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.