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Update from PHEFREE: The National Institutes of Health Rare Disease Consortium for Hyperphenylalaninemia 

Biochemical/Metabolic and Therapeutics
  • Primary Categories:
    • Metabolic Genetics
  • Secondary Categories:
    • Metabolic Genetics
Introduction:
 The PHEFREE Consortium for the study of genetic disorders causing hyperphenylalaninemia (phenylalanine hydroxylase (PAH) deficiency, biopterin synthesis/ recycling disorders, or DNAJC12 deficiency) is composed of eight academic centers and the National PKU Alliance (USA). We report here an update on the longitudinal natural history study examining the bone health, cognitive, behavioral, psychiatric, and patient reported outcomes.

Methods:
 Assessments are collected annually on individuals with a hyperphenylalaninemia disorder detected by newborn screening including medical, dietary, and laboratory information, patient-reported outcome measures and neurocognitive assessments.

Results:
 As of November 1, 2024, 159 participants with PAH deficiency ranging in age from 3 months to 58 years have completed initial baseline visits and 64 have completed at least one additional annual study visit. Self-reported racial background was 93% white, 4% Asian, and 3% multi-racial.

 

DEXA bone mineral density data of the hip, spine, and total body (adults)/total body less head (children ages 6-17 years) were available on a subset of PAH deficient patients.  Emerging data reveal reduced bone density beginning in childhood and apparent by age 6 years (when testing was initiated).  Mean z-scores for hip/spine and total body revealed negative mean scores for all parameters:  -0.30 (s.d.0.90) hip/-0.23 (0.96) spine and -0.15 (0.92) total body for adults, and -0.42 (1.43) hip/-0.24 (1.11) spine and -0.45 (1.19) total body less head in children.  6.5% of adults and 17.6% of children had at least one bone density z-score of -2 sd or lower, and 34% of adults and 45.1% of children had at least one z-score of -1 sd or lower.  This is particularly concerning given that fracture risk is reported to double for every standard deviation below the mean for a young adult, and low bone mineral density remains a strong predictor of future fracture risk. Overall, 21% of children reported having had a previous fracture, with slightly more boys than girls reporting a fracture (55% vs 45%).  There was a non-significant trend toward lower spine and total body less head z scores between those reporting vs not reporting a fracture (-0.34 vs. -0.14 and 0.76 vs. -0.33, respectively).  37% of adults reported having had a previous fracture, with more women than men reporting a fracture (65% vs 36%).  The group reporting fractures were slightly older (9.7 vs 7.2 years for children and 36.5 vs 33.0 years for adults).  Correlations between bone density and age were weakly negative.  Serial bone density measurements in a larger subset are planned to assess changes over time.  As additional data are gathered the relationship between bone density and phenylalanine levels and nutritional biomarkers will be assessed. 

 

Patient self-reported psychological outcomes noted attention deficit hyperactivity disorder in 11.5% of adults and 15.4% of children, presenting with equal frequency of primarily inattentive vs mixed hyperactive/inattentive.  Self-reported developmental delay and/or intellectual disability were recorded in13.1% of adults and 16.5% of children, even though on average phenylalanine levels seemed well controlled (310 mmol in children and 462mmol in adults).  40.1% of adults and 8.2% of children self-reported anxiety and/or depression.

Conclusion:
Emerging assessment of participants with PAH deficiency reveals persistent decrements in bone density with a number having z-scores as low as -2 or lower, suggesting potentially significant effects on bone health.  Psychological effects on well-being including anxiety and depression are common at all ages, but appear particularly significant in adults.  Ongoing longitudinal assessment are necessary to define the persistence and clinical meaningfulness of these deficits. Recruitment of additional individuals is necessary to expand the diagnostic, racial and ethnic diversity of the study cohort.

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