RARE DISEASE
Mild hyperphenylalaninemia
Mild hyperphenylalaninemia
Mild hyperphenylalaninemia
Synonyms: Mild HPA, Non-PKU HPA, mHPA
Synonyms: Mild HPA, Non-PKU HPA, mHPA
Synonyms: Mild HPA, Non-PKU HPA, mHPA
Drug discovery
5
drugs
With orphan designations
Overview
Mild hyperphenylalaninemia (mHPA) is characterized by blood phenylalanine (Phe) levels of 120–600 μmol/L without consistent evidence of neurocognitive impairment in untreated patients [1][9]. While patients with Phe <360 μmol/L rarely require intervention, those with levels 360–600 μmol/L may benefit from selective dietary management or BH4 supplementation [1][7][9]. Most individuals achieve normal developmental outcomes without treatment, though monitoring is recommended [6][10].
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
145 drug discovery papers about Mild hyperphenylalaninemia, with 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
145 drug discovery papers about Mild hyperphenylalaninemia, with 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-24 | 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.
2026-06-01 | Sepiapterin approved for children and adults with phenylketonuria (PKU): A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG)
Phenylketonuria (PKU), also known as phenylalanine hydroxylase (PAH) (HGNC:8582) deficiency, is an autosomal recessive disorder of phenylalanine (Phe) metabolism due to deficiency of the enzyme PAH, which normally converts Phe to tyrosine (Tyr) (HGNC:12442) in the presence of the cofactor tetrahydrobiopterin (BH4).1 Deficient PAH activity results in elevated blood and brain Phe concentrations, resulting in profound neurocognitive delays if left untreated. PKU represents a spectrum of disease severity correlating to residual enzyme activity, from mild hyperphenylalaninemia to classic PKU, the most severe form.
2026-04-17 | Variant-dependent pharmacological rescue of phenylalanine hydroxylase supports a precision therapeutic strategy for phenylketonuria.
Phenylketonuria (PKU) is an inherited metabolic disorder caused by pathogenic variants in phenylalanine hydroxylase (PAH), leading to toxic phenylalanine accumulation and severe neurological complications if untreated. Current pharmacological treatment relies on tetrahydrobiopterin (BH4), which benefits only a subset of patients, highlighting a major unmet need for alternative therapies. Here, we combined high-throughput screening, computational modelling, and drug repurposing to identify pharmacological chaperones capable of rescuing PAH function. We evaluated 26 structurally diverse small molecules in HEK293T cells expressing wild-type PAH or one of eight PKU-associated variants spanning phenotypes from mild to classical disease. Chaperoning efficacy was strongly variant-dependent, and for every variant tested at least one compound produced a greater activity increase than BH4 under identical assay conditions. Notably, belinostat, a clinically approved histone deacetylase inhibitor, emerged as the most effective compound for several clinically severe variants. Mechanistically, functional rescue consistently correlated with an increased population of tetrameric, catalytically competent PAH, as quantified by mass photometry. The crystal structure of the PAH-belinostat complex (PDB ID: 9T1O), together with structural models for all compounds, provide a framework for rational optimization. These results establish a preclinical proof-of-concept for genotype-guided pharmacological chaperone therapy in PKU and support the feasibility of personalized, variant-specific treatment strategies.
2026-01-23 | Developmental and Cognitive Outcomes in 342 Patients With Different Types of Hyperphenylalaninemia.
The aim of this study is to evaluate neurodevelopmental and cognitive outcomes in patients diagnosed with different types of hyperphenylalaninemia (HPA), identify the factors influencing these outcomes, and contribute to the debate regarding the thresold for initiating dietary treatment based on plasma phenylalanine (Phe) levels. Patients with hyperphenylalaninemia (HPA) who were followed up and had developmental and/or cognitive evaluations at the Division of Pediatric Metabolism and Nutrition, Department of Pediatrics, between 1984 and 2018, were retrospectively assessed. The study included patients with mild (Phe:360-600 μmol/L), moderate (Phe:600-1200 μmol/L), or classic Phenylketonuria (PKU) (Phe ≥1200 μmol/L) treated with diet and/or tetrahydrobiopterin (BH4), along with untreated HPA patients (Phe:240-360 μmol/L). This classification was based on plasma Phe levels measured at the time of diagnosis. Denver Developmental Screening Test (DDST), Stanford-Binet test, and Wechsler Intelligence Scale for Children (WISC-R) adapted for Turkish children were applied for developmental and cognitive evaluation. Intellectual disability or developmental delay (ID/DD) was defined as a full-scale intelligence quotient (IQ) <70 on the Stanford-Binet or WISC-R, or as delay in two or more developmental domains on the DDST, with children meeting any of these criteria classified as having ID/DD. The relationships between ID/DD, age at diagnosis, diagnostic methods, plasma Phe levels, and brain MRI findings were analyzed. A total of 342 patients were included in the study, comprising 182 (53.2%) females and 160 (46.8%) males. Of these, 53 (15.5%) had mild PKU, 97 (28.4%) had moderate PKU, 102 (29.8%) had classic PKU, and 90 (26.3%) were diagnosed with HPA. A significant association was found between ID/DD and both the age at diagnosis and diagnostic method in patients treated with diet and/or BH4 (p < 0.001 and p < 0.01, respectively). In patients with ID/DD, the median plasma Phe levels at the first, third, and last years of follow-up were significantly higher compared to patients without ID/DD (p < 0.024). White matter abnormalities observed on brain MRI were significantly associated with PKU severity, the presence of ID/DD, and the median plasma Phe levels in the last year of follow-up (p = 0.01, p < 0.001, and p < 0.001, respectively). Notably, 9 (10%) of untreated HPA patients exhibited ID/DD, despite regular follow-up and the absence of known risk factors. In addition to early diagnosis and treatment, lifelong adherence and regular follow-up are essential for achieving normal neurodevelopmental and cognitive outcomes in individuals with PKU. However, clinical management remains heterogeneous across centers. The presence of developmental delay in 10% of untreated HPA patients underscores the need to urgently re-evaluate current plasma Phe thresholds for treatment initiation and follow-up.
2025-11-20 | Quantitative Ultrasound for the Assessment of Bone Quality in Hyperphenylalaninemia/Phenylketonuria Patients: Vitamin D Supplementation Versus No Supplementation
Background/Objectives: Skeletal impairment has been reported as a common finding in Hyperphenylalaninemia (HPA)/Phenylketonuria (PKU) patients regardless of age and method of diagnosis, both in children and adults. Quantitative Ultrasound (QUS) is a radiation-free and low-cost method for assessing bone quality, used in various chronic conditions. Methods: Bone quality was evaluated using a calcaneal QUS device. Auxological parameters, nutritional intakes, and plasma levels of key bone biomarkers were also registered. The population was divided into four groups: PKU patients under diet therapy and HPA patients on a free diet, both divided into receiving or not receiving single vitamin D supplementation. Results: All HPA/PKU patients had median bone quality index (BQI) Z- and T-score values lower than -1, with slightly better values in HPA children and PKU-supplemented adults. Dietary vitamin D intake in PKU patients was significantly higher than in HPA subjects (p < 0.001), due to protein substitute supplementation. However, plasma 25(OH) vitamin D levels, although increased compared to baseline, were still overlapping among groups (p = 0.845) after supplementation. Approximately a quarter of both pediatric and adult non-supplemented PKU patients had Z-score and T-score levels below -2, and this percentage decreased with vitamin D supplementation in all groups. In PKU-supplemented patients, the Broadband Ultrasound Attenuation (BUA) was significantly higher than in the other groups (p = 0.040). Conclusions: The improvement in BUA may represent preliminary evidence of the effect of vitamin D on bone architecture, which could encourage this supplementation to prevent the worsening of bone structure and reduce the risk of fractures.
proteins
2026-08-26 | Bone mineral density in participants with phenylalanine hydroxylase (PAH) deficiency: a report from the PHEFREE rare disorders consortium.
Low bone mineral density (BMD) in individuals with phenylketonuria (PKU) due to phenylalanine hydroxylase (PAH) deficiency has been variably reported in the medical literature, but the clinical significance of this observation has been uncertain. We measured BMD in a cross-sectional cohort of 117 individuals with PAH deficiency between 6.2 and 56.8 years age who participate in the PHEFREE Consortium Longitudinal Natural History Study. 49% of children under age 18 years and 26% of adults were consuming a phenylalanine (Phe)-restricted diet, supplemented with low Phe or Phe-free medical foods and treated with sapropterin dihydrochloride. 22% of adults and 32% of children were not responsive to sapropterin and were treated with dietary Phe restriction and supplementary medical foods alone. 20 adults (37%) reported receiving enzyme replacement therapy with pegvaliase. Phenotype predictions from the genotypes of the participants in these three treatment groups were predominantly classical PKU. Participants with mild PKU or mild hyperphenylalaninemia (HPA) phenotypes treatable with sapropterin alone without the need for medical foods made up 9% of adults and 14% of children in the study cohort. Mean (± SD) blood phenylalanine (Phe) concentrations over the year prior to bone densitometry studies measured 449 ± 336 μM in the entire study cohort. Mean BMD z-scores for both adults and children in all body regions were negative with the difference between study participants and the comparator non-PKU population reaching statistical significance (p < 0.05). At least one z-score was <-2 in 15% of children and 10% of adults with PKU (2.3% expected). These differences were apparent in some children already at 6 years age, the earliest time point measured. Mean BMD was more negative in individuals with history of fracture than in those without, but this difference did not reach statistical significance. Multivariate analysis revealed a positive correlation between BMD and body mass index (BMI) in children, with minor contributions from age and natural protein intake. There was no correlation between BMD and blood Phe concentration measured in the year prior to BMD measurement. The pathophysiologic mechanism causing and the clinical significance of these differences remain uncertain, but concern persists that low BMD in this relatively well-treated cohort could portend frank osteopenia and increased fracture risk as these individuals reach advanced age. Whether novel therapeutics, that both correct hyperphenylalaninemia and allow increased dietary intact protein intake, will impact bone mineralization is yet unknown. Longitudinal monitoring of BMD throughout the lifespan is warranted.
2025-02-13 | Genotype-Phenotype Correlation in a Large Cohort of Eastern Sicilian Patients Affected by Phenylketonuria: Newborn Screening Program, Clinical Features, and Follow-Up.
Background: Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, leading to impaired amino acid metabolism. Early diagnosis through newborn screening (NBS) enables prompt treatment, preventing neurological complications. This study aims to describe the genetic and phenotypic spectrum of PKU and mild hyperphenylalaninemia (m-HPA) in patients diagnosed at the Department of Inborn Errors of Metabolism and Newborn Screening, Hospital G. Rodolico-S. Marco, Catania, over four decades (1987-2023). Materials and Methods: The retrospective analysis included 102 patients with elevated blood phenylalanine (Phe) levels born in Sicily and followed at the Institute. The phenotype evaluation comprised the Phe levels at birth/diagnosis, dietary tolerance, and sapropterin dihydrochloride responsiveness. The dietary compliance and Phe/Tyr ratios were assessed and compared across phenotypic classes and age groups. Results: Of 102 patients, 34 were classified as having classic PKU, 9 as having moderate PKU, 26 as having mild PKU, and 33 as having m-HPA, with a median age of 21.72 years. Common PAH variants included c.1066-11G>A (26/204 alleles), c.782G>A (18/204 alleles), and c.165delT (13/204 alleles). The phenotypes sometimes diverged from the genotype predictions, emphasizing dietary tolerance over the initial Phe levels for classification: m-HPA was statistically associated with a higher dietary tolerance (p < 0.001) compared to the classic, moderate, or mild forms of PKU. Conclusions: This study highlights the importance of large databases (e.g., BioPKU) for phenotype prediction and treatment optimization. Regular assessment of Phe/Tyr ratios is crucial for monitoring adherence and health. Phenotype determination, dietary management, and emerging therapies (Pegvaliase and gene therapy) are key to improving outcomes for PKU patients.
small molecules
2026-06-24 | 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.
2026-06-01 | Sepiapterin approved for children and adults with phenylketonuria (PKU): A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG)
Phenylketonuria (PKU), also known as phenylalanine hydroxylase (PAH) (HGNC:8582) deficiency, is an autosomal recessive disorder of phenylalanine (Phe) metabolism due to deficiency of the enzyme PAH, which normally converts Phe to tyrosine (Tyr) (HGNC:12442) in the presence of the cofactor tetrahydrobiopterin (BH4).1 Deficient PAH activity results in elevated blood and brain Phe concentrations, resulting in profound neurocognitive delays if left untreated. PKU represents a spectrum of disease severity correlating to residual enzyme activity, from mild hyperphenylalaninemia to classic PKU, the most severe form.
2026-04-17 | Variant-dependent pharmacological rescue of phenylalanine hydroxylase supports a precision therapeutic strategy for phenylketonuria.
Phenylketonuria (PKU) is an inherited metabolic disorder caused by pathogenic variants in phenylalanine hydroxylase (PAH), leading to toxic phenylalanine accumulation and severe neurological complications if untreated. Current pharmacological treatment relies on tetrahydrobiopterin (BH4), which benefits only a subset of patients, highlighting a major unmet need for alternative therapies. Here, we combined high-throughput screening, computational modelling, and drug repurposing to identify pharmacological chaperones capable of rescuing PAH function. We evaluated 26 structurally diverse small molecules in HEK293T cells expressing wild-type PAH or one of eight PKU-associated variants spanning phenotypes from mild to classical disease. Chaperoning efficacy was strongly variant-dependent, and for every variant tested at least one compound produced a greater activity increase than BH4 under identical assay conditions. Notably, belinostat, a clinically approved histone deacetylase inhibitor, emerged as the most effective compound for several clinically severe variants. Mechanistically, functional rescue consistently correlated with an increased population of tetrameric, catalytically competent PAH, as quantified by mass photometry. The crystal structure of the PAH-belinostat complex (PDB ID: 9T1O), together with structural models for all compounds, provide a framework for rational optimization. These results establish a preclinical proof-of-concept for genotype-guided pharmacological chaperone therapy in PKU and support the feasibility of personalized, variant-specific treatment strategies.
2026-01-23 | Developmental and Cognitive Outcomes in 342 Patients With Different Types of Hyperphenylalaninemia.
The aim of this study is to evaluate neurodevelopmental and cognitive outcomes in patients diagnosed with different types of hyperphenylalaninemia (HPA), identify the factors influencing these outcomes, and contribute to the debate regarding the thresold for initiating dietary treatment based on plasma phenylalanine (Phe) levels. Patients with hyperphenylalaninemia (HPA) who were followed up and had developmental and/or cognitive evaluations at the Division of Pediatric Metabolism and Nutrition, Department of Pediatrics, between 1984 and 2018, were retrospectively assessed. The study included patients with mild (Phe:360-600 μmol/L), moderate (Phe:600-1200 μmol/L), or classic Phenylketonuria (PKU) (Phe ≥1200 μmol/L) treated with diet and/or tetrahydrobiopterin (BH4), along with untreated HPA patients (Phe:240-360 μmol/L). This classification was based on plasma Phe levels measured at the time of diagnosis. Denver Developmental Screening Test (DDST), Stanford-Binet test, and Wechsler Intelligence Scale for Children (WISC-R) adapted for Turkish children were applied for developmental and cognitive evaluation. Intellectual disability or developmental delay (ID/DD) was defined as a full-scale intelligence quotient (IQ) <70 on the Stanford-Binet or WISC-R, or as delay in two or more developmental domains on the DDST, with children meeting any of these criteria classified as having ID/DD. The relationships between ID/DD, age at diagnosis, diagnostic methods, plasma Phe levels, and brain MRI findings were analyzed. A total of 342 patients were included in the study, comprising 182 (53.2%) females and 160 (46.8%) males. Of these, 53 (15.5%) had mild PKU, 97 (28.4%) had moderate PKU, 102 (29.8%) had classic PKU, and 90 (26.3%) were diagnosed with HPA. A significant association was found between ID/DD and both the age at diagnosis and diagnostic method in patients treated with diet and/or BH4 (p < 0.001 and p < 0.01, respectively). In patients with ID/DD, the median plasma Phe levels at the first, third, and last years of follow-up were significantly higher compared to patients without ID/DD (p < 0.024). White matter abnormalities observed on brain MRI were significantly associated with PKU severity, the presence of ID/DD, and the median plasma Phe levels in the last year of follow-up (p = 0.01, p < 0.001, and p < 0.001, respectively). Notably, 9 (10%) of untreated HPA patients exhibited ID/DD, despite regular follow-up and the absence of known risk factors. In addition to early diagnosis and treatment, lifelong adherence and regular follow-up are essential for achieving normal neurodevelopmental and cognitive outcomes in individuals with PKU. However, clinical management remains heterogeneous across centers. The presence of developmental delay in 10% of untreated HPA patients underscores the need to urgently re-evaluate current plasma Phe thresholds for treatment initiation and follow-up.
2025-11-20 | Quantitative Ultrasound for the Assessment of Bone Quality in Hyperphenylalaninemia/Phenylketonuria Patients: Vitamin D Supplementation Versus No Supplementation
Background/Objectives: Skeletal impairment has been reported as a common finding in Hyperphenylalaninemia (HPA)/Phenylketonuria (PKU) patients regardless of age and method of diagnosis, both in children and adults. Quantitative Ultrasound (QUS) is a radiation-free and low-cost method for assessing bone quality, used in various chronic conditions. Methods: Bone quality was evaluated using a calcaneal QUS device. Auxological parameters, nutritional intakes, and plasma levels of key bone biomarkers were also registered. The population was divided into four groups: PKU patients under diet therapy and HPA patients on a free diet, both divided into receiving or not receiving single vitamin D supplementation. Results: All HPA/PKU patients had median bone quality index (BQI) Z- and T-score values lower than -1, with slightly better values in HPA children and PKU-supplemented adults. Dietary vitamin D intake in PKU patients was significantly higher than in HPA subjects (p < 0.001), due to protein substitute supplementation. However, plasma 25(OH) vitamin D levels, although increased compared to baseline, were still overlapping among groups (p = 0.845) after supplementation. Approximately a quarter of both pediatric and adult non-supplemented PKU patients had Z-score and T-score levels below -2, and this percentage decreased with vitamin D supplementation in all groups. In PKU-supplemented patients, the Broadband Ultrasound Attenuation (BUA) was significantly higher than in the other groups (p = 0.040). Conclusions: The improvement in BUA may represent preliminary evidence of the effect of vitamin D on bone architecture, which could encourage this supplementation to prevent the worsening of bone structure and reduce the risk of fractures.
proteins
2026-08-26 | Bone mineral density in participants with phenylalanine hydroxylase (PAH) deficiency: a report from the PHEFREE rare disorders consortium.
Low bone mineral density (BMD) in individuals with phenylketonuria (PKU) due to phenylalanine hydroxylase (PAH) deficiency has been variably reported in the medical literature, but the clinical significance of this observation has been uncertain. We measured BMD in a cross-sectional cohort of 117 individuals with PAH deficiency between 6.2 and 56.8 years age who participate in the PHEFREE Consortium Longitudinal Natural History Study. 49% of children under age 18 years and 26% of adults were consuming a phenylalanine (Phe)-restricted diet, supplemented with low Phe or Phe-free medical foods and treated with sapropterin dihydrochloride. 22% of adults and 32% of children were not responsive to sapropterin and were treated with dietary Phe restriction and supplementary medical foods alone. 20 adults (37%) reported receiving enzyme replacement therapy with pegvaliase. Phenotype predictions from the genotypes of the participants in these three treatment groups were predominantly classical PKU. Participants with mild PKU or mild hyperphenylalaninemia (HPA) phenotypes treatable with sapropterin alone without the need for medical foods made up 9% of adults and 14% of children in the study cohort. Mean (± SD) blood phenylalanine (Phe) concentrations over the year prior to bone densitometry studies measured 449 ± 336 μM in the entire study cohort. Mean BMD z-scores for both adults and children in all body regions were negative with the difference between study participants and the comparator non-PKU population reaching statistical significance (p < 0.05). At least one z-score was <-2 in 15% of children and 10% of adults with PKU (2.3% expected). These differences were apparent in some children already at 6 years age, the earliest time point measured. Mean BMD was more negative in individuals with history of fracture than in those without, but this difference did not reach statistical significance. Multivariate analysis revealed a positive correlation between BMD and body mass index (BMI) in children, with minor contributions from age and natural protein intake. There was no correlation between BMD and blood Phe concentration measured in the year prior to BMD measurement. The pathophysiologic mechanism causing and the clinical significance of these differences remain uncertain, but concern persists that low BMD in this relatively well-treated cohort could portend frank osteopenia and increased fracture risk as these individuals reach advanced age. Whether novel therapeutics, that both correct hyperphenylalaninemia and allow increased dietary intact protein intake, will impact bone mineralization is yet unknown. Longitudinal monitoring of BMD throughout the lifespan is warranted.
2025-02-13 | Genotype-Phenotype Correlation in a Large Cohort of Eastern Sicilian Patients Affected by Phenylketonuria: Newborn Screening Program, Clinical Features, and Follow-Up.
Background: Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene, leading to impaired amino acid metabolism. Early diagnosis through newborn screening (NBS) enables prompt treatment, preventing neurological complications. This study aims to describe the genetic and phenotypic spectrum of PKU and mild hyperphenylalaninemia (m-HPA) in patients diagnosed at the Department of Inborn Errors of Metabolism and Newborn Screening, Hospital G. Rodolico-S. Marco, Catania, over four decades (1987-2023). Materials and Methods: The retrospective analysis included 102 patients with elevated blood phenylalanine (Phe) levels born in Sicily and followed at the Institute. The phenotype evaluation comprised the Phe levels at birth/diagnosis, dietary tolerance, and sapropterin dihydrochloride responsiveness. The dietary compliance and Phe/Tyr ratios were assessed and compared across phenotypic classes and age groups. Results: Of 102 patients, 34 were classified as having classic PKU, 9 as having moderate PKU, 26 as having mild PKU, and 33 as having m-HPA, with a median age of 21.72 years. Common PAH variants included c.1066-11G>A (26/204 alleles), c.782G>A (18/204 alleles), and c.165delT (13/204 alleles). The phenotypes sometimes diverged from the genotype predictions, emphasizing dietary tolerance over the initial Phe levels for classification: m-HPA was statistically associated with a higher dietary tolerance (p < 0.001) compared to the classic, moderate, or mild forms of PKU. Conclusions: This study highlights the importance of large databases (e.g., BioPKU) for phenotype prediction and treatment optimization. Regular assessment of Phe/Tyr ratios is crucial for monitoring adherence and health. Phenotype determination, dietary management, and emerging therapies (Pegvaliase and gene therapy) are key to improving outcomes for PKU patients.
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Drug Discovery Landscape
5 orphan drug designations for Mild hyperphenylalaninemia, including 2 approved therapies.
5 orphan drug designations for Mild hyperphenylalaninemia, including 2 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Adeno-associated virus vector serotype SNY001 containing the human PAH gene | gene therapies | EMA | Sanofi B.V. | |
Sapropterin [Teshirin] | small molecules | EMA | Dr Gunter Schaub | |
sapropterin [Kuvan] | small molecules | FDA | Approved | BioMarin Pharmaceutical, Inc. |
Valine, isoleucine and leucine | small molecules | FDA | — | Leas Research Products |
pegvaliase-pqpz [PALYNZIQ] | proteins | FDA | Approved | BioMarin Pharmaceutical Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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