One case of mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency and literature review / 中国基层医药

Objective:To summarize the clinical phenotype and genetic characteristics of one child patient with mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (mHS) caused by HMGCS2 gene mutation. Methods:One child patient with mHS who received treatment in Chongqing University Three Gorges Hospital on April 10, 2020 was included in this patient. The child was hospitalized due to cough, shortness of breath and deep coma. After admission, gas chromatography-mass spectrometry of the blood and urine samples and high-throughput whole genome sequencing were performed. The pedigree of the child with gene mutation was analyzed. The child was diagnosed with mHS. Related publications published by June, 2020 were searched in Wanfang database, Chinese Journal Full Text Database, PubMed and HGMD databases using search terms "mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency", "HMGCS2" "mHS deficiency". Forty-three papers addressing mHS deficiency were retrieved. The clinical phenotype and genotypes of the child with HMGCS2 mutation were summarized. Results:As of June 2020, there were 44 children with mHS deficiency, including the child reported in this study. These children consisted of 15 males, 11 females and 18 unknown genders. Among these children, 29 were aged 0-24 months, 4 were aged > 24 months, 6 had no symptoms, and 5 were of unknown age of disease onset. The first symptoms of most children were fever, cough, acute gastroenteritis, and coma. Twenty-seven children had hypoglycemia, 21 children had metabolic acidosis, 15 children developed hepatomegaly, 16 children had increased FFA/D-3-HB, and 10 children were tested 4-hydroxy-6-methyl-2-pyrone positive. The child included in this study had hepatomegaly, elevated alanine aminotransferase and metabolic acidosis. Gas chromatography-mass spectrometry results showed that a variety of metabolites were increased. Tandem mass spectrometry results showed that C40 level was elevated, and long-chain carnitine contents were increased. High-throughput whole genome sequencing results revealed that there were two heterozygous mutations in HMGCS2 gene, (NM_0055) c.559+1G > A; c. 758 T > C heterozygous mutation. Sanger sequencing and parental origin analysis showed that the mutations in this child were from parents. The two gene mutations in this child were new mutations, which have not been reported in China and countries outside China. According to the criteria and guidelines for interpretation of ACMG sequence variation, the variation was determined to be pathogenic. Conclusion:When a child has hypoketotic hypoglycemia and/or metabolic acidosis, increased FFA/D-3-HB and acetylcarnitine levels, mHS deficiency should be considered. HMGCS2 gene examination can help diagnose mHS deficiency.

Defectos de la oxidación de ácidos grasos como causa de hipoglucemia no cetósica en el niño / Fat acid oxidation defects produce nonketotic hypoglycemia in childhood

Fatty acid oxidation defects (FAOD) cause a group of inherited metabolic diseases that impair mitochondrial energy production from lipids. The clinical presentation includes hypoketotic hypoglycaemia, acute liver failure, myocardiopathy and myopathy after a prolonged fasting. Inheritance is autosomal recessive and the global incidence is 1:10.000 newborn, varying between 1:9.000 and 1:60.000 newborns for medium-chain acyl-CoA dehydrogenase deficiency (MCAD), the most frequent FAOD. Therapy is dietary and pharmacological. As soon as the diagnosis is confirmed enough glucose to prevent lipolysis must be introduced, especially in the neonatal period and during metabolic derangements caused by infections. Nutritional treatment consists in avoiding any period of fasting by giving carbohydrate supplement when appetite is diminished, which is easy and inexpensive to do. The prognosis with presymptomatic diagnosis is excellent when done with a blood sample obtained in the neonatal period and analysed by tandem mass spectrometry, and when treatment is started immediately.

Los defectos de oxidación de los ácidos grasos corresponden a un grupo de alteraciones metabólicas hereditarias que afectan la producción intramitocondrial de energía a partir de los lípidos. Clínicamente se expresan con hipoglucemia no cetósica, insuficiencia hepática aguda, miocardiopatía o miopatía desencadenada por un ayuno prolongado. La herencia es autosómica recesiva y su frecuencia global se estima en 1:10.000 recién nacidos (RN), y entre 1 por 9 000 a 1 por 60 000 RN para el déficit de acil-CoA deshidrogenasa de cadena media (abreviado MCAD) defecto más frecuente en este grupo de patologías. Las medidas terapéuticas pueden ser dietéticas y farmacológicas. Una vez establecido el diagnóstico diferencial del tipo de defecto, es importante proporcionar suficiente cantidad de glucosa para prevenir la lipólisis del tejido adiposo, siendo fundamental en el período neonatal y las en descompensaciones metabólicas por infecciones. El tratamiento es fácil de aplicar y de bajo costo y consiste en fraccionar la alimentación para evitar el ayuno prolongado. El pronóstico es excelente cuando el diagnóstico es presintomático, a través del análisis de una muestra de sangre en papel filtro, para el estudio de acilcarnitinas por espectrometría en tandem durante el período de RN e iniciando el fraccionamiento de la dieta inmediatamente.

Fatty acid oxidation disorders / 한양의대학술지

Inborn errors of fatty acid mitochondrial oxidation (FAOD) have drawn considerable attention in recent years because of rapid pace of discovery of new defects and an ever-increasing spectrum of clinical phenotypes. This review describes a clinical and biochemical phenotypes, diagnosis and treatment of FAOD. Some of FAOD can not be detected by conventional biochemical investigations, even when a patient is symptomatic with fasting intolerance or functional failure of fatty acid dependent tissue (s). Diagnosis must ultimately be based on direct assay of the involved enzyme, however, preliminary indicators may come from determination of carnitine and intermediate metabolites in plasma, profiling of urine organic acid, and radioisotopic screening assays with lymphocytes or cultured fibroblasts. We are faced with the following major challenges: whether to include FAOD in newborn screening programs, the investigation of the rules played by individual disorders in maternal complication during pregnancy, sudden and unexpected death in early life, and pediatric acute/fulminant liver failure.