• Journal of The Korean Society of Inherited Metabolic disease
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• v.16 no.2
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• pp.86-92
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• 2016

Purpose: The $BH_4$ loading test is an important test that distinguishes PKU from $BH_4$ deficiency and identifies the $BH_4$ reactivity of PKU patients. Phenylalanine and $BH_4$ loading tests are useful methods that can shorten the length of hospital stay while improving patients' convenience. However, sufficient research on the dose of phenylalanine loading and $BH_4$ administration time after the loading has not been carried out. The present study investigates the effectiveness of the existing phenylalanine loading method by analyzing the medical records of six patients who underwent the $BH_4$ loading test after taking 100 mg/kg of phenylalanine patients. Methods: The medical records of six patients who underwent the $BH_4$ load test after taking 100 mg/kg of phenylalanine were examined out of 207 patients who were followed up in the Genetic Metabolic Clinic in Soonchunhyang University Hospital. All of the six patients had a low phenylalanine diet. First, they were taking 100 mg/kg of phenylalanine. 3 hours later, 20 mg/kg of $BH_4$ were loaded. The phenylalanine levels in the blood were continuously measured at 1, 2, 4, 6, 8, 12, and 24 hours by setting the time the $BH_4$ was loaded as the basal. Results: The average of the highest phenylalanine concentrations of six patients was $20.0{\pm}11.70mg/dL$. One reached the highest concentration seven hours after taking phenylalanine; another reached it five hours after that, and the remaining three reached it four hours after that. Only one patient reached the highest concentration within three hours. The phenylalanine levels of four out of six patients (66%) rose above $400{\mu}mol/L$ after being loaded with phenylalanine. The phenylalanine levels of the remaining two were 6.1 mg/dL ($366{\mu}mol/L$) and 5 mg/dL ($300{\mu}mol/L$), respectively. Conclusion: One of six patients (16%) reached the highest concentration three hours after taking 100 mg/kg of phenylalanine and four patients (66%) reached $400{\mu}mol/L$ or higher phenylalanine levels. There were patients whose phenylalanine levels did not rise above $400{\mu}mol/L$ using a commonly known test method; moreover, this method had the disadvantage of reaching the highest concentration after more than three hours. Therefore, it is considered that taking 200 mg/kg or more of phenylalanine and performing $BH_4$ loading four to six hours after taking phenylalanine are helpful in proper diagnosis.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.17 no.1
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• pp.11-17
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• 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
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• v.16 no.2
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• pp.79-85
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• 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.

• Journal of The Korean Society of Inherited Metabolic disease
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• v.3 no.1
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• pp.22-27
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• 2003

고페닐알라닌혈증의 경우 모든 환자들이 저페닐알라닌 식이를 엄격히 지키는 것은 아니기 때문에 기대만큼의 치료효과를 거두지 못하는 경우가 종종 있다. 모든 페닐알라닌 수산화 효소 결핍에 의한 페닐케톤뇨증 환자에서 테트라하이드로바이오프테린의 복용이 효과를 거두는 것은 아니나 식이조절과 비교해 볼 때 이는 식이 제한에 대한 어려움이 없고 복용이 간편하므로 치료효과가 있다면 일부 환자에서라 하더라도 페닐케톤뇨증 환자의 치료에 새로운 방향을 제시하는데 충분한 의미가 있다고 본다. 이러한 시점에서 저자들은 고전적 페닐케톤뇨증으로 진단되었던 6명의 환아에서 식이제한없이, 또는 식이제한을 완화한 상태에서 테트라하이드로바이오프테린을 복용함으로써 치료 효과를 거둔 6례에 대해서 문헌 고찰과 함께 보고하는 바이다.

• Proceedings of the Korean Nuclear Society Conference
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• 1998.10a
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• pp.353-353
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• 1998

• Proceedings of the Korean Nuclear Society Conference
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• 1999.05a
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• pp.402-402
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• 1999

• Korean Journal of Microbiology
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• v.52 no.3
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• pp.278-285
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• 2016

The bifunctional PheA protein, having chorismate mutase and prephenate dehydratase (CMPD) activities, is one of the key regulatory enzymes in the aromatic amino acid biosynthesis in Escherichia coli, and is negatively regulated by an end-product, phenyalanine. Therefore, PheA protein has been thought as useful for protein engineering to utilize mass production of essential amino acid phenylalanine. To obtain feedback resistant PheA protein against phenylalanine, we mutated by using random mutagenesis, extensively screened, and obtained $pheA^{FBR}$ gene encoding a feedback resistant PheA protein. The mutant PheA protein contains substitution of Leu to Phe at the position of 118, displaying that higher affinity (about $290{\mu}M$) for prephenate in comparison with that (about $850{\mu}M$) of wild type PheA protein. Kinetic analysis showed that the saturation curve of $PheA^{FBR}$ against phenyalanine is hyperbolic rather than that of $PheA^{WT}$, which is sigmoidal, indicating that the L118F mutant enzyme has no cooperative effects in prephenate binding in the presence of phenylalanine. In vitro enzymatic assay showed that the mutant protein exhibited increased activity by above 3.5 folds compared to the wild type enzyme. Moreover, L118F mutant protein appeared insensitive to feedback inhibition with keeping 40% of enzymatic activity even in the presence of 10 mM phenylalanine at which the activity of wild type $PheA^{WT}$ was not observed. The substitution of Leu to Phe in CMPD may induce significant conformational change for this enzyme to acquire feedback resistance to end-product of the pathway by modulating kinetic properties.

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

• Clinical and Experimental Pediatrics
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• v.51 no.5
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• pp.546-550
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• 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
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• v.2 no.1
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• pp.89-94
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• 2002

Purpose : This study was performed to determine the safety and efficacy of recently developed specific formulas for phenylketonuria(PKU) patient by observing the growth and developmental pattern and serum phenylalanine level. Methods : We observed 14 patients diagnosed with PKU at Soon Chung Hyang University Hospital fed with formula for 1 year by checking daily diet diary and plasma aminoacids, Hb, Hct, WBC, Platelet count, ferritin, GOT, GPT, protein, albumin, globulin and urinalysis. Results : The 14 patients all liked the formula and height, weight and head circumference showed normal growth. Hemoglobin levels were in normal range, but 4 out of the 14 patients showed ferritin level lower than 12 ng/mL and needed iron supplements. Serum albumin, liver enzyme levels, urinalysis showed within normal range. The plasma phenyalanine levels were normal ranged 0.7-15.6 mg/dL. Adverse reactions such as rash, diarrhea or constipation were not observed. Conclusion : We confirmed that the specific formulas for PKU patients developed in Korea, PKU-1 and PKU-2 showed favorable results In development and treatment of PKU patients and could be used safely to children.