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Multicenter Study
. 2026 Jan;147(1):109706.
doi: 10.1016/j.ymgme.2025.109706. Epub 2025 Dec 16.

Neurological and psychiatric issues in 187 adults with early-treated PKU: The ECOPHEN study

Chloé Giret  1 , Sybil Charrière  2 , François Feillet  3 , Alain Fouilhoux  4 , Leonardo Astudillo  5 , Christian Lavigne  6 , Jean-Baptiste Arnoux  7 , Sylvie Odent  8 , Claire Gay  9 , Manuel Schiff  10 , Karin Mazodier  11 , Alice Kuster  12 , Vincent Rigalleau  13 , Christel Thauvin  14 , Vanessa Leguy-Seguin  15 , Hervé Lêvesque  16 , Elise Sacaze  17 , Gérard Besson  18 , Benjamin Thoreau  1 , Amélie Le Gouge  19 , Valérie Gissot  19 , Claire Douillard  20 , François Maillot  21
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Free article
Multicenter Study

Neurological and psychiatric issues in 187 adults with early-treated PKU: The ECOPHEN study

Chloé Giret et al. Mol Genet Metab. 2026 Jan.
Free article

Abstract

Introduction: Phenylketonuria (PKU) is an autosomal recessive disorder caused by mutations in the PAH gene leading to phenylalanine hydroxylase deficiency. This results in the accumulation of phenylalanine (Phe) in blood and brain, causing neurological and psychiatric impairments if untreated. Newborn screening (NBS) introduced in the 1960s enables early PKU diagnosis, allowing prompt dietary or sapropterin treatment. The long-term outcomes in adults with early-treated PKU, however, may include subtle neurocognitive deficits alongside somatic neurological and psychiatric complications, which remain incompletely characterized.

Patients and methods: The ECOPHEN study was a French 5-year multicenter prospective cohort assessing neuropsychiatric disorders in adults with early-treated PKU.

Results: Here are presented the data at inclusion. The study recruited 187 patients who were classified by PKU severity-classic, mild, or mild persistent hyperphenylalaninemia-and diet adherence status. Neurological history revealed symptoms in 11.2 % of patients, exclusively in classic PKU, including tremor, migraines, and balance disorders, without significant differences between diet groups. Neurological examination abnormalities predominantly included abnormal deep tendon reflexes in classic PKU patients. Psychiatric issues affected 25.7 % of patients across severity groups, mainly depressive episodes and anxiety, with no clear influence of diet adherence.

Discussion/conclusion: The present study highlights neurological complications persisting despite early treatment, particularly in classic PKU. Diet adherence and current plasma Phe levels did not correlate significantly with neurological or psychiatric outcomes, possibly due to suboptimal metabolic control. Limitations included the cross-sectional design, absence of control group, and retrospective data collection. Overall, adults with early-treated PKU show a generally favorable outcome but remain at risk for neuropsychiatric manifestations, supporting the need for lifelong follow-up including neurologic and psychiatric evaluation.

Keywords: Adults; Anxiety; Depression; Neurological disorders; Phenylketonuria; Psychiatric disorders; Tremor.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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