• Clinical and Experimental Pediatrics
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• v.51 no.9
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• pp.964-970
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• 2008

Purpose : Methylmalonic aciduria (MMA) and propionic aciduria (PA) are inborn errors in the catabolism of branched-chain amino acids. The study was undertaken to investigate the genotypes and clinical features of Korean patients with MMA and PA. Methods : This study examined 12 patients with MMA and eight with PA. We analyzed various clinical features, laboratory findings, treatments, and neuro-developmental outcomes. Diagnoses were based on the presence of characteristic compounds detected by amino acid analysis in serum and organic acid analysis in urine. Mutation analysis was performed in the genes of MUT, MMAA, MMAB, and MMACHC for MMA and PCCA and PCCB for PA. Results : Among the 20 patients, six patients were diagnosed before one month of age and nine patients were diagnosed after the newborn period. Five patients were diagnosed via a neonatal screening test. Patients with early-onset forms had more severe illness at presentation and generally poor outcomes. A favorable outcome was obtained in 55% patients; most of them were of a late-onset type or diagnosed by neonatal mass screening test without symptoms. Genotypes were confirmed in all patients with MMA. We detected 11 different mutations by MUT gene analysis in 10 patients, and three different mutations in MMACHC genes in two patients. PCCA and PCCB gene mutations were identified in 14 of the 16 alleles, in eight patients with PA. Conclusion : Organic aciduria is a fatal disease; however, better outcomes are expected whenever early diagnosis and prompt management are made possible. Mutation analysis is useful for confirming diagnoses and planning management strategies.

• Journal of Genetic Medicine
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• v.4 no.1
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• pp.53-63
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• 2007

Purpose : Tandem mass spectrometry (MS/MS) is effective screening test for inherited metabolic diseases. In this study, we estimate potential costs and benefits of using tandem mass spectrometry (MS/MS) to screen new borns for inherited metabolic diseases (phenylketonuria, BH4 deficiency, citrullinemia, maple syrup urine disease, propionic aciduria, isovaleric aciduria, glutaric aciduria type 1, LCHAD deficiency) in Korea. Methods : From April 2001 to March 2004, 79,179 new borns were screened for amino acid disorders, organic acid disorders, and fatty acid oxidative disorders. Twenty-eight new borns were diagnosed with one of the metabolic disorder and the collective estimated prevalence amounted to 1 in 2,800 with a sensitivity of 97.67%, a specificity of 99.28%, a recall rate of 0.05%, and a positive preditive value of 6.38%. We calculated and compared the total costs in case when neonatal screening on pheny lketonuria, BH4 deficiency, citrullinemia, maple syrup urine disease, propionic aciduria, isovaleric aciduria, glutaric aciduria type 1, LCHAD deficiency is implemented, and when not. Results : If the neonatal screening on pheny lketonuria, BH4 deficiency, citrullinemia, maple syrup urine disease, propionic aciduria, isovaleric aciduria, glutaric aciduria type 1, LCHAD deficiency is implemented, total benefits far exceed costs at a ratio of 1.40:1. Conclusion : Although, this study only concerns the monetary aspects of the neonatal screening, tandem mass spcetrometry for neonatal screening is cost-effective compared with not screening. The study appears to support the introduction of tandem mass spectrometry into a Korea neonatal screening programme for inherited metabolic diseases.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.18 no.1
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• pp.1-12
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• 2018

Purpose: Disorders of organic acid metabolism have various clinical manifestations and it may be life-threatening. The prognoses of affected children are dependent on early diagnosis and treatment. We report this study to find out detection rate of referred samples, clinical manifestations and age distribution after introduction of neonatal screening test using tandem mass spectrometry in Hallym University Chuncheon Sacred Heart Hospital during 8 years and 9 months. Methods: The 2,794 patients referred from Jan. 2007 to Sep. 2015 were divided into four groups according to age. We conducted organic acid analysis of urine samples of patients and analyzed clinical manifestations and distributions of age at the diagnosis. For patients with ambiguous results, reanalysis of urine organic acid after diet restriction, protein loading and restriction, has been done. Results: A total of 626 patients with 20 disorders were diagnosed. Mitochondrial disorders (482 patients) were the most common diagnosis, followed by ketolytic defects (67), 3-hydroxyisobutyric aciduria (32), EPEMA syndrome (8), 3-methylcrotonyl glycinuria (7), glutaric aciduria type II (6) and type I (4), methylmalonic aciduria (3), isovaleric aciduria (3) and medium chain acyl-CoA dehydrogenase deficiency (3). Conclusion: As neonatal screening test using tandem mass spectrometry is increasingly common and medical environment is changed, detection rate of disorders of organic acid metabolism in this study has decreased compared to previous report. Because the deterioration can be prevented by early diagnosis and treatment, many pediatricians have to pay special attention to possibility of the disorders and make an effort for early diagnosis in clinical setting.

• Clinical and Experimental Pediatrics
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• v.46 no.3
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• pp.295-301
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• 2003

Glutaric aciduria type 1(GA1) is an autosomal recessive disorder of the lysine, hydroxylysine and tryptophan metabolism caused by the deficiency of mitochondrial glutaryl-CoA dehydrogenase. This disease is characterized by macrocephaly at birth or shortly after birth and various neurologic symptoms. Between the first weeks and the 4-5th year of life, intercurrent illness such as viral infections, gastroenteritis, or even routine immunizations can trigger acute encephalopathy, causing injury to caudate nucleus and putamen. But intellectual functions are well preserved until late in the disease course. We report a one-month-old male infant with macrocephaly and hypotonia. In brain MRI, there was frontotemporal atrophy(widening of sylvian cistern). In metabolic investigation, there were high glutarylcarnitine level in tandem mass spectrometry and high glutarate in urine organic acid analysis, GA1 was confirmed by absent glutaryl-CoA dehydrogenase activity in fibroblast culture. He was managed with lysine free milk and carnitine and riboflavin. He developed well without a metabolic crisis. If there is macrocephaly in an infant with neuroradiologic sign of frontotemporal atrophy, GA1 should have a high priority in the differential diagnosis. Because current therapy can prevent brain degeneration in more than 90% of affected infants who are treated prospectively, recognition of this disorder before the brain has been injured is essential for treatment.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.16 no.3
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• pp.123-134
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• 2016

Mitochondrial disease is a group of disorders caused by dysfunctional mitochondria, the organelles that generate energy for the cell. Diagnosis of mitochondrial disease is difficult, subtle, and has many problems. It is more likely to miss the diagnosis of mitochondrial disease, especially in borderline cases where the symptoms of the disease are not severe. In this regard, urine organic acid analysis is noninvasive and can increase the sensitivity and specificity through repeated load test with few changes according to the specimen. And, It is considered to be suitable as a screening test for mitochondrial diseases because it has a great advantage of distinguishing from organic aciduria, urea cycle disorder and fatty acid oxidation disorder which may have similar symptoms. The purpose of this study was to investigate the clinical features and age distribution of mitochondrial diseases diagnosed by organic acid analysis and to establish the policy of diagnosis and treatment based on this study.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.18 no.1
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• pp.13-17
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• 2018

Methylmalonic acidemia is an autosomal recessive disorder caused by complete (mut0) or partial (mut-) deficiency of methylmalonyl-CoA mutase (MUT) or by defects in the synthesis of adenosylcobalamin (cblA, cblB, cblD variant 2). Long term complications of methylmalonic acidemia include tubulointerstitial nephritis with progressive renal failure, intellectual impairment, pancreatitis, and growth failure. We report a case of methylmalonic acidemia in a girl who diagnosed at 6 days after birth. She has developed recurrent metabolic crises with hyperammonemia and metabolic acidosis. In addition, she suffered from the chronic complications including tubulointerstitial nephritis, electrolyte imbalance associated with renal dysfunction, growth failure and fracture of femur shaft. At the age of 10 years, hypercalcemia and severe osteoporosis were noted, and pamidronate therapy was given for two years, which relieved hypercalcemia and osteoporosis.

• Analytical Science and Technology
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• v.19 no.1
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• pp.107-114
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• 2006

Early diagnosis and medical intervention are critical for the treatment of patients with metabolic disorders. A rapid analytical method was developed for simultaneous quantification of organic acids and amino acids in urine without labor-intensive pre-extraction procedure showing high sensitivity and specificity. A new method consisted of simple two-step trimethylsilyl (TMS)-trifluoroacetyl (TFA) derivatization using GC/MS-selective ion monitoring (SIM). Filter paper urine specimens were dried under nitrogen after being fortified with internal standard (tropate) in a mixture of distilled water and methanol. Methyl orange was added to the residue as indicator reagent. Silyl derivative of carboxylic functional group was followed by trifluoroacetyl derivative for amino functional group. N-methyl-N-(trimethylsilyl-trifluoroacetamide) and N-methyl-bistrifluoroacetamide were consecutively added and heated for 15-20 min at $65^{\circ}C-70^{\circ}C$, for TMS-TFA derivative, respectively. This reactant was analyzed by GC/MS-SIM. Linear dynamic range showed 0.001-50 mg with the detection limit of (S/N=3) 10-200 ng, and the quantification limit of 80-900 ng in urine. Correlation coefficient of regression line was 0.994-0.998. When the method was applied to the patients 'urine, it clearly differentiated the normal from the patient with metabolic disorder. The study showed that the developed method could be the method of choices in rapid and sensitive screening for organic aciduria and amino acidopathy.

• Clinical and Experimental Pediatrics
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• v.53 no.4
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• pp.598-602
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• 2010

Transient hyperammonemia in a newborn is an overwhelming disease manifested by hyperammonemic coma. The majority of affected newborns are premature and have mild respiratory syndrome. The diagnosis may be difficult to determine. This metabolic disorder is primarily characterized by severe hyperammonemia in the postnatal period, coma, absence of abnormal organic aciduria and normal activity of the enzymes of the urea cycle. Hyperammonemic coma may develop within 2-3 days of life, although its etiology is unknown. Laboratory studies reveal marked hyperammonemia (>$4,000{\mu}mol/L$). The degree of neurologic impairment and developmental delay in this disorder depends on the duration of hyperammonemic coma. Moreover, the infant may succumb to the disease if treatment is not started immediately and continued vigorously. Hyperammonemic coma as a medical emergency requires dialysis therapy. Here, we report a case of severe transient hyperammonemia in a preterm infant (35 week of gestation) presented with respiratory distress, seizure, and deep coma within 48 hours and required ventilatory assistance and marked elevated plasma ammonia levels. He survived with aggressive therapy including peritoneal dialysis, and was followed 2 years later without sequelae.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.16 no.1
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• pp.18-23
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• 2016

Objective: Newborn screening leads to improved treatment and disease outcomes, but false-positive newborn screening results may impact include parental stress and anxiety, perception of child as unhealthy, parent-child relationship dysfunction, and increased infant hospitalizations. The purpose of this study was to investigate of the false positive rates and the causative factors of false positive results in Tandem Mass Spectrometry (TMS) in single center. Methods: Records were reviewed for all 18,872 subjects who were born in Cheill General Hospital, during January 1st, 2012 to December 31st, 2014. 17,292 neonates (91.62%) were tested for tandem mass screening almost in 2-5th day of life. Newborn babies whose first results were abnormal had been tested repeatedly by same methods in 7-14 day. If the results were abnormal again, further evaluation was performed. TMS analysis included data for the 43 disorders screened for using TMS broken down into three categories: fatty acid oxidation disorders, organic acidurias, and aminoacidopathies. The impact of several factors on increased false positive rates was analyzed using a multivariate analysis: time from birth to sample collection, birth weight, birth height, BMI, gender, gestational age, delivery type. Results: Males of the subjects were 8942 (51.7%), female 8350 (48.3%), the mean gestational age was $38.6{\pm}1.7$ weeks, the average birth weight $3,155.6{\pm}502.4g$, the average birth height $49.1{\pm}2.9cm$, and the average BMI $13.0{\pm}3.8(kg/m^2)$. Vaginal delivery cases were 9713 (56.2%), caesarean section 7,579 (43.8%). The average date of the inspection was $2.8{\pm}1.1$ days. 224 cases were identified as TMS positive. All the subjects were false positive (222/17,292, 1.30%) except 2 cases (1 male; benign phenylketonuria and 1 female; Short chain acyl-CoA dehydrogenase deficiency). The false positive rates were 0.61% in fatty acid oxidation disorders, 0.25% in organic acidurias, and 0.45% in aminoacidopathies. In our study, the date of inspection got late, the false positive rates got higher. Because almost the cases of late test date were in treatment in neonatal intensive care unit so their test date was affected by their medical conditions. False positive rate was higher in extreme immaturity${\leq}27$ weeks than newborns of gestational age >27 weeks [OR=6.957 (CI=1.273-38.008), p<0.025] and extremely low birth weight<1,000 g than newborns of birthweight ${\geq}1,000g$ [OR=5.616 (CI=1.134-27.820), p<0.035]. Conclusion: False positive rate of TMS was 1.30% in Cheil General Hospital. Lower gestational age and birth weight impacted on increased false positive rates. Better understanding of factors that influence the reporting of screening tests, and the ability to modify these important factors, may improve the screening process and reduce the need for retesting. of screening tests, and the ability to modify these important factors, may improve the screening process and reduce the need for retesting.