Journal of Autism and Developmental Disorders, Vol. 33, No.

2, April 2003 (© 2003)

Autism and Phenylketonuria

Sabrina Baieli,1,4 Lorenzo Pavone,1 Concetta Meli,2 Agata Fiumara,1,2

and Mary Coleman3

Phenylketonuria (PKU) has been also reported in children with infantile autism (IA); how-
ever, the frequency of this association is variably reported. Patients with various forms of
hyperphenylalaninemia (HPA) were evaluated applying two methods: the Autism Diagnostic
Interview-Revised (ADI-R) and the Childhood Autism Rating Scale (CARS). A total of 243
patients were investigated, 97 with classical PKU, 62 identified by neonatal screening, and
35 late diagnosed. None out of 62 patients with classic PKU diagnosed early met criteria for
autism. In the group of 35 patients diagnosed late, two boys (5.71%) ages 16 and 13 years ful-
filled the diagnostic criteria for autism. The present study confirms that classical PKU is one
of the causes of autism, but the prevalence seems to be very low.

KEY WORDS: Phenylketonuria; autism association.

INTRODUCTION common pathway in the central nervous system and see

Infantile autism (IA) is a behaviorally defined syn-
drome, beginning at a very young age in children, which
is characterized by pervasive deficits in reciprocal social
interaction, impairment in verbal and nonverbal com-
munication and the presence of stereotypes. There are
several theoretical constructs concerning what is dys-
functional in the developing brain of a child who present
with the symptoms of autism.
According to DeLong, the core of autism is related
to a rigidity and constriction affecting thought, mem-
ory, emotion, attention and action particularly within
the social sphere (DeLong, 1999). Gillberg and Cole-
man emphasize the behavioral dysfunction of a final
1 the majority of patients do not have autism. The second
Division of Paediatric Neurology, Department of Paediatrics, Uni-
versity of Catania, Italy.
2
Regional Center for Inborn Errors of Metabolism, Department of
Paediatrics, University of Catania, Italy.
3
Department of Paediatrics, Georgetown University School of Med-
icine, Washington, DC, USA.
4 disease phenylketonuria (PKU) suggests that this com-
Correspondence should be addressed to Sabrina Baieli, Division of
Paediatric Neurology, Department of Paediatrics, University of Cata-
nia, Via S. Sofia 78, 95123 Catania, Italy; Tel: ⫹39.095.256682; Fax:
⫹39.095.222532; e-mail: sabrinabaieli@tiscali.it
201
the autistic syndromes as the behavioral equivalent of
the cognitive deficit of mental retardation (Gillberg &
Coleman, 2000).
These authors divide the autistic population into two
broad groups. The largest group, the disease entities of
autism, contains children who usually meet classical
Kanner phenotypes and whose medical disease entities
were identified originally in individuals with autism.
A much smaller group of patients, the double syn-
dromes, have dual diagnoses of an autistic syndrome
plus an already described medical condition. In order
to meet the criteria of a double syndrome, these chil-
dren with autistic symptoms should have (1) a second
syndrome that is a disease originally described in
nonautistic patients and (2) within that second syndrome
syndromes identified in this group of autistic children
are rare diseases, which may help explain why they
sometimes have been overlooked. The co-morbidity in
some children of an autistic syndrome and the metabolic
bination may be one of the double syndromes.
PKU is one of the most prevalent disorders of amino
acid metabolism, occurring in approximately 1 out of
0162-3257/03/0400-0201/0 © 2003 Plenum Publishing Corporation
202
every 10,000 live births (Scriver, Kaufman, Eisensmith,
& Woo, 1995). This autosomal recessive disease can be
caused by more than 200 different genetic mutations af-
fecting the functioning of the phenylalanine hydroxilase
(PAH) enzyme. Most mutations are on the gene for PAH
itself, but some patients have mutations lowering the
level of its essential cofactor tetrahydrobiopterin (BH4)
(Bartholomè, Byrd, Kaufman, & Milstein, 1977). If PAH
is not working well because of the enzyme itself or be-
cause of problems with cofactors, there is a back-up of
phenylalanine that can reach a threshold level in the
extracellular fluid. This excessive level, called hyper-
phenylalaninemia (HPA) may cause reduction of myelin,
neuronal loss, and decreased levels of interneuronal con-
nections and neurotransmitter density, damaging the
brain. The successful treatment of PKU depends on early
detection, which can only be done by newborn metabolic
screening. When treatment is started early enough, a
normal neuropsychological development occurs, pre-
venting the inevitable various presentations of brain
dysfunction in the child, which sometimes include an
autistic picture.
In this study, patients with various forms of HPA
were evaluated by neurological and psychodiagnos-
tic testings with the aim of more clearly defining the
occurrence of HPA with autistic symptoms.
PATIENTS AND METHODS
Five hundred PKU patients have been diagnosed
and followed at the Regional Center for Inborn Errors
of Metabolism, Department of Paediatrics, of the Uni-
versity of Catania, Italy in the past 10 years (1990–2000).
A total of 243 patients, 141 males and 102 females, were
enrolled in this study after obtaining the parents in-
formed consent. Chronological age ranged from 2 to
24 years (M 8.4 SD 5.02). They included 97 patients with
classical PKU; 62 of them, identified by neonatal screen-
ing, were on dietary treatment, 35 out of the 97 were
diagnosed late because they were born before the intro-
duction of screening. Moreover, the investigation in-
cluded 144 patients with mild HPA and 2 patients with
BH4 deficiency. Of the remaining 257 HPA patients, 147
were not regularly followed because they were initially
referred from other towns or regions; 58 were not in-
cluded because the parents did not agree to participate
to this study, and 52 did not complete testing for per-
sonal reasons. Investigated patients were evaluated
according to the following:
1. Detailed family history (carefully gathered
by parent interview, paying attention to the
Baieli, Pavone, Meli, Fiumara, and Coleman
recurrence of autism, Asperger’s syndrome,
“autistic-like conditions,” learning disor-
ders, mental retardation, affective disorders,
obsessive-compulsive disorders, schizophre-
nia, prenatal and perinatal history).
2. General physical examination (measurements
of head circumference, height, weight, skin
anomalies, or malformation signs).
3. Neurodevelopmental evaluation (was obtained by
applying the following psychological tests, ac-
cording to different age-groups: Brunet-Lezine,
24–30 months; Stanford-Binet, 3–6 years;
WISC-R 7–16 years; WAIS over 16 years. For
a standardized definition of intellectual func-
tioning, the IQ scores were classified according
to DSM IV).
With the aim to obtain a double check of test results,
evaluation for autism was performed applying two
methods to all patients: the Autism Diagnostic Interview–
Revised (ADI-R; Lord, Rutter, & Le Couteur, 1994) and
the Childhood Autism Rating Scale (CARS; Schopler,
Reichler, & Renner, 1988).
PROCEDURE
Patients were tested at the Paediatric Department
of the University of Catania. Informed consent was
obtained from parents. The study was conduct over a
2-year period. Full participation required three testing
sessions of approximately 2 hours each, during which
respectively IQ testing and a rating on the CARS and
ADI-R were obtained.
RESULTS
Results are summarized in Tables I and II. Detailed
family and personal history failed to detect any signif-
icant clinical data. Based on ADI-R and CARS, none
of 62 participants with classic PKU early diagnosed,
met criteria for autism, and all patients were function-
ing in the normal intellectual range (IQ scores ranged
from 88 to 102, M IQ ⫽ 94.4, SD ⫽ 4.58). A few of
them showed behavioral problems not related to autism,
such as pica (1.6%), learning disabilities (3.2%), and
attention deficit hyperactivity disorder (3.2%).
In the group of 35 participants with classic PKU
late diagnosed, all patients had mental retardation
(IQ scores ranged from 37 to 49, M IQ ⫽ 45.4, SD ⫽
3.56). Moreover, 17(48.5%) had microcephaly and
12(34.2%) presented seizures. Five subjects (14.2%)
Autism and Phenylketonuria 203

Table I. Mean IQ scores and Age and Sex Distribution of 243 PKU and HPA Patients

Classic PKU, Classic PKU,

early diagnosed late diagnosed Persistent HPA BH4 deficiency
(n ⫽ 62) (n ⫽ 35) (n ⫽ 144) (n ⫽ 2)

Males 37 (59%) 25 (70%) 77 (54%) 2

Females 25 (41%) 10 (30%) 67 (46%) –
Age
M 5.7 yr 18.5 yr 6.1 yr
Range 2/10 12/24 2/11
SD 2.5 2.4 2.3
IQ
M 94.4 45.4 97
Range 88/102 37/49 89/100
SD 4.58 3.56 5.1

were submitted to brain MRI, and in 3 of them hyper-
intensity of occipital and parietal white matter was
observed. Two boys out of 35(5.71%), ages 16 and
13 years, fulfilled the diagnostic criteria for autism,
their CARS score being respectively, 38 and 35. Both
patients were functioning in the mentally retarded range
(IQ ⬍70; M ⫽ 50) but had no seizures or microcephaly.
They were similar to age-matched autistic controls in
all domains contemplated by ADI-R, with quite low
scores in social interaction. In the group of 144 patients
with mild HPA a 19-year-old boy had Asperger’s syn-
drome. All patients in this group were functioning in
the normal intellectual range (IQ scores ranged from
89 to 100, M ⫽ 97, SD ⫽ 5.1). One of the two patients
with BH4 deficiency showed severe mental retardation
and characteristic features of IA confirmed by a CARS
score of 58.
DISCUSSION
The association PKU-IA has been documented;
however, the frequency of this condition varies widely
among studies. By 1969, Friedman was able to collect
from the medical literature more than 50 cases of PKU
with autistic symptoms (Friedman, 1969). Fourteen
cases of autistic symptoms in children with PKU were
reported by Knobloch and Pasamanick in 1975. Also
in 1975, Bliumina reported a child with autistic-like
symptoms and PKU (Bliumina, 1975). In 1980, while

Table II. CARS and ADI-R Scores in Four Patients with PKU and Autism

PKU phenotype Familial history

and autism Age Gender of autism/PDD CARS ADI-R

Late diagnosed 16 Male Negative 38 a) 11

classic PKU b) 9
and autism c) 8
Late diagnosed 13 Male Negative 35 a) 11
classic PKU b) 9
and autism c) 8
Persistent HPA and 19 Male Negative 36 a) 12
Asperger’s syndrome b) 9
c) 8
BH4 deficiency 18 Male Negative 58 a) 12
and autism b) 11**
c) 7**

Note: ADI-R a) Quantitative defect social interaction.

b) Communication (verbal patients, **non verbal patients).
c) Stereotyped behavior and restricted interests.
204
testing 65 children and atypical childhood psychosis,
Lowe et al. found three children with PKU. One of
these children had received a neonatal screening test
that was reported as negative (Lowe, Tanaka, Seashore,
Young, & Cohen, 1980).
In 1986, Reiss et al., reporting a review of the lit-
erature regarding linking of autistic behavior with
genetic conditions, found the rate of prevalence of
autism in PKU ranking 20% (Reiss, Feinstein, & Rosen-
baum, 1986). Fombonne and du Mazaubrun compared
a sample of 154 autistic children with a large group of
mentally retarded patients and found a significantly
higher frequency of untreated PKU patients in the for-
mer group (Fombonne & du Mazaubrun, 1992). The one
point on which all authors agree is that untreated forms
of PKU can be one of the etiologies of an autistic be-
havior pattern. Abnormal brain development resulting
from dysfunctional myelination and reduced neuronal
connections with dopamine deficiency are proposed as
potential etiological factors for autism. In the present
study, brain MRI has been already performed only in
five patients of the classical PKU late diagnosed group,
because of the excessive restlessness of these children.
In three of them, occipital and parietal white matter
hyperintensity was detected. This finding agrees with
the pathological pattern of PKU but does not offer a
model for the autistic behavior, because in our series it
was present in subjects without autistic features.
The present study confirms that classical PKU is
one of the several causes of mental retardation,
epilepsy, and behavioral disorders, but autism itself was
only present in a small percentage (5.7%), among the
group of late-diagnosed PKU. However, taking 5 per
10,000 as the best available prevalence estimate for
autism in children (Fombonne, 1997), according to
Poisson distribution, the chance to find autism in our
PKU sample is very low [P␮ (␯) ⫽ 0.6%], then the ob-
served percentage of autism in our patients is statisti-
cally significantly higher than what we would have
predicted. The social scores on the ADI-R in our PKU-
autistic patients are quite low if compared to other pub-
lished samples of autistic subjects with a diagnosis of
“double syndrome,” where the ADI-R has been used, for
example in tuberous sclerosis and autism (Gutierrez,
Smalley, & Tanguay, 1988). This finding raises the
Baieli, Pavone, Meli, Fiumara, and Coleman
question of whether these PKU subjects share a pecu-
liar autistic phenotype or whether their behavior rep-
resents the evolution of autism with age, and stress the
need of further controls in following years.
ACKNOWLEDGMENT
Thanks to Alessandro Pino for his help in manu-
script preparation.
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