Inherited Metabolic Diseases as a Multisystem Model of Mental Disorders Research

Abstract Recent biological and genetic research data confirm shared pathological mechanisms of inherited metabolic diseases and mental disorders. We suggest that for further research a model of synergistic heterozygosity can become a convenient tool. In that case the use of inherited metabolic disorders as a multisystem research model can provide both significant theoretical and practical results. At the initial stage of this hypothesis evaluation, it seems efficient to screen for mental symptoms the families of patients with inherited metabolic disorders.

Paying attention to the underlying inherited metabolic disorders and endocrine diseases for the cases of critical illness and sudden death / 中国实用儿科杂志

Sudden death syndrome is the leading cause of child death in high income countries. It affects neonates to adults. The seemly healthy person suddenly died during a daily activity,sleep or exercise. Underlying genetic disorders are main causes of sudden cardiac death or brain death. Sudden unexplained death syndrome was first noted in 1977 in the United States of America. In some countries such as the United States of America,England,Thailand and Japan,the etiological studies were performed in the cases died suddenly. Those studies showed that heart attack and encephalopathy due to varied genetic disorders are the two major causes. Sudden cardiac death accounts for more than half of the cases. Sudden death or sudden death-like syndrome,would be the first manifestation of underlying inherited metabolic disorders and endocrine disorders,such as primary carnitine deficiency,long QT syndrome,arrhythmia,hypomagnesemia,hypokalemia,hyperkalemia,hypocalcemia,hypoglycemia,mitochondrial diseases,etc. Inherited metabolic disorders and endocrine disorders include thousands of diseases,such as amino acids,organic acids,glucose,fatty acids and electrolytes metabolic disturbance. Some patients presented as acute critical illness and sudden death. Some disorders could be detected by newborn screening or selective screening using biochemical,electrophysiological,imaging,pathological or genetic techniques. The mortality and disability could be reduced by effective intervention of diet and medicine.

Application of tandem mass spectrometry in newborn genetic metabolic disease screening / 中华检验医学杂志

Inherited metabolic disorders, also known as congenital metabolic diseases, refer to a group of diseases that cause a series of clinical symptoms due to gene mutations, such as enzyme deficiency, dysfunction of cell membrane or receptor deficiency, resulting in biochemical metabolic disorders, accumulation of intermediate or bypass metabolites, or lack of final metabolites. Inherited metabolic disordersoften occur in childhood, progressively aggravating, irreversible nervous system damage, and even death. Tandem mass spectrometry (MS/MS) has been widely used in newborn screening abroad and in China. This technology not only expands the screening spectrum of newborn screening, but also improves the screening efficiency, specificity and sensitivity, which opens up a new field for disease screening. With deepening the understanding of the mechanism of inherited metabolic disorders and mass spectrometry technology, its clinical application becomes more significant in diseases screening and diagnosing.

Heterogeneous phenotypes, genotypes, treatment and prevention of 1 003 patients with methylmalonic acidemia in the mainland of China / 中华儿科杂志

Objective@#To analyz the current situation of the diagnosis, treatment and prevention of methylmalonic acidemia, the phenotypes, biochemical features and genotypes of the patients in the mainland of China, were investigated.@*Methods@#Tottally 1 003 patients of methylmalonic acidemia from 26 provinces and municipalities of the mainland of China were enrolled. The clinical data, biochemical features and gene mutations were studied. Blood aminoacids and acylcarnitines, urine organic acids, and plasma total homocysteine were determined for the biochemical diagnosis. Gene analyses were performed for the genetic study of 661 patients. The patients were treated with individual intervention and long-term follow up. Prenatal diagnoses were carried out for 165 fetuses of the families.@*Results@#Among 1 003 patients (580 boys and 423 girls), 296 cases (29.5%) had isolated methylmalonic acidemia; 707 cases (70.5%) had combined homocysteinemia; 59 patients (5.9%) were detected by newborn screening; 944 patients (94.1%) had the onset at the ages from several minutes after birth to 25 years and diagnosed at 3 days to 25 years of age. The main clinical presentations were psychomotor retardation and metabolic crisis. Multi-organ damage, including hematological abnormalities, pulmonary hypertension, kidney damage, were found. MMACHC, MUT, MMAA, MMAB, HCFC1, SUCLG1, SUCLA2 mutations were found in 631 patients (96.6%) out of 661 patients who accepted gene analysis. MMACHC mutations were detected in 460 patients (94.7%) out of 486 cases of methylmalonic acidemia combined with homocysteinemia. MUT mutations were found in 158 (90.3%) out of 169 cases of isolated methylmalonic acidemia. The development of 59 patients detected by newborn screening were normal; 918 cases (97.2%) were diagnosed after onset accepted the treatment. Forty-five of them completely recovered with normal development. Twenty-six patients (2.7%) died; 873 (92.5%) patients had mild to severe psychomotor retardation. Methylmalonic acidemia were found in 35 out of 165 fetuses by metabolites assay of amniotic fluid and amniocytes gene analysis.@*Conclusion@#Combined methylmalonic acidemia and homocysteinemia is the common type of methylmalonic acidemia in the mainland of China. CblC defect due to MMACHC mutations is the most common type of methylmalonic acidemia combined with homocysteinemia. MUT gene mutations are frequent in the patients with isolated methylmalonic acidemia. Newborn screening is key for the early diagnosis and the better outcome. Combined diagnosis of biochemical assays and gene analysis are reliable for the prenatal diagnosis of methylmalonic acidemia.

Diagnosis and identification of related inherited metabolic disorders in children with hypoglycemia / 中华实用儿科临床杂志

Hypoglycemia is a common metabolic disorder in children,and its incidence is about 10％.Among them,the incidence of hereditary related diseases is about 1/30 000-10/30 000.More and more genetic diseases leading to hypoglycemia have been discovered in recent years.Children with the disease may have mild nervous system damage at the earliest stage,and liver encephalopathy,respiratory failure,confusion or even death in severe cases.Therefore,more and more attention has been paid to the study of hypoglycemia related genetic diseases,but the diagnosis and differential diagnosis of hypoglycemia has not yet formed an unified consensus.Now,the diagnosis and treatment of this kind of related diseases were summarized in order to provide data for clinical practice.

The distal renal tubular acidosis caused by ATP6V1B1 gene mutation:a case report / 临床儿科杂志

Objective To explore the clinical features and gene diagnosis of the distal renal tubular acidosis (dRTA). Methods The clinical data and gene detection results of one child with dRTA were retrospectively analyzed. The related literatures were reviewed. Results Four-month-old female was admitted with frequent vomiting and hearing impairment. The laboratory examination showed refractory hypokalemia and it was difficult to correct metabolic acidosis. Gene detection found a new mutation on ATP6V1B1 gene. The diagnosis of dRTA was confirmed. Conclusions dRTA is a rare disease, ATP6V1B1 gene is the causative gene of the dRTA with sensorineural deafness.

Neonatal Screening Tests for Inherited Metabolic Disorders using Tandem Mass Spectrometry: Experience of a Clinical Laboratory in Korea

BACKGROUND: The purpose of this study is to investigate the positive rates of screening tests for inherited metabolic disorders, set cutoff values, and report the actual status of internal quality controls in LabGenomics Clinical Laboratories by using LC-MS/MS system. METHODS: We use Agilent 1260 Infinity HPLC System (Agilent Technologies, USA) for liquid chromatography, and API 2000 (AB Sciex, Canada) for MS/MS system. We set up screening tests for 55 diseases, which include metabolic disorders of 25 amino acids, 16 organic acids, and 14 fatty acids. RESULTS: We determined the analyte cutoff values as 99.9 or 0.1 percentiles in 15,000 newborn samples. The total number of samples tested from January 2012 to September 2014 was 119,948; of these, 6,681 were repeated. Of the repeated samples, 713 were presumed to be positive in the screening tests. Repeat screening with newly obtained dried blood spot specimens was recommended for these 713 samples and 600 specimens were obtained. Thus, the recall rate was 0.5% (600/119,948) for all samples and 84.2% (600/713) for the samples presumed to be positive in the screening tests. About 70 samples, that is, 0.06% of the total samples and 11.7% of the "reobtained" samples, again tested positive; we recommended confirmatory tests for these samples. CONCLUSIONS: We have presented data on the status of neonatal screening tests for inherited metabolic disorders using LC-MS/MS, including positive rates and recall rates of screening tests, set up cutoff values and reported the actual status of internal quality controls in a clinical laboratory in Korea.

Syncope and metabolic disorders in children / 中国小儿急救医学

Syncope is a common pediatric emergency event,which can be caused by various metabolic disorders different from other illness. The major metabolic anomalies include hypoglycemia, hyperventilation,electrolytes imbalance,hypoxemia and others, in which hypoglycemia is caused by hyperinsulinemia,pituitary and adrenal disease, diabetes, ketotic hypoglycemia, inherited metabolic disorders of sugar, organic acids and amino-acids,etc. This article introduced the common metabolic anomalies and their causes,diagnosis and therapy.

Diagnosis of inherited metabolic disorders based on their diverse clinical features and laboratory tests / 소아과

Inherited metabolic disorders are individually rare but as a whole, they are nor rare. Since Archibald Garrod introduced a concept of "inborn error of metabolism" or "chemical individuality", more than 500 diseases are currently known, affecting approximately one in 500 newborns cumulatively. They frequently manifest with acute, life-threatening crisis that require immediate specific intervention or they present with insidious diverse symptoms and signs involving multiple visceral organs or tissues as well as central nervous system, hampering a correct diagnosis. In addition, many pediatricians are not familiar with all diagnostic and therapeutic strategies for diverse inherited metabolic disorders. However, the prognosis of affected children are heavily dependent on rapid and effective treatment. In this lecture, practical guidelines for the specific diagnosis based on diverse clinical features of inherited metabolic disorders will be described. Many sophisticated laboratory tests are available for confirmatory diagnosis of each disease, which challenge to general pediatricians with respect to knowledge about biochemical metabolite assay test, enzymatic test and DNA diagnostic tests. Sample collections, indications, methods and interpretation of results in varying laboratory tests will be listed as well.