Cognitive and behavioral impairment in mild hyperphenylalaninemia

Abstract

Cognitive and behavioral impairment in mild hyperphenylalaninemia. Turk J Pediatr 2018; 60: 617-624.As elevated phenylalanine (Phe) is detrimental to brain functions, determining a safe upper limit of blood Phe is important for initiation of treatment plans and setting Phe targets in hyperphenlalaninemic patients. It is accepted that Phe levels below 360 μmol/L does not impair brain function and hence does not require treatment. Therefore, we aimed to compare cognitive functions and attention-related problems among healthy children and untreated patients with hyperphenylalaninemia (HPA). This study included 41 hyperphenylalaninemic patients ("all HPA group") aged 6-16 years with untreated blood Phe between 240 and 600 μmol/L and 29 healthy controls. "All HPA group" was further divided into 2 subgroups according to their lifetime median blood Phe levels as "Phe 360-600 μmol/L" and "Phe 240-360 μmol/L" groups. Wechsler Intelligence Scale for Children-IV (WISC-IV), Conners' Continuous Performance Test (CPT), Strength and Difficulties Questionnaire (SDQ) and Schedule for Affective Disorders and Schizophrenia for School-Age Children: Present and Lifetime Version (K-SADS-PL) were performed as a comprehensive neurocognitive, attention and behavioral assessment. The study illustrated that "all HPA" patients had significantly lower scores on all WISC-IV indexes compared to controls, except for Working Memory. Both "Phe 360-600 μmol/L" and "Phe 240-360 μmol/L" subgroups had lower Full Scale intelligence quotient (IQ) and Verbal Comprehension scores compared to controls. "All HPA" patients also had longer reaction times and more peer problems than controls, indicating attention deficits and behavioral problems. Since the results demonstrated that children with untreated Phe levels between 240-360 μmol/L are at higher risk for cognitive and attention-related problems, lowering the "safe" upper Phe level should be considered.

Management of early treated adolescents and young adults with phenylketonuria: Development of international consensus recommendations using a modified Delphi approach

“…Currently, the US guidelines for the management of patients with PKU recommend maintaining blood Phe levels between 120 and 360 μmol/L for patients of all ages, while the European guidelines recommend blood Phe concentrations below 600 μmol/L for patients aged 12 years and older [3,4]. A growing body of evidence supports the stricter recommendation by the US guidelines as poorer socialcognition and executive functioning and more severe mental health outcomes have been reported in adolescents and young adults with blood Phe levels above 240-360 μmol/L [36,[82][83][84]. However, some findings have been equivocal, with a recent study focused solely on neurocognitive endpoints supporting the less strict European guidelines though highlighting that Phe sensitivity is prone to individual differences [85].…”

Recommendations on phenylketonuria in Turkey

“…3 In a recent single-center study in Turkey, cognitive functions and attention-related problems were compared between healthy children and untreated patients with HPA. 8 A total of 60 children were recruited to the study, 41 hyperphenylalaninemia patients aged 6-16 years with untreated blood Phe levels between 240 and 600 μmol/L and 29 healthy controls. The children with untreated Phe levels between 240-360 μmol/L compared to their healthy peers, and the children with Phe levels 360-600 μmol/L compared to the children with Phe levels between 240-360 μmol/L were found at higher risk for cognitive and attention-related problems.…”

“…The outcome indicates that the "safe" upper Phe level should be considered to be lowered. 8 Considering Turkish PKU patients, the experts have decided that <6 mg/dl level indicates mild disease and patients can be followed up closely without treatment if their clinical pictures denote no sign of the disease. However, it is agreed that a decimal system should be accepted for the classification of patients in the national PKU database such as 6-10 mg/dl mild, 10-20 mg/dl moderate, and >20 mg/dl severe.…”

“…Generally accepted blood Phe level for initiation of diet is 6 mg/dl (360 μmo/L). 8 Still there is no current consensus on whether to initiate treatment between 6-10 mg/ dl (360-600 μmol/L) because evidence regarding the clinical outcome in untreated patients within these limits is not definite. [10][11][12] However, the cut-off value to initiate treatment is accepted as 6 mg/dl (360 μmol/L) both in USA and EU guidelines.…”

Pieces of evidences of reliability of the Brazilian version of the Child Executive Functions Battery (CEF-B)

“…In addition, social and cultural conditions such as maternal nutrition, abuse of alcohol, and other drugs by the mother during pregnancy, inadequate living conditions, physical violence, and sexual abuse, among others, represent potential risk conditions for developmental dysfunctions. These clinical settings greatly impact executive functions (EF) as central symptoms (Craig et al 2016;Evinç et al 2018;Lonergan et al 2019;Mauger et al 2018;Zelazo 2020). In fact, the early and prolonged physiological maturation of the prefrontal circuits involved in the development of EF imposes a substantial vulnerability to these high-level skills (Dennis 2006).…”