , Humans , Hyperammonemia , Infant, Newborn , Mitochondrial Membrane Transport Proteins/genetics , Muscular Diseases , Mutation , Solute Carrier Family 22 Member 5
PURPOSE: A considerable number of diabetic foot ulcer (DFU) patients require amputation every year, which worsens their quality of life, aggravates the social burden, and shortens their life expectancy. Considering these negative effects, it is important to explore the relative risk factors affecting amputation in DFU patients. METHODS: The PubMed, SCIE and Embase databases were comprehensively searched for prospective or retrospective studies published before October 31, 2019. All English language studies involving DFU patients were included, and RevMan 5.3 software was used to analyse the data. RESULTS: This meta-analysis includes 21 studies involving 6505 participants, including 2006 patients who required a lower limb amputation. The following variables were associated with an increased risk of amputation: male sex (odds ratios (OR) = 1.30, 95% confidence interval (CI) = 1.16~1.46, P<0.00001), smoking history (OR = 1.19, 95% CI = 1.04~1.35, P = 0.009), a history of foot ulcers (OR = 2.48, 95% CI = 2.00~3.07, P<0.00001), osteomyelitis (OR = 3.70, 95% CI = 3.02~4.53, P<0.00001), gangrene (OR = 10.90, 95% CI = 5.73~20.8, P<0.00001), a lower body mass index (mean difference IV (MD) = -0.88, 95% CI = -1.30~-0.47, P<0.0001), and a higher white blood cell count (MD = 2.42, 95% CI = 2.02~2.82, P<0.00001). However, age (MD = 1.24, 95% CI = -0.45~2.93, P = 0.15), type of diabetes (OR = 0.96, 95% CI = 0.61~1.52, P = 0.86), hypertension (OR = 1.19, 95% CI = 0.96~1.47, P = 0.12), and HbA1c level (MD = 0.02, 95% CI = -0.28~0.33, P = 0.87) were not associated with amputation in patients with DFU. CONCLUSIONS: Our meta-analysis identified several risk factors for amputation in DFU patients, including the male sex, a smoking history, a history of foot ulcers, osteomyelitis, gangrene, a lower body mass index, and a higher white blood cell count. Once gangrene occurs, the risk of amputation rapidly increases.
Diabetes Mellitus, Type 2/surgery , Diabetic Foot/surgery , Foot Ulcer/surgery , Lower Extremity/surgery , Amputation, Surgical/methods , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/physiopathology , Diabetic Foot/etiology , Diabetic Foot/physiopathology , Foot Ulcer/physiopathology , Humans , Lower Extremity/physiopathology , Quality of Life , Risk Factors
BACKGROUND AND AIMS: Acyl-CoA dehydrogenase deficiencies are a group of mitochondrial fatty-acid oxidation disorders rarely reported in mainland China. We assessed the biochemical and genetic characteristics of patients with short- and very-long-chain-acyl-CoA dehydrogenase deficiencies (SCADD/VLCADD) discovered through newborn screening. MATERIALS AND METHODS: We investigated the effects of genetic variations on protein function using in silico prediction and structural modelling. RESULTS: Of 364,545 screened newborns, four were diagnosed with SCADD and four with VLCADD. SCADD and VLCADD incidences in our population were 1:91,136. All patients exhibited elevated C4 or C14:1 levels. Three SCADD patients had increased urinary ethylmalonic acid concentrations. Six ACADS and eight ACADVL variants were identified, with no hotspot variants, and five were unreported, including four missense variants and one splice site variant. ACADVL c.1434 + 2 T > C is a splice site variant that could affect splicing, leading to exon 14 skipping. In silico tools predicted the missense variants as pathogenic. Structural modelling confirmed that the missense variants may affect quaternary structures, causing protein instability. CONCLUSIONS: Our findings expanded the ACADS and ACADVL mutational spectra. The combination of in silico prediction and structural modelling can improve our understanding of the pathogenicity of unreported genetic variants, providing an explanation for variant assessment.
Acyl-CoA Dehydrogenase, Long-Chain , Lipid Metabolism, Inborn Errors , Carnitine , China , Congenital Bone Marrow Failure Syndromes , Humans , Infant, Newborn , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/genetics , Mitochondrial Diseases , Muscular Diseases , Neonatal Screening
Identification of a new agent from natural products for the protection of embryonic anomalies is potentially valuable. To investigate the protective effect exerted by lycopene against nicotine-induced malformations, mouse embryos in embryonic day 8.5 with yolk sac placentas were cocultured with 1 mM nicotine and/or lycopene (1 × 10-6, 1 × 10-5 µM) for 48 h. The morphological defects and apoptotic cell deaths in the embryo and yolk sac placenta of the nicotine group were significantly increased. Exposure to nicotine resulted in reduced superoxide dismutase (SOD) activity and cytoplasmic SOD and cytoplasmic glutathione peroxidase mRNA levels, but increased lipid peroxidation level in embryos. Moreover, treatment with nicotine resulted in aggravated expressions of the mRNA or protein level of antiapoptotic (BCL2-associated X protein, B-cell lymphoma-extralarge, and caspase 3), anti-inflammatory (nuclear factor kappa-light-chain-enhancer of activated B cells and tumor necrosis factor-alpha), and vasculogenic (vascular endothelial growth factor-alpha, insulin-like growth factor-1, alpha smooth muscle actin, transforming growth factor-beta 1, and hypoxia inducible factor-1 alpha) factors in the embryo and yolk sac placenta. However, all the parameters were significantly improved by treatment with lycopene, as compared to the nicotine group. These findings indicate the potential of lycopene as a protective agent against embryonic anomalies and yolk sac vasculogenic and placenta-forming defects induced by nicotine through modulations of oxidative, apoptotic, vasculogenic, and inflammatory activities.
Embryo, Mammalian/drug effects , Lycopene/pharmacology , Nicotine/toxicity , Protective Agents/pharmacology , Yolk Sac/drug effects , Animals , Apoptosis/drug effects , Embryo, Mammalian/pathology , Female , Fetus/drug effects , Fetus/pathology , Inflammation/metabolism , Mice , Neovascularization, Physiologic/drug effects , Placenta/drug effects , Pregnancy , Yolk Sac/blood supply , Yolk Sac/pathology
OBJECTIVE: To summarize newborn screening for methionine adenosyltransferase I/III (MAT I/III) deficiency in Quanzhou region of Fujian Province. METHODS: A total of 364 545 neonates were screened for inherited metabolic diseases by tandem mass spectrometry. High-throughput next generation sequencing combined with Sanger sequencing was used to detect potential variants in newborns with MAT I/III deficiency. Pathogenicity of suspected variants was predicted by using MutationTaster and HSF software. RESULTS: Three newborns were identified with MAT I/III deficiency by newborn screening, which yielded an incidence rate of 1 in 121 515. Amino acid and acylcarnitine analysis suggested that the serum methionine of the three patients have increased to various extents. All patients showed normal growth and development during follow-up, and were found to carry MAT1A gene variants including two missense variants [c.776C>T (p.Ala259Val) and c.791G>A (p.Arg264His)] and a synonymous variant [c.360C>T (p.Cys120Cys)]. Among these, c.776C>T (p.Ala259Val) and c.791G>A (p.Arg264His) were known to be pathogenic, whereas c.360C>T (p.Cys120Cys) was a novel variant. Bioinformatics analysis suggested that this variant may alter RNA splicing and affect the structure and function of the MAT1A protein. CONCLUSION: A systematic review of newborn screening for MAT I/III deficiency was provided. Discovery of the novel variant has enriched the variant profile of the MAT1A gene and provided a basis for the diagnosis of this disease.
Amino Acid Metabolism, Inborn Errors , Genetic Variation , Methionine Adenosyltransferase , Neonatal Screening , Amino Acid Metabolism, Inborn Errors/diagnosis , China , Humans , Infant, Newborn , Methionine Adenosyltransferase/deficiency , Methionine Adenosyltransferase/genetics
Pregnant women drink caffeinated beverages using bisphenol A (BPA)-coated cans without knowing the potential risks. In this study, mouse embryos (embryonic day 8.5) surrounded by yolk sac placenta were cultured with caffeine (30, 60, and 120 µg/ml) and/or BPA (35 µg/ml) for 48 h. In response to a single administration of BPA or caffeine dose, embryonic development was similar to normal control embryos. However, the combined exposure to caffeine and BPA dose-dependently increased embryonic anomalies, and thinner ventricular wall and trabeculae disorders of heart were observed. The mRNA levels of various anti-oxidative, apoptotic, and hypoxic genes were significantly altered in the treated embryos. Furthermore, abnormal vasculogenesis, reduced vasculogenic growth factor expressions, and apoptotic cell death were detected in yolk sac placentas. These findings indicate that the combined exposure to caffeine and BPA induces embryonic anomalies and injuries of the yolk sac placentas through oxidative stress, apoptosis, hypoxia, and vasculogenic defects.
Benzhydryl Compounds/toxicity , Caffeine/toxicity , Embryo, Mammalian/drug effects , Phenols/toxicity , Animals , Apoptosis/drug effects , Embryonic Development/drug effects , Female , Gene Expression Regulation, Developmental/drug effects , Hypoxia/chemically induced , Male , Mice , Mice, Inbred ICR , Oxidative Stress/drug effects , Placenta , Pregnancy , Rats, Sprague-Dawley , Yolk Sac
Short/branched chain acyl-CoA dehydrogenase deficiency (SBCADD) is an autosomal recessive disorder of impaired isoleucine catabolism caused by mutations in the ACADSB gene. There are limited SBCADD cases worldwide and to date no Chinese patients with SBCADD have been reported. The aim of this study was to investigate the biochemical, clinical information, and genotypes of twelve patients with SBCADD in China for the first time. The estimated incidence of SBCADD was 1 in 30,379 in Quanzhou, China. The initial newborn screening (NBS) results revealed that all patients showed slightly or moderately elevated C5 concentrations with C5/C2 and C5/C3 ratios in the reference range, which has the highest risk of being missed. All patients who underwent urinary organic acid analysis showed elevation of 2-methylburtyrylglycine in urine. All patients were asymptomatic at diagnosis, and had normal growth and development during follow-up. Eight different variants in the ACADSB gene, including five previously unreported variants were identified, namely c.596A > G (p.Tyr199Cys), c.653T > C (p.Leu218Pro), c.746del (p.Pro249Leufs*15), c.886G > T (p.Gly296*) and c.923G > A (p.Cys308Tyr). The most common variant was c.1165A > G (33.3%), followed by c.275C > G (20.8%). All previously unreported variants may cause structural damage and dysfunction of SBCAD, as predicted by bioinformatics analysis. Thus, our findings indicate that SBCADD may be more frequent in the Chinese population than previously thought and newborn screening, combined with genetic testing is important for timely diagnosis. Although the clinical course of Chinese patients with SBCADD is likely benign, longitudinal follow-up may be helpful to better understand the natural history of SBCADD.
Isobutyryl-CoA dehydrogenase deficiency (IBDHD) is a rare autosomal recessive metabolic disorder related to valine catabolism and results from variants in ACAD8. Here, we present the clinical, biochemical, and genotypes of seven patients with IBDHD in China for the first time. Five patients remained asymptomatic during follow-up, whereas one juvenile had speech delay and one newborn exhibited clinical symptoms. All patients showed remarkably increased concentrations of C4-aclycarnitine with elevated C4/C2 and C4/C3 ratios. In urine organic acid tests, only one patient presented with an increased concentration of isobutyrylglycine excretion. Genetic testing was performed to detect the causative variants. Five previously unreported variants, c.235Câ¯>â¯G, c.286Gâ¯>â¯A, c.444Gâ¯>â¯T c.1092â¯+â¯1Gâ¯>â¯A, and c.1176Gâ¯>â¯T, and one known variant, c.1000Câ¯>â¯T, in ACAD8 were identified. These previously unreported variants in ACAD8 were predicted to be disease-causing and the c.1092â¯+â¯1Gâ¯>â¯A variant was confirmed to cause skipping of exon 9 by reverse transcription PCR. The most common variant was c.286Gâ¯>â¯A, which showed an allelic frequency of 50% (7/14), and thus may be a prevalent variant among Chinese patients. Our results broaden the mutational spectrum of ACAD8 and improve the understanding of the clinical phenotype of IBDHD.
Acyl-CoA Dehydrogenase/deficiency , Acyl-CoA Dehydrogenases/genetics , Amino Acid Metabolism, Inborn Errors/genetics , Computational Biology , High-Throughput Nucleotide Sequencing , Acyl-CoA Dehydrogenase/genetics , Acyl-CoA Dehydrogenase/metabolism , Acyl-CoA Dehydrogenases/metabolism , Amino Acid Metabolism, Inborn Errors/metabolism , China , Female , Genotype , Humans , Infant , Infant, Newborn , Male , Mutation , Phenotype
BACKGROUND: Methylmalonic acidemia (MMA) is an autosomal recessive inherited disorder caused by complete or partial deficiency of the enzyme methylmalonyl-CoA mutase (mut0 enzymatic subtype or mut- enzymatic subtype, respectively); a defect in the transport or synthesis of its cofactor, adenosyl-cobalamin (cblA, cblB, or cblD-MMA); or deficiency of the enzyme methylmalonyl-CoA epimerase. The cblA type of MMA is very rare in China. This study aimed to describe the biochemical, clinical, and genetic characteristics of two siblings in a Chinese family, suspected of having the cblA-type of MMA. METHODS: The Chinese family of Han ethnicity of two siblings with the cblA-type of MMA, was enrolled. Target-exome sequencing was performed for a panel of MMA-related genes to detect causative mutations. The influence of an identified missense variant on the protein's structure and function was analysed using SIFT, PolyPhen-2, PROVEAN, and MutationTaster software. Moreover, homology modelling of the human wild-type and mutant proteins was performed using SWISSMODEL to evaluate the variant. RESULTS: The proband was identified via newborn screening (NBS); whereas, her elder brother, who had not undergone expanded NBS, was diagnosed later through genetic family screening. The younger sibling exhibited abnormal biochemical manifestations, and the clinical performance was relatively good after treatment, while the older brother had a mild biochemical and clinical phenotype, mainly featuring poor academic performance. A novel, homozygous missense c.365T>C variant in exon 2 of their MMAA genes was identified using next-generation sequencing and validated by Sanger sequencing. Several different types of bioinformatics software predicted that the novel variant c.365T>C (p.L122P) was deleterious. Furthermore, three-dimensional crystal structure analysis revealed that replacement of Leu122 with Pro122 led to the loss of two intramolecular hydrogen bonds between the residue at position 122 and Leu188 and Ala119, resulting in instability of the MMAA protein structure. CONCLUSIONS: The two siblings suspected of having the cblA-type of MMA showed mild phenotypes during follow-up, and a novel, homozygous missense variant in their MMAA genes was identified. We believe that the clinical features of the two siblings were associated with the MMAA c.365T>C variant; however, further functional studies are warranted to confirm the variant's pathogenicity.
Amino Acid Metabolism, Inborn Errors/genetics , Asian People/genetics , Mitochondrial Membrane Transport Proteins/genetics , Amino Acid Sequence , Child , Female , Homozygote , Humans , Infant , Male , Mutation, Missense/genetics , Phenotype , Siblings
