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

Chloe Giret, Sybil Charrière, François Feillet, Alain Fouilhoux, Léonardo Astudillo, Christian Lavigne, Jean-Baptiste Arnoux, Sylvie Odent, Claire Gay, Manuel Schiff, et al.

► To cite this version:

Chloe Giret, Sybil Charrière, François Feillet, Alain Fouilhoux, Léonardo Astudillo, et al. Neurological and psychiatric issues in 187 adults with early-treated PKU: The ECOPHEN study. Molecular Genetics and Metabolism, 2026, 147 (1), pp.109706. 10.1016/j.ymgme.2025.109706. hal-05454297

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

Chloé Giret<sup>a</sup>, Sybil Charrière<sup>b,c,d</sup>, François Feillet<sup>e</sup>, Alain Fouilhoux<sup>c</sup>, Leonardo Astudillo<sup>f</sup>, Christian Lavigne<sup>g</sup>, Jean-Baptiste Arnoux<sup>h</sup>, Sylvie Odent<sup>i</sup>, Claire Gay<sup>j</sup>, Manuel Schiff<sup>k</sup>, Karin Mazodier<sup>l</sup>, Alice Kuster<sup>m</sup>, Vincent Rigalleau<sup>n</sup>, Christel Thauvin<sup>o</sup>, Vanessa Leguy-Seguin<sup>p</sup>, Hervé Lêvesque<sup>q</sup>, Elise Sacaze<sup>r</sup>, Gérard Besson<sup>s</sup>, Benjamin Thoreau<sup>a</sup>, Amélie Le Gouge<sup>t</sup>, Valérie Gissot<sup>t</sup>, Claire Douillard<sup>u</sup>, François Maillot<sup>a,v,*</sup>

## ARTICLE INFO

**Keywords:**

Phenylketonuria

Adults

Neurological disorders

Tremor

Psychiatric disorders

Depression

Anxiety

## 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

<footnote><sup>a</sup> Service de Médecine Interne, Centre de Référence des Maladies Héréditaires du Métabolisme, CHU de Tours, Tours, France</footnote>

<footnote><sup>b</sup> Fédération d'Endocrinologie, Maladies Métaboliques, Diabète, et Nutrition, Hôpital Louis Pradel, Hospices Civils de Lyon, Bron, France.</footnote>

<footnote><sup>c</sup> Hospices Civils de Lyon, Centre de Référence Des Maladies Héréditaires du Métabolisme de Lyon, Groupement Hospitalier Est, 69677, Bron Cedex, France.</footnote>

<footnote><sup>d</sup> CarMen Laboratory, INSERM, INRAE, Université Claude Bernard Lyon 1, Pierre Bénite, France</footnote>

<footnote><sup>e</sup> Centre de Référence des Maladies Métaboliques, Service de Pédiatrie, CHRU de Nancy, INSERM 1256 NGERE, Nancy, France</footnote>

<footnote><sup>f</sup> Service de Médecine Interne, CHU de Toulouse, clinique Saint-Exupéry, Toulouse, France</footnote>

<footnote><sup>g</sup> Service de Médecine Interne et d'Immunologie Clinique, CHU d'Angers, Angers, France</footnote>

<footnote><sup>h</sup> Centre de Référence des Maladies Métaboliques, Hôpital Necker-Enfants Malades, AP-HP, Paris, France</footnote>

<footnote><sup>i</sup> Service de Génétique Clinique, Centre de référence CLAD-Ouest, Univ Rennes, IGDR Institut de Génétique et Développement de Rennes, CNRS INSERM UMR 6290 URL 1305, Rennes, France</footnote>

<footnote><sup>j</sup> Service de Pédiatrie, Centre de Compétence des Maladies Héréditaires du Métabolisme de St Etienne, CHU de Saint-Étienne, Hôpital Nord, Saint-Étienne, France</footnote>

<footnote><sup>k</sup> Reference Center for Inborn Errors of Metabolism, Necker University Hospital, APHP and University of Paris Cité, Filière G2M, MetabERN, INSERM UMRS 1163, Institut Imagine Paris, France</footnote>

<footnote><sup>l</sup> Centre de Référence des Maladies Métaboliques de Marseille, Service de Médecine Interne et Immunologie Clinique, Hôpital de La Conception, AP-HM, Marseille, France</footnote>

<footnote><sup>m</sup> Service de Pédiatrie, CHU de Nantes, Nantes, France</footnote>

<footnote><sup>n</sup> Service d'Endocrinologie, Diabétologie, Nutrition, CHU de Bordeaux, Hôpital Haut-Lèveque, Pessac, France</footnote>

<footnote><sup>o</sup> Centre de Référence Déficiences Intellectuelles de Causes Rares, Centre de Génétique, Hôpital d'Enfants, CHU Dijon Bourgogne, Inserm - Université de Bourgogne, U1231 GAD, Génétique des Anomalies du Développement, Dijon, France</footnote>

<footnote><sup>p</sup> Service de Médecine Interne et d'Immunologie Clinique, CHU de Dijon, Dijon, France</footnote>

<footnote><sup>q</sup> Service de Médecine Interne, CHU de Rouen, Rouen, France</footnote>

<footnote><sup>r</sup> Service de pédiatrie, CHU de Brest, Brest, France</footnote>

<footnote><sup>s</sup> Service de Neurologie, CHU de Grenoble, Grenoble, France</footnote>

<footnote><sup>t</sup> Centre d'investigation Clinique CIC 1415 INSERM, CHRU de Tours, Tours, France</footnote>

<footnote><sup>u</sup> Service d'Endocrinologie et des Maladies Métaboliques, CHU de Lille, Centre de Référence des Maladies héréditaires du Métabolisme, Lille, France</footnote>

<footnote><sup>v</sup> UMR INSERM 1253 « iBraiN », université de Tours, Tours, France</footnote>

<footnote>* Corresponding author at: Service de Médecine Interne Hôpital Bretonneau, CHU de Tours, ²Bd Tonnellé, 37044 cedex, Tours, France.
E-mail address: francois.maillot@univ-tours.fr (F. Maillot).</footnote>
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.

# 1. Introduction

Phenylketonuria (PKU, OMIM 261600) is an autosomal recessive genetic disorder in relation with a phenylalanine hydroxylase (PAH) deficiency due to mutations in the *PAH* gene. The incidence of PKU varies worldwide, reaching a prevalence of 1/10,000 newborns in Europe [1]. Because of PAH deficiency, phenylalanine (Phe) is not converted into tyrosine and then accumulates in both blood and brain. Untreated PKU induces phenylalanine intoxication which is responsible for motor developmental abnormalities, delayed acquisition, neurocognitive disorders and behavioral disturbances [2]. Late treated patients may also exhibit neurological and psychiatric issues at the adult age [3]. Thanks to the Guthrie test developed in the 1960s, PKU became the first genetic disease to benefit from newborn screening (NBS). In France, NBS has been nationally implemented since 1972. Thus, individuals detected through NBS are promptly treated using a Phe-controlled diet or sapropterin therapy for those who are BH4 responders. Long term evolution is classically considered as satisfactory in adults with early-treated PKU [4]. However, in this group of patients, some questions have been raised about a potential suboptimal outcome [5-7]. Beyond subtle neurocognitive issues, some somatic neurological complications have been reported in adults with early-treated PKU, mostly as publications of case reports and case-series [8-12]. Psychiatric issues have also been studied in these patients. They mostly include low mood, anxiety, depression, mood swings and phobias [13-18]. However, no systematic screening for such neuropsychiatric issues has been performed in a large group of patients. The ECOPHEN study, which was a French prospective 5-year multicenter cohort study, was designed to collect health outcome data in this specific group of patients. As such, the aim of the present study was to gather data about neurological and psychiatric issues in a large number of adults with early-treated PKU. Here we present the cross-sectional data obtained at the inclusion visit of the ECOPHEN study.

# 2. Patients and methods

## 2.1. Study design and settings

Patients were included in the national 5-year prospective ECOPHEN cohort from 17 centers of expertise/reference for inherited metabolic diseases in France (Tours, Lyon, Lille, Nancy, Toulouse, Angers, Paris-Necker, Rennes, Saint-Etienne, Paris-Robert Debré, Marseille, Nantes, Bordeaux, Dijon, Rouen, Brest, Grenoble). The duration of the study was 5 years, following an inclusion period of 3 years (start on 5/03/2012; end on 06/07/2020).

## 2.2. Ethics

Written informed consent was obtained from all patients. The study was conducted in accordance with the principles of the Helsinki Good Clinical Practice Guidelines and registered on [ClinicalTrial.Gov (NCT01619722)](http://ClinicalTrial.Gov/NCT01619722). Legal authorizations were obtained in 2011 (CPP Ouest-I Tours n°2011-R11, 24/05/2011; ANSM n°B110423-80, 26/04/2011). The ECOPHEN study was funded by the public national research

program "PHRC" (Programme Hospitalier de Recherche Clinique).

## 2.3. Patients

The patients' inclusion criteria were:

- age ≥ 18 years, diagnosis of PKU established at newborn screening (ET-PKU)

- Enrollment in a social security plan

Exclusion criteria were:

- presence of any severe chronic neurological/psychiatric history that could interfere with the screening for PKU-related neurological disorders (major cognitive deficit, schizophrenia)

- late diagnosis of PKU, and cancer at inclusion

## 2.4. Classification

Patients were classified into 3 groups according to the classification in use at the time of inclusion: classic PKU (cPKU), mild PKU (mPKU) and mild persistent hyperphenylalaninemia (MPH), corresponding to plasma Phe concentrations at PKU diagnosis following newborn screening above 1200 µmol/L, between 600 and 1200 µmol/L or below 600 µmol/L respectively. Patients were also classified by investigators according to whether they maintained or not a Phe-controlled diet in adulthood ("on diet" vs "off diet"), within the total population and within the cPKU patients subgroup.

## 2.5. Data collection

The present article only included the results from the baseline visit of the ECOPHEN study. At this inclusion visit, demographic data were collected, such as age, sex, marital and family status, and occupation. Data about therapeutic management of adults with early-treated PKU were also collected: continuation or cessation of the Phe-restrictive diet ("on diet" vs "off diet"), amino acid mixtures intake, treatment with sapropterin. Plasma concentrations of Phe and other amino acids were measured in each center at baseline by ion exchange chromatography. Neonatal Phe concentrations at diagnosis were collected retrospectively from the database of each participating center. Plasma vitamin B12 at baseline was measured by radioimmunology in each center.

The collection of neurological and psychiatric manifestations occurring at the adult age was performed by the referring physicians of investigating centers: collection of neurological and/or psychiatric history (clinical diagnosis, specialist requirement, admissions into neurological/psychiatric wards, specific therapy), medical interview and physical examination during the inclusion visit, including a thorough standardized somatic neurological examination. All clinical diagnoses were coded according to ICD10 into the ECOPHEN study database, hosted by the Center for Clinical Investigation of the University Hospital of Tours.
## 2.6. Statistical analysis

The results were analyzed in 3 parts, one dedicated to the analysis of neurological history, another dedicated to the analysis of neurological examination abnormalities, and the last part dedicated to the analysis of psychiatric history. In each part, the prevalence of abnormalities between the cPKU, mPKU and MPH groups were compared. A second analysis was performed concerning the presence or not of a PKU diet independently of the inclusion group, and then repeated only for the cPKU group. Continuous data are expressed as mean and standard deviation or median and interquartile range. Quantitative variables were analyzed using Wilcoxon-Mann-Whitney or Kruskal Wallis test. Categorical variables are expressed as frequencies and percentages and analyzed using the Chi-square test or Fisher's exact test. A *p* value <0.05 was considered as statistically significant. Statistical analyses were performed using SAS®, version 9.4 (SAS Institute).

# 3. Results

## 3.1. Patient characteristics

In the ECOPHEN cohort study, 191 patients were included, of whom 4 were secondarily excluded (Fig. 1). Of the remaining 187 patients, 68 % were women (n = 127). Median age at inclusion was 27.2 years [22.3; 32.3]. Among included patients, 152 (81 %) had cPKU, 26 (14 %) had mPKU, and 9 (5 %) had MPH. The general characteristics of the patients are summarized in Table 1. Considering Phe-controlled diet, 104 patients (56 %) were considered to be “on diet”. In this group of 104 patients, 88 were in the cPKU group, 14 in the mPKU group, and 2 in the MPH group. Two patients of the cPKU group and 3 patients of the mPKU group were treated with sapropterin. No patients of the MPH group were treated with sapropterin (Table 1).

In the cPKU group, plasma Phe was significantly higher as compared to both mPKU and MPH groups: 1156 µmol/L [833;1488] vs 730 µmol/L [636;914] vs 321 µmol/L [156;419] respectively (*p* < 0.0001). For the whole set of PKU patients, plasma Phe was 907 µmol/L [621;1280] in patients “on diet” vs 1177 µmol/L [875;1512] in patients “off diet” (*p* = 0.0024). Considering only patients with cPKU, plasma Phe was 1016 µmol/L [710;1340] in patients “on diet” vs 1350 µmol/L [1113;1583] in patients “off diet” (*p* < 0.0001). For the whole set of patients except for 7 patients for whom the dosage has not been performed, median plasma vitamin B12 was 282 pmol/L (209–400). Plasma vitamin B12 was not different between the 3 groups of patients (*p* = 0.95).

## 3.2. Neurological history

Neurological data are summarized in Table 2. Twenty-one patients (11.2 %) among 187 included patients had had one or more neurological issues in their medical history. All of these patients were among the cPKU group, representing 13.8 % of the total number of patients in this group. Among these 21 patients, 5 (23.8 %) reported a history of tremor, 4 (19 %) had a history of migraine, 3 (14.2 %) had memory loss, 3 had balance disorders, 1 had cortical blindness (4.8 %), 2 had cramps and spasms (9.5 %). Other neurological manifestations were reported as non-specific headache and monocular blindness were described in 1 patient. No neurological history was reported in both mPKU and MPH groups. When comparing the prevalence of neurological history of the cohort, there was no significant statistical difference between “on diet” and “off diet” patients (*p* = 0.28).

## 3.3. Neurological examination

The most common abnormality reported from neurological examination was the presence of abnormal osteotendinous reflexes in 54 patients of the cohort (28.9 %). Of these patients, 51 (33.6 %) were in the cPKU group and 3 (11.5 %) in the mPKU group. There was no abnormality of deep tendon reflexes in patients from the MPH group. The prevalence of deep tendon reflexes abnormalities was higher in the cPKU group compared to mPKU and MPH groups (*p* = 0.0085). Among all patients with abnormal deep tendon reflexes, 47 (87 %) had sharp reflexes, including 44 patients in the cPKU group and 3 in the mPKU group. Eleven patients (20.4 %) had polykinetic reflexes, all being in the cPKU group. Eleven patients had diffuse reflexes, all being in the cPKU group as well (11.1 %). No functional impairment was clearly associated with these findings. Extremity tremor was observed in 24 patients (12.8 %) of the whole sample and in 23 patients (15.1 %) in the cPKU group. Regarding neurological examination of the whole cohort, there were no differences between “on diet” and “off diet” patients (data not shown). For all patients with neurological abnormalities, plasma vitamin B12 was normal. For the 7 patients without vitamin B12 result, none had neurological manifestations.

## 3.4. Psychiatric disorders

Among the 187 included patients, 48 (25.7 %) had psychiatric issues in their medical history. The repartition was 41 (27 %) patients in the cPKU group, 5 (19.2 %) in the mPKU group and 2 (22.2 %) in the MPH group. Such prevalence of psychiatric diseases was not different between the 3 groups of PKU patients (*p* = 0.75) (Table 2). The most commonly reported psychiatric disease was the existence of a depressive episode,

<figure><img src="image_4.png" /><figcaption>Fig. 1. Flowchart of the ECOPHEN cohort study at inclusion. MPH = moderate persistent hyperphenylalaninemia.</figcaption></figure>
<caption>**Table 1**</caption>

Characteristics of patients included in the ECOPHEN study. cPKU = classic PKU, mPKU = mild PKU, MPH = mild persistent hyperphenylalaninemia. Phe = phenylalanine, BH4 = tetrahydrobiopterin.

<table><thead><tr><th rowspan="2"></th><th rowspan="2"></th><th colspan="2">Total</th><th colspan="2">cPKU</th><th colspan="2">mPKU</th><th colspan="2">MPH</th><th rowspan="2">p-value</th></tr><tr><th>n</th><th></th><th>n</th><th></th><th>n</th><th></th><th>n</th><th></th></tr></thead><tbody><tr><td rowspan="2">Age</td><td></td><td>187</td><td>27,2 (22,3-32,3)</td><td>152</td><td>27,5 (22,5-32,4)</td><td>26</td><td>24,4 (21,0-28,6)</td><td>9</td><td>29,6 (24,1-31,4)</td><td>0,24</td></tr><tr><td>Female sex</td><td>187</td><td>127 (67,9)</td><td>152</td><td>102 (67,1)</td><td>26</td><td>18 (69,2)</td><td>9</td><td>7 (77,8)</td><td>0,79</td></tr><tr><td colspan="11"><strong>Phe-controlled diet</strong></td></tr><tr><td>Patients "on diet" (n, %)</td><td></td><td>187</td><td>104 (55,6)</td><td>152</td><td>88 (57,9)</td><td>26</td><td>14 (53,9)</td><td>9</td><td>2 (22,2)</td><td>0,11</td></tr><tr><td>Sapropterin therapy (n, %)</td><td></td><td>177</td><td>5 (2,8)</td><td>147</td><td>2 (1,4)</td><td>21</td><td>3 (14,3)</td><td>9</td><td>0 (0)</td><td>0,02</td></tr><tr><td>BH4 responsiveness (n, %)</td><td></td><td>94</td><td>16 (17,0)</td><td>78</td><td>8 (10,3)</td><td>14</td><td>6 (42,9)</td><td>2</td><td>2 (100)</td><td>0,004</td></tr><tr><td>Plasma Phe before treatment (µmol/L)</td><td></td><td>105</td><td>1620 (1100-2520)</td><td>79</td><td>2100 (1428-2724)</td><td>19</td><td>727 (605-1080)</td><td>7</td><td>420 (270-510)</td><td>&lt;0,0001</td></tr><tr><td>Plasma Phe at inclusion (µmol/L)</td><td></td><td>145</td><td>1050 (709-1410)</td><td>115</td><td>1156 (833-1488)</td><td>23</td><td>730 (636-914)</td><td>7</td><td>321 (156-419)</td><td>&lt;0,0001</td></tr></tbody></table>

found in 29 patients, which represented a prevalence of 15.5 % of the cohort and 60.4 % among overall psychiatric manifestations. Depressive episodes were observed in 25 patients of cPKU group, 2 patients of the mPKU group and 2 patients in MPH group (Table 2). A history of anxiety disorders has been observed in 25 patients of the cohort (13.4 %), 22 in the cPKU group and 3 in the mPKU group. Four patients presented a history of bulimia, all being in the cPKU group. Other issues such as aggressiveness, anorexia nervosa, delirious flashes, or claustrophobia and sleep disturbances have been reported and summarized in Table 2. All these patients were included in the cPKU group, with the exception of the patient with "mood sadness" in the mPKU group.

The analysis of all psychiatric disorders in patients "on diet" (n = 22, 21.2 %) and "off diet" (n = 26, 31.3 %) independently of the inclusion group did not find any statistically significant difference (p = 0.11). Ten of the patients "on diet" and 19 of the patients "off diet" had a history of depression, 14 of the patients "on diet" and 11 of the patients "off diet" had a history of anxiety disorders. The analysis of the prevalence of psychiatric disorders focusing only on patients included in the cPKU group and according to the presence of a current diet (n = 20, 22.7 %) or not (n = 21, 32.8 %) found no statistically significant difference (p = 0.20).

## 4. Discussion

The present study has included a significant number of adults with early-treated PKU and therefore provides an indication about the prevalence and the characteristics of neurological and psychological/psychiatric disorders in this population. Indeed, our data describe the variety of somatic neurological impairment that may occur in this group of patients, as well as manifestations that can be considered as psychiatric. The prevalence of neurological disorders in patients' history was estimated at 11.1 % in our cohort. This result is indicative of an overall good outcome in adults with early-treated PKU, but suggests that some neurological complications may persist from childhood or and adolescence, or may occur at adulthood. From the literature, it is difficult to estimate such prevalence as the published studies are usually include heterogeneous groups of PKU patients [12]. Moreover, in adults with early-treated PKU, neurological issues were mostly described as case reports/small case series [8-12]. It is also of note that most published studies usually focused on neurocognitive outcome of PKU and not specifically on somatic neurological diseases [19,20].

Our study did not include non-PKU controls for comparison, it is therefore not possible to determine whether the prevalence of 11,1 % of neurological issues is increased in comparison with non-PKU adults. A recent study using healthcare insurance claim data of French patients has shown that adults with early-treated PKU had more prescriptions of drugs to treat the nervous system in comparison to non-PKU controls which suggests that these individuals have an increased risk of neurological diseases to that of healthy controls [21]. Overall, it is usually considered by experts that these patients have a significant risk for

neurological complications in their lifespan, which is a justification for a lifelong follow-up²². Thus, consideration should also be given to involving a neurologist as part of the adult metabolic team.

Regarding neurological issues in adults with early-treated PKU, the question of the influence of metabolic control is crucial. So far, no study has shown that keeping Blood Phe within the recommended target range throughout adolescence and adulthood may prevent from somatic neurological impairment [23]. Moreover, it is now established that early treatment of PKU following newborn screening and good metabolic control during childhood has a positive influence on neurocognitive outcome [17], but there are not any data about such influence on somatic neurological outcome. As stated by Merkel et al., there is an absence of studies including a cohort of adults with early-treated PKU with a good metabolic control [12], that could show an overall good neurological outcome. Our study is not able to demonstrate that the onset of any neurological event was influenced by Phe control, neither in childhood nor at adolescence as retrospective metabolic data were not collected. However, it is of interest to note that neurological complications have exclusively occurred in the group of adults with cPKU, which is the most severe form of the disease and for which plasma Phe was significantly higher as compared to mPKU and MPH groups. This result could suggest a negative influence of elevated Phe levels on somatic neurological outcome in some patients with cPKU. More convincing data may come from the prospective part of the ECOPHEN study, in which we were able to collect longitudinal data over a 5y period along with Phe measurements every 3 months. These data will be analyzed in 2026 and published in a forthcoming publication.

The results of the analysis of neurological disorders showed a statistically significant difference in the presence of abnormal deep tendon reflexes (sharp reflexes) in patients of the cPKU group, whose plasma Phe was higher. This abnormality was statistically more frequent in comparison to the other groups, without being influenced by the presence of a current diet or not. However, a poor metabolic control has been observed in the Phe-controlled diet group (plasma Phe was 907 and 1016 µmol/L in the whole set of patients and in the cPKU group, respectively). Indeed, such Phe results were higher than expected in patients who are supposed to be "on diet". They may explain the absence of difference between "on diet" and "off diet" groups of patients. It is of note that such data were collected before the publication of the European PKU guidelines which suggested a Phe target of 120-600 µmol/L for adult patients [22]. Sharp reflexes have already been reported in previous studies other than case reports/series [24,25]. They are commonly recognized as a sign of poor metabolic control of PKU, although this has not been clearly demonstrated. Moreover, from our data and the literature analysis, deep tendon reflex abnormalities have never been shown to be clearly associated with functional impairment in adults with early-treated PKU. Regarding tremor, we identified 23 affected patients (15.1 %) in the cPKU group. This rate of tremor is lower as those described in adults with early-treated PKU by Pietz et al [26] and Nardecchia et al [27], which were 28 % and 32 %, respectively. It is
<table><caption>**Table 2**
Report of neurological and psychiatric issues in a group of 187 adults with early-treated PKU. MPH = moderate persistent hyperphenylalaninemia.</caption><thead><tr><th></th><th>n</th><th>Total<br>187</th><th>n</th><th>Classic PKU<br>152</th><th>n</th><th>Mild PKU<br>26</th><th>n</th><th>Mild HPA<br>9</th><th>p-value*</th></tr></thead><tbody><tr><td colspan="10"><strong>Neurological history</strong></td></tr><tr><td>Total abnormal history (n patients (%))</td><td>187</td><td>21 (11.2)</td><td>152</td><td>21</td><td>26</td><td>0</td><td>9</td><td>0 (0)</td><td>0,0740</td></tr><tr><td>Cortical cecity</td><td>21</td><td>1 (4.8)</td><td>21</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Cramps and spasm</td><td>21</td><td>2 (9.5)</td><td>21</td><td>2</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Monocular cecity</td><td>21</td><td>1 (4.8)</td><td>21</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Non specific headache</td><td>21</td><td>1 (4.8)</td><td>21</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>White brain substance demyelinization</td><td>21</td><td>1 (4.8)</td><td>21</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Diploplia</td><td>21</td><td>1 (4.8)</td><td>21</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Idiopathic encephalopathy</td><td>21</td><td>1 (4.8)</td><td>21</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Lumbar disc hernia</td><td>21</td><td>1 (4.8)</td><td>21</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Non specific periventricular leucoencephalopathy</td><td>21</td><td>1 (4.8)</td><td>21</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Meningioma</td><td>21</td><td>1 (4.8)</td><td>21</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Migraine</td><td>21</td><td>4 (19)</td><td>21</td><td>4</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Myoclonus</td><td>21</td><td>1 (4.8)</td><td>21</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Hemicorporeal paresthesia</td><td>21</td><td>1 (4.8)</td><td>21</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Loss of memory</td><td>21</td><td>3 (14.2)</td><td>21</td><td>3</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Balance loss</td><td>21</td><td>3 (14.2)</td><td>21</td><td>3</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Tremors</td><td>21</td><td>5 (23.8)</td><td>21</td><td>5</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Benign pituitary tumor</td><td>21</td><td>1 (4.8)</td><td>21</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="10"><strong>Neurological examination</strong></td></tr><tr><td>Extremity tremor</td><td>187</td><td>24 (12.8)</td><td>152</td><td>23</td><td>26</td><td>1</td><td>9</td><td>0 (0)</td><td>0,1952</td></tr><tr><td>Abnormal Deep Tendon Reflexes</td><td>187</td><td>54 (28.9)</td><td>152</td><td>51</td><td>26</td><td>3</td><td>9</td><td>0 (0)</td><td>0,0085</td></tr><tr><td>Sharp reflexes</td><td>54</td><td>47 (87)</td><td>51</td><td>44</td><td>3</td><td>3</td><td></td><td></td><td></td></tr><tr><td>Polycinetic reflexes</td><td>54</td><td>11 (20.4)</td><td>51</td><td>11</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Diffuse reflexes</td><td>54</td><td>11 (20.4)</td><td>51</td><td>11</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Decreased reflexes</td><td>54</td><td>6 (11.1)</td><td>51</td><td>6</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Absent reflexes</td><td>54</td><td>1 (1.9)</td><td>51</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Pyramidal syndrome</td><td>187</td><td>4 (2.1)</td><td>152</td><td>4</td><td>26</td><td>0</td><td>9</td><td>0 (0)</td><td>1</td></tr><tr><td>Extrapyramidal syndrome</td><td>186</td><td>1 (0.5)</td><td>151</td><td>1</td><td>26</td><td>0</td><td>9</td><td>0 (0)</td><td>1</td></tr><tr><td>Cerebellar syndrome</td><td>187</td><td>2 (1.1)</td><td>152</td><td>2</td><td>26</td><td>0</td><td>9</td><td>0 (0)</td><td>1</td></tr><tr><td>Others neurological disorder</td><td>187</td><td>11 (5.9)</td><td>152</td><td>11</td><td>26</td><td>0</td><td>9</td><td>0 (0)</td><td>1</td></tr><tr><td>Ataxia</td><td>11</td><td>1 (9)</td><td>11</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Monocular blindness</td><td>11</td><td>1 (9)</td><td>11</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Headache</td><td>11</td><td>1 (9)</td><td>11</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Visual defect</td><td>11</td><td>1 (9)</td><td>11</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Hearing loss</td><td>11</td><td>1 (9)</td><td>11</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Memory disorder</td><td>11</td><td>1 (9)</td><td>11</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Sciatica</td><td>11</td><td>1 (9)</td><td>11</td><td>1</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Vestibular syndrome</td><td>11</td><td>2 (18.1)</td><td>11</td><td>2</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Sensitivity defect</td><td>11</td><td>2 (18.1)</td><td>11</td><td>2</td><td></td><td></td><td></td><td></td><td></td></tr><tr><td colspan="10"><strong>Psychological and psychiatric history</strong></td></tr><tr><td>Total abnormal history (n patient (%)) (a)</td><td>187</td><td>48 (25.7)</td><td>152</td><td>41 (27,0)</td><td>26</td><td>5 (19,2)</td><td>9</td><td>2 (22,2)</td><td>0,7492</td></tr><tr><td>Agressiveness (b)</td><td>48</td><td>1 (2.1)</td><td>41</td><td>1</td><td>5</td><td></td><td>2</td><td></td><td></td></tr><tr><td>Anorexia</td><td>48</td><td>1 (2.1)</td><td>41</td><td>1</td><td>5</td><td></td><td>2</td><td></td><td></td></tr><tr><td>Delirious access</td><td>48</td><td>2 (4.2)</td><td>41</td><td>2</td><td>5</td><td></td><td>2</td><td></td><td></td></tr><tr><td>Bulimia</td><td>48</td><td>4 (8.3)</td><td>41</td><td>4</td><td>5</td><td></td><td>2</td><td></td><td></td></tr><tr><td>Claustrophobia</td><td>48</td><td>1 (2.1)</td><td>41</td><td>1</td><td>5</td><td></td><td>2</td><td></td><td></td></tr><tr><td>Depressive episode</td><td>48</td><td>29 (60.4)</td><td>41</td><td>25</td><td>5</td><td>2</td><td>2</td><td>2</td><td></td></tr><tr><td>Irritability, anger</td><td>48</td><td>1 (2.1)</td><td>41</td><td>1</td><td>5</td><td></td><td>2</td><td></td><td></td></tr><tr><td>Somnambulism</td><td>48</td><td>1 (2.1)</td><td>41</td><td>1</td><td>5</td><td></td><td>2</td><td></td><td></td></tr><tr><td>Sadness</td><td>48</td><td>1 (2.1)</td><td>41</td><td></td><td>5</td><td>1</td><td>2</td><td></td><td></td></tr><tr><td>Anxious disorders</td><td>48</td><td>25 (5.1)</td><td>41</td><td>22</td><td>5</td><td>3</td><td>2</td><td></td><td></td></tr><tr><td>Sleep disorders</td><td>48</td><td>2 (4.2)</td><td>41</td><td>2</td><td>5</td><td></td><td>2</td><td></td><td></td></tr><tr><td>Obsessive compulsive disorders</td><td>48</td><td>1 (2.1)</td><td>41</td><td>1</td><td>5</td><td></td><td>2</td><td></td><td></td></tr><tr><td>Drug suicide attempt</td><td>48</td><td>1 (2.1)</td><td>41</td><td>1</td><td>5</td><td></td><td>2</td><td></td><td></td></tr></tbody></table>

of note that in both studies, tremor was detected and characterized with sensitive tools that we did not use in the present study.

An argument in favor of an association between Phe levels and neurological manifestations would be the reversibility of neurological disorders when treatment is resumed. From the present study and in many data from the literature, diet does not seem to influence the onset of neurological manifestations regardless of the group of PKU analyzed. Notably, we do not find a statistical association between current diet and the frequency of deep tendon reflex abnormalities in our cohort, but this result is likely related to the average suboptimal metabolic control in the restrictive diet group. Our data are consistent with the literature,

including the cohort of Pietz et al. [26] The work of Thompson et al. did not find any improvement in neurological status despite the implementation of a PKU diet, but showed an improvement in brain MRI with a significant decrease in demyelinating white matter lesions [10]. In Brenton et al.'s study including 132 patients, the benefit of diet on the incidence of neurological disorders was not clearly established as well [28]. On the other hand, Jaulent et al. reported 8 patients who presented neurological manifestations such as tremors, cortical blindness, and reflex abnormalities, and all of whom recovered *ad integrum* after a decrease in blood Phe levels below 1000 µmol/L⁹. In this study, one patient had decreased visual acuity, tremors, and cerebellar ataxia but
had vitamin B9 and B12 deficiency supplemented at the same time as the diet was started. These observations suggest that subacute neurological manifestations in adults with early-treated PKU can resolve when a Phe restrictive diet is resumed.

In our study, there was no significant difference in psychiatric history in the prevalence of psychiatric issues between the cPKU (27 %), mPKU (19.2 %) and MPH (22.2 %) groups (p = 0.75). The presence or absence of a current diet, independently of the inclusion group and only in the cPKU group did not highlight any significant statistical difference, suggesting the absence of influence of the diet in the occurrence of psychiatric issues. We also found that the most frequently reported psychiatric disorders were anxiety disorders and a history of depressive syndrome. Indeed, anxiety and depression were reported in 25 and 29 patients, representing a prevalence of 13,6 % and 15.5 % of our cohort respectively. As the present study is a non-comparative cohort study, it is difficult to conclude whether the prevalence of both anxiety and depression was increased as compared to a non-PKU control group. However, a French epidemiological study showed a prevalence of depression in 2017 of 9.8 % in a population of 25,319 individuals aged from 18 to 67 years [29]. Interestingly, such prevalence was higher in women (13 %) and in individuals aged 15-44 years (11,5 %). As our study included more women than men and patients with a median age of 27.2 years, we could therefore estimate that the prevalence of depression was higher in adults with early-treated PKU than in the general population. The systematic review and meta-analysis of Bilder et al. also showed a higher prevalence of anxiety disorders (15.6 %) and depressive syndromes (19.5 %) than other psychiatric disorders [30]. However, the relation between anxiety/depression and phenylalanine levels in adults with early-treated PKU has not been established to date [31,32]. We also acknowledge that psychiatric manifestations in PKU may partly result from psychosocial and adherence-related factors.

Our study has some strengths and limitations. To our knowledge, this is the first to specifically report neuropsychiatric issues in a significant number of adults with early-treated PKU. As designed as a cohort study, the ECOPHEN project was able to provide "real life" information about this group of patients. The consistency of our results has also to be underlined as neurological disorders have only been described in the cPKU group which is the most severe form of the disease. However, the present study has also some limitations. First, the cross-sectional design limits causal inference of data. It is of note that our statistical analyses were not adjusted for multiplicity, so the findings should be interpreted as exploratory. The representativity of adults with early-treated PKU population can be questioned, as we only include patients followed in expert centers. This is illustrated in particular by the female preponderance of our patients which is linked to the fact that women with PKU are made aware from pre-adolescence about the risk of phenylketonuric embryofoetopathy. Therefore, the frequency of neuropsychiatric disorders might have been underestimated, due to patients' loss of follow-up. The absence of a control group does not make it possible to determine whether the prevalence of neuropsychiatric disorders was higher in PKU than in the general population. Our study does not permit us to establish whether the metabolic balance during childhood and/or adolescence could have influenced the occurrence of neuropsychiatric disorders in adulthood, because pediatric data were not collected. Thus, the influence of long-term metabolic control and historical Phe variability could not be assessed. Finally, neurological and psychiatric history has been retrospectively collected, constituting a potential measurement bias.

## 5. Conclusion

The present study displayed neurological and psychiatric issues that can be observed in a "real life" context of adults with PKU. It describes clinical features that have been documented in previous studies, but in smaller groups. Overall, our data showed that 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. The influence of Phe levels on the occurrence of neuropsychiatric issues has to be explored in prospective studies comparing patients with poor metabolic control vs good metabolic control.

## CRediT authorship contribution statement

Chloé Giret: Writing – original draft, Visualization, Formal analysis.
Sybil Charrière: Writing – review & editing, Investigation, Data cura-
tion. François Feillet: Writing – review & editing, Investigation. Alain
Fouilhoux: Writing – review & editing, Investigation. Leonardo Astu-
dillo: Writing – review & editing, Investigation. Christian Lavigne:
Writing – review & editing, Investigation. Jean-Baptiste Arnoux:
Writing – review & editing, Investigation. Sylvie Odent: Writing – re-
view & editing, Investigation. Claire Gay: Writing – review & editing,
Investigation. Manuel Schiff: Writing – review & editing, Investigation.
Karin Mazodier: Writing – review & editing, Investigation. Alice
Kuster: Writing – review & editing, Investigation. Vincent Rigalleau:
Writing – review & editing, Investigation. Christel Thauvin: Writing –
review & editing, Investigation. Vanessa Leguy-Seguin: Writing – re-
view & editing, Investigation. Hervé Lèvesque: Writing – review &
editing, Investigation. Elise Sacaze: Investigation. Gérard Besson:
Writing – review & editing, Investigation. Benjamin Thoreau: Writing –
review & editing, Data curation, Conceptualization. Amélie Le Gouge:
Writing – original draft, Validation, Formal analysis, Data curation.
Valérie Gissot: Writing – review & editing, Investigation, Conceptual-
ization. Claire Douillard: Writing – review & editing, Investigation.

## 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.

## Acknowledgement

Mrs. Penelope HODGES, for English review.

## Data availability

Data will be made available on request.

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