Original article

Progressive neuropsychiatric manifestations ofphenylketonuria in adulthood

Phenylcetonurie progressant a l’age adulte : manifestationsneurologiques et modalites evolutives

L. Daelman a,b, F. Sedel c,d, A. Tourbah a,*,b,e

aDepartment of Neurology, CHU de Reims, 45, rue Cognacq-Jay, 51100 Reims, FrancebURCA, UFR Medecine, 45, rue Cognacq-Jay, 51100 Reims, FrancecDepartment of Neurology, Neurometabolic Unit and Reference Center for Lysosomal Diseases, Salpetriere Hospital,

47-83, boulevard de l’Hopital, 75651 Paris cedex 13, FrancedGroupe de recherche en neurometabolisme (GRC13), Universite Pierre-et-Marie-Curie, 4, place Jussieu, 75005 Paris,

FranceeEA 2027 LPN, UFR psychologie, Universite Paris VIII, 2, rue de la Liberte, 93526 Saint-Denis cedex, France

r e v u e n e u r o l o g i q u e 1 7 0 ( 2 0 1 4 ) 2 8 0 – 2 8 7

i n f o a r t i c l e

Article history:

Received 14 May 2013

Received in revised form

14 August 2013

Accepted 13 September 2013

Available online 13 April 2014

Keywords:

Phenynylketonuria

MRI

Leukoencephalopathy

Paraparesis

Mots cles :

Phenylcetonurie

IRM

Leucoencephalopathie

Paraparesie spastique

a b s t r a c t

Introduction. – Neuropsychiatric signs and MRI abnormalities can occur in patients with

phenylketonuria in adulthood. We describe clinical and radiological features of phenylke-

tonuric patients and we discuss the advantage of continuing diet in adulthood.

Method. – We report late onset neuropsychiatric symptoms of four phenylketonuric

patients (33–45 years) diagnosed in infancy and report the case of a patient (33 years)

diagnosed with phenylketonuria because of late onset neurological signs. We describe

clinical and radiological features of these 5 patients, and their evolution under diet and

propose a review of the literature.

Results. – The main neurological abnormalities in phenylketonuric patients diagnosed in

infancy are: brisk reflexes, spastic paraparesis, psychiatric signs that appear 10.5 years after

the diet arrest. A leukoencephalopathy was present in 93% of cases and 91.7% improve

clinically after poor phenylalanine diet reintroduction. In 4 patients, neurological abnor-

malities (spastic paraparesis, dementia, Parkinsonism) led to the late diagnosis. Two of

them had a leukoencephalopathy on brain MRI. Patients had high levels of phenylalanine

(above 1500 mmol/L) when neuropsychiatric signs occurred. Improvement after diet sug-

gests that hyperphenylalaninemia has a direct toxic effect on the brain.

Discussion/Conclusion. – The long-term follow-up of phenylketonuric patients is mandatory

to depict and treat neurological complications in time. Diet reintroduction is efficacious in

most cases.

# 2014 Published by Elsevier Masson SAS.

* Corresponding author.E-mail addresses: atourbah@chu-reims.fr, ayman.tourbah@psl.aphp.fr (A. Tourbah).

Available online at

ScienceDirectwww.sciencedirect.com

http://dx.doi.org/10.1016/j.neurol.2013.09.0120035-3787/# 2014 Published by Elsevier Masson SAS.

1. Introduction� articles published in French or English;

� patients with clear neurological or psychiatric syndromes,

excluding patients with minor cognitive abnormalities only;

r e s u m e

Introduction. – La phenylcetonurie peut entraıner a l’age adulte des troubles neuropsychia-

triques et des anomalies a l’IRM cerebrale. Nous decrivons l’evolution des manifestations

cliniques et IRM de patients phenylcetonuriques.

Methode. – Etude de cas et revue de la litterature. Nous rapportons les manifestations

neuropsychiatriques tardives de 5 patients phenylcetonuriques et nous presentons une

revue de la litterature.

Resultats. – Les sympto mes neurologiques chez les phenylcetonuriques connus apparais-

sent en moyenne 10,5 ans apres la suspension du regime. Une leucoencephalopathie est

presente dans 93 % des cas. Lors de l’apparition des troubles, les patients ont une hyper-

phenylalaninemie elevee. Apres reprise du regime, une amelioration clinique est constatee

dans 91,7 % des cas suggerant un effet toxique direct de la phenylalanine.

Discussion/Conclusion. – La surveillance de la phenylalaninemie a l’age adulte permettrait

d’eviter les complications neuropsychiatriques grace a la reprise du regime.

# 2014 Publie par Elsevier Masson SAS.

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Phenylketonuria (PKU) is an autosomal recessive genetic

disorder characterized by a deficiency in the hepatic enzyme

phenylalanine hydroxylase (PAH). Incidence is about 1:10,000

in Europe [1]. The level of phenylalaninemia correlates with

the prognosis, as patients with moderate hyperphenylanani-

nemia (180–600 mmol/L) usually remain asymptomatic whe-

reas untreated patients with classical PKU (Phe > 1200 mg/dL),

will suffer from neurological or psychiatric disorders (mental

retardation, behavioural problems, epilepsy, movement dis-

orders, or spasticity) [2]. Postnatal screening diagnosis

followed by early treatment with a Phe free diet results in a

nearly normal cognitive development [2]. Treatment guide-

lines vary among countries. In France, it is recommended to

maintain Phe between 120 and 300 mmol/L until 10–11 years of

age then below 900 mmol/L until the end of school age and then

below 1200 mmol/L in adulthood [3]. Many patients show white

matter abnormalities on brain MRI. These abnormalities are

not correlated to intellectual or neurological signs and can be

reversible after reintroduction of the diet [4]. A very small

proportion of adolescent and adult patients will develop frank

neurological symptoms that may improve under dietary

treatment [5]. In addition, very few publications reported

the cases of adult patients that escaped neonatal screening

and remained poorly symptomatic until neurological symp-

toms progressed in adulthood. Here, we took advantage of 5

personal cases and of a literature review to delineate the

neuropsychiatric signs observed in adults with PKU.

2. Methods

Five patients were referred to the Adult Neurometabolic Unit,

Ho pital de la Salpetriere for adult-onset neurological or

psychiatric symptoms in the context of PKU. A literature

review was performed, using the Pubmed database and the

authors own bibliography to gather previous published cases.

Inclusion criteria were:

� age at onset of neuropsychiatric signs after 15 years old;

� neuropsychiatric signs not explained by other causes.

3. Description of our cases

3.1. Patient 1

A man, aged 32 years, was evaluated for a 2 years history of

slowly progressive spastic paraparesis. He was diagnosed with

PKU by neonatal screening and low Phe diet was introduced at

1 month (see Table 1 for a summary). Observance of the diet

was reported to be non-optimal with poor metabolic control

during infancy and childhood. He walked at 16 months and

spoke at 2 years. He went in a specialised school, but he never

learned to read or to write. He totally stopped the diet at

30 years. Clinical examination at 32 revealed a marked low

limbs pyramidal syndrome with spastic gait. Brain MRI

disclosed a leukoencephalopathy involving the posterior

and periventricular white matter. A poor Phe diet was then

introduced leading to disappearance of the spasticity and

normalisation of the gait while brain MRI remained unchan-

ged. Follow-up during the next years revealed that high Phe

values above 900 mmol/L were associated with reappearance

of the spastic gait and that strict Phe control below this range

was associated with gait normalization.

3.2. Patient 2

This woman was aged 38 when she was evaluated for

psychiatric symptoms. She was diagnosed with PKU at 10 days

of age through neonatal screening. The patient was abando-

ned by her parents and lived in an institution until she was

adopted at the age of 6 years. A low Phe diet was introduced

from 1.5 months to 4.5 years old and interrupted thereafter.

The metabolic control in infancy and childhood is difficult to

evaluate but was probably bad, as Phe was measured once at

2650 mmol/L when she was 5 years old. Walking and speaking

Table 1 – Literature data: PKU patients diagnosed during infancy and our patients 1 to 4.

Patients Sex Phe levels ondiet duringinfancy (mmol/L)

Age at dietonset (m)

Age at dietarrest (y)

Age at onsetof neurologicalworsening (y)

Phe at neurologicaldeterioration(mmol/L)

Improvement withreintroduction ofthe diet

Phe withre-institutionof the diet(mmol/L)

Genetics

Villasana et al. M NA 36 12 28 1660 + 217 NA

M NA Neonat 6 18 1640 + NA NA

McCombe et al. M 893–1200 0.5 18 19 1900 + 1760–2410 Haplotype 2

Wood et al. M 120–480 10 14 15 1600 + 340 NA

Thompson et al. M NA 1.75 16 20 1334 + NA NA

M 60–1100 1.5 18 16 NA No diet No diet NA

M 180–1600 0.25 19 19 NA No diet No diet NA

M NA 36 7 25 1386 – 180 NA

F 330–1400 15 7 20 1533 + NA NA

F 180–1000 18 7 15 NA + NA NA

Evans et al. F 180–360 24 13 33 590 NA NA NA

Patient 1 M 790–1520 1 30 30 1200 + 670–1360 NA

Patient 2 F NA 1.5 4.5 16 2000 + 750–1540 NA

Patient 3 F NA 42 7 40 NA + NA NA

Patient 4 F NA 1 5 26 1380 + 60–480 NA

Patients Leukoen-cephalopathy

Brisk reflexes Spastic paraparesis Tremor Psychiatric signs Epilepsy Dystonia Ataxia Parkinsonism IQ

Villasana et al. + + + + – + – – – Mental retardation

+ – – + + – – – – 81

McCombe et al. + + + – + – – – – 88

Wood et al. NA + + + + + – – – 59

Thompson et al. 5/6 + + – + – – – – Mental retardation

+ – + + + – – – 64

+ + – – – – + – 61

+ + + – – + – – 95

+ + – – – – – – 45

+ + + – – + – – 45

Evans et al. + + – + – – – – + NA

Patient 1 + + + – – – – – – Mental retardation

Patient 2 + + – – + – – – – 53

Patient 3 + – – – + – – – – Mental retardation

Patient 4 + – – + + – – – – NA

r e

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e n

e u

r o

l o

g i

q u

e 1

7 0

(

2 0

1 4

) 2

8 0

– 2

8 7

28

2

Fig. 1 – FLAIR sequences, axial plane. a: patient 2: leukoencephalopathy appearing as a mild hyperintensity, involving

posterior areas, both centrum semi-oval and outlining the splenium of corpus callosum; b and c: patient 3:

leukoencephalopathy involving frontal, parieto-occipital areas and both centrum semi-oval before diet (b); decrease of

hypersignal intensity, 6 months after diet reintroduction, with persistence in optic radiations (c).

r e v u e n e u r o l o g i q u e 1 7 0 ( 2 0 1 4 ) 2 8 0 – 2 8 7 283

were delayed (IQ around 50 at 7 years). In late teens, she

started to develop psychotic symptoms including auditory

hallucinations, interpretative thoughts, and hypochondriac

complaints. These psychiatric symptoms remained during the

following years, leading to social and familial withdrawal.

Neurological examination showed brisk reflexes and a left

Babinski’s sign. Brain MRI disclosed a mild posterior leukoen-

cephalopathy (Fig. 1a). Introduction of a low Phe diet was

followed by a marked improvement of psychiatric symptoms

with disappearance of hallucinations within few months.

3.3. Patient 3

This woman started to suffer from attention deficits and

psychiatric problems including marked irritability and anxiety

when she was 40 years old. She had been diagnosed with PKU

at 3.5 years of age when investigated for severe walking and

speech delay. A low phenylalanine diet was introduced from

3.5 to 7 years and interrupted thereafter. She started walking

at 5 years, and learned to write and read in a specialised

school. At 41 years old, neurological examination was normal,

Table 2 – Literature data: patients with diagnosis in adulthood and our patient 5.

Sex Age at onsetof neurologicalworsening

Age atdiagnosis(y)

Phe atdiagnosis(mmol/L)

Briskreflexes

Spasticparaparesis

Leukoence-phalopathy

Dementia Tremor

Kasim et al. F 53 57 2153 + + – + –

Weglage et al. F 45 45 882 + + + + +

Jousserand et al. M 54 55 1140 + + + – –

Patient 5 F 33 47 2358 – – – – +

Parkinsonism Epilepsy Ataxia IQ Diet Phe on diet(mmol/L)

Improvementwith diet

Genetic

Kasim et al. – – – 108 Protein

restricted

diet

NA + R158Q/IVS12+g>a

Weglage et al. – – + 95 + 240 + R408W/R68S

Jousserand et al. – – – Mental

retardation

Protein

restricted

diet

NA NA I65T/R252W

Patient 5 + + – Mental

retardation

No diet – – IVS4+5G>T/p.P281L

r e v u e n e u r o l o g i q u e 1 7 0 ( 2 0 1 4 ) 2 8 0 – 2 8 7284

but intelligence was low. Brain MRI showed a periventricular

and posterior leukoencephalopathy. A poor Phe diet was re-

introduced resulting in marked improvement of anxiety and

attention difficulties.

3.4. Patient 4

This woman noted at the age of 26, walking difficulties,

anxiety and depression leading her to stop working. She was

diagnosed with PKU after neonatal screening and started a

poor Phe diet at 1 month with good metabolic control then

stopped the diet at 5 years. She attended normal school with

some difficulties in reading and arithmetic. In her late teens,

she developed lupus erythematosous and cutaneous sclero-

dermia. Although neurological examination was considered

normal, a brain MRI showed a severe periventricular leu-

koencephalopathy (Fig. 1b). A poor Phe diet was re-introduced

with complete disappearance of the leukoencephalopathy

(Fig. 1c) and psychiatric symptoms. A mild ataxia remained.

3.5. Patient 5

This 47-year-old woman of Iranian origin presented with a 14-

year history of Parkinsonism. She exhibited speech delay

(7 years) and went in a specialized school. She experienced

two epileptic seizures at 10 years. When she was 33 years, she

noticed a rest upper limbs tremor. Examination revealed

rigidity and akinesia. Parkinson’s disease was suspected with

a dramatic response to levodopa. After 14 years of evolution,

the UPDRS III score was 47 during the ‘‘off’’ state but levodopa

responsiveness was still excellent without obvious dyskinesia.

A metabolic workup was performed because of the association

of mental retardation with early onset Parkinsonism. Ami-

noacids chromatography showed high serum Phe levels

(39.3 mg/dL, 2370 mmol/L). DaTSCAN imaging showed a loss

in dopaminergic terminals predominating on the right side.

Levels of neurotransmitter metabolites in CSF were low

(5HIAA at 27 nM, N = 66–141; HVA at 85 nM, N = 115–488)

whereas neopterins and biopterins were normal. Molecular

genetic studies revealed mutations in the PAH gene. Since

Parkinsonism was well equilibrated with levodopa, no specific

diet was introduced.

4. Literature review and compilation of data

Only 14 cases of PKU patients with late onset neuropsychiatric

manifestations were found during our literature survey [5–12].

These cases are summarized in Tables 1 and 2.

In 11 cases, PKU was diagnosed and treated in infancy or

childhood but neuropsychiatric manifestations appeared in

adulthood [5–8,11]. Characteristics of these 11 patients and of

our 4 patients diagnosed in childhood are pooled in Table 1.

Overall, there were 9 men and 6 women. Most patients were

diagnosed with newborn screening. The genotype was not

available for most of them. Seven patients were diagnosed

because of psychomotor delay (Patient 3, Wood, Villasana-

patient 1, Evans, Thompson-patients 4, 5, 6). Mean age at diet

introduction was 13.5 months (1 week to 3.5 years). Mean age

at diet withdrawal was 12.2 years (4.5 to 30 years). Mean age at

onset of neuropsychiatric symptoms was 22.7 years (15 to

40 years), with a delay of 10.5 years after stopping diet (0 to

33 years). One patient had neurological complications while

still on diet, but the observance was probably low in this

patient. Mean Phe level at onset of neuropsychiatric signs was

1475 mmol/L (590 to 2000 mmol/L). Among 14 patients with

available brain MRI, 13 patients (93%) displayed white matter

changes reminiscent of a diffuse leukoencephalopathy.

Clinical signs encompassed brisk reflexes (80%), spastic

paraparesis (60%), tremor (53%), psychiatric manifestations

(53%), epilepsy (20%), dystonia (13%), ataxia (7%) and Parkin-

sonism (7%). Moreover, all the patients had mild mental

retardation with low IQ. In 91.7% of the patients, improvement

of the clinical signs was noticed after reintroduction of the

diet.

In 3 patients reported in the literature and in our patient 5,

PKU was diagnosed in adulthood because of late onset

neurological abnormalities [9,10,12]. Clinical, biological and

radiological data of these 4 patients as well as genotypes are

summarized in Table 2. There were 1 man and 3 women. The

r e v u e n e u r o l o g i q u e 1 7 0 ( 2 0 1 4 ) 2 8 0 – 2 8 7 285

mean age at onset of neurological abnormalities was

46.25 years (33 to 54 years) with a mean age at diagnosis of

51 years (45 to 57 years). Mean Phe level at diagnosis was

1633 mmol/L (882 to 2358 mmol/L). Clinical signs included brisk

reflexes (3/4), spastic paraparesis (3/4), dementia (2/4), tremor

(2/4), Parkinsonism (1/4), epilepsy (1/4), bilateral visual loss (1/

4) and ataxia (1/4). Only 2/4 patients exhibited leukoencepha-

lopathy on brain MRI. It is noticeable that none of these

patients presented with psychiatric symptoms. Most of them

(3/4) had mental retardation. Improvement of clinical signs

with diet was noticed in two patients and not available for the

two others.

5. Discussion

Here we describe late neuropsychiatric signs occurring in

classic PKU patients. Two categories of patients are indivi-

dualized: those diagnosed with neonatal screening who

stopped diet in childhood or adulthood and those who never

received diet and developed neurological signs only in

adulthood. In both groups the same MRI and clinical

abnormalities (spastic paraparesis, epilepsy and Parkinso-

nism) were noticed.

Most of the cases reported in this article do not describe

true adult-onset neuropsychiatric manifestations of PKU but

rather patients who already had symptoms since childhood

and who showed deterioration of their clinical status in

adulthood. For instance, although most of our patients

exhibited late onset neuropsychiatric manifestations in

adulthood, including spastic paraparesis, psychiatric signs

or Parkinsonism, 4 out of 5 patients already presented some

intellectual delay in childhood or seizures (patient 5). As a

consequence although some progressive neuropsychiatric

signs may occur in adulthood, they can be viewed as clinical

worsening in adulthood rather than true adult-onset neuro-

psychiatric signs.

In PKU, several cerebral tissue damages have been

described in untreated patients, such as reduction of white

matter volume, diffuse cortical atrophy, and myelin changes

including spongiosis and gliosis [13,14]. To our knowledge,

there are no available histological data concerning early

treated patients. As a consequence, MRI appears as the most

adapted examination for brain abnormalities. Periventricular

parietal and occipital regions are the most concerned.

Abnormalities may be extensive observed in one of the

patients described in this series. However, hypersignal can

extend to frontal and temporal lobes and corpus callosum

[15,16]. They may be detected in PKU patients free of

neurological symptoms [16–18], and are not always related

to early diagnosis and treatment. Some studies have shown

correlations between Phe level at the time of MRI and the

extension of white matter abnormalities [16–18]. These

radiologic alterations are subsequently reversible and can

decrease with reintroduction of a phenylalanine restricted

diet [4,5,17], within a delay that seems to be correlated to

myelin turnover [4]. These white matter abnormalities may be

explained by cytotoxic oedema [19], dysmyelination due to

increased myelin content in water [20,21], increase in free

water trapped in myelin sheaths [17,22]. The absence of

neuronal damage [17] is confirmed with MR Spectroscopy that

shows normal Choline and NAA peaks together with a high

Phe peak [15].

In children with PKU, many studies have shown increased

attention deficit hyperactivity disorder (ADHD) [23–25] and

increased behaviour disturbances that correlate with the age

at poor Phe diet withdrawal [26]. In adults PKU, depressive

mood and anxiety are more common than in controls [27].

Women are particularly subjected to depression [28].

In early treated children, IQ is lower than in healthy

patients but remains in the average range [29,30]. Dietary

treatment that is strictly controlled and early introduced is the

best condition for normal intellectual development [31]. The

main parameters that are correlated with final IQ and

behavioural problems are the age at interruption of a strict

Phe level control and the initial IQ at dietary treatment onset

[32]. No correlation has been established between white

matter abnormalities on brain MRI and neuropsychological

alterations or psychiatric disturbances [28].

Gait disturbance as spastic paraparesis was reported in 11

patients [5–10,12]. The bladder function was normal for all

patients. In one case, vitamin B12 deficiency was detected and

supplemented [8]. In another case, spastic paraparesis

appeared after nitrous oxide anaesthesia in a PKU patient

with low B12 serum level [33]. Strict diet permits improvement

of walking and spasticity in most cases. Spastic paraparesis

started in the second decade of life in all cases, even in

patients without Phe low diet [34]. In the same review, spastic

paraparesis was reported in 5% of untreated PKU patients. The

fact that diet reintroduction in most cases led to improvement

of the paraparesis (as shown in our patient No. 1) indicates

that this complication is directly related to high Phe levels and

not a consequence of low B12 caused by the diet.

Electroencephalogram abnormalities are reported in 80% of

untreated PKU patients but epilepsy occurs in only 25% [34].

Correlation has been established in mice between serum Phe

level and epilepsy [35]. In this review, epilepsy was present in 4

patients [5–7]. Three had generalised epilepsy and one

complex partial seizure. Before systematic birth screening,

few child were diagnosed because of acquisitions delay and

infantile spasms. When diet was re- introduced, cessation of

seizures and improvement of electroencephalogram occurred

even in patients with hypsarrythmia [13]. Finally, epilepsy in

adults with PKU seems less common than epilepsy in

childhood and is highly responsive to the diet.

Parkinsonism was present in 2 cases [11]. Biochemical

modifications due to PKU include increased Phe level, reduced

tyrosine in blood, and decreased dopamine synthesis in brain.

DaTSCAN in the 2 cases are in favour of a typical Parkinson’s

disease (bilateral and asymmetrical loss in dopaminergic

terminals). Moreover, tremor and akinesia responded well to

L-dopa. In addition to true Parkinsonism, hand tremor has

been noticed in around 33% of untreated PKU patients [34].

It remains unclear why some adults will develop neuropsy-

chiatric signs and others not. All patients had high levels of Phe

(above 12 mg/dL, 720 mmol/L) at onset of neurological signs

suggesting a direct effect of Phe. The fact that clear improve-

ment was noticed in most patients after diet introduction

reinforces this hypothesis. In general, most adults who

interrupt their diet do not develop neuropsychiatric signs

r e v u e n e u r o l o g i q u e 1 7 0 ( 2 0 1 4 ) 2 8 0 – 2 8 7286

despite very high levels of Phe. Therefore, high Phe levels

should not be the sole explanation for the development of

neuropsychiatric symptoms and other explanations must be

hypothesized. The first is poor metabolic control in infancy

and childhood. Indeed, the fact that almost all patients who

develop late onset neuropsychiatric problems have a low IQ

suggests early brain toxicity of high Phe levels. Unfortunately,

it is difficult to conclude from our study since precise follow-

up of Phe values in childhood were not available for most

patients, and especially for those who did not follow their diet

rigorously. Another explanation is that some mutations in

Phe gene may predispose to late neuropsychiatric problems.

To date, more than 400 mutations have been described and

each mutation has an influence on the enzyme residual

activity. However, until now, no correlations have been found

between genotype and phenotype in PKU. Although genetic

data are lacking in early treated patients described in this

study (including literature review), they were available in

patients with late diagnosis and mutations were all different.

Therefore, it seems that the occurrence of late neuropsy-

chiatric symptoms is not correlated with a specific mutation.

A third explanation may concerns modifiers gene that

represent risk factors. Overall, most patients who stopped

their diet after the age of 7 years will never develop any

neuropsychiatric signs. However, this study suggests that all

patients with PKU need to be followed in adulthood to depict

very late onset complications or clinical worsening that are

potentially reversible upon diet reintroduction.

Disclosure of interest

The authors declare that they have no conflicts of interest

concerning this article.

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