Global developmental delay (GDD) is a relatively common early-onset chronic neurological condition, which may have prenatal, perinatal, postnatal, or undetermined causes. Family history, physical and neurological examinations, and detailed history of environmental risk factors might suggest a specific disease. However, diagnostic laboratory tests, brain imaging, and other evidence-based evaluations are necessary in most cases to elucidate the causes. Diagnosis of GDD has recently improved because of remarkable advances in genetic technology, but this is an exhaustive and expensive evaluation that may not lead to therapeutic benefits in the majority of GDD patients. Inborn metabolic errors are one of the main targets for the treatment of GDD, although only a small proportion of GDD patients have this type of error. Nevertheless, diagnosis is often challenging because the phenotypes of many genetic or metabolic diseases often overlap, and their clinical spectra are much broader than currently known. Appropriate and cost-effective strategies including up-to-date information for the early identification of the "treatable" causes of GDD are needed for the development of well-timed therapeutic applications with the potential to improve neurodevelopmental outcomes.
Child* ; Developmental Disabilities ; Diagnosis ; Humans ; Metabolic Diseases ; Metabolism ; Neuroimaging ; Neurologic Examination ; Phenotype ; Risk Factors

Cystathionine is well-known intermediate in the metabolism of methionine. It is cleaved to cysteine and homoserine by gamma-cystathionase. This enzyme utilize pyridoxal 5'-phosphate as coenzyme. gamma-cystathionase deficiency leads to persistent excretion of large amount of cystathionine in urine, as well as to accumulation of cystathionine in body tissues and fluids. It is inherited as an autosomal recessive trait and shows wide variety of clinical manifestations. No clinical abnormality seems to be specifically associated with gamma-cystathionase deficiency. The majority of patients responded to high dose administration of pyridoxine. We report the first case of cystathioninuric patient in Korea, 19 months of female with developmental delay. In brain MRI, there was generalized mild brain atrophy. There were several times of brief paroxysmal generalized polyspike and wave discharges in electroencephalography(EEG). In amino acid analysis of urine, there was elevated level of cystathionine. She was treated with high dose of pyridoxine. In follow up analysis of urinary amino acid, the cystathionine level was markedly decreased to normal range, and EEG was normalized. Her development shows improvement.
Atrophy ; Brain ; Cystathionine ; Cystathionine gamma-Lyase ; Cysteine ; Electroencephalography ; Female ; Follow-Up Studies ; Homoserine ; Humans ; Korea ; Magnetic Resonance Imaging ; Metabolism ; Methionine ; Pyridoxal ; Pyridoxine ; Reference Values

PURPOSE: This study aimed to determine the amino acids composition, safety and efficacy of formulas recently developed by Korean dairy companies for children with inherited metabolic disorder. METHODS: The determination of amino acids concentration was performed on eight Korean formula samples. The samples were hydrolyzed with 6N HCL or performic acid and analyzed by amino acid analyzer. RESULTS: No phenylalanine, methionine or leucine was observed in PKU-1 and PKU-2 Formulas, Methionine-Free and Leucine-Free Formula, respectively. BCAA-Free Formula was free from leucine, isoleucine, and valine and MPA Formula did not contain methionine and valine. Protein-Free formula did not include any amino acids. UCD Formula contained arginine but was free of alanine, aspartic acid, glutamic acid, glycine, histidine, proline and serine. Methionine-Free Formula contained higher amounts of cystine and tyrosine was higher in PKU-1 and 2 Formulas. The amounts of isoleucine and threonine were minimal in MPA Formula. CONCLUSION: This study confirmed that the eight special formulas, developed for the first time by a Korean dairy company for children with inherited metabolic disorder contain appropriate amino acids with proper contents. Both the total amino acid amounts and specific amino acid concentrations of the formulas were appropriate for related diseases, which could be used safely by the patients with inherited metabolic disorder. For UCD Formula that contains arginine, we suggest that arginine be removed from the formula in order to use for any urea cycle defect patients before the specific diagnosis is made.
Alanine ; Amino Acids ; Arginine ; Aspartic Acid ; Child* ; Cystine ; Diagnosis ; Glutamic Acid ; Glycine ; Histidine ; Humans ; Isoleucine ; Leucine ; Methionine ; Phenylalanine ; Proline ; Serine ; Threonine ; Tyrosine ; Urea ; Valine

Metallothioneins (MT), small molecular weight metal binding proteins are known to play an important protective role against heavy metal toxicity, either as antioxidants or pre-oxidants. However, the mode of metabolic fate of MTs in various metal complexes is not clearly understood. This study was carried out to better understand the mode of selective turnover rate of various form of MT in complexes with different metals. The degradation of in vitro translated mouse 35S-cysteine-MT was examined in lysosomal or cytosolic fractions from mouse liver by gel electrophoresis and autoradiography. Overnight incubations of MT showed extensive proteolysis in the lysosomal fraction but not in cytosolic fractions. However, Cu2+-MT was found to be stable under the same experimental condition. In contrast, Zn did not interfere with MT degradation. These results suggest that lysosomes are chiefly responsible for MT removal and appears to be selective on the metals involved in the MT complex. In vitro, translated, radiolabeled MT provides a suitable substrate for investigating the characteristics of MT degradation.
Animal ; Copper/*metabolism/pharmacology ; Ions ; Liver/drug effects/*metabolism ; Lysosomes/metabolism ; Metallothionein/drug effects/*metabolism ; Mice ; Sulfur Radioisotopes ; Support, Non-U.S. Gov't ; Zinc/*metabolism/pharmacology

PURPOSE: Wilson's disease is an autosomal recessive disorder characterized by copper accumulation in the liver, brain, and other organs due to defected copper metabolism. The incidence of Wilson's disease is approximately one in 30,000 population in the world, more common than phenylketonuria in Korea. The early diagnosis or presymptomatic diagnosis of Wilson's disease is critical in order for them to live a normal life. However, unfortunately, there are no commercial kits available for Wilson's disease screening in the world yet. METHODS: We developed a mass-screening kit for the purpose of early diagnosis and prevention of Wilson's disease using sandwich ELISA method. This kit can handle a large number of samples at the same time by using filter paper as in newborn screening. Using the polyclonal or monoclonal anti-ceruloplasmin antibodies, this kit determines the plasma ceruloplasmin levels-one of the main markers for Wilson's disease. RESULTS: The plasma levels of the ceruloplasmin were considerably lower in the Wilson's disease (4.5+/-1.6 mg/dL) group compared to normal controls(22.1+/-1.4 mg/dL), sufficient to be used for mass screening. In addition, the results using this screening kit showed 100% positive and negative concordance rates with the test results obtained from immuno-turbidimetry analysis which is the currently used in most test centers for ceruloplasmin measurement in the serum or plasma after centrifugation. CONCLUSION: Taken together, we successfully developed a screening kit which is very effective for the early diagnosis and prevention of Wilson's disease. By using simple filter paper method for sample collection, this kit provides suitable mass screening. We suggest the screening for Wilson's disease at the age of 3-5 years.
Antibodies ; Brain ; Centrifugation ; Ceruloplasmin ; Copper ; Diagnosis ; Early Diagnosis* ; Enzyme-Linked Immunosorbent Assay ; Hepatolenticular Degeneration* ; Humans ; Incidence ; Infant, Newborn ; Korea ; Liver ; Mass Screening* ; Metabolism ; Phenylketonurias ; Plasma

Kinky hair disease is X-linked recessive neurodegenerative disorder produced by defects in a gene(ATP7A) that encodes an intracellular copper-transporting ATPase. About 90-95% of the patients have a severe clinical course leading to death in early childhood. ATP7A mutations associated with Menkes disease show great variety from cytogenetic abnormalities to partial gene deletions to single base-pair changes. We experienced a 15 month-old boy with loss of developmental milestones, hypotonia, seizures and failure to thrive. On laboratory findings, the levels of serum copper and ceruloplasmin were low. Electron microscopy of hair illustrated pathognomic pili torti and other abnormalities such as trichorrhexis nodosa and trichoptilosis(longitudinal splitting of the shaft). Brain magnetic resonance image showed diffuse cerebral and cerebellar atrophy with tortousity of cerebral blood vessels. Genetic defect was evaluated. Our sequencing data on the amplified exon 19 of ATP7ase genomic DNA confirmed point mutation, G1255A, resulting in a glycine-to-arginine conversion. So, we report a brief view with the related literatures.
Adenosine Triphosphatases ; Atrophy ; Blood Vessels ; Brain ; Ceruloplasmin ; Chromosome Aberrations ; Copper ; DNA ; Exons ; Failure to Thrive ; Gene Deletion ; Hair ; Humans ; Infant ; Male ; Menkes Kinky Hair Syndrome* ; Microscopy, Electron ; Muscle Hypotonia ; Neurodegenerative Diseases ; Point Mutation ; Seizures

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.
Diagnosis ; Health Expenditures ; Humans ; Infant ; Infant, Newborn* ; Intellectual Disability ; Mass Screening* ; Metabolic Diseases ; Neonatal Screening ; Neuroblastoma

Hereditary hemochromatosis (HFE), which affects 1 in 400 and has an estimated carrier frequency of 1 in 10 individuals in Western population, results in multiple organ damage caused by iron deposition, and is treatable if detected early. C282Y mutation in HFE gene has been known to be responsible for the most hereditary hemochromatosis cases and 5-10% of white subjects are heterozygous for this mutation. However, the prevalence of hemochromatosis in the Asian population was reported to be very low and ethnic heterogeneity has been suspected. The aim of our study was to determine the prevalence of heterozygosity and homozygosity for the C282Y HFE gene mutations in 502 unrelated Koreans. Results revealed that none of them had the mutant gene, suggesting a significant ethnic difference when compared with Caucasians. Our study excluded underlying possibility of hereditary hemochromatosis in Korean which could mimic the findings of alcoholic liver disease with iron overload or liver cirrhosis with chronic hepatitis C.
Alleles ; Caucasoid Race/genetics* ; DNA Primers ; Genetic Screening ; Genotype ; HLA Antigens/genetics ; Hemochromatosis/genetics* ; Hemochromatosis/ethnology* ; Histocompatibility Antigens Class I/genetics ; Human ; Korea/epidemiology ; Mongoloid Race/genetics* ; Point Mutation* ; Prevalence

BACKGROUND: Spinal muscular atrophy (SMA) is the second most common disease with autosomal recessive mode of inheritance in children and characterized by degeneration of anterior horn cells of the spinal cord resulting in weakness and wasting of voluntary muscles. This disease is caused by deletion of many candidate genes including SMN, p44, NAIP on chromosome 5q11.2-13.3. Although molecular characteristics of candidate genes were identified, genotype-phenotype correlation has not been clearly elucidated yet. Nevertheless, gene conversion, previously described as simply as gene deletion, appears to be very important mechanism as a molecular pathogenesis, and even makes more difficult to pursue the correlation. PURPOSE: This study was aimed to define the correlation between genotype and phenotype of SMA in Korean patients. The significance of SMN gene as well as NAIP gene, p44 gene in the progress of disease process and phenotypic correlation with gene conversion was evaluated. This study was also undertaken to determine the frequency of gene rearrangements in normal population. METHOD: Eight type I SMA patients and two type II SMA patients were studied. SMN, NAIP, and p44 gene deletion were analyzed by PCR amplification and restriction enzyme digestion with DraI, DdeI and AluI, respectively. p44 gene was also analyzed by SSCP. Gene conversion was defined by centromeric and telomeric SMN gene exon 7 to exon 8 PCR amplification followed by DdeI restiction enzyme digestion. RESULT: 1) Five of eight type I patients showed deletion of SMN, NAIP and p44 gene, while the rest of type 1 and all type II patients showed deletion of SMN gene only. 2) We examined SMN and NAIP gene deletion on 100 normal newborns, which showed the deletion of centromeric SMN gene in two newborns, the relative frequency of 2% in gene rearrangement. 3) There was one case of type I SMA showing deletion of telomeric SMN exon 7 but not SMN exon 8 suggestive of gene conversion occurred during the recombination as a molecular pathogenesis. CONCLUSION: The major deletion of SMA candidate genes, SMN, NAIP, and p44 gene appear to be involved in severe phenotype since these three candidate genes deletion were noted only in type 1 cases. However, SMN gene deletion only identified both in type 1 and type 2 explains that SMN gene may plan an major role in the pathogenesis of SMA and also suggests that other factors may be affecting the severity in spinal muscular atrophy. One patient with type I which showed the conversion of the centromeric SMN gene to the teleomeric gene strongly supports that SMN gene copy number may not be correlated with the severity in SMA. Our molecular findings suggest that phenotype is not clearly correlated with genotype. Prenatal screening should be carefully undertaken to interpretate because of high frequency of gene rearrangements in normal populations.
Anterior Horn Cells ; Child ; Digestion ; Exons ; Gene Conversion ; Gene Deletion ; Gene Dosage ; Gene Rearrangement ; Genetic Association Studies ; Genotype* ; Humans ; Infant, Newborn ; Muscle, Skeletal ; Muscular Atrophy, Spinal* ; Phenotype* ; Polymerase Chain Reaction ; Polymorphism, Single-Stranded Conformational ; Prenatal Diagnosis ; Recombination, Genetic ; Spinal Cord ; Wills

Meckel-Gruber syndrome is a multiple malformation syndrome featuring occipital meningoencephalocele, multicystic dysplasia of kidney, cystic and fibrotic change of liver, polydactyly, and other characteristics inherited by the autosomal recessive trait. We exprienced a case of Meckel-Gruber syndrome in a newborn male diagnosed clinically and confirmed pathologically. Abnormalities of the fetus were found prenataly by ultrasonogram, and subsequently the baby was terminated by cesarean section delivery at 32 weeks of gestational age. We report this case with brief review of literature.
Cesarean Section ; Female ; Fetus ; Gestational Age ; Humans ; Infant, Newborn ; Kidney Diseases, Cystic ; Liver ; Male ; Polydactyly ; Pregnancy ; Ultrasonography