External quality assessment (EQA) trials of conventional newborn screening tests for phenylketonuria, galactosemia, congenital adrenal hyperplasia, maple syrup urine disease, homocystinuria, and congenital hypothyroidism, as well as extended newborn screening tests using tandem mass spectrometry, were performed twice in 2016 and 2017. A total of 44 specimens in the form of dried blood spots were distributed in each trial to 16 laboratories. The response rate of these laboratories was 100%. The mean, standard deviation, coefficient of variation, median, and cut-offs were evaluated for each analyte in the newborn screening tests. EQA trials for the analyses of methylmalonic acid, vanillylmandelic acid, catecholamines, metanephrines, organic acids, and amino acids were also performed. A well-designed EQA program and continuous education would improve the performance of metabolite testing.
Adrenal Hyperplasia, Congenital ; Amino Acids ; Catecholamines ; Congenital Hypothyroidism ; Education ; Galactosemias ; Homocystinuria ; Humans ; Infant, Newborn ; Korea* ; Maple Syrup Urine Disease ; Mass Screening ; Methylmalonic Acid ; Phenylketonurias ; Tandem Mass Spectrometry ; Vanilmandelic Acid

Two external quality assessment (EQA) trials of conventional newborn screening tests for phenylketonuria, galactosemia, congenital adrenal hyperplasia, maple syrup urine disease, homocystinuria, and congenital hypothyroidism, as well as newborn screening tests using tandem mass spectrometry, were performed in 2015. A total of 44 specimens in the form of dried blood spots were distributed to 16 laboratories and the response rate of these laboratories was 100%. The mean, standard deviation, coefficient of variation, median, and cut-offs were evaluated for each analyte in the newborn screening tests. Two EQA trials for the analyses of methylmalonic acid, vanillylmandelic acid, catecholamines, metanephrines, organic acids, and amino acids were also performed. A well-designed EQA program and continuous education would improve the performance of biochemical genetics tests.
Adrenal Hyperplasia, Congenital ; Amino Acids ; Catecholamines ; Congenital Hypothyroidism ; Education ; Galactosemias ; Homocystinuria ; Humans ; Infant, Newborn ; Korea* ; Maple Syrup Urine Disease ; Mass Screening ; Methylmalonic Acid ; Molecular Biology* ; Phenylketonurias ; Tandem Mass Spectrometry ; Vanilmandelic Acid

Two trials of external quality assessment (EQA) of conventional newborn screening tests for phenylketonuria, galactosaemia, congenital adrenal hyperplasia, maple syrup urine disease, homocystinuria, and congenital hypothyroidism, as well as newborn screening tests were performed using tandem mass spectrometry in 2014. A total of 39 specimens in the form of dried blood spots were distributed to 16 laboratories and the response rate of these laboratories was 100%. Screening tests for phenylketonuria and congenital hypothyroidism did not meet the accepted performance criteria in some laboratories. The mean, standard deviation, coefficient of variation, median, and cut-offs were evaluated for each analyte in the newborn screening tests. Two trials of EQA for the analyses of methylmalonic acid, vanillylmandelic acid, catecholamines, metanephrines, organic acids, and amino acids were also performed. A well-designed EQA program and continuous education would improve the performance of biochemical genetic testing.
Adrenal Hyperplasia, Congenital ; Amino Acids ; Catecholamines ; Congenital Hypothyroidism ; Education ; Homocystinuria ; Humans ; Infant, Newborn ; Korea ; Maple Syrup Urine Disease ; Mass Screening ; Methylmalonic Acid ; Molecular Biology* ; Phenylketonurias ; Tandem Mass Spectrometry ; Vanilmandelic Acid

OBJECTIVEWe report the first case of acute encephalopathy induced by vaccination in an infant with methylmalonic aciduria cblA in China.

METHODThe clinical presentation, blood acylcarnitines analysis, urine organic acids analysis and gene studies of the patient were summarized.

RESULTThe proband, a boy, was admitted at the age of 15 months because of recurrent vomiting, acidosis and development delay for 8 months. The previously healthy boy presented vomiting and coma just one hour after hepatitis B vaccination at the age of seven months. Moderate dehydration, electrolyte disturbance and metabolic acidosis had been found. Although his acute metabolic crisis had been corrected soon after intravenous transfusion, psychomotor retardation and recurrent vomiting had been observed. When he was 15 months old, vomiting and lethargy occurred again 3 hours after DTaP vaccination. He was weakened as the illness became worse and got coma with dyspnea 7 days later. He was hospitalized with the suspected diagnosis of viral encephalitis. Blood acylcarnitines analysis, urine organic acids analysis and gene study had been performed for the etiologic investigation.His blood propionylcarnitine (16.3 µmol/L vs. normal range 1.0-5.0 µmol/L) and propionylcarnitine/free carnitine ratio (0.27 vs. normal range 0.03 to 0.25) increased. Markedly elevated urinary methylmalonic acid (388.21 mmol/mol creatinine vs. normal range 0.2 to 3.6 mmol/mol creatinine) and normal plasma total homocysteine supported the diagnosis of isolated methylmalonic aciduria. Two mutations, c.650 T>A (p.L217X) and c.742 C>T (p.Q248X), were identified in his MMAA gene, confirmed the diagnosis of cblA. Each parent carried one of the two mutations. Progressive clinical and biochemical improvement has been observed after hydroxylcobalamin injection, protein-restricted diet with the supplements of special formula and L-carnitine. He is currently 2 years and 7 months old with normal development and general condition.

CONCLUSIONA boy with cblA was firstly detected after the acute encephalopathy induced by vaccination in China. It is important to pay more attention to the patients with metabolic crisis or organ damage after vaccination. Metabolic studies are keys to the diagnosis of potential diseases and improve the outcome.

Amino Acid Metabolism, Inborn Errors ; complications ; Brain Diseases ; chemically induced ; Carnitine ; analogs & derivatives ; Diet, Protein-Restricted ; Hepatitis B Vaccines ; adverse effects ; Humans ; Infant ; Male ; Methylmalonic Acid ; urine ; Mutation ; Vaccination ; adverse effects ; Vitamin B Complex ; Vomiting

Two trials of external quality assessment (EQA) of conventional newborn screening tests for phenylketonuria, galactosaemia, congenital adrenal hyperplasia, maple syrup urine disease, homocystinuria, and congenital hypothyroidism, as well as of newborn screening tests using tandem mass spectrometry were performed in 2013. A total of 32 specimens in the form of dried blood spots were distributed to 16 laboratories and the response rate of these laboratories was 100%. Total T4, free T4, 17-hydroxyprogesterone, leucine, isoleucine, galactose, methionine, alanine, C8/C2, C8/C10, and C5-OH did not meet the accepted performance criteria. The mean, standard deviation, coefficient of variation, median, and cut-offs were evaluated for each analyte in the newborn screening tests. Two trials of EQA for the analyses of methylmalonic acid, vanillylmandelic acid, very long fatty acids, organic acids, and amino acids were also performed. A well-designed EQA program and continuous education would improve the performance of biochemical genetic tests.
17-alpha-Hydroxyprogesterone ; Adrenal Hyperplasia, Congenital ; Alanine ; Amino Acids ; Congenital Hypothyroidism ; Education ; Fatty Acids ; Galactose ; Homocystinuria ; Humans ; Infant, Newborn ; Isoleucine ; Korea ; Leucine ; Maple Syrup Urine Disease ; Mass Screening ; Methionine ; Methylmalonic Acid ; Molecular Biology* ; Phenylketonurias ; Tandem Mass Spectrometry ; Vanilmandelic Acid

Adult ; Age of Onset ; Amino Acid Metabolism, Inborn Errors ; complications ; diagnosis ; genetics ; therapy ; Betaine ; administration & dosage ; therapeutic use ; Carrier Proteins ; genetics ; metabolism ; Child ; China ; epidemiology ; DNA Mutational Analysis ; Gas Chromatography-Mass Spectrometry ; Genotype ; Homocysteine ; urine ; Humans ; Hydroxocobalamin ; administration & dosage ; therapeutic use ; Hyperhomocysteinemia ; complications ; diagnosis ; genetics ; therapy ; Infant ; Methylmalonic Acid ; blood ; urine ; Mutation ; Vitamin B 12 ; metabolism

OBJECTIVECombined methylmalonic acidemia with homocystinuria is a common form of methylmalonic acidemia in China. Patients with this disease can progress to death without timely and effective treatment. This study aimed to analyze the treatment outcomes of patients with combined methylmalonic acidemia and homocystinuria.

METHODFrom September 2004 to April 2012, 58 patients with combined methylmalonic acidemia and homocystinuria (34 males and 24 females) were diagnosed and treated in our hospital. Fifty cases were from clinical patients including 42 early-onset cases and 8 late-onset cases. Their age when they were diagnosed ranged from 18 days to 30.8 years. The other 8 cases were from newborn screening. All the patients were treated with vitamin B12, betaine, folic acid, vitamin B6, and L-carnitine. The physical and neuropsychological development, general laboratory tests, the levels of amino acids, acylcarnitines, and homocysteine in blood, and organic acids in urine were followed up.

RESULTThe follow-up period ranged from 1 month to 7.1 years. Three cases died (all were early-onset cases). In the other patients after treatment, the symptoms such as recurrent vomiting, seizures, lethargy, and poor feeding disappeared, muscle strength and muscle tension were improved, and general biochemical abnormalities such as anemia and metabolic acidosis were corrected. Among the surviving 55 cases, 49 had neurological impairments such as developmental delay and mental retardation. The median levels of blood propionylcarnitine and its ratio with acetylcarnitine, serum homocysteine, and urine methylmalonic acid were significantly decreased (P < 0.01), from 7.73 µmol/L (ranged from 1.5 to 18.61 µmol/L), 0.74 (ranged from 0.29 to 2.06), 97.3 µmol/L (ranged from 25.1 to 250 µmol/L) and 168.55 (ranged from 3.66 to 1032.82) before treatment to 2.74 µmol/L (ranged from 0.47 to 12.09 µmol/L), 0.16 (ranged from 0.03 to 0.62), 43.8 µmol/L (ranged from 17 to 97.8 µmol/L) and 6.81 (ranged from 0 to 95.43) after treatment, respectively.

CONCLUSIONPatients with combined methylmalonic acidemia and homocystinuria respond to a combined treatment consisting of supplementation of hydroxycobalamin, betaine, folic acid, vitamin B6 and L-carnitine with clinical and biochemical improvement. But the long-term outcomes are unsatisfactory, with neurological sequelae in most patients.

Adolescent ; Adult ; Amino Acid Metabolism, Inborn Errors ; blood ; diagnosis ; therapy ; Betaine ; administration & dosage ; therapeutic use ; Carnitine ; analogs & derivatives ; blood ; Child ; Child, Preschool ; Female ; Follow-Up Studies ; Homocystine ; blood ; Homocystinuria ; blood ; diagnosis ; therapy ; Humans ; Hydroxocobalamin ; administration & dosage ; therapeutic use ; Infant ; Infant, Newborn ; Male ; Methylmalonic Acid ; urine ; Neonatal Screening ; Treatment Outcome ; Vitamin B 12 ; administration & dosage ; therapeutic use ; Vitamin B 12 Deficiency ; congenital ; Young Adult

OBJECTIVEMethylmalonic aciduria is the most common disorder of organic acidurias in the mainland of China. It is also the one of treatable metabolic disorders. The clinical spectrum of the patients varies from severe neonatal-onset forms with neonatal brain injury and high mortality to milder forms with adult-onset. The clinical manifestations of neonates with methylmalonic aciduria are non-specific. Early diagnosis and adequate treatment contribute a lot to improving the prognosis of the patients. In this study, the abnormal clinical and laboratory findings in neonatal period of 160 Chinese patients with early-onset methylmalonic aciduria were investigated.

METHODFrom 1996 to 2011, a total of 398 patients with methylmalonic aciduria were diagnosed in our hospital; 286 (71.9%) patients had early-onset before 1 year of age. Among 286 patients, 160 (55.9%) presented symptoms in neonatal period. Their urine organic acids were analyzed by gas chromatography-mass spectrometry. Blood amino acids and acylcarnitine profiles were determined by liquid chromatography tandem mass spectrometry. Serum and urine total homocysteine were measured using a fluorescence polarization immunoassay. In some patients, gene analysis was performed. Based on the disease types and general condition, individual dietary and medical interventions were started soon after diagnosis.

RESULTOut of the 160 patients, 131 (81.9%) had combined methylmalonic aciduria and homocysteinemia. Isolated methylmalonic aciduria was found in 29 cases (18.1%). The common presentations in neonatal period were feeding difficulty, seizures, lethargy and dyspnea. Megaloblastic anemia, liver dysfunction, hyperammonemia and metabolic acidosis were the frequent findings in the routine laboratory test. The most common initial clinical diagnosis was suspected hypoxic-ischemic encephalopathy. Even in 36 cases with abnormal family history, only 3 patients were admitted with suspected inborn errors of metabolism. Five cases (3.1%) were diagnosed by postmortem metabolic examination; 7 cases (4.4%) were detected by newborn screening. In 148 cases (92.5%), the diagnosis was much delayed to the age of one month to 8 years and 5 months (mean 13 months). Methylmalonic aciduria combined with homocysteinemia (MMACHC) gene analyses were performed in 31 cases with combined methylmalonic aciduria. CblC defect was confirmed. The patients with isolated methylmalonic aciduria were treated with protein-restricted diet, cobalamin and L-carnitine. The patients of methylmalonic aciduria combined with homocysteinemia were treated with cobalamin, L-carnitine, calcium folinate, betaine and common diet. Seven patients died without treatment. Clinical improvement was observed in 153 patients. Only 2 patients detected by newborn screening had normal mental and physical development. Mild to severe psychomotor retardation was observed in 151 cases.

CONCLUSIONHigh mortality and disability rates were observed in the patients with early-onset methylmalonic aciduria. Combined methylmalonic aciduria and homocysteinemia is the common type of methylmalonic aciduria. The clinical manifestation in neonatal period of the patients with early-onset methylmalonic aciduria is complex. Feeding difficulty, seizures, lethargy and dyspnea are the common symptoms in neonatal period of the patients. Megaloblastic anemia, liver dysfunction, hyperammonemia and metabolic acidosis were the frequent laboratory findings.

Amino Acid Metabolism, Inborn Errors ; complications ; diagnosis ; genetics ; therapy ; Carnitine ; therapeutic use ; Child ; Child, Preschool ; China ; epidemiology ; Female ; Folic Acid ; therapeutic use ; Gas Chromatography-Mass Spectrometry ; Homocysteine ; blood ; urine ; Humans ; Hyperhomocysteinemia ; diagnosis ; etiology ; therapy ; Infant ; Infant, Newborn ; Male ; Methylmalonic Acid ; urine ; Neonatal Screening ; Retrospective Studies ; Vitamin B 12 ; therapeutic use

Homocysteine ; analogs & derivatives ; blood ; Humans ; Infant ; Infant Nutrition Disorders ; complications ; Male ; Methylmalonic Acid ; urine ; Skin Diseases ; etiology ; Vitamin B 12 ; administration & dosage

From June 1998 to May 2007, 9566 urine samples were collected from patients with psychomotor deficits, seizures, vomiting and unconsciousness in Peking University First Hospital. Their urine organic acids profiles were analysed using gas chromatography - mass spectrometry (GCMS), GCMS solution and Inborn Errors of Metabolism Screening System software. In all patients, blood acylcarnitines were analysed using tandem mass spectrometry. One hundred and sixty-eight patients (1.76%) with organic acidurias were detected. Among them, 116 (116/ 168, 69.0%) had methylmalonic aciduria, 63 (54.3%) of these 116 patients had methylmalonic aciduria combined with homocysteinemia. Sixteen (9.5%) of those patients detected with organic acidurias had propionic aciduria, and 15 (8.9%) had multiple carboxylase deficiency. Seven (4.2%) had glutaric aciduria type 1. After dietary treatment, medicine and rehabilitation, clinical improvements were observed in more than half of the patients. Twenty-eight of the 168 patients (16.7%) recovered and led a normal life. The method of urine organic acid analysis by gas chromatography - mass spectrometry and blood acylcarnitines analysis by tandem mass spectrometry have been established and applied successfully in China, namely Beijing, Shanghai, Wuhan and Guangzhou. The prognoses of Chinese patients with organic acidurias have also improved significantly.
Child ; Child, Preschool ; China ; Humans ; Infant ; Infant, Newborn ; Metabolic Diseases ; urine ; Methylmalonic Acid ; urine ; Multiple Acyl Coenzyme A Dehydrogenase Deficiency ; urine ; Propionic Acidemia ; urine