Long-term preservation of intellectual functioning in sapropterin-treated infants and young children with phenylketonuria: A seven-year analysis

Susan Waisbren; Barbara K. Burton; Annette Feigenbaum; Laura L. Konczal; Joshua Lilienstein; Shawn E. McCandless; Richard Rowell; Amarilis Sanchez-Valle; Kaleigh B. Whitehall; Nicola Longo

doi:10.1016/j.ymgme.2021.01.001

Long-term preservation of intellectual functioning in sapropterin-treated infants and young children with phenylketonuria: A seven-year analysis

Susan Waisbren, Barbara K. Burton, Annette Feigenbaum, Laura L. Konczal, Joshua Lilienstein, Shawn E. McCandless, Richard Rowell, Amarilis Sanchez-Valle, Kaleigh B. Whitehall, Nicola Longo^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Sapropterin dihydrochloride has been approved for the treatment of hyperphenylalaninemia in infants and young children with phenylketonuria (PKU). Sapropterin can reduce phenylalanine (Phe) levels in tetrahydrobiopterin (BH4)-responsive patients, potentially preventing the intellectual impairment caused by elevated Phe levels. The long-term effect of sapropterin on intellectual functioning was assessed using the Full-Scale Intelligence Quotient (FSIQ) in 62 children who began treatment before the age of 6 years. Over each 2-year interval, the estimate of mean change in FSIQ was −0.5768 with a lower limit of the 95% confidence interval (CI) of −1.60. At the end of the follow-up period (Year 7), the least squares mean estimate of the change in FSIQ from baseline was 1.14 with a lower limit of the 95% CI of −3.53. These lower limits were both within the clinically expected variation of 5 points. During the whole study period, mean blood Phe levels remained within the American College of Medical Genetics (ACMG) target range of 120–360 μmol/L. In addition, height, weight, and head circumference were maintained within normal ranges throughout follow-up, as defined by growth charts from the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) for children below and above the age of 24 months, respectively. All patients (n = 65) enrolled in this study experienced at least one adverse event, as expected from previous studies. In conclusion, long-term use of sapropterin in individuals with PKU helps to control blood Phe, preserve intellectual functioning, and maintain normal growth in BH4-responsive children who initiated treatment between the ages of 0 to 6 years.

Original language	English (US)
Pages (from-to)	119-127
Number of pages	9
Journal	Molecular Genetics and Metabolism
Volume	132
Issue number	2
DOIs	https://doi.org/10.1016/j.ymgme.2021.01.001
State	Published - Feb 2021

Funding

This study and support in the process of manuscript development were funded by BioMarin Pharmaceutical Inc., Novato, CA, USA.BKB has received personal fees from BioMarin outside the submitted work. AF has received payments from BioMarin during the conduct of the study. SEM and NL have received grants and personal fees from BioMarin during the conduct of the study. AS-V is a principal investigator for several BioMarin clinical trials, has received payment from serving in advisory boards funded by BioMarin, and participated in a speakers bureau for BioMarin. SW has received consulting fees from BioMarin during the conduct of the study, and from Homology, Pfizer and Synlogic outside the submitted work. JL, KBW, and RR are employees of BioMarin Pharmaceutical Inc. LLK has nothing to declare.

Keywords

Intellectual functioning
Phenylketonuria
Sapropterin

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Biochemistry
Molecular Biology
Genetics
Endocrinology

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10.1016/j.ymgme.2021.01.001

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Waisbren, S., Burton, B. K., Feigenbaum, A., Konczal, L. L., Lilienstein, J., McCandless, S. E., Rowell, R., Sanchez-Valle, A., Whitehall, K. B., & Longo, N. (2021). Long-term preservation of intellectual functioning in sapropterin-treated infants and young children with phenylketonuria: A seven-year analysis. Molecular Genetics and Metabolism, 132(2), 119-127. https://doi.org/10.1016/j.ymgme.2021.01.001

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title = "Long-term preservation of intellectual functioning in sapropterin-treated infants and young children with phenylketonuria: A seven-year analysis",

abstract = "Sapropterin dihydrochloride has been approved for the treatment of hyperphenylalaninemia in infants and young children with phenylketonuria (PKU). Sapropterin can reduce phenylalanine (Phe) levels in tetrahydrobiopterin (BH4)-responsive patients, potentially preventing the intellectual impairment caused by elevated Phe levels. The long-term effect of sapropterin on intellectual functioning was assessed using the Full-Scale Intelligence Quotient (FSIQ) in 62 children who began treatment before the age of 6 years. Over each 2-year interval, the estimate of mean change in FSIQ was −0.5768 with a lower limit of the 95% confidence interval (CI) of −1.60. At the end of the follow-up period (Year 7), the least squares mean estimate of the change in FSIQ from baseline was 1.14 with a lower limit of the 95% CI of −3.53. These lower limits were both within the clinically expected variation of 5 points. During the whole study period, mean blood Phe levels remained within the American College of Medical Genetics (ACMG) target range of 120–360 μmol/L. In addition, height, weight, and head circumference were maintained within normal ranges throughout follow-up, as defined by growth charts from the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) for children below and above the age of 24 months, respectively. All patients (n = 65) enrolled in this study experienced at least one adverse event, as expected from previous studies. In conclusion, long-term use of sapropterin in individuals with PKU helps to control blood Phe, preserve intellectual functioning, and maintain normal growth in BH4-responsive children who initiated treatment between the ages of 0 to 6 years.",

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author = "Susan Waisbren and Burton, {Barbara K.} and Annette Feigenbaum and Konczal, {Laura L.} and Joshua Lilienstein and McCandless, {Shawn E.} and Richard Rowell and Amarilis Sanchez-Valle and Whitehall, {Kaleigh B.} and Nicola Longo",

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doi = "10.1016/j.ymgme.2021.01.001",

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Waisbren, S, Burton, BK, Feigenbaum, A, Konczal, LL, Lilienstein, J, McCandless, SE, Rowell, R, Sanchez-Valle, A, Whitehall, KB & Longo, N 2021, 'Long-term preservation of intellectual functioning in sapropterin-treated infants and young children with phenylketonuria: A seven-year analysis', Molecular Genetics and Metabolism, vol. 132, no. 2, pp. 119-127. https://doi.org/10.1016/j.ymgme.2021.01.001

TY - JOUR

T1 - Long-term preservation of intellectual functioning in sapropterin-treated infants and young children with phenylketonuria

T2 - A seven-year analysis

AU - Waisbren, Susan

AU - Burton, Barbara K.

AU - Feigenbaum, Annette

AU - Konczal, Laura L.

AU - Lilienstein, Joshua

AU - McCandless, Shawn E.

AU - Rowell, Richard

AU - Sanchez-Valle, Amarilis

AU - Whitehall, Kaleigh B.

AU - Longo, Nicola

PY - 2021/2

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N2 - Sapropterin dihydrochloride has been approved for the treatment of hyperphenylalaninemia in infants and young children with phenylketonuria (PKU). Sapropterin can reduce phenylalanine (Phe) levels in tetrahydrobiopterin (BH4)-responsive patients, potentially preventing the intellectual impairment caused by elevated Phe levels. The long-term effect of sapropterin on intellectual functioning was assessed using the Full-Scale Intelligence Quotient (FSIQ) in 62 children who began treatment before the age of 6 years. Over each 2-year interval, the estimate of mean change in FSIQ was −0.5768 with a lower limit of the 95% confidence interval (CI) of −1.60. At the end of the follow-up period (Year 7), the least squares mean estimate of the change in FSIQ from baseline was 1.14 with a lower limit of the 95% CI of −3.53. These lower limits were both within the clinically expected variation of 5 points. During the whole study period, mean blood Phe levels remained within the American College of Medical Genetics (ACMG) target range of 120–360 μmol/L. In addition, height, weight, and head circumference were maintained within normal ranges throughout follow-up, as defined by growth charts from the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) for children below and above the age of 24 months, respectively. All patients (n = 65) enrolled in this study experienced at least one adverse event, as expected from previous studies. In conclusion, long-term use of sapropterin in individuals with PKU helps to control blood Phe, preserve intellectual functioning, and maintain normal growth in BH4-responsive children who initiated treatment between the ages of 0 to 6 years.

AB - Sapropterin dihydrochloride has been approved for the treatment of hyperphenylalaninemia in infants and young children with phenylketonuria (PKU). Sapropterin can reduce phenylalanine (Phe) levels in tetrahydrobiopterin (BH4)-responsive patients, potentially preventing the intellectual impairment caused by elevated Phe levels. The long-term effect of sapropterin on intellectual functioning was assessed using the Full-Scale Intelligence Quotient (FSIQ) in 62 children who began treatment before the age of 6 years. Over each 2-year interval, the estimate of mean change in FSIQ was −0.5768 with a lower limit of the 95% confidence interval (CI) of −1.60. At the end of the follow-up period (Year 7), the least squares mean estimate of the change in FSIQ from baseline was 1.14 with a lower limit of the 95% CI of −3.53. These lower limits were both within the clinically expected variation of 5 points. During the whole study period, mean blood Phe levels remained within the American College of Medical Genetics (ACMG) target range of 120–360 μmol/L. In addition, height, weight, and head circumference were maintained within normal ranges throughout follow-up, as defined by growth charts from the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) for children below and above the age of 24 months, respectively. All patients (n = 65) enrolled in this study experienced at least one adverse event, as expected from previous studies. In conclusion, long-term use of sapropterin in individuals with PKU helps to control blood Phe, preserve intellectual functioning, and maintain normal growth in BH4-responsive children who initiated treatment between the ages of 0 to 6 years.

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Long-term preservation of intellectual functioning in sapropterin-treated infants and young children with phenylketonuria: A seven-year analysis

Abstract

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