Advances on the research of 3-hydroxy-3-methylglutaric aciduria / 中华实用儿科临床杂志

3-hydroxy-3-methylglutaric aciduria is a rare organic aciduria inherited by autosomal recessive trait.It is caused by the mutations in 3-hydroxy-3-methylglutaryl-CoA lyase gene.The clinical onset usually occurs in the neonatal and infant period.In recent years,with the development of technology for screening inherited metabolic diseases,the number of children with 3-hydroxy-3-methylglutaric aciduria are increasing.The incidence of this disease is about 1 ∶ 100 000 in reports of Europe and the United States.The incidence in China is unknown.In this paper,the advances on pathogenesis,clinical manifestations,diagnosis and treatment of 3-hydroxy-3-methylglutaric aciduria will be reviewed so as to improve the understanding of this disease and provide reference for its clinical diagnosis and treatment.

Inborn Errors of Ketone Body Metabolism and Transport: An Update for the Clinic and for Clinical Laboratories

Abstract Major progress occurred in understanding inborn errors of ketone body transport and metabolism between the International Congresses on Inborn Errors of Metabolism in Barcelona (2013) and Rio de Janeiro (2017). These conditions impair either ketogenesis (presenting as episodes of hypoketotic hypoglycemia) or ketolysis (presenting as ketoacidotic episodes); for both groups, immediate intravenous glucose administration is the most critical and (mHGGCS, HMGCS2) effective treatment measure. Ketogenesis Deficiencies: New biomarkers were described for mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (mHGGCS, HMGCS2) deficiency. New patient series refined clinical knowledge of 3-hydroxy-3-methylglutaryl-CoA lyase (HGGCL, HMGCL) deficiency. Although affected humans have not been described, two animal model phenotypes are pertinent: zebrafish deficient in monocarboxylate transporter 7 (MCT7, slc16a6) (decreased ketone body exit from hepatocytes) or mice lacking D-3-hydroxy-n-butyrate dehydrogenase (BDH1, BDH1) (isolated hyperacetoacetatemia; fatty liver). Ketolysis Deficiencies: Monocarboxylate transporter 1 (MCT1, SLC16A1) deficiency is a newly described defect of ketone body transport, joining deficiencies of succinyl-CoA:3-oxoacid CoA transferase (SCOT, OXCT1) and methylacetoacetyl-CoA thiolase (MAT, ACAT1). Some heterozygotes for MCT1 or SCOT deficiency develop ketoacidosis.

Mimicking Ketonuria in the Ketogenesis Defect 3-Hydroxy-3-MethylglutarylCoenzyme A Lyase Deficiency: An Artefact in the Analysis of Urinary Organic Acids

Abstract 3-Hydroxy-3-methylglutaryl-coenzyme A lyase (HMGCL, HMGCL) deficiency is a rare inborn error of ketogenesis. Even if the ketogenic enzyme is fully disrupted, an elevated signal for the ketone body acetoacetic acid is a frequent observation in the analysis of urinary organic acids, at least if derivatization is performed by methylation. We provide an explanation for this phenomenon and trace it back to degradation of the derivatized 3-hydroxy-3-methylglutaric acid and high temperature of the injector of the gas chromatograph.

L-2-Hydroxyglutaric Aciduria - A rare type of organic Aciduria presenting as seizures and developmental delay in a Filipino child

@#L-2-hydroxyglutaric aciduria (L-2-HGA) is a rare, autosomal recessive organic aciduria with increased levels of L-2hydroxyglutaric acid in the urine and other body fluids. Clinical presentation includes developmental delay, epilepsy, and typical neuroimaging findings. This is a report of the clinical, neuroimaging, and biochemical findings of the first diagnosed case of L-2-hydroxyglutaric aciduria in the Philippines. This paper likewise reaffirms the importance of locally available biochemical tests in diagnosing inborn error of metabolism.

Phenotypes and genotypes of 126 patients with isolated methylmalonic aciduria / 中华实用儿科临床杂志

Objective To investigate the clinical,biochemical and genetic findings in patients with isolated methylmalonic aciduria. Methods From January 2001 to December 2014,a total of 126 patients with isolated methyl-malonic aciduria from Peking University First Hospital were enrolled in this study. In 60 patients,gene analysis was per-formed. The clinical characteristics,laboratory findings,treatment and outcomes were retrospectively analyzed. Results Among the 126 patients,only 3 cases(2. 4% )were detected through newborn screening and treated with dietary in-tervention,cobalamin and L - camitine. The age at onset of 123 cases(97. 6% )varied from a few hours after birth to 7 years and 11 months old. The common presentations were recurrent vomiting,mental retardation,poor feeding,lethargy, respiratory distress,coma,seizures,cutaneous lesion and jaundice with 11 patients(8. 73% )dead. Abnormal family his-tory was found in 27(21. 4% )patients. Metabolic acidosis and anemia were frequent laboratory findings. Basal ganglia damage and white matter changes were observed in most patients. Sixty patients got genetic analysis,and 58 cases of them had MUT gene mutations. One case had MMAA defect. One case had MMAB defect. In MUT gene,12 novel muta-tions were identified. After treatment,mild to severe psychomotor retardation was observed in 112 patients with isolated methylmalonic aciduria. Conclusions The clinical manifestation of patients with isolated methylmalonic aciduria is complex,and prone to appear metabolic crisis. MUT defect is the main cause. Early metabolic investigation is very im-portant to reach diagnosis. Newborn screening,early diagnosis and adequate therapy are key points to reduce the morta-lity and handicap.

Organic acidemia/aciduria and therapy / 中国小儿急救医学

The organic acidemia/aciduria is one of the most common inherited metabolic disorders in clinic,more than 50 species have been found until now.The illness is believed to be caused by gene mutation,leading to the reduction or loss of enzyme activity and the accumulation of carboxylic acid and its metabolites.The manifestations of increased blood organic acids include refractory metabolic acidosis,paroxysmal vomiting,feeding difficulties,hypotonia,convulsions and disturbance of consciousness.Most of the organic acidemia begins in neonatal period or infancy,accompanied by progressive neurological damages at most of the time.There are little specific clinical features can be found in this kind of diseases,therefore,early diagnosis and treatment must be initiated in order to decrease risk of neurological induries and damages or acute deaths.So application of the gas chromatography-mass spectrometry and tandem mass spectrometry is important to the early diagnosis,helpful for improving the outcomes and reducing child mortality.

A Chinese girl with ethylmalonic encephalopathy and a novel mutation on ETHE1 gene / 临床儿科杂志

Objective To introduce a case of ethylmalonic encephalopathy which is an autosomal recessive metabolic disorder caused by mutations in the ETHE1 gene. Methods The clinical course and gene mutation in a case of ethylmalonic encephalopathy was retrospectively analysed. Results A previously healthy girl presented with intractable diarrhea from the age of 7 months. Since then, progressive psychomotor regression has been observed. When she was 23 months, her blood butyr-ylcarnitine was signiifcantly increased (4.48μmol/L vs. normal range 0.0~1.0μmol/L), and isovalerylcarnitine (0.70μmol/L vs. normal range 0.0~0.65μmol/L) was also elevated. Her urine levels of ethylmalonic acid and methylsuccinate acid were markedly increased. Cranial MRI revealed bilateral basal ganglia lesions supporting the diagnosis of ethylmalonic encephalopathy. On her ETHE1 gene, a reported mutation (c.488G>A, p.R163Q) and a novel mutation (c.203T>C, p.L68P) were identiifed. After lactose-free dietary treatment and the supplements of L-carnitine, coenzyme Q10, vitamins B1, B2 and C, gradual improvement in general condition, intelligence and motor development has been observed. Conclusions Ethylmalonic aciduria is common in the patients with inborn errors of mitochondrial fatty acid beta-oxidation. In ethylmalonic encephalopathy, elevated blood levels of butyrylcarnitine and isovalerylcarnitine are common and ETHE1 sequencing is helpful in its diagnosis.

Clinical and genetic features of three patients with non-classical isovaleric aciduria / 临床儿科杂志

Objective To explore the clinical, therapeutic and genetic features of IVD gene in late-onset non-classical isovaleric aciduria. Methods One boy and two girls presented with intractable vomiting were admitted. Urine organic acids and blood acylcarnitines proifles were analyzed. Isovaleric aciduria was diagnosed and conifrmed by IVD gene analysis. The patients were treated with leucine-restricted diet and the supplements of L-carnitine and glycine. Results Three patients had recurrent vomiting, drowsiness, odor of sweaty feet and metabolic acidosis from the age of 1 to 2 years. All of them had normal intelligence and leukopenia. One had oligocythemia. The blood isovalerylcarnitines (4.6 to 8.2μmol/L) and urine isovalerylglycines (36.1 to 1783.56 mmol/mmol creatinine) were elevated. Six mutations were found in their IVD gene. Four mutations (c.157C>T, c.214G>A, c.1183C>G and c.1208A>G) were reported. Two (c.1039G>A and c.1076A>G) were novel. The patients completely recovered after treatment with protein-restricted diet and the supplements of L-carnitine and glycine. Currently, they were aged 19 months to 14 years with normal physical and psychomotor development. Conclusions The clinical features of late-onset non-classical isovaleric aciduria are complex. It is onset in infants and young children and characteristic of recurrent vomiting and metabolic acidosis, which can be diagnosed by the blood acylcarnitine spectrum, urine organic acid analysis, and conifrmed by genetic analysis. L-carnitine supplement and diet intervention has signiifcant effects.

Organic acidemias in Korea / 한양의대학술지

Since we started organic acid analysis in July 1997, we have collected data about organic acidemias in Korea. The data presented herein constitute our 3 years experience in organic acid analysis. We have collected 712 samples from major university hospitals in all over Korea, which are large enough for relatively accurate estimation of incidence of organic acid disorders. We used solvent extraction method with ethylacetate, MSTFA for derivatization and simultaneously quantitation of 83 organic acids. Out of 712 patients sample, 498 samples (70%) showed no evidence of organic acid abnormalities. Out of the 214 remaining samples, we found very diverse disorders such as methylmalonic aciduria (6), propionic aciduria (10), biotinidase deficiency (6), maple syrup urine disease (3), isovaleric aciduria (4), tyrosinemia type II (4), tyrosinemia type IV (1), glutaric aciduria type I (1), glutaric aciduria type II (22), 3-methylglutaconic aciduria type I (3), 3-methylglutaconic aciduria type III (7), HMG-CoA lyase deficiency (1), hyperglyceroluria (2), cytosolic 3-ketothiolase deficiency (55), mitochondrial 3-ketothiolase deficiency (3), 3-hydroxyisobutyric aciduria (2), L-2-hydroxyglutaric aciduria (2), fumaric aciduria (2), lactic aciduria with combined elevation of pyruvate (most likely PDHC deficiency) (28), lactic aciduria without combined elevation of pyruvate (most likely mitochondrial respiratory chain disorders) (35), SCAD deficiency (3), MCAD deficiency (1), 3-methylcrotonylglycineuria (1), orotic aciduria (most likely urea cycle disorders) (7) and 2-methylbranched chain acyl-CoA dehydrogenase deficiency (1). In conclusion, although the incidence of individual organic acidemia is low, the incidence of overall organic acidemia is relatively high in Korea. Most of the patients showed some signs of neurological dysfunction. Therefore, organic acid analysis should be included in the diagnostic work up of all neurological dysfunctions.

Quantification of Organic Acids in Amniotic Fluid for Prenatal Diagnosis of Organic Acidemia / 소아과

PURPOSE: Since 1997, the quantification of organic acids in urine has become possible in Korea. This helped to diagnose a great variety of inborn errors of metabolism. However, we still don't know the normal value of organic acids in amniotic fluid, therefore it is impossible for doctors to make a correct diagnosis of inborn errors of metabolism in prenatal care. We tried to confirm the normal value of organic acid in amniotic fluid. METHODS: From Jan. 1998 to Dec. 2001, we carried out amniocentesis and were able to obtain 43 samples of amniotic fluid from between 16 and 20 weeks of gestation, and quantified 82 organic acids to come up with a normal value. Organic acid concentrations were quantified with gas chromatography, and the individual acids were identified with mass spectrometry. To isolate organic acids from amniotic fluid, we used a solvent extraction method with ethylacetate. Derivatization was done with MSTFA(N-methy-N-trimethylsilylfluoroacetamide). RESULTS: The results of this study showed that when organic acid concentrations in amniotic fluid were compared with those in urine, TCA cycle intermediates(lactate, pyruvate, malate, 2-ketoglutarate, citrate etc) and ketone body(3-hydroxybutyric acid, acetoacetate etc) were found at significantly higher levels. CONCLUSION: Because TCA cycle intermediate in amniotic fluid is found at high concentrations, we could expect that diagnosis of mitochondria disorder is difficult. Organic acids other than TCA cycle intermediates were undetectable in amniotic fluid. Therefore, prenatal diagnosis of organic acidemias is possible. In our study, the prenatal diagnosis of methylmalonic acidemia could be made by using the measurement of methylmalonic acid in the amniotic fluid taken at high risk pregnancy with a family history of methylmalonic acidemia.

Organic Acidemias in Korea: Three Years Experience of Organic Acid Analysis

PURPOSE: We have done this retrospective study to know the relative incidences and clinical manifestations of organic acidopathies in Korea. METHODS: The results of quantitative organic acid analysis of 1,125 samples of 712 patients, referred from Jul. 1997 to Jun. 2000, were analyzed retrospectively according to four age groups (-2 mon, 3 mon-2 year, 3 years-12 years, over 12 years) and major clinical manifestations. Quantification of 83 organic acids was done with gas chromatography and mass spectrometry(GC/MS). RESULTS: We diagnosed 214 patients with 27 diseases of organic acid metabolism during this study period. Diseases found more than 10 cases are cytosolic 3-ketothiolase deficiency, mitochondrial repsiratory chain disorders, PDHC deficiency, glutaric aciduria type II and propionic aciduria. Other diseases were diagnosed in less than 10 cases, mostly one or two cases during this study period. Most of the patients had some symptoms of neurological dysfunction such as seizure activity(195 patients), developmental delay(122), mental retardation(99), hypotonia(84), movement disorders(81) and vomiting(68). CONCLUSION: Though the incidence of individual organic acidemia is low, the overall incidence of organic acidemia as a whole seems to be relatively high in Korea. Most of the patients showed some signs of neurological dysfunction.

Organic Acid Analysis on Urine Sample Obtaine3d from Dried Filter Paper in Newborns: Development of Screening Method for Organic Aciduria in Neborns

PURPOSE: Neonatal screening for inherited metabolic disease is aimed at identifying affected infants early, thus permitting medical intervention to prevent or minimize the effect of the disease. However, organic aciduria, most of which causes severe disease and mental retardation, is not yet screened routinely because of the difficulty of tests, sample collection, and expenditure of time and financial resources. This study was designed to develop a screening method for the detection of multiple organic aciduria and neuroblastoma, using dried urine filter paper. METHODS: The standard markers used for screening of organic aciduria were placed on the filter paper and analysed with the modified organic acid analysis method. The extraction efficiency and stability of standard markers were tested for the purpose of adequacy as screening markers, and the method described herein was evaluated by analyzing filter paper samples obtained from both normal newborns and patients with known organic aciduria. RESULTS: The standard markers in the filter paper left in the room temperature over a period of 5 days were still stable without significant degradation. The level of specific organic acids obtained from known organic aciduria patients were easily detectable-enough to make the diagnosis. CONCLUSION: The filter papers soaked with urines obtained from newborns or patients with suspicious metabolic diseases are adequate for screening of organic acidurias and neuroblastoma. Sample delivery to the laboratory can be handled more easily with this method and even newborn screening could be applied in the future.