Very-long chain acyl-coA dehydrogenase deficiency: report of a Chinese pedigree and a literature review / 中华医学遗传学杂志

OBJECTIVE@#To explore the correlation between clinical classification and genotype and prognosis among Chinese children with Very-long chain acyl-CoA dehydrogenase deficiency (VLCADD).@*METHODS@#A Chinese pedigree affected with VLCADD admitted at the First People's Hospital of Yunnan Province in February 2019 was selected as the study subject. The characteristics of disease onset, diagnosis and treatment and prognosis were retrospectively analyzed. Relevant literature was also systematically searched and reviewed.@*RESULTS@#The proband, a 1-year-old boy, had the clinical manifestations of frequently vomiting, hypoglycemia, abnormal liver function and myocardial enzymes. Tandem mass spectrometry screening showed significantly elevated C14, C14:1, C16:1, C16:2, C18 and C14/C8. Genetic testing revealed that he has harbored compound heterozygous variants of the ACADVL gene, namely c.664G>A (p.G222R) and c.1345G>A (p.E449K), which were respectively derived from his father and mother. The child was diagnosed with VLCADD cardiomyopathy type and deceased 2 weeks later. Literature review has identified 60 Chinese children with VLCADD. The clinical classifications were mainly cardiomyopathy type and liver disease type, which accounted for 73.3% (43/60). The combination of ACADVL gene variants were correlated with the clinical classifications of VLCAD. Children with one or two loss-of-function (LOF) mutations showed more severe clinical manifestation and a higher mortality. Cardiomyopathy type had the poorest prognosis, with a mortality rate of 76.9% (20/26). C14:1 may be used as an indicator for the diagnosis of VLCADD, but cannot be used for clinical subtyping and prognosis evaluation. The c.1349G>A (p.R450H) variant had the highest frequency among the Chinese patients, accounting for 10.8% (13/120).@*CONCLUSION@#The clinical classifications of VLCADD are strongly correlated with the prognosis, and LOF mutations are more common in those with severe clinical manifestations. c.1349G>A (p.R450H) may be the most common variant among the Chinese patients, and early screening and diagnosis can greatly improve the prognosis of patients.

Therapeutic potential of NADH: in neurodegenerative diseases characterizde by mitochondrial dysfunction / 临床耳鼻咽喉头颈外科杂志

Nicotinamide adenine dinucleotide（NADH） in its reduced form of is a key coenzyme in redox reactions, essential for maintaining energy homeostasis.NADH and its oxidized counterpart, NAD+, form a redox couple that regulates various biological processes, including calcium homeostasis, synaptic plasticity, anti-apoptosis, and gene expression. The reduction of NAD+/NADH levels is closely linked to mitochondrial dysfunction, which plays a pivotal role in the cascade of various neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease.Auditory neuropathy（AN） is recognized as a clinical biomarker in neurodegenerative disorders. Furthermore, mitochondrial dysfunction has been identified in patients with mutations in genes like OPA1and AIFM1. However, effective treatments for these conditions are still lacking. Increasing evidence suggests that administratering NAD+ or its precursors endogenously may potentially prevent and slow disease progression by enhancing DNA repair and improving mitochondrial function. Therefore, this review concentrates on the metabolic pathways of NAD+/NADH production and their biological functions, and delves into the therapeutic potential and mechanisms of NADH in treating AN.

Analysis of clinical phenotype and genetic variants in a child with mitochondrial F-S disease due to variants of FDXR gene / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical phenotype and genetic variants of a child suspected for mitochondrial F-S disease.@*METHODS@#A child with mitochondrial F-S disease who visited Department of Neurology, Hunan Provincial children's Hospital on November 5, 2020 was selected as research subject of this study. Clinical data of the child was collected. The child was subjected to whole exome sequencing (WES). Bioinformatics tools were used to analyze the pathogenic variants. Candidate variants were verified by Sanger sequencing of the child and her parents.@*RESULTS@#WES revealed that the child has harbored compound heterozygous variants of the FDXR gene, namely c.310C>T (p.R104C) and c.235C>T (p.R79C), which were inherited from her father and mother, respectively. Neither variant has been reported in HGMD, PubMed, 1000 Genomes, and dbSNP databases. Both of the variants have been suggested as deleterious according to the prediction results from different bioinformatics analysis software.@*CONCLUSION@#Mitochondrial diseases should be suspected for patients with multiple system involvement. The compound heterozygous variants of the FDXR gene probably underlay the disease in this child. Above finding has enriched the spectrum of FDXR gene mutations underlying mitochondrial F-S disease. WES can facilitate the diagnosis of mitochondrial F-S disease at the molecular level.

A case of combined oxidative phosphorylation deficiency 32 caused by MRPS34 gene variation and literature review / 中华儿科杂志

Objective: To investigate the clinical features and genetic features of combined oxidative phosphorylation deficiency 32 (COXPD32) caused by MRPS34 gene variation. Methods: The clinical data and genetic test of a child with COXPD32 hospitalized in the Department of Neurology, Children's Hospital, Capital Institute of Pediatrics in March 2021 were extracted and analyzed. A literature search was implemented using Wanfang, China biology medicine disc, China national knowledge infrastructure, ClinVar, human gene mutation database (HGMD) and Pubmed databases with the key words "MRPS34" "MRPS34 gene" and "combined oxidative phosphorylation deficiency 32" (up to February 2023). Clinical and genetic features of COXPD32 were summarized. Results: A boy aged 1 year and 9 months was admitted due to developmental delay. He showed mental and motor retardation, and was below the 3rd percentile for height, weight, and head circumference of children of the same age and gender. He had poor eye contact, esotropia, flat nasal bridge, limbs hypotonia, holding instability and tremors. In addition, Grade Ⅲ/6 systolic murmur were heard at left sternal border. Arterial blood gases suggested that severe metabolic acidosis with lactic acidosis. Brain magnetic resonance imaging (MRI) showed multiple symmetrical abnormal signals in the bilateral thalamus, midbrain, pons and medulla oblongata. Echocardiography showed atrial septal defect. Genetic testing identified the patient as a compound heterozygous variation of MRPS34 gene, c.580C>T (p.Gln194Ter) and c.94C>T (p.Gln32Ter), with c.580C>T being the first report and a diagnosis of COXPD32. His parents carried a heterozygous variant, respectively. The child improved after treatment with energy support, acidosis correction, and "cocktail" therapy (vitaminB1, vitaminB2, vitaminB6, vitaminC and coenzyme Q10). A total of 8 cases with COXPD32 were collected through 2 English literature reviews and this study. Among the 8 patients, 7 cases had onset during infancy and 1 was unknown, all had developmental delay or regression, 7 cases had feeding difficulty or dysphagia, followed by dystonia, lactic acidosis, ocular symptoms, microcephaly, constipation and dysmorphic facies(mild coarsening of facial features, small forehead, anterior hairline extending onto forehead,high and narrow palate, thick gums, short columella, and synophrys), 2 cases died of respiratory and circulatory failure, and 6 were still alive at the time of reporting, with an age range of 2 to 34 years. Blood and (or) cerebrospinal fluid lactate were elevated in all 8 patients. MRI in 7 cases manifested symmetrical abnormal signals in the brainstem, thalamus, and (or) basal ganglia. Urine organic acid test were all normal but 1 patient had alanine elevation. Five patients underwent respiratory chain enzyme activity testing, and all had varying degrees of enzyme activity reduction. Six variants were identified, 6 patients were homozygous variants, with c.322-10G>A was present in 4 patients from 2 families and 2 compound heterozygous variants. Conclusions: The clinical phenotype of COXPD32 is highly heterogenous and the severity of the disease varies from development delay, feeding difficulty, dystonia, high lactic acid, ocular symptoms and reduced mitochondrial respiratory chain enzyme activity in mild cases, which may survive into adulthood, to rapid death due to respiratory and circulatory failure in severe cases. COXPD32 needs to be considered in cases of unexplained acidosis, hyperlactatemia, feeding difficulties, development delay or regression, ocular symptoms, respiratory and circulatory failure, and symmetrical abnormal signals in the brainstem, thalamus, and (or) basal ganglia, and genetic testing can clarify the diagnosis.

The pulmonary toxicity of e-cigarette vaping exposure and the benefits of air cleaner application / 中华预防医学杂志

To evaluate e-cigarette vaping-induced respiratory toxicity and the interventional effects of air cleaners. A randomized controlled trial study of toxic vaping by the respiratory tract were conducted at the Key Laboratory of Environmental Medical Engineering, Ministry of Education, the School of Public Health, Southeast University from January to December 2022. 8-week-old male C57BL/6JGpt mice selected with a random number table method were used to establish a vaping-exposure model at different periods (0 d, 3 d, 7 d or 14 d), or exposed to clean air as a control group. Mice were exposed to regular heated vaping (200 ℃) and high-temperature heated vaping (280 ℃). Total lung RNA was extracted from control and e-cigarette exposed mice for transcriptome sequencing analysis. Reactive Oxygen Species (ROS) generation and mitochondrial membrane potential (MMP) were detected by flow cytometry. Total superoxide dismutase (SOD) and superoxide (O2-) were evaluated using a microplate reader. Real-Time Quantitative PCR (RT-qPCR) was used to detect gene expression. Air filter and ionizer were used to intervene the toxicity of vaping. Data were expressed as (x¯±s), differences between multiple groups were compared using one-way or two-way ANOVA. The results showed that, RNA sequencing assays suggested that the differential genes between the control and vaping exposure groups were significantly enriched in the oxidative stress (Fold Enrichment=3.18) and mitochondrial oxidative phosphorylation (OXPHOS) (Fold Enrichment=5.74) pathways. Both types of heated vaping exposure caused significantly increased the score of alveolitis (F=10.8, P<0.001), increased endogenous ROS generation (F=16.8, P<0.001), decreased MMP (F=13.6, P<0.01), and gene expression of mitochondrial complex I dysfunction. The toxic effects of high-temperature heated vaping were stronger compared to regular heated vaping (F=2.9, P<0.05). The filter demonstrated better protective effects against vaping than the ionizer by reducing pulmonary alveolitis (F=7.4, P<0.01). Air cleaners could partially alleviate oxidative stress and mitochondrial dysfunction. In conclusion, this study demonstrate that vaping brings potential health risks. Air cleaners could partially reverse mitochondrial dysfunction, but cannot completely prevent the toxic effects, effective interventions remain to be investigated.

The pulmonary toxicity of e-cigarette vaping exposure and the benefits of air cleaner application / 中华预防医学杂志

To evaluate e-cigarette vaping-induced respiratory toxicity and the interventional effects of air cleaners. A randomized controlled trial study of toxic vaping by the respiratory tract were conducted at the Key Laboratory of Environmental Medical Engineering, Ministry of Education, the School of Public Health, Southeast University from January to December 2022. 8-week-old male C57BL/6JGpt mice selected with a random number table method were used to establish a vaping-exposure model at different periods (0 d, 3 d, 7 d or 14 d), or exposed to clean air as a control group. Mice were exposed to regular heated vaping (200 ℃) and high-temperature heated vaping (280 ℃). Total lung RNA was extracted from control and e-cigarette exposed mice for transcriptome sequencing analysis. Reactive Oxygen Species (ROS) generation and mitochondrial membrane potential (MMP) were detected by flow cytometry. Total superoxide dismutase (SOD) and superoxide (O2-) were evaluated using a microplate reader. Real-Time Quantitative PCR (RT-qPCR) was used to detect gene expression. Air filter and ionizer were used to intervene the toxicity of vaping. Data were expressed as (x¯±s), differences between multiple groups were compared using one-way or two-way ANOVA. The results showed that, RNA sequencing assays suggested that the differential genes between the control and vaping exposure groups were significantly enriched in the oxidative stress (Fold Enrichment=3.18) and mitochondrial oxidative phosphorylation (OXPHOS) (Fold Enrichment=5.74) pathways. Both types of heated vaping exposure caused significantly increased the score of alveolitis (F=10.8, P<0.001), increased endogenous ROS generation (F=16.8, P<0.001), decreased MMP (F=13.6, P<0.01), and gene expression of mitochondrial complex I dysfunction. The toxic effects of high-temperature heated vaping were stronger compared to regular heated vaping (F=2.9, P<0.05). The filter demonstrated better protective effects against vaping than the ionizer by reducing pulmonary alveolitis (F=7.4, P<0.01). Air cleaners could partially alleviate oxidative stress and mitochondrial dysfunction. In conclusion, this study demonstrate that vaping brings potential health risks. Air cleaners could partially reverse mitochondrial dysfunction, but cannot completely prevent the toxic effects, effective interventions remain to be investigated.

Analysis of 6 cases with hepatocerebral mitochondrial DNA depletion syndrome and literature review / 中华儿科杂志

Objective: To explore the clinical features of hepatocerebral mitochondrial DNA depletion syndrome (MDS). Methods: The clinical data of 6 hepatocerebral MDS patients diagnosed in the Jinshan Hospital of Fudan University from January 2012 to December 2019 were retrospectively collected and analyzed. Related literature published before January 2020 were searched with the key words of "DGUOK""MPV17""POLG""C10orf2" in PubMed, China national knowledge infrastructure (CNKI) and Wanfang database. Results: All the 6 hepatocerebral MDS cases were male. The age of onset ranged from 3 days to 8 months. The most common initial symptoms were cholestasis and developmental retrogression. The main clinical manifestations included hepatomegaly (4 cases), hypotonia (3 cases), growth retardation (4 cases), cholestasis (5 cases), coagulopathy (5 cases), hypoalbuminemia (3 cases), hypoglycemia (4 cases), hyperlactacidemia (5 cases), and abnormal blood metabolism screening (6 cases). The isotope hepatobiliary imaging revealed no gallbladder and intestinal tract development within 24 hours in 2 patients. Regarding the cranial imaging examination, the head CT found widening of the extracranial space in 1 case, the brain magnetic resonance imaging (MRI) found ventricular enlargement in 2 cases, and the brain ultrasound found peripheral white matter injury in 1 case. Two cases were lost to follow-up, one died of liver failure, and three died of multiple organ failure due to aggravated infection. Among the 6 cases, there were 3 with MPV17 variation (c.182T>C and c.279G>C were novel), 1 with POLG variation (c.2993G>A was novel), 1 with DGUOK variation (c.679G>A homozygous mutation, parthenogenetic diploid of chromosome 2) and 1 with C10orf2 variation (c.1186C>T and c.1504C>T were novel). The literature review found that 129, 100, 51 and 12 cases of hepatocerebral MDS were caused by DGUOK, MPV17, POLG and C10orf2 gene variations, respectively. And the most common clinical manifestations were liver dysfunction presented with cholestasis and elevated transaminase, metabolic disorders including hypoglycemia and hyperlactacidemia, and diverse neurologic symptoms including developmental retardation, hypotonia, epilepsy and peripheral neuropathy. Besides, 1/3 of the patients with C10orf2 variation developed renal tubular injury. Conclusions: Hepatocerebral MDS mainly present with liver dysfunction, metabolic disorder and neuromuscular impairment. Different genotypes show specific clinical manifestations.

Tandem mass spectrometry and genetic variant analysis of four neonates with very long chain acyl-coenzyme A dehydrogenase deficiency / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical features and genetic variants in four neonates with very long chain acyl-coenzyme A dehydrogenase (VLCAD) deficiency.@*METHODS@#Neonates with a tetradecenoylcarnitine (C14:1) concentration at above 0.4 μmol/L in newborn screening were recalled for re-testing. Four neonates were diagnosed with VLCAD deficiency by MS-MS and genetic testing, and their clinical features and genotypes were analyzed.@*RESULTS@#All cases had elevated blood C14:1, and the values of first recalls were all lower than the initial test. In 2 cases, the C14:1 had dropped to the normal range. 1 case has remained at above 1 μmol/L after the reduction, and the remainder one case was slightly decreased. In total eight variants of the ADACVL genes were detected among the four neonates, which included 5 missense variants and 3 novel variants (p.Met344Val, p.Ala416Val, c.1077+6T>A). No neonate showed salient clinical manifestations.@*CONCLUSION@#Above findings have enriched the spectrum of ADACVL gene mutations and provided a valuable reference for the screening and diagnosis of VLCAD deficiency.

Síndrome Pos-COVID y Síndrome de Fatiga Crónica: ¿Dos caras de la misma moneda? / POST-COVID SYNDROME AND CHRONIC FATIGUE SYNDROME: TWO SIDES OF THE SAME COIN

El síndrome de fatiga crónica es una enfermedad caracterizada, principalmente, por la manifestación de la fatiga, el dolor muscular difuso, y alteraciones en el sueño, en un periodo de no menos de 6 meses y que no son explicables por alguna causa. Es llamativo que, luego de un periodo de tiempo de padecer la COVID-19, los pacientes presenten síntomas similares a los hallados en el síndrome de fatiga crónica. A esta afección se la denomino síndrome pos-COVID. Los virus son los principales sospechosos en la aparición de ambos síndromes, estos podrían ocasionar la generación de daño mitocondrial, una neuroinflamación, alteración en el sistema glinfático o la disfunción en el eje hipotálamo-pituitario-adrenal entre otros. Dichos mecanismos serían los implicados en la aparición de los síntomas que padecen los pacientes con estos síndromes. El objetivo de esta revisión literaria es analizar y describir los posibles mecanismos que explicarían la manifestación de los síntomas del síndrome de fatiga crónica en los pacientes que hayan sufrido la COVID-19. Hasta el momento no existen tratamientos totalmente efectivos para erradicar los síntomas en ambos síndromes. Dado el abanico de síntomas que padecen estos pacientes, el enfoque terapéutico debe ser interdisciplinario para tratar de mejorar su calidad de vida.

Síndrome de Pearson en un niño trasplantado debido a anemia de Diamond-Blackfan / Pearson syndrome in a child transplanted for Diamond-Blackfan anemia

El síndrome de Pearson (SP) comparte varias características con la anemia de Diamond-Blackfan (ADB), incluida la anemia grave de inicio temprano, por lo que es importante hacer un diagnóstico diferencial. El diagnóstico diferencial de la ADB y el SP es fundamental, ya que los pacientes con ADB podrían res-ponder al tratamiento con corticoesteroides, presentar remisión o beneficiarse del trasplante de células madre hematopoyéti-cas (TCMH). Sin embargo, los pacientes con SP tienen un pronós-tico diferente, con un riesgo muy elevado de acidosis, problemas metabólicos y disfunción pancreática, y una expectativa de vida menor en comparación con aquellos con ADB. En este artículo, presentamos el caso de un paciente sometido a TCMH para la ADB, pero que luego fue diagnosticado con SP tras desarrollar algunas complicaciones.

Pearson syndrome (PS), shares a number of overlapping features with Diamond-Blackfan anemia (DBA), including early onset of severe anemia, making differential diagnosis important. Differential diagnosis of DBA and PS is critical, since those with DBA may respond to treatment with steroids, may undergo remission, or may benefit from hematopoietic stem cell transplantation (HSCT). However, patients with PS have a different prognosis, with a very high risk of developing acidosis, metabolic problems, and pancreatic dysfunction, and a shorter life expectancy than those with DBA. Here we present a patient who underwent HSCT for DBA but was subsequently diagnosed with PS after developing some complications