• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.15 no.2
• /
• pp.55-58
• /
• 2015

Tetrahydrobiopterin ($BH_4$) can normalize blood phenylalanine (Phe) levels in $BH_4$ deficiency, but typically not in phenylketonuria (PKU). In 1999, Kure et al. reported that some PKU patients showed decreased blood Phe levels after $BH_4$ loading, and thereafter, those PKU patients were identified by neonatal PKU screening. A natural cofactor for phenylalanine hydroxylase (PAH) is a 6R-isomer of $BH_4$, which is first synthesized in Japan as Sapropterin dihydrochloride (Biopten$^{(R)}$) in 1982. In Japan, Biopten$^{(R)}$ is first approved for the treatment of $BH_4$ deficiency in 1992, and then for $BH_4$-responsive PAH deficiency (BPKU) in 2008. The discovery of BPKU has vast clinical implications. After Biopten$^{(R)}$ (Kuvan$^{(R)}$) is available for the treatment of BPKU, the QOL of both patients and their families were improved very much, since the serum phenylalanine levels were controlled within 4 mg/dL by $BH_4$ mono-therapy with a normal diet or $BH_4$ combined use of mild phenylalanine-restricted diet. Biopten$^{(R)}$ therapy in patients with BPKU is highly efficacious (70%) at maintaining serum Phe levels within recommended control range and provides excellent safety at least average use period of 10 years (range, 1-17 years) with no unwarranted side effects in Japan. In addition it has been confirmed that sapropterin therapy initiated before 4 years of age was very effective to maintain plasma Phe levels within the favorable range and was safe in Japanese patients with BPKU.

• Clinical and Experimental Pediatrics
• /
• v.51 no.5
• /
• pp.546-550
• /
• 2008

In this untreated classic phenylketonuria (PKU) case, mental retardation is severe; however, there have been individuals- like the mother of this case- who have escaped mental retardation and all the other potential sequelae of phenylketonuria, despite having high blood phenylalanine levels, and very poor dietary control. It appears that they have nearly normal brain phenylalanine levels despite high blood phenylalanine (Phe) levels. A number of studies have now demonstrated considerable variability in blood vs. brain phenylalanine levels in phenylketonuria patients. Outcome of phenylketonuria appears to be related to brain phenylalanine levels. We report a case of "undiagnosed" maternal phenylketonuria syndrome. A female infant had low birth weight (2,400 g) with microcephaly. We examined her family and discovered that her mother was an undiagnosed phenylketonuria patient with a borderline intelligence quotient (IQ). The infant's sister, six years old, was diagnosed with phenylketonuria at the age of four years was mentally retarded and had received an operation for cleft lip and palate. the sister had also had a low birth weight (2,300 g). Her sister and mother were compound heterozygotes (mother: R243Q/Y325X; sister: Y325X/P407S). The infant and father were heterozygous carriers (baby: R243Q/ -; father: P407S/ - ).

• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.14 no.1
• /
• pp.1-9
• /
• 2014

Many inborn errors of metabolism can be completely cured with early detection and early treatment. This is why neonatal screening on inborn errors of metabolism is implemented worldwide. In 1991, the Ministry of Health & Social affairs adopted a nationwide service program for neonatal screening of phenylketonuria, galactosemia, maple syrup urine disease, homocystinuria, histidinemia and congenital hypothyroidism for newborns delivered from low class pregnant women registered in health centers. Government decreased the test items from six to two, PKU and congenital hypothyroidism to increase test numbers with same budget from 1995. 78 laboratories wanted to participate for neonatal screening test in 1999. Government decided to screen six items of PKU, congenital hypothyroidism, maple syrup urine disease, homocystinuria, galactosemia and congenital adrenal hyperplasia from 2006. In 2014, thirteen laboratories are participating. Inter laboratory quality control was started 6 times a year from 1994. In case a patient with an inherited metabolic disease is diagnosed by screening of government program, special milk is provided at government's expense. According to the government project, from 1997 to 2013, 7,080,569 newborns were screened. 144 PKU, 2.451 congenital hypothyroidism were detected. So incidence of PKU is 1/49,170 and congenital hypothyroidism is 1/2,888. The cost benefit of performing screening procedures coupled with treatment has been estimated to be as high as 1.77 times in PKU, 11.11 times in congenital hypothyroidism than cost without screening. By January 2007, many European countries had expanded of their newborn screening programs by inclusion of Tandem mass spectrometry. We are trying to increase the budget to test all newborns for Tandem mass spectrometry from 2016. We are considering four to five central laboratories which cover all newborns and are equipped with tandem mass spectrometer & enzyme immunoassay for TSH, 17OHP & enzyme colorimetric assay for galactose. And I hope to expand test including Wilson disease screening test and lysosomal storage diseases.

• Journal of Genetic Medicine
• /
• v.5 no.1
• /
• pp.26-33
• /
• 2008

Purpose : Phenylketonuria(PKU) is an inborn error of metabolism and a genetic disorder resulting from a deficiency of phenylalanine hydroxylase(PAH) and decreased activity of tetrahydrobiopterin(BH4).In this study the correlation between the DNA mutation and clinical manifestations was investigated and PAH DNA mutations were compared bewteen Asian and Caucasian populations. Methods : DNA was isolated from peripheral leukocytes. The PAH gene was amplified by Polymerase Chain Reaction(PCR) and the sequence was analyzed with Multiplex Ligation-dependent Probe Amplification(MLPA). Results : We characterized the PAH gene of 102 independent Korean patients with PKU. PAH nucleotide sequence analysis revealed 44 different mutations, including 10 novel mutations comprising 9 missense mutations(N207D, K95del, A447P, G344D, P69S, S391I, A202T, G103S, and I306L) and 1 novel splice-site variant mutation(IVS10-3C>G). R243Q was the most prevalent mutation in this study. A259T has not previously been reported in Asian populations, but we found that this mutation had a frequency of 10.1% in our study. Furthermore, the genotypes of $BH_4$ responsive patients were analyzed and were divided into two groups: $BH_4$ medication-only group and $BH_4$ medication with diet therapy group. In the $BH_4$ medication-only group and $BH_4$ medication with diet therapy group, R241C was the most common mutation. Conclusion : Novel mutations in the PAH gene of PKU patients are still being discovered. Additional information as to the frequency of mutations in the tetrahydrobiopterine responsive gene is also accumulating. We anticipate that knowledge of these PKU gene mutations will assist the diagnosis, genetic counseling, and therapeutic treatment of PKU patients in future.

• Journal of Preventive Medicine and Public Health
• /
• v.32 no.3
• /
• pp.317-324
• /
• 1999

Objectives: Since 1991, nationwide massive neonatal screening program for phenylketonuria (PKU) and congenital hypothyroidism have been performed in Korea. As in many other countries, efficiency of this program has not been definitely concluded. For the purpose of evaluation of this program, from the perspective of efficiency, a cost-benefit analysis was carried out. Methods: Costs of the detection and the treatment program were compared with the projected benefit(avoided costs) that results from the prevention of the mental retardation associated with the disorders due to PKU and hypothyroidism. Costs and benefits were discounted at an annual rate of 5%, and duration of life-long labor was assumed to be 30 years. Cost and benefit were estimated based on the detection rates of one case of PKU per 5,572 and one case of congenital hypothyroidism per 32,554 babies screened during 1991-1997. Results: The benefit-cost ratio was 0.418. The sensitivity analysis for the discount rates and labor durations showed that most cost-benefit ratios were lower than one(1.0) except when discount rate was changed to 3% and detection rate to two- or threefold and/or labor duration to 40 years. Conclusion: The result of this study suggested that present program of mass screening for PKU and congenital hypothyroidism could not be justified in terms of efficiency. It doesn't coincide with the results of previous studies in major developed countries, presumably because of difference in detection rates and welfare cost for the disabled.

• The Journal of Pediatrics of Korean Medicine
• /
• v.13 no.2
• /
• pp.41-77
• /
• 1999

The purpose of this research is that infant artificial feeding products is used in clonic with the study on characteristic, ingredients and indication of geneal and special modified milks. The result is as follows. 1. The main ingredients of four company products-Maeil , Namyang, Pasteur, Aebout is similar but the functional is different 2. General infant formula is divided into 100days, 5-6months, 12months, 24months and 36months out of consideration for growth and development of infant. 3. The indication and sorts of the special infant formula used at a hospital is as follows. PKU-1, PKU-2 formula is available for phenylketonuria. MPA formula is available for propionic acidemia and methylmalonic acidomia. UCD is available for urea cycle disorder Leucine-free formula is available for isovaleric acidemia. Maeil LP is available for hypocalcemia. MCT formula is available for indigestion and malabsorption of fat. BCAA-free formula is available for Maple syrup urine disease. Protein-free formula is available for limit of protein uptake or mixture of peculiar amino acid or higher uptake of mineral, vitamin, calory. Methionine-free formula is available for homocystinuria and hypermethioninemia. Premature infant is available for premature and low birth weight. 4. The special infant formula published in nation is as follows. Maeil soy A, Maeil MF1, Namyang hope doctor and Maeil HA is available for diarrhea. Maeil HA, Maeil HA-21 and Namyang hope allergy is available for hypoallergy. Maeil soy A is available for diarrhea of milk allergy. Maeil MF1 or Namyang hope doctor is available for acute bacterial or viral temporal diarrhea. Maeil HA is available for allergic chronic diarrhea. Maeil HA and Namyang hope allergy as eHP-formula is available for chronic diarrhea for lactose intolerance and milk allergy. Maeil-21 as pHP-formula for neonates with allergy family, allergic symptoms such as atopic dermatitis, asthma except digestive system.

• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.17 no.1
• /
• pp.11-17
• /
• 2017

Purpose: Phenylketonuria (PKU) results from a deficiency of phenylalanine hydroxylase (PAH). The mutation of the PAH gene results in decreased phenylalanine hydroxylase enzyme activity in hyperphenylalaninemia (HPA) patients. This study reports ten cases of patients with the benign HPA genotype c.158G>A (p.Arg53His, R53H) variant in the PAH gene and aims to evaluate the clinical significance of the R53H variant. Methods: Ten Korean patients with the HPA genotype the R53H variant were included in this study. A retrospective medical record review was conducted. We characterized the phenotypes of the patients with HPA with the R53H variant using the following system: classic PKU, moderate PKU, mild PKU, Mild HPA, and benign HPA. Results: Five patients had the R53H variant with the "Pathogenic" variants (R413P, R241C, $Y356^*$, c.442-1G>A, $Y325^*$), Two patients had the "Likely pathogenic" variants ($W187^*$, A259T), Two patients had the "Uncertain significance" variants (R53H, G344D), and One patient had the "Not provided" variant (c.1066-14C>G). Nine patients genotyped with the R53H variant were the patient with benign HPA and One patient genotyped with the R53H homozygote was within normal range of plasma phenylalanine. None of the ten patients required dietary restriction of phenylalanine or pharmacotherapy to maintain their plasma phenylalanine levels and showed no clinical symptoms of HPA. Conclusion: Ten patients with HPA genotype the R53H variant were the patient with benign HPA and showed no clinical symptoms of HPA. Thus, the R53H variant, which was previously classified as an "Uncertain significance" mutation in HPA patients, should be re-classified as "Benign."

• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.20 no.2
• /
• pp.37-43
• /
• 2020

Phenylketonuria is the most prevalent disorder caused by an inborn error in aminoacid metabolism. It results from mutations in the phenylalanine hydroxylase (PAH) gene. If untreated or late treated, results in profound and irreversible mental disability. Newborn screening test identify patients with phenylketouria. The early initiation of a phenylalanine restricted diet very soon prevents most of the neuropsychiatric complications. However, the diet therapy is difficult to maintain and compliance is poor, especially in adolescents and adulthood. Since 2015, American Medical College of Medical Genetics and Genomics (ACMG) recommended more strong restrictive diet therapy for target blood level of phenylalanine (<360 umol/L). For over four decades the only treatment was a very restrictive low phenylalanine diet. This changed in 2007 with the approval of cofactor therapy (Tetrahydrobiopterin, BH4) which is effective in up to 30% of patients. Data from controlled clinical trials with sapropterin dihydrochloride indicate a similar occurrence of all-cause adverse events with this treatment and placebo. Large neutral aminoacids (LNAA) competes with phenylalanine for transport across the blood-brain-barrier and have a beneficial effect on executive functioning. A new therapy has just been approved that can be effective in most patients with PAH deficiency regardless of their degree of enzyme deficiency or the severity of their phenotype. Phenylalanine ammonia lyase (PAL-PEG) was approved in the USA by FDA in May of 2018 for adult patients with uncontrolled blood phenylalanine concentrations on current treatment. Nucleic acid therapy (therapeutic mRNA or gene therapy) is likely to provide longer term solutions with few side effects.

• Journal of Life Science
• /
• v.19 no.9
• /
• pp.1226-1231
• /
• 2009

Enzyme substitution with recombinant phenylalanine ammonia-lyase (PAL, EC 4.3.1.5) is currently being explored for treatment of phenylketonuria (PKU), an autosomal recessive genetic disorder with mutations of the gene encoding phenylalanine-4-hydroxylase (EC 1.14.16.1). However, oral administration of PAL is limited because of proteolytic digestion in the gastrointestinal tract. The aim of this study was to determine the biochemical properties of PAL and delinate the susceptibility of wild-type PAL to pancreatic proteolysis by exploring several mutants, and to develop therapeutic drugs with PAL for PKU. The specific activity of PAL was assayed and its optimal pH, temperature stability, and intestinal protease susceptibility were investigated. Its $V_{max}$ values for phenylalanine and tyrosine were 1.77 and $0.47{\mu}mol$/ min/mg protein, respectively, and its $K_m$ values were $4.77{\times}10^{-4}$ and $4.37{\times}10^{-4}\;M$, respectively. PAL showed an optimal pH at 8.5, corresponding to the average pH range of the small intestine. It showed no loss of activity at $-80^{\circ}C$ for 5 months and possessed 93.4% of its activity under $4^{\circ}C$ for 4 wks. PAL was susceptible to chymotrypsin digestion and, to a lesser extent, to trypsin, elastase, carboxypeptidase A, and B. The trypsin and chymotrypsin cleaving sites were mutated to investigate protection from pancreatic digestion and the specific activities of these mutants were evaluated. The six mutants displayed low specific activities compared to the wild-type, suggesting that the primary trypsin and chymotrypsin cleaving sites may be essential for catalytic reaction. The PAL mutants could therefore be applied as a pretreatment modality without susceptibility to proteolytic attack, however, additional modification for enhancing enzymatic activity is needed to reduce the Phe levels effectively.

• Journal of The Korean Society of Inherited Metabolic disease
• /
• v.16 no.2
• /
• pp.79-85
• /
• 2016

Purpose: This study aimed to analyze genetic mutations, clinical manifestations, and treatment of patients with benign HPA in Korea. Methods: This case series study involved ten HPA patients who were referred to our hospital because of high phenylalanine concentration. We investigated their demographic features, clinical manifestations, and mutations of the PAH gene through direct DNA sequencing. Results: Among ten patients with benign HPA, two pairs of patients were related (father-daughter, mother-daughter relationship) cases, and all of them showed no specific clinical manifestations or notable past history. Their plasma phenylalanine levels ranged between 1.2 and 4.2 mg/dL. In the tetrahydrobiopterin (BH4) loading test, all patients were nonresponsive to BH4. In the confirmation test of PAH mutation analysis, we identified eleven different alleles out of twelve. The most common allele was R53H (c.158G> A). In addition, two novel PAH gene mutations, V423A (c.1268T>C) and V51A (c.152T>C), were identified. Although the patients did not receive any pharmacologic treatment or continuous phenylalanine restriction dietary therapy, their neurocognitive development was normal. Moreover, on serial outpatient follow-up tests, all patients maintained phenylalanine levels below 6 mg/dL. Conclusion: This study is the first in Korea to analyze benign HPA patients. All patients with benign HPA could maintain phenylalanine levels below 6 mg/dL with normal neurocognitive development, without continuous therapy. Therefore, performing mutation analysis and distinguishing benign HPA from phenylketonuria (PKU) are important to help improve life quality in patients with benign HPA by avoiding unnecessary lifelong therapy.