Indian Pediatr 2015;52:
Factors Influencing Verbal Intelligence and
Spoken Language in Children with Phenylketonuria
Rohani and $Shohre Jalaei
*Zahra Soleymani, Nasrin Keramati,
From the Departments of *Speech therapy and
$Physiotherapy, School of Rehabilitation, Tehran University of Medical
Sciences; and #Department of Pediatrics, Institute of Endocrinology and
Metabolism, Iran University of Medical Sciences; Tehran, Iran.
Correspondence to: Dr Zahra Soleymani, Department of
Speech Therapy, School of Rehabilitation, Tehran University of Medical
Sciences, Enghelab Avenue, Pitch-e-shemiran, Tehran 11489, Iran.
Received: July 18, 2014;
Initial review: September 01,2014;
Accepted: February 20, 2015.
To determine verbal intelligence and spoken language of children with
phenylketonuria and to study the effect of age at diagnosis and
phenylalanine plasma level on these abilities.
Setting: Children with phenylketonuria were
recruited from pediatric hospitals in 2012. Normal control subjects were
recruited from kindergartens in Tehran.
Participants: 30 phenylketonuria and 42 control
subjects aged 4-6.5 years. Skills were compared between 3
phenylketonuria groups categorized by age at diagnosis/treatment, and
between the phenylketonuria and control groups.
Main outcome measures: Scores on Wechsler
Preschool and Primary Scale of Intelligence for verbal and total
intelligence, and Test of Language Development-Primary, third edition
for spoken language, listening, speaking, semantics, syntax, and
Results: The performance of control subjects was
significantly better than that of early-treated subjects for all
composite quotients from Test of Language Development and verbal
intelligence (P <0.001). Early-treated subjects scored
significantly higher than the two groups of late-treated subjects for
spoken language (P =0.01),
speaking (P =0.04),
syntax (P =0.02), and verbal intelligence (P
There was a negative correlation between phenylalanine level and verbal
intelligence (r= –0.79) in early-treated subjects and between
phenylalanine level and spoken language (r= –0.71), organization (r=
–0.82) and semantics (r= –0.82) for late-treated subjects diagnosed
before the age one year.
Conclusion: The study confirmed that diagnosis of
newborns and control of blood phenylalanine concentration improves
verbal intelligence and spoken language scores in phenylketonuria
Keywords: Development, Management, Outcome, Pheylalanine.
he prevalence of phenylketonuria (PKU) is high in
Iran [1,2]. Elevated levels of phenylalanine (Phe) in plasma cause
mental retardation, seizures, behavioral problems, and delay in motor
and language development [3,4]. Although early-treated children with PKU
have been found to be of average intelligence, they have shown
differences in cognitive function with normally developing peers [5-7].
The academic and cognitive functions of children with PKU are
significantly lower than age–matched controls [8,9].
Some investigations have reported conflicting results
for language development in early-treated PKU children [10-13]. Although
language problems have been reported , some studies do not confirm
language delay in children with PKU [11,12]. A relationship between
cognitive function, verbal ability and blood Phenylalanine level has
been demonstrated [6,11,14]. Early and consistent dietary therapy for
PKU has been shown to increase the IQ of afflicted children [15-17].
The present study investigated the effect of age at
diagnosis, treatment onset, and Phenylalanine concentration on language
In this cross-sectional study, children diagnosed
with PKU aged 4-6.5 years were recruited from three pediatric hospitals
in Tehran. All enrolled patients had been assessed for one year
(2012-13). It was observed during assessment that the late-treated group
was heterogeneous. In order to produce more homogenous groups, the
children were placed into one of three groups based on age at diagnosis:
early-treated PKU subjects (diagnosed by newborn screening),
late-treated PKU subjects (diagnosed before the age of one year) and
late-treated PKU subjects (diagnosed after age one). The age at
diagnosis, treatment onset and blood Phe level were taken from patient
Inclusion criteria for subjects were blood Phe higher
than 6 mg% in the first stage of diagnosis , treatment only by
control of Phenylalanine, normal hearing, Intelligence Quotient (IQ)
above 50, native speaker of Farsi, and able to undergo verbal testing
(nonverbal patients were excluded). The average blood Phe levels were
calculated for the six months prior to onset of the study. A level of
Phe £6 mg%
indicated strict dietary control of PKU .
An audiologist assessed hearing by Otoacoustic
emissions (OtoRead Handheld OAE device; Interacoustics). Pure tone
audiometric screening was carried out bilaterally for 25 dB HL ISO at
500, 1000, 2000 and 4000 Hz. A psychologist assessed verbal intelligence
and total intelligence using the validated and standardized Farsi
version of the Wechsler Preschool and Primary Scale of Intelligence
(WPPSI) . WPPSI sub-tests used for assessment of verbal intelligence
were information, vocabulary, arithmetic, comprehension, and
similarities. A speech therapist assessed language skills of subjects
using the validated and standardized Farsi version of the Test of
Language Development-Primary, third edition (TOLD-P: 3) . The main
TOLD-P: 3 subtests used were: Picture vocabulary: evaluates
understanding of the meaning of spoken words; Relational vocabulary:
evaluates understanding of the relationship between two spoken words and
ability to explain the relationship orally; Oral vocabulary: evaluates
the skill in relating oral meanings of words spoken by the examiner;
Syntactic understanding: evaluates the skill to understand the meaning
of sentences; Sentence imitation: evaluates the skill to reproduce
sentences spoken by the examiner; and Morphological completion:
evaluates the skill to recognize, comprehend, and use usual
Several subtests were combined to develop composite
scores for semantics, syntax, listening, organizing, speaking, and
spoken language. The Farsi version of TOLD-P: 3 utilizes standard scores
with a mean of 100 and SD of 15 for composites and a mean of 10 and SD
of 3 for its subtests.
Children with apparently normal development were
selected as control group randomly from kindergartens in Tehran and were
matched with the PKU subjects for age, gender, and level of mother’s
education. Their hearing and IQ were tested to be in normal ranges and
they were native speakers of Farsi.
All procedures were in accordance with the ethical
standards of the Committee for Ethical Study of Human Subjects at Tehran
University of Medical Sciences and with the Helsinki Declaration. The
purpose of the study was explained to the parents of the subjects. The
parents of all PKU and control subjects signed written informed consent
forms before participation in the study.
Statistical analysis: The normal distribution of
data was assessed using the Kolmogorov-Smirnov test. One way ANOVA and
Tukey honestly significant difference (HSD) test in post-hoc multiple
comparisons were used to compare the composite quotients from TOLD-P:3
and verbal IQ independently for the PKU and control groups. The Spearmen
correlation used to detect relationships between mean blood Phe levels
and composite quotients of TOLD-P: 3 and verbal IQ and to find the
relationship between the spoken language quotient with total IQ and
verbal IQ (P<0.05).
A total of 42 PKU patients were assessed for the
study, and a similar number of controls were selected. Twelve PKU
patients were excluded. Their age at diagnosis was between 8 to 24
months. One had hearing loss, 1 was diagnosed with autism, and 10 were
severely intellectually disabled and nonverbal. The 30 PKU subjects
included 13 late-treated subjects diagnosed before age one, 9
late-treated diagnosed after age one, and 8 early-treated. The mean (SD)
age of early treated, late treated <1 year age, later treated
³1 year age and
control groups was 51.1 (8.04), 58.3 (8.87), 68.8 (9.25) and 59.6
(10.81), respectively. Phe levels £6
mg were seen in 50%, 41.7% and 46.2% of the three study group,
respectively. Treatment for all PKU subjects had begun when the disorder
was diagnosed. The lowest age at diagnosis was newborn and the highest
was 26 months. All late-treated children but none of the early-treated
subjects had received rehabilitation. The mean Phe level in the subjects
in the treatment groups was 2.50 to 14.5 mg%.
Table I shows the trend of mean for
verbal and total IQ and all composite quotients. There were significant
differences between all PKU groups and the control group for verbal and
total IQ and all composite quotients (P<0.001). The mean of
spoken language (P=0.01), speaking (P=0.04), and syntax (P=0.02)
were significantly higher in early-treated subjects compared to
late-treated subjects diagnosed before age one year. The mean of all
composite quotients were significantly higher in early-treated subjects
compared to late-treated subjects diagnosed after age one year (P£0.002).
A significant difference was observed between the two groups of
late-treated subjects for all composite quotients (P£0.04),
TABLE I Mean (SD) Results of Intelligence and Language Testing of Study Population
Values are expressed as Mean (SD), P <0.001; IQ by Wechsler
Preschool and primary scale of intelligence and Language testing
by Test of Language Development, 3rd edition.
*Late treated subjects diagnosed before or after 1 year of age.
The results of Phe level versus composite quotients
for TOLD-P: 3 showed significant negative correlations between Phe level
and the spoken language, organizing and semantics quotients for
late-treated PKU subjects diagnosed before age one year. There was no
significant correlation between Phe level and composite quotients in
early-treated PKU subjects and late-treated PKU subjects diagnosed after
age one. The relation between verbal IQ and blood Phe level showed a
significant negative correlation in early-treated PKU subjects. This
correlation was not observed for the late-treated PKU groups (Table
TABLE II Relation Between Phenylalanine Level and Language Ability in Children With Phenylketonuria
Mean blood Phe level
$P<0.05, #P<0.01; *Late treated
subjects diagnosed before or after 1 year of age.
There were significant correlations between total IQ
and spoken language quotient for the control group (r= 0.54, P<0.001)
and late-treated PKU groups (r = 0.68, P<0.001). There was
no significant correlation for the early-treated PKU group (r =
A significant correlation was observed between verbal
IQ and spoken language quotient for the control group (P<0.001)
and late-treated PKU groups (P= 0.02). There was no significant
correlation for the early-treated PKU group (P= 0.38).
We found verbal IQ for all PKU groups to differ from
that of the control group. The composite quotients for TOLD-P:3 showed
that the performance of the early-treated group was lower than average,
the late-treated group diagnosed before age one performed poorly, and
late-treated group diagnosed after age one performed very poorly for
language skills. This study did not show a consistent relationship
between Phe level and language performance using TOLD-P:3 and verbal IQ.
The present study had some limitations. The first was
that there has been little study of language abilities in children
treated late for PKU, because most countries now test for the condition
in newborns. This means that it is was not possible to compare the
results of the present study with those of previous studies to assess
language impairment in late-treated PKU subjects. The second limitation
was not being able to test for serum Phe concentration on the day of
assessment. The most recent assessment time was up to six months prior
to onset of the study to calculate mean blood Phe level.
The present results support the findings of previous
researchers [5,6,9] who reported that early diagnosis and intervention
prevents mental retardation. The spoken language results demonstrated
that this metabolic disorder affected language even in subjects who were
diagnosed early. These results conflict with the findings of Melnick,
et al. , Michel, et al.  and Ozanne, et al.
. They found no pattern of linguistic deficit in early-treated
subjects. Zartler and Sassaman  found that language skills in
early-treated children were in the average range. The source of the
disagreement with the findings of the present study apparently stems for
the different aspects of language that were assessed. We found that
subjects with PKU were more vulnerable to problems with organizing than
for other language skills. This may have been related to the type of the
tasks that were used for assessment. These tasks involved memory and
semantic clustering, which are related to executive functioning .
These results must be interpreted with some caution because the
executive function was not measured as extensively as in other studies
[23,24]; however, it appears that children with PKU experience
difficulty with executive functioning.
The findings on total IQ in late-treated children
agreed with the findings of other researchers [3,14]; however, no study
was found that investigated language skills in such children. A clear
deficiency in intelligence and language from early stages of development
is illustrated by the findings of the late-treated subjects for the
relationship between verbal IQ and the spoken language quotient. The
reason that most previous studies did not find significant differences
between normally developing and early-treated PKU subjects probably
stems from the usage of verbal IQ as a scale for language assessment.
The results correspond to those of previous studies
[11,14] that increased blood Phe levels decreased verbal IQ in
early-treated children. Ozanne, et al.  did not report a
consistent relationship between language skills, cognitive abilities, or
dietary control ratings in early-treated children. The relationship
between Phe level and organizing, spoken language ability, and semantics
in late-treated subjects diagnosed before age one year suggests that
these skills can improve with strict control of Phe level. This result
confirms that strict dietary control is necessary for late-treated
The results of the present study suggest that
authorities in developing countries must be diligent in carrying out
newborn screening and education of families with children afflicted with
PKU about dietary control. More research focused on language assessment
is needed to better understand the mechanism of language impairment, to
investigate causality and for continued longitudinal follow-up.
Acknowledgements: We would like to thank the PKU
Society and the families who participated in this study for their time,
commitment, and reliability.
Contributors: ZS: created and designed the study
and revised the manuscript for important intellectual content. She is
the guarantor of the study; NK, FR: collected data and drafted the
paper; NK: also conducted the tests, and interpreted the tests; SJ:
analyzed the data and contributed to writing of the manuscript. The
final manuscript was approved by all authors.
Funding: Tehran University of Medical Sciences.
Competing interests: None stated.
What is Already Known?
• Impaired language skills occur in children
What This Study Adds?
• Early-treated and late-treated subjects
with PKU experience language impairment, but impairment is more
severe in late-treated subjects.
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