RARE DISEASE
Hyperphenylalaninemia due to tetrahydrobiopterin deficiency
Hyperphenylalaninemia due to tetrahydrobiopterin deficiency
Hyperphenylalaninemia due to tetrahydrobiopterin deficiency
Synonyms: Hyperphenylalaninemia due to BH4 deficiency
Synonyms: Hyperphenylalaninemia due to BH4 deficiency
Synonyms: Hyperphenylalaninemia due to BH4 deficiency
Drug discovery
7
drugs
With orphan designations
Overview
Hyperphenylalaninemia due to tetrahydrobiopterin (BH4) deficiency is a rare autosomal recessive disorder caused by defects in BH4 biosynthesis or recycling, impairing phenylalanine metabolism and neurotransmitter synthesis. BH4 serves as a cofactor for phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase, leading to elevated phenylalanine levels and dopamine/serotonin deficiency. Clinical features include progressive neurological deterioration, dystonia, seizures, and developmental delays. Diagnosis combines newborn screening for hyperphenylalaninemia with urinary pterin analysis and genetic testing [1][3][7].
Therapies
BH4 supplementation (2–20 mg/kg/day) or phenylalanine-restricted diet to normalize phenylalanine levels [3][7].
Neurotransmitter replacement (L-dopa/carbidopa and 5-hydroxytryptophan) to address dopamine/serotonin deficiency [3][7].
Folinic acid for dihydropteridine reductase (DHPR) deficiency to prevent cerebral folate depletion [7][9].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
502 drug discovery papers about Hyperphenylalaninemia due to tetrahydrobiopterin deficiency, with 6 first-in-class and 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
502 drug discovery papers about Hyperphenylalaninemia due to tetrahydrobiopterin deficiency, with 6 first-in-class and 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-24 | DNAJC12 Stabilizes Phenylalanine Hydroxylase and Facilitates Its Substrate-Dependent Activation.
Phenylalanine hydroxylase (PAH) is a tetrahydrobiopterin (BH4)-dependent enzyme that converts L-phenylalanine (L-Phe) to L-tyrosine. PAH dysfunction leads to the accumulation of L-Phe in the blood (hyperphenylalaninemia; HPA), which may reach neurotoxic levels, resulting in phenylketonuria (PKU). PKU is associated with pathogenic variants in PAH, mostly causing misfolding and instability, leading to decreased levels of PAH protein and activity. Recently, variants in the J-domain protein DNAJC12 have also been associated with HPA in patients, demonstrating the importance of protein homeostasis regulation for proper PAH function. DNAJC12 and PAH have previously been reported to interact, but the molecular and structural mechanisms behind complex formation have remained unclear. In this work, we show that DNAJC12 binds to PAH but presents higher affinity for its L-Phe activated form, which resembles the conformation of unliganded tyrosine hydroxylase, a structurally and functionally related enzyme that also binds to DNAJC12. At saturation, four DNAJC12 monomers bind and stabilize the PAH tetramer, protecting it from aggregation and lowering the L-Phe concentration necessary for substrate-induced activation, without affecting the interaction of the enzyme with its cofactor BH4. Importantly, DNAJC12 also stabilizes and delays the aggregation of the PKU-associated variant PAH-p.R261Q. This study provides the first detailed characterization of the molecular determinants driving PAH:DNAJC12 complex formation and reveals how this interaction modulates enzyme stability and activity, and stimulates Hsc70 ATPase activity. These findings provide mechanistic insight into the pathogenic basis of DNAJC12 deficiency and identify the PAH:DNAJC12 complex as a promising therapeutic target for HPA.
2026-07-15 | Blood Phenylalanine Control in Paediatric and Adult Centres in the UK: Data from 2012-2018.
Background: Metabolic control in phenylketonuria (PKU) is known to deteriorate with age, but national-level data describing blood phenylalanine (Phe) control across the United Kingdom (UK) are limited. Objective: To characterise blood Phe control in individuals with PKU attending UK metabolic centres. Methods: Sixteen UK centres (nine paediatric, six adult, one mixed) retrospectively extracted blood Phe results collected between 2012 and 2018. Demographic, phenotypic and monitoring-related variables were analysed. Written consent for data collection was obtained from all patients or their caregivers. Results: Data were available for 871 individuals (55% female), of whom 744 (85%) were classified as follows: classical PKU, 75%, mild PKU, 22% and hyperphenylalaninaemia, 3%. Mean blood Phe concentrations were significantly higher in adults than children (491 ± 308 vs. 303 ± 199 µmol/L; p < 0.001), and the proportion of samples within target range declined steadily with age, from 78% in children < 2 years to 36% in adults ≥ 41 years. Individuals with classical PKU had higher mean Phe concentrations and lower target attainment than those with HPA (386 vs. 300 µmol/L; 61% vs. 78%; p < 0.001), while mild PKU and HPA showed comparable control. Females generally demonstrated better metabolic control than males. More frequent dried blood spot sampling for blood Phe was strongly associated with improved metabolic control: weekly (254 ± 175 µmol/L; 82% within target), fortnightly (319 ± 207 µmol/L; 70%), monthly (397 ± 231 µmol/L; 61%), and less than monthly (624 ± 349 µmol/L; 44%). Nearly half of the blood Phe samples (47%) with recorded timing were taken in a non-fasting state. Conclusions: Achieving lifelong metabolic stability on a Phe-restricted diet alone remains challenging. These national data highlight the need for broader therapeutic options to support individuals with PKU across the lifespan.
2026-06-26 | Molecular Genetic and Biochemical Characterization of Hyperphenylalaninemia Based on Expanded Neonatal Screening Data from 2023 to 2024 in the Russian Federation.
Since January 2023, the Russian Federation has implemented expanded neonatal screening for 36 hereditary disorders, which has changed the diagnostic algorithm for hyperphenylalaninemia/phenylketonuria (HPA/PKU) by introducing tandem mass spectrometry (MS/MS) on the second day of life, followed by confirmatory biochemical and molecular testing in newborns at risk. We analyzed 1247 newborns aged 5-15 days with elevated phenylalanine levels (≥120 µmol/L) and a phenylalanine to tyrosine ratio of at least 1 detected during the first stage of screening using MS/MS. At the reference center, newborns underwent repeat biochemical testing and stepwise molecular analysis of HPA-associated genes. Two pathogenic variants in HPA-associated genes were identified in 538 newborns, including 534 newborns with biallelic pathogenic variants in PAH and 4 with BH4-deficient forms (PTS, QDPR). The incidence of molecularly confirmed HPA was 1:4518 newborns (95% CI: 1:4152-1:4925). The PAH variant spectrum was dominated by p.Arg408Trp (c.1222C>T) (33.4%). Genotype-based analysis indicated that 73 newborns (13.7%) were likely responsive to cofactor therapy, whereas 222 (41.6%) were potentially responsive. These findings define the molecular epidemiology of HPA in Russia and support early genetic stratification for diagnosis and treatment.
2026-05-13 | Sepiapterin: From sapropterin to next-generation therapy.
Sepiapterin is a naturally occurring pteridine and BH4 precursor that links classic pterin chemistry to tetrahydrobiopterin biology. Tetrahydrobiopterin (BH4; sapropterin) is an essential redox-active cofactor for phenylalanine hydroxylase (PAH), the aromatic amino acid hydroxylases, and nitric oxide synthases, whereas 7,8-dihydrobiopterin (BH2) reflects pterin redox balance and can antagonize BH4-dependent nitric oxide signaling. This review integrates historical and chemical perspectives with current biochemical and clinical understanding of BH4 homeostasis, including de novo synthesis, recycling/oxidation, and the sepiapterin salvage pathway. Sepiapterin is taken up by cells through equilibrative nucleoside transport mechanisms and is intracellularly converted through sepiapterin reductase and dihydrofolate reductase to expand BH4 pools. In healthy volunteers, oral sepiapterin produced marked systemic BH4 exposure with minimal parent-drug exposure (geometric mean Cmax 640 ng/mL for BH4 versus 1.74 ng/mL for sepiapterin after 60 mg/kg) and increased cerebrospinal fluid BH4 after 7 days of 60 mg/kg/day dosing. In phenylketonuria (PKU), the Phase 3 APHENITY trial showed a placebo-adjusted least-squares mean blood phenylalanine reduction of 395.9 μmol/L at Week 6 among sepiapterin-responsive participants, and the Phase 3 AMPLIPHY trial showed greater lowering with sepiapterin 60 mg/kg/day than with sapropterin 20 mg/kg/day (least-squares mean difference 180.4 μmol/L; 95% CI 131.4-229.5; p < 0.0001). Together, these data position sepiapterin as a next-step therapy beyond sapropterin, while underscoring the importance of biomarker studies that quantify BH4, BH2, and the BH4/BH2 ratio in plasma and cerebrospinal fluid.
2026-04-17 | Ethnic Bridging of Sepiapterin in Chinese and Korean Populations Based on Predictions From Genetic Polymorphism of Breast Cancer Resistance Protein.
Ethnic differences are crucial when considering the efficacy, safety, and dose of pharmaceuticals across diverse populations. The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline E5 addresses the acceptability of extrapolating foreign clinical data taking ethnic factors into consideration. Sepiapterin has recently been approved for the treatment of hyperphenylalaninemia (HPA) in patients with phenylketonuria (PKU) in Europe, the USA, and multiple additional countries worldwide. To date, no clinical trials have been conducted in the Chinese or Korean populations. An ethnic sensitivity analysis identified that the breast cancer resistance protein (BCRP) c.421C>A variant was the primary factor leading to ethnic differences in BH4 exposures. A correlation was established and validated between the frequency of BCRP c.421C>A variant in ethnic groups and the relative Cmax and AUC0-24h of sepiapterin major active metabolite 5,6,7,8-tetrahydrobiopterin (BH4). Based on this correlation, it was predicted that compared to White, the mean BH4 Cmax and AUC0-24h were 1.16-fold and 1.23-fold higher, respectively, in Chinese subjects, and 1.12-fold and 1.17-fold higher, respectively, in Korean subjects. These findings, including the clinically insignificant differences in PK exposures, the comprehensive evidence of sepiapterin's efficacy and safety, the recognition of PKU as a rare disease and designation of sepiapterin as an orphan drug for treatment of PKU in EU, the USA, Japan, South Korea, and several other countries, and the urgent unmet medical need, collectively support that conducting an ethnic bridging study in Chinese and Korean populations is not warranted.
2026-07-24 | DNAJC12 Stabilizes Phenylalanine Hydroxylase and Facilitates Its Substrate-Dependent Activation.
Phenylalanine hydroxylase (PAH) is a tetrahydrobiopterin (BH4)-dependent enzyme that converts L-phenylalanine (L-Phe) to L-tyrosine. PAH dysfunction leads to the accumulation of L-Phe in the blood (hyperphenylalaninemia; HPA), which may reach neurotoxic levels, resulting in phenylketonuria (PKU). PKU is associated with pathogenic variants in PAH, mostly causing misfolding and instability, leading to decreased levels of PAH protein and activity. Recently, variants in the J-domain protein DNAJC12 have also been associated with HPA in patients, demonstrating the importance of protein homeostasis regulation for proper PAH function. DNAJC12 and PAH have previously been reported to interact, but the molecular and structural mechanisms behind complex formation have remained unclear. In this work, we show that DNAJC12 binds to PAH but presents higher affinity for its L-Phe activated form, which resembles the conformation of unliganded tyrosine hydroxylase, a structurally and functionally related enzyme that also binds to DNAJC12. At saturation, four DNAJC12 monomers bind and stabilize the PAH tetramer, protecting it from aggregation and lowering the L-Phe concentration necessary for substrate-induced activation, without affecting the interaction of the enzyme with its cofactor BH4. Importantly, DNAJC12 also stabilizes and delays the aggregation of the PKU-associated variant PAH-p.R261Q. This study provides the first detailed characterization of the molecular determinants driving PAH:DNAJC12 complex formation and reveals how this interaction modulates enzyme stability and activity, and stimulates Hsc70 ATPase activity. These findings provide mechanistic insight into the pathogenic basis of DNAJC12 deficiency and identify the PAH:DNAJC12 complex as a promising therapeutic target for HPA.
2026-07-15 | Blood Phenylalanine Control in Paediatric and Adult Centres in the UK: Data from 2012-2018.
Background: Metabolic control in phenylketonuria (PKU) is known to deteriorate with age, but national-level data describing blood phenylalanine (Phe) control across the United Kingdom (UK) are limited. Objective: To characterise blood Phe control in individuals with PKU attending UK metabolic centres. Methods: Sixteen UK centres (nine paediatric, six adult, one mixed) retrospectively extracted blood Phe results collected between 2012 and 2018. Demographic, phenotypic and monitoring-related variables were analysed. Written consent for data collection was obtained from all patients or their caregivers. Results: Data were available for 871 individuals (55% female), of whom 744 (85%) were classified as follows: classical PKU, 75%, mild PKU, 22% and hyperphenylalaninaemia, 3%. Mean blood Phe concentrations were significantly higher in adults than children (491 ± 308 vs. 303 ± 199 µmol/L; p < 0.001), and the proportion of samples within target range declined steadily with age, from 78% in children < 2 years to 36% in adults ≥ 41 years. Individuals with classical PKU had higher mean Phe concentrations and lower target attainment than those with HPA (386 vs. 300 µmol/L; 61% vs. 78%; p < 0.001), while mild PKU and HPA showed comparable control. Females generally demonstrated better metabolic control than males. More frequent dried blood spot sampling for blood Phe was strongly associated with improved metabolic control: weekly (254 ± 175 µmol/L; 82% within target), fortnightly (319 ± 207 µmol/L; 70%), monthly (397 ± 231 µmol/L; 61%), and less than monthly (624 ± 349 µmol/L; 44%). Nearly half of the blood Phe samples (47%) with recorded timing were taken in a non-fasting state. Conclusions: Achieving lifelong metabolic stability on a Phe-restricted diet alone remains challenging. These national data highlight the need for broader therapeutic options to support individuals with PKU across the lifespan.
2026-06-26 | Molecular Genetic and Biochemical Characterization of Hyperphenylalaninemia Based on Expanded Neonatal Screening Data from 2023 to 2024 in the Russian Federation.
Since January 2023, the Russian Federation has implemented expanded neonatal screening for 36 hereditary disorders, which has changed the diagnostic algorithm for hyperphenylalaninemia/phenylketonuria (HPA/PKU) by introducing tandem mass spectrometry (MS/MS) on the second day of life, followed by confirmatory biochemical and molecular testing in newborns at risk. We analyzed 1247 newborns aged 5-15 days with elevated phenylalanine levels (≥120 µmol/L) and a phenylalanine to tyrosine ratio of at least 1 detected during the first stage of screening using MS/MS. At the reference center, newborns underwent repeat biochemical testing and stepwise molecular analysis of HPA-associated genes. Two pathogenic variants in HPA-associated genes were identified in 538 newborns, including 534 newborns with biallelic pathogenic variants in PAH and 4 with BH4-deficient forms (PTS, QDPR). The incidence of molecularly confirmed HPA was 1:4518 newborns (95% CI: 1:4152-1:4925). The PAH variant spectrum was dominated by p.Arg408Trp (c.1222C>T) (33.4%). Genotype-based analysis indicated that 73 newborns (13.7%) were likely responsive to cofactor therapy, whereas 222 (41.6%) were potentially responsive. These findings define the molecular epidemiology of HPA in Russia and support early genetic stratification for diagnosis and treatment.
2026-05-13 | Sepiapterin: From sapropterin to next-generation therapy.
Sepiapterin is a naturally occurring pteridine and BH4 precursor that links classic pterin chemistry to tetrahydrobiopterin biology. Tetrahydrobiopterin (BH4; sapropterin) is an essential redox-active cofactor for phenylalanine hydroxylase (PAH), the aromatic amino acid hydroxylases, and nitric oxide synthases, whereas 7,8-dihydrobiopterin (BH2) reflects pterin redox balance and can antagonize BH4-dependent nitric oxide signaling. This review integrates historical and chemical perspectives with current biochemical and clinical understanding of BH4 homeostasis, including de novo synthesis, recycling/oxidation, and the sepiapterin salvage pathway. Sepiapterin is taken up by cells through equilibrative nucleoside transport mechanisms and is intracellularly converted through sepiapterin reductase and dihydrofolate reductase to expand BH4 pools. In healthy volunteers, oral sepiapterin produced marked systemic BH4 exposure with minimal parent-drug exposure (geometric mean Cmax 640 ng/mL for BH4 versus 1.74 ng/mL for sepiapterin after 60 mg/kg) and increased cerebrospinal fluid BH4 after 7 days of 60 mg/kg/day dosing. In phenylketonuria (PKU), the Phase 3 APHENITY trial showed a placebo-adjusted least-squares mean blood phenylalanine reduction of 395.9 μmol/L at Week 6 among sepiapterin-responsive participants, and the Phase 3 AMPLIPHY trial showed greater lowering with sepiapterin 60 mg/kg/day than with sapropterin 20 mg/kg/day (least-squares mean difference 180.4 μmol/L; 95% CI 131.4-229.5; p < 0.0001). Together, these data position sepiapterin as a next-step therapy beyond sapropterin, while underscoring the importance of biomarker studies that quantify BH4, BH2, and the BH4/BH2 ratio in plasma and cerebrospinal fluid.
2026-04-17 | Ethnic Bridging of Sepiapterin in Chinese and Korean Populations Based on Predictions From Genetic Polymorphism of Breast Cancer Resistance Protein.
Ethnic differences are crucial when considering the efficacy, safety, and dose of pharmaceuticals across diverse populations. The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline E5 addresses the acceptability of extrapolating foreign clinical data taking ethnic factors into consideration. Sepiapterin has recently been approved for the treatment of hyperphenylalaninemia (HPA) in patients with phenylketonuria (PKU) in Europe, the USA, and multiple additional countries worldwide. To date, no clinical trials have been conducted in the Chinese or Korean populations. An ethnic sensitivity analysis identified that the breast cancer resistance protein (BCRP) c.421C>A variant was the primary factor leading to ethnic differences in BH4 exposures. A correlation was established and validated between the frequency of BCRP c.421C>A variant in ethnic groups and the relative Cmax and AUC0-24h of sepiapterin major active metabolite 5,6,7,8-tetrahydrobiopterin (BH4). Based on this correlation, it was predicted that compared to White, the mean BH4 Cmax and AUC0-24h were 1.16-fold and 1.23-fold higher, respectively, in Chinese subjects, and 1.12-fold and 1.17-fold higher, respectively, in Korean subjects. These findings, including the clinically insignificant differences in PK exposures, the comprehensive evidence of sepiapterin's efficacy and safety, the recognition of PKU as a rare disease and designation of sepiapterin as an orphan drug for treatment of PKU in EU, the USA, Japan, South Korea, and several other countries, and the urgent unmet medical need, collectively support that conducting an ethnic bridging study in Chinese and Korean populations is not warranted.
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Drug Discovery Landscape
7 orphan drug designations for Hyperphenylalaninemia due to tetrahydrobiopterin deficiency, including 1 approved therapy.
7 orphan drug designations for Hyperphenylalaninemia due to tetrahydrobiopterin deficiency, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
2,4-Diamino-5-[[5-(1H-pyrazol-5-yl)-2-thienyl]methyl]-1H-pyrimidin-6-one | small molecules | EMA | 2024-05-24 | — | Pluvia AS |
Escherichia coli, strain Nissle 1917, expressing High affinity phenylalanine transporter, Phenylalanine ammonia lyase and L-amino acid deaminase | cell therapies | EMA | 2022-06-21 | — | Orphix Consulting GmbH |
(S)-2-amino-6-(2-hydroxypropanoyl)-7,8-dihydropteridin-4(3H)-one [Sephience] | small molecules | EMA | 2021-05-20 | 2025-06-25 | PTC Therapeutics International Limited |
sepiapterin | small molecules | FDA | 2020-02-19 | — | PTC Therapeutics, Inc. (PTC) |
Particles comprised of methacrylic acid based co-polymer, cross-linked with a bi-functional cross-linker, purified to bind L-phenylalanine and L-phenylalanine containing peptides | small molecules | EMA | 2016-11-18 | — | MipSalus ApS |
5,6,7,8-Tetrahydrobiopterin | small molecules | EMA | 2003-10-02 | — | Orphanetics Pharma Entwicklungs GmbH |
L-5-hydroxytryptophan | small molecules | FDA | 1999-01-20 | — | Watson Laboratories, Inc. |
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