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

OBJECTIVETo analyze mutation types, clinical features, and treatment outcomes of cobalamin C (cblC) type combined methylmalonic aciduria and homocystinuria (MMA-HC) and to investigate the relationship of genotypes with clinical phenotypes and outcomes.

METHODSThe clinical data of 16 Chinese children diagnosed with cblC type MMA-HC by gene analysis were retrospectively analyzed. According to the onset age, the patients were classified into early onset (≤1 year) and late onset (>1 year). According to the clinical phenotype, the patients were classified into mild, moderate, and severe groups. All the patients were treated with vitamin B12 (cyanocobalamin) or hydroxocobalamin, betaine, folate, vitamin B6, and L-carnitine.

RESULTSFifteen patients belonged to the early onset type, including 11 in the severe group and 4 in the moderate group. The remaining one belonged to the late onset type. Seven reported mutations and two novel mutations (c.445_446delTG and c.349G>c) were detected. The c.609G>A and c.658_660delAAG were the most common mutations detected in 13 (81%) out of 16 patients. The genotype caused by compound heterozygous mutations of these two alleles (c.609 G>A/c.658_660delAAG) was the most common in the patients, detected in 4 (25%) out of 16 patients. Patients with this genotype had severe microcephaly and eye diseases and these clinical manifestations were not improved after the treatment. The patient with late-onset cblC type MMA-HC had normal clinical phenotypes after treatment. In the 15 early onset patients, the more severe the clinical phenotype, the worse the treatment outcome.

CONCLUSIONSThe cblC type MMA-HC mainly manifests as early onset in China and c.609G >A and c.658_660delAAG are the most common mutations causing this disease. The clinical phenotypes are associated with the outcomes in children with cblC type MMA-HC.

Child ; Child, Preschool ; Female ; Genotype ; Homocystinuria ; genetics ; Humans ; Infant ; Infant, Newborn ; Male ; Mutation ; Phenotype ; Vitamin B 12 Deficiency ; congenital ; genetics

PURPOSE: Purpose: To report a case of modified capsular tension ring scleral fixation and in-the-bag toric intraocular lens (IOL) implantation in a pediatric patient with severe crystalline lens subluxation due to homocystinuria. CASE SUMMARY: A 9-year-old male diagnosed with homocystinuria and crystalline lens subluxation presented with progressive decrease of visual acuity. Uncorrected distant visual acuity (UDVA) and corrected distant visual acuity were 0.03 and 0.6 in the right eye and 0.01 and 0.5 in the left eye, respectively. Slit-lamp examination showed severe crystalline lens subluxation toward the inferiomedial side in both eyes. Corneal astigmatism in the right eye and left eye was 2.75 diopters (D) and 3.00 D, respectively based on keratometry. A combination of subluxated crystalline lens aspiration, scleral-fixated modified capsular tension ring insertion and in-the-bag toric IOL implantation were performed in both eyes. After continuous curvilinear capsulorhexis, nucleus and cortex of the crystalline lens were removed by irrigation and aspiration. A modified capsular tension ring with 2 fixation hooks (Model 2-L) was inserted into the capsular bag and fixed at the scleral wall. Next, toric IOL was inserted into the capsular bag. UDVA was 0.8 in the right eye and 0.9 in the left eye and 3 months postoperatively, the IOL rotation was less than 3 degrees from intended axis in both eyes. CONCLUSIONS: In a patient with severe congenital crystalline lens subluxation and moderate to severe corneal astigmatism, scleral fixation of modified capsular tension ring and in-the-bag toric IOL implantation is a possible surgical option.
Astigmatism ; Axis, Cervical Vertebra ; Capsulorhexis ; Child ; Homocystinuria* ; Humans ; Lens Implantation, Intraocular* ; Lens, Crystalline ; Lenses, Intraocular ; Male ; Visual Acuity

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

Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. It is known that MTHFR deficiency may result in hyperhomocysteinemia, but MTHFR deficiency-induced schizophrenia has been rarely reported. Here we present the clinical course, biochemical and genetic characteristics of schizophrenia resulted from MTHFR deficiency in a school-age boy. He was 13 years old. He was admitted with a two-year history of fear, auditory hallucination, learning difficulty, sleeping problems, irascibility, drowsing and giggling. At admission, he had significantly elevated plasma and urine levels of total homocysteine, significantly decreased levels of folate in serum and cerebrospinal fluid, and a normal blood concentration of methionine. Further DNA sequencing analysis showed 665C>T homozygous mutations in the MTHFR gene. The patient was diagnosed with MTHFR deficiency-associated schizophrenia and treatment with calcium folinate, vitamin B12, vitamin B6, and betaine was initiated. After the treatment for 1 week, his plasma and urine levels of homocysteine were decreased to a normal range and the clinical symptoms were significantly improved. After 3 months of treatment, the patient returned to school. He is now living with normal school life. In summary, children with late-onset MTHFR deficiency and secondary cerebral folate deficiency may lead to schizophrenia. This rare condition can be early diagnosed through analyses of blood and urine total homocysteine, amino acids in blood and folate in blood and cerebral fluid and successfully treated with folinic acid, vitamin B6, vitamin B12 and betaine.
Adolescent ; Base Sequence ; Homocystinuria ; complications ; diagnosis ; drug therapy ; Humans ; Male ; Methylenetetrahydrofolate Reductase (NADPH2) ; deficiency ; Molecular Sequence Data ; Muscle Spasticity ; complications ; diagnosis ; drug therapy ; Psychotic Disorders ; complications ; diagnosis ; drug therapy ; Schizophrenia ; etiology

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

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

PURPOSE: The neonatal screening test for homocystinuria primarily measures methionine by using a dried blood specimen. We investigated the incidence and clinical manifestations of homocystinuria, isolated hypermethioninemia, and transient hypermethioninemia among patients with hypermethioninemia on a neonatal screening test. METHODS: We performed a retrospective study of 58 patients transferred to Shoonchunhyang Hospital because of hypermethioninemia on a neonatal screening test between January 1996 and August 2009. We analyzed the level of amino acid from plasma and urine, as well as blood homocysteine. RESULTS: Almost half of the 58 patients were identified as normal. Whereas only 3 (5.1%) patients were identified as having homocystinuria, about 20.7% (12 cases) of the patients had isolated hypermethioninemia. The ages of these two groups at initial detection of hypermethioninemia on plasma amino acid analysis were 50.0+/-22.5 days and 34.9+/-13.5 days, respectively. Both groups were put on diets, and they showed a normal developmental course as a result of early diagnosis and treatment. CONCLUSION: Hypermethioninemia without homocystinuria, referred to as isolated hypermethioninemia, was also detected. Thus, the impact of hypermethioninemia on a neonatal screening test should be carefully evaluated through analysis of amino acid levels from blood and urine, and we need to detect and treat an early stage of isolated hypermethioninemia as well as homocystinuria.
Diet ; Early Diagnosis ; Homocysteine ; Homocystinuria ; Humans ; Incidence ; Infant, Newborn ; Methionine ; Neonatal Screening ; Plasma ; Retrospective Studies

PURPOSE: Neonatal screening tests are increasingly being used forearly diagnosis of inborn errors of metabolism (IEM) in the hope of avoiding the severe developmental delay, acute illness, and death that may result from these diseases. In this study, a cost-benefit analysis was performed on the neonatal screening of maple syrup urine disease, homocystinuria, galactosemia, and congenital adrenal hyperplasia in Korea. MATERIALS AND METHODS: This study included 1,259,220 Korean newborns born between January 2005 to December 2007, who were screened for maple syrup urine disease, homocystinuria, galactosemia, and congenital adrenal hyperplasia. We calculated and compared the total costs in cases where these four screening tests were implemented, and those where they were not. RESULTS: There were no benefits to screening for maple syrup urine disease or homocystinuria due to their low prevalence for these two tests, the costs exceeded the benefits at benefit:cost ratios of 0.5:1 and 0.6:1, respectively. In contrast, benefits far exceed costs at a ratio of 4.1:1 for galactosemia and 2.9:1 for congenital adrenal hyperplasia. The average benefit:cost ratio for all four tests was 2.0:1. CONCLUSION: Neonatal screening tests for maple syrup urine disease, homocystinuria, galactosemia, and congenital adrenal hyperplasia are financially viable.
Acer ; Adrenal Hyperplasia, Congenital ; Cost-Benefit Analysis ; Galactosemias ; Homocystinuria ; Humans ; Infant, Newborn ; Korea ; Maple Syrup Urine Disease ; Mass Screening ; Metabolism, Inborn Errors ; Neonatal Screening ; Prevalence