Phenylalanine hydroxylase deficiency treatment and management: A systematic evidence review of the American College of Medical Genetics and Genomics (ACMG)

Adams, April D.; Fiesco-Roa, Moisés Ó.; Wong, Lawrence; Jenkins, Gabrielle P.; Malinowski, Jennifer; Demarest, Olivia M.; Rothberg, Paul G.; Hobert, Judith A.

doi:10.1016/j.gim.2022.12.005

Cited by 5 publications

References 134 publications

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Efficacy and safety of sapropterin before and during pregnancy: Final analysis of the Kuvan® Adult Maternal Paediatric European Registry (KAMPER) maternal and Phenylketonuria Developmental Outcomes and Safety (PKUDOS) PKU‐MOMs sub‐registries

Feillet,

Ficicioglu,

Lagler

et al. 2024

J of Inher Metab Disea

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Infants born to mothers with phenylketonuria (PKU) may develop congenital abnormalities because of elevated phenylalanine (Phe) levels in the mother during pregnancy. Maintenance of blood Phe levels between 120 and 360 μmol/L reduces risks of birth defects. Sapropterin dihydrochloride helps maintain blood Phe control, but there is limited evidence on its risk–benefit ratio when used during pregnancy. Data from the maternal sub‐registries—KAMPER (NCT01016392) and PKUDOS (NCT00778206; PKU‐MOMs sub‐registry)—were collected to assess the long‐term safety and efficacy of sapropterin in pregnant women in a real‐life setting. Pregnancy and infant outcomes, and the safety of sapropterin were assessed. Final data from 79 pregnancies in 57 women with PKU are reported. Sapropterin dose was fairly constant before and during pregnancy, with blood Phe levels maintained in the recommended target range during the majority (82%) of pregnancies. Most pregnancies were carried to term, and the majority of liveborn infants were reported as ‘normal’ at birth. Few adverse and serious adverse events were considered related to sapropterin, with these occurring in participants with high blood Phe levels. This report represents the largest population of pregnant women with PKU exposed to sapropterin. Results demonstrate that exposure to sapropterin during pregnancy was well‐tolerated and facilitated maintenance of blood Phe levels within the target range, resulting in normal delivery. This critical real‐world data may facilitate physicians and patients to make informed treatment decisions about using sapropterin in pregnant women with PKU and in women of childbearing age with PKU who are responsive to sapropterin.

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Efficacy and safety of sapropterin before and during pregnancy: Final analysis of the Kuvan® Adult Maternal Paediatric European Registry (KAMPER) maternal and Phenylketonuria Developmental Outcomes and Safety (PKUDOS) PKU‐MOMs sub‐registries

Feillet,

Ficicioglu,

Lagler

et al. 2024

J of Inher Metab Disea

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Metabolic control and clinical outcome in adolescents with phenylketonuria

De Giorgi,

Nardecchia,

Romani

et al. 2023

Molecular Genetics and Metabolism

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PAH deficient pathology in humanized c.1066-11G>A phenylketonuria mice

Martínez-Pizarro,

Picó,

López-Márquez

et al. 2024

Human Molecular Genetics

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We have generated using CRISPR/Cas9 technology a partially humanized mouse model of the neurometabolic disease phenylketonuria (PKU), carrying the highly prevalent PAH variant c.1066-11G>A. This variant creates an alternative 3′ splice site, leading to the inclusion of 9 nucleotides coding for 3 extra amino acids between Q355 and Y356 of the protein. Homozygous Pah c.1066-11A mice, with a partially humanized intron 10 sequence with the variant, accurately recapitulate the splicing defect and present almost undetectable hepatic PAH activity. They exhibit fur hypopigmentation, lower brain and body weight and reduced survival. Blood and brain phenylalanine levels are elevated, along with decreased tyrosine, tryptophan and monoamine neurotransmitter levels. They present behavioral deficits, mainly hypoactivity and diminished social interaction, locomotor deficiencies and an abnormal hind-limb clasping reflex. Changes in the morphology of glial cells, increased GFAP and Iba1 staining signals and decreased myelinization are observed. Hepatic tissue exhibits nearly absent PAH protein, reduced levels of chaperones DNAJC12 and HSP70 and increased autophagy markers LAMP1 and LC3BII, suggesting possible coaggregation of mutant PAH with chaperones and subsequent autophagy processing. This PKU mouse model with a prevalent human variant represents a useful tool for pathophysiology research and for novel therapies development.

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Phenylalanine hydroxylase deficiency treatment and management: A systematic evidence review of the American College of Medical Genetics and Genomics (ACMG)

Cited by 5 publications

References 134 publications

Efficacy and safety of sapropterin before and during pregnancy: Final analysis of the Kuvan® Adult Maternal Paediatric European Registry (KAMPER) maternal and Phenylketonuria Developmental Outcomes and Safety (PKUDOS) PKU‐MOMs sub‐registries

Efficacy and safety of sapropterin before and during pregnancy: Final analysis of the Kuvan® Adult Maternal Paediatric European Registry (KAMPER) maternal and Phenylketonuria Developmental Outcomes and Safety (PKUDOS) PKU‐MOMs sub‐registries

Metabolic control and clinical outcome in adolescents with phenylketonuria

PAH deficient pathology in humanized c.1066-11G>A phenylketonuria mice

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Phenylalanine hydroxylase deficiency treatment and management: A systematic evidence review of the American College of Medical Genetics and Genomics (ACMG)

Cited by 5 publications

References 134 publications

Efficacy and safety of sapropterin before and during pregnancy: Final analysis of the Kuvan® Adult Maternal Paediatric European Registry (KAMPER) maternal and Phenylketonuria Developmental Outcomes and Safety (PKUDOS) PKU‐MOMs sub‐registries

Efficacy and safety of sapropterin before and during pregnancy: Final analysis of the Kuvan® Adult Maternal Paediatric European Registry (KAMPER) maternal and Phenylketonuria Developmental Outcomes and Safety (PKUDOS) PKU‐MOMs sub‐registries

Metabolic control and clinical outcome in adolescents with phenylketonuria

PAH deficient pathology in humanized c.1066-11G&gt;A phenylketonuria mice

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PAH deficient pathology in humanized c.1066-11G>A phenylketonuria mice