Digital Comprehensive Summaries of Uppsala Dissertations

from the Faculty of Medicine 1570

Intellectual Disability and

coexisting Autism and ADHD in
Down syndrome - a population-
based study

ULRIKA WESTER OXELGREN

ACTA
UNIVERSITATIS
UPSALIENSIS ISSN 1651-6206
ISBN 978-91-513-0649-0
UPPSALA urn:nbn:se:uu:diva-381779
2019
Dissertation presented at Uppsala University to be publicly examined in Rosénsalen,
Akademiska Barnsjukhuset, Uppsala, Friday, 7 June 2019 at 13:15 for the degree of Doctor
of Philosophy (Faculty of Medicine). The examination will be conducted in Swedish. Faculty
examiner: Professor Maj-Britt Posserud (Bergens universitet).

Abstract
Wester Oxelgren, U. 2019. Intellectual Disability and coexisting Autism and ADHD in
Down syndrome - a population-based study. Digital Comprehensive Summaries of Uppsala
Dissertations from the Faculty of Medicine 1570. 61 pp. Uppsala: Acta Universitatis
Upsaliensis. ISBN 978-91-513-0649-0.

The thesis investigated associated neurodevelopmental/neuropsychiatric aspects in a

population-based cohort of 60 children and adolescents (5–17 years) with Down syndrome (DS).
Forty-one subjects were comprehensively assessed by a clinical research team; 17 (41%)
and 14 (34%) met DSM criteria for autism spectrum disorder (ASD) and attention-deficit/
hyperactivity disorder (ADHD), respectively.
Forty-nine subjects had a formal cognitive test and 11 had clinical assessments due to
profound intellectual disability (ID). Mild ID (IQ 50–70) was found in 9% of the teenagers (13–
18 years) and in 35% of the younger (5–12 years) children. Corresponding figures for severe
ID (IQ <50) were 91% and 65%, respectively. The ID was more severe in individuals with
coexisting ASD.
Levels and profiles of autistic symptoms, according to ADOS Module-1, were analysed.
Children with DS and ASD, with different levels of ID, had significantly more symptoms within
all autism domains, than those with DS only – a difference which remained when subgroups
with severe ID were compared. A considerable proportion of subjects with DS had ASD in
addition to ID, but there was a group with DS and severe ID without ASD. The autism profiles
of children with DS and ASD were similar to those of children with idiopathic autism. The
commonly used investigation tools used to diagnose ASD in the study, seemed to be appropriate
in this patient group.
An intervention programme, including education for parents and school staff, adapted to the
specific needs of schoolchildren with DS and ASD was performed and evaluated. Although the
studied group comprised older children and adolescents, most of whom with severe or profound
ID, they could achieve goals and skills previously not managed. In addition, the parents’ views
on the intervention were encouraging.
In conclusion, there is a need of awareness of the increased prevalence of ASD and ADHD
in children with DS. We suggest that screening for ASD and ADHD should be implemented for
children with DS at the age of 3–5 years and at early school years, respectively. We also suggest
that children with DS should be re-evaluated regarding level of ID before entering secondary
school.

Keywords: Down syndrome, intellectual disability, autism spectrum disorder, attention-deficit/

hyperactivity disorder, autism phenotype, autism intervention.

Ulrika Wester Oxelgren, Department of Women's and Children's Health, Akademiska

sjukhuset, Uppsala University, SE-75185 Uppsala, Sweden.

© Ulrika Wester Oxelgren 2019

ISSN 1651-6206
ISBN 978-91-513-0649-0
urn:nbn:se:uu:diva-381779 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-381779)
To the children and teenagers who
participated in this study
List of Papers

This thesis is based on the following papers, which are referred to in the text
by their Roman numerals.

I Oxelgren UW, Myrelid Å, Annerén G, Ekstam B, Göransson C,

Holmbom A, Isaksson A, Åberg M, Gustafsson J, Fernell E.
(2017) Prevalence of autism and attention-deficit-hyperactivity
disorder in Down syndrome: a population-based study. Develop-
mental Medicine and Child Neurology, 59(3):276-283
II Oxelgren UW, Myrelid Å, Annerén G, Westerlund J, Gus-
tafsson J, Fernell E. (2019) More severe intellectual disability
found in teenagers compared to younger children with Down
syndrome. Acta Paediatrica, 108(5):961-966
III Wester Oxelgren U, Åberg M, Myrelid Å, Annerén G, Wester-
lund J, Gustafsson J, Fernell E. (2019) Autism needs to be con-
sidered in children with Down syndrome. Submitted
IV Wester Oxelgren U, Westerlund J, Myrelid Å, Annerén G, Jo-
hansson L, Åberg M, Gustafsson J, Fernell E. (2019) Children
and adolescents with Down syndrome and autism: an interven-
tion targeting social/communication and daily activity skills.
Submitted

Reprints were made with permission from the respective publishers.

Contents

Prologue ........................................................................................................ 11
Introduction ................................................................................................... 13
Down syndrome ....................................................................................... 13
Genetics ............................................................................................... 13
Prevalence and trend for survival ........................................................ 14
Associated medical conditions ............................................................ 15
National Medical Guidelines ............................................................... 16
Medical conditions in relation to cognitive outcome ........................... 16
Intellectual disability ................................................................................ 17
Intellectual disability in Down syndrome ............................................ 19
Autism spectrum disorder ........................................................................ 19
Autism spectrum disorder – Diagnostic assessments .......................... 20
Intellectual disability and autism spectrum disorder ........................... 21
Autism spectrum disorder in Down syndrome .................................... 21
Attention-deficit/hyperactivity disorder ................................................... 22
Attention-deficit/hyperactivity disorder in Down syndrome ............... 22
Other neurodevelopmental/neuropsychiatric disorders in Down
syndrome .................................................................................................. 23
Behavioural phenotype ............................................................................. 23
Intervention .............................................................................................. 24
Interventions in intellectual disability in childhood ............................ 24
Autism intervention in childhood ........................................................ 25
Aim ............................................................................................................... 28
Subjects and Methods ................................................................................... 29
The study cohort ....................................................................................... 30
Paper I – Prevalence study ................................................................... 31
Paper II – Intellectual disability study ................................................. 31
Paper III – Autism phenotype study .................................................... 33
Paper IV – Intervention study .............................................................. 33
Statistics ................................................................................................... 36
Ethics ........................................................................................................ 36
Results ........................................................................................................... 37
Paper I – Prevalence study ....................................................................... 37
 Autism spectrum disorder .................................................................... 37
Attention-deficit/hyperactivity disorder .............................................. 37
Comorbidity – ASD and ADHD.......................................................... 37
Paper II – Intellectual disability study ...................................................... 38
Intellectual function ............................................................................. 38
Adaptive function ................................................................................ 38
Level of ID in relation to ASD and ADHD ......................................... 39
Gender distribution .............................................................................. 39
Paper III – Autism phenotype study ......................................................... 39
Autism phenotype ................................................................................ 39
Paper IV – Intervention study .................................................................. 40
Evaluation of goals achieved, after intervention ................................. 40
Family strain index questionnaire ........................................................ 40
Parents´ perception of the intervention ................................................ 40
Discussion ..................................................................................................... 42
Prevalence study ....................................................................................... 42
Intellectual disability study ...................................................................... 43
Autism phenotype study ........................................................................... 44
Intervention study ..................................................................................... 45
Sex ratio ................................................................................................... 46
Strengths and limitations .......................................................................... 47
Conclusions and clinical implications........................................................... 48
Epilogue ........................................................................................................ 49
Summary in Swedish .................................................................................... 50
Acknowledgements ....................................................................................... 52
References ..................................................................................................... 53
Abbreviations

AAC Augmentative Alternative Communication

ABA Applied Behavioural Analysis
ABAS-II Adaptive Behavior Assessment System-II
ADHD Attention-Deficit/Hyperactivity Disorder
ADI-R Autism Diagnostic Interview-Revised
ADOS Autism Diagnostic Observation Schedule
ASD Autism Spectrum Disorder
DISCO Diagnostic Interview for Social and Communi-
cation Disorders
DS Down Syndrome
DSM Diagnostic and Statistical Manual of Mental Dis-
orders
EIBI Early Intensive Behavioral Intervention
ESSENCE Early Symptomatic Syndromes Eliciting Neuro-
developmental Clinical Examinations
FSI Family Strain Index
ICD-10 International Classification of Diseases-10
ID Intellectual Disability
IDD Intellectual Developmental Disorder
IQ Intelligence Quotient
PECS Picture Exchange Communication System
SCQ Social Communication Questionnaire
SDQ Strengths and Difficulties Questionnaire
SNAP-IV Swanson, Nolan, and Pelham-IV
TEACCH Treatment and Education of Autistic and Com-
munication related handicapped Children
VABS-II Vineland Adaptive Behavior Scales-II
WISC-IV Wechsler Intelligence Scales for Children-IV
WPPSI-III Wechsler Preschool and Primary Scale of Intel-
ligence-III
Prologue

There is a specialized outpatient clinic for children with Down syndrome (DS)
in Uppsala County. While working at this clinic for many years I have met all
the children with DS in the county and I have had the opportunity to follow
them from birth to adulthood. I have worked with excellent colleagues at the
University Children´s Hospital and devoted professionals in the rehabilitation
teams in our county. I have also had the opportunity to coordinate the work of
the National medical guidelines for children with Down syndrome in Sweden.
In the clinical work, I have noticed that many children with DS, in addition
to intellectual disability (ID), exhibit autistic symptoms, hyperactivity and im-
pulsiveness. Searching for scientific literature, I was surprised to find that
there were very few studies concerning the prevalences of autism and atten-
tion-deficit/hyperactivity disorder (ADHD) in DS and that very little was re-
ported about intervention for these conditions in children with DS. In 2012,
we therefore set out to study these additional disorders in a group of children
with DS.
I am grateful to all the families taking part in our studies for giving me and
the team a possibility to investigate these issues in detail.

Figure 1. Members of
the research team and
of the Swedish Down
Association

11
12
Introduction

Down syndrome

Figure 2. Girl with Down syndrome

Down syndrome (DS) is named after John Langdon Down. He was the first
clinician to identify this specific group of patients with common characteris-
tics in 1866 and suggested that they were responsive to treatment.
In 1958, the French geneticist and paediatrician Jerome Lejeune and col-
leagues discovered that the syndrome was caused by a gene defect resulting
in 47 chromosomes, with three copies of chromosome 21 rather than two,
namely trisomy 21.1 Down syndrome may emerge due to classic trisomy
21 (94%), unbalanced translocation (4%), mosaicism (2%) and partial trisomy
21 (<1%) where only a part of chromosome 21 is triplicated. In trisomy 21
mosaicism the clinical picture can vary depending on the actual percentage of
trisomy in different organs. The phenotype of DS depends on gene dosage
effects from specific genes on chromosome 21. In partial trisomy 21 the clin-
ical picture depends on the triplicated part of the chromosome.

Genetics
A few defined sets of dosage sensitive key genes on chromosome 21 have
been linked to the phenotypic characteristics in DS. Two genes (DYRK1A
and RUNX1) on chromosome 21 appear to be important for the neurodevel-
opment and the trisomy of these genes seems to be responsible for the intel-
lectual disability (ID) in DS.2,3 Future research on these genes may lead to

13
better understanding of the neurodevelopmental problems in DS and hopefully
in new therapies.
The DYRK1A gene encodes an enzyme that plays a role in neurodevelop-
ment. Several studies point to a crucial role of DYRK1A protein for brain
defects in patients with DS. DYRK1A inhibition in mouse models of DS has
resulted in benefits including improvement in cognitive behaviour. A clinical
trial has shown that a DYRK1A inhibitor given to young patients with DS
improved visual recognition memory, working memory performance as well
as adaptive behaviour.4-6

Figure 3. Karyotype with trisomy 21

Prevalence and trend for survival

Down syndrome is the most common single cause of ID and occurs in 12–14
per 10 000, or in about one per 800 live births in Sweden.7 The total number
of pregnancies with DS has increased due to increased maternal age, but has
so far been balanced by an increase of the number of terminations of pregnan-
cies with trisomy 21.7,8
The life expectancy of children with DS is primarily dependent on the risk
of mortality in the first year of life.8,9 The fall in mortality has mainly been
related to the successful surgical treatment of congenital heart disease (CHD)
and to the improved treatment of congenital anomalies of the gastrointestinal
tract. Both mortality and morbidity in childhood could be reduced further, and
in this respect respiratory infections and neonatal problems are the most im-
portant issues to be solved.
Median survival of individuals with DS has increased considerably result-
ing in an increase of the total population of individuals.10 The median age at

14
death in individuals with DS in the United States has risen from 25 years in
1983 to 49 years in 199711, while the median age at death in Sweden is close
to 60 years.8 The longer life expectancy requires medical care for individuals
with DS over their total lifespan. In this context, the importance of national
medical guidelines enabling a preventive health care programme should be
emphasized, both for children and adults with DS.

Associated medical conditions

Down syndrome is associated with many prenatal and acquired medical con-
ditions. Cardiac and other congenital anomalies are common in DS affecting
almost every second child.12 There is also an increased risk of disorders related
to the central nervous system such as infantile spasm, or West syndrome,
which is the most common type of seizure in infants with DS.13 Children with
DS are furthermore at increased risk of endocrine, metabolic and gastrointes-
tinal disorders, e.g. coeliac disease. In addition, ear, nose and throat and eye
problems are overrepresented in DS.14 Solid tumours and other types of cancer
is, apart from childhood leukaemia, uncommon in DS.
Respiratory and cardiac problems as well as sleep disorders are good ex-
amples of conditions where advances in knowledge and treatment options rel-
evant for children with DS have been seen during the last years.15
Children with DS have an increased incidence of respiratory infections, in-
cluding a 30% incidence of pneumonia and 10% will be hospitalised for res-
piratory syncytial virus bronchiolitis before the age of two years. The abnor-
mal anatomy of the upper airways predisposes to upper respiratory infections,
while hypotonia, tracheobronchomalacia, abnormalities in immunological
function and increased pulmonary vascular reactivity predispose to lower res-
piratory tract infections.16
Respiratory infections can also result from silent aspiration due to swal-
lowing difficulties and gastroesophageal reflux (GERD). Aspiration and
GERD should be treated, as should any comorbidity such as asthma. Since
certain high-risk infants, such as those with complex congenital heart disease
or those who are oxygen dependent, are at particular risk of severe RSV bron-
chiolitis and passive immunisation should be considered.15
Pulmonary arterial hypertension is more common in DS than in the general
population and is often caused by the presence of a cardiac left-to-right shunt
and chronic upper airway obstruction.16
Children with DS have an increased risk of obstructive sleep apnoea syn-
drome, affecting 30-50%.16 Because of the high prevalence of asymptomatic
airways obstructive disease (OSAS) and the risks of developing irreversible
pulmonary arterial hypertension, routine sleep studies in children with DS,
even in those without symptomatic airway disease, is recommended. A sleep

15
study or polysomnogram continues to be the criterion standard test for evalu-
ation of sleep-disorder breathing and OSAS.16 However, this is still difficult
to implement.
Infantile spasm, also known as West syndrome, is a severe epileptic syn-
drome with early onset and increased risk of cognitive disability. This is the
most common type of epilepsy in infants with DS, and it has also been reported
to be more prevalent among children with DS compared to children in gen-
eral.17 In adulthood, there is a risk of early development of Alzheimer dis-
ease.17
Hypothyroidism is common in DS and the risk of developing thyroid dys-
function increases with age. Congenital hypothyroidism occurs in 1/100 chil-
dren with DS, representing 30-fold increase compared to other newborns, and
acquired hypothyroidism occurs in 20-30% of children and in 50% of adults
with DS. The thyroid gland in DS is known to be vulnerable to autoimmune
diseases such as Hashimoto thyroiditis and more rarely Graves’ disease.18 The
general opinion is that screening for thyroid dysfunction should be performed
every 1-2 years throughout life.12,19
The majority of individuals with DS will experience impaired hearing some
time in life. Hearing losses may be conductive (such as in case of otitis media
with effusion occurring in up to 90% of children with DS before one year of
age), sensorineural (6% in newborn screening) or mixed.20 Since hearing is
very important for development, particular as far as language is concerned, a
hearing screening programme is recommended.12,19
Ocular abnormalities which may have impact on visual function are found
in up to 60% of subjects with Down syndrome. Congenital cataract is seen in
1.4% in DS and warrants neonatal screening.21 Refractive errors are common
and regular eye examinations should continue through life.12,19

National Medical Guidelines

The complex medical situation for children with DS has resulted in medical
guidelines to meet the extensive medical needs of this group of patients. The
first Swedish national medical guidelines were presented in 199522-24 fifteen
years prior to the US guidelines “Health supervision for children with Down
syndrome”.12 New national medical guidelines from the Swedish Neuropedi-
atric Society were published in 2013 and the 4th revised version in 2017.19

Medical conditions in relation to cognitive outcome

Theoretically, medical conditions, associated with DS, could affect the neuro-
development of the child. The impact of congenital heart disease (CHD) on
intellectual, cognitive, and learning deficits in children with DS was studied
by Alsaied et al25, who reported that infants/toddlers with cardiac surgery had
lower scores for language compared to those without CHD. However, at

16
school age there were no differences in intelligence quotient (IQ) scores or
language scores nor in the incidence of ADHD.25
The possible role of birth defects requiring early surgery has been studied
in children with DS. However, no evidence of an association between such
defects and a poor outcome regarding cognitive function and behaviour could
be found.26
On the other hand, a follow-up study of children with DS and infantile
spasm demonstrated significantly lower scores in domains measuring cogni-
tive, motor, and language functions.27

Intellectual disability
Intellectual disability (ID) implies deficits in abstract, theoretical thinking, i.e.
deficits in problem solving, reasoning and learning entailing difficulties to
cope with daily life situations. The prevalence of ID all severities has been
reported to be about 2% in the general population in the Nordic countries.28-30
The Diagnostic and statistical manual of mental disorders (DSM)31-33 is the
standard classification system of mental disorders used by mental health pro-
fessionals in United States and many other countries. It is applied in clinical
settings as well as in research on clinical and community populations, and it
is also used for collecting public-health statistics.
Mental retardation is, in DSM-IV, characterized by significantly impaired
intellectual (IQ<70) and adaptive functioning and onset of symptoms before
age of 18 years.32 The terminology was changed to Intellectual disability/In-
tellectual Developmental Disorder (ID/IDD), when DSM-5 was published in
2013, and is defined as an IQ<70±5 in addition to deficits in adaptive func-
tioning that without ongoing support will affect activities of daily life33.

Figure 4. Normal distribution of IQ and the levels of intellectual disability

17
Diagnostic examination starts with a thorough neuropaediatric assessment,
which is followed by cognitive tests to evaluate the intellectual function in
detail. The Wechsler preschool and primary scale of intelligence34 (WPPSI)
and the Wechsler intelligence scale for children35 (WISC) are widely used in
clinical practice by psychologists for the assessment of specific and general
cognitive abilities. Both yields information of general cognition based on full-
scale IQ as an index of overall intelligence including verbal and performance
IQ.34,35
While intelligence reflects the maximum performance, adaptive behaviour
refers to typical performance in everyday – behaviours that are possible to
influence to a certain degree by training. Adaptive function includes commu-
nication, daily living skills, social and motor skills necessary for everyday
function. The instrument Vineland Adaptive Behavior Scales-II36 (VABS-II)
is often used to measure these skills. Another instrument for evaluating adap-
tive behaviour is the Adaptive Behavior Assessment System-II37 (ABAS-II).
VABS-II is used from infancy and onwards, ABAS-II only from 5 to 21 years
of age.
Assessment of adaptive functioning is an important complement to cogni-
tive testing to determine a person’s all-around functioning in everyday life. In
the general population adaptive behaviour and IQ are highly correlated.38 In-
dividuals with ASD, however, are not acquiring skills in these areas at a pace
consistent with chronological development or intellectual growth. IQ has been
found to be a strong predictor of adaptive behaviour, although the gap between
IQ and adaptive ability has been observed to decrease in the more cognitively
impaired individuals compared to otherwise “high functioning” individuals
with ASD.39,40 Deficits in both intellectual functioning and adaptive behaviour
are central to intellectual disability.
Table 1. Definition of mental retardation according to DSM-IV. Throughout this
thesis the terminology used is intellectual disability.
Intellectual disability
A Significant subaverage intellectual functioning: an IQ of approximately 70 or
below on an individually administered IQ test
B Concurrent deficits or impairments in present adaptive functioning in at least
two of the following areas: communication, self-care, home living, social/in-
terpersonal skills, use of community resources, self-direction, functional aca-
demic skills, work, leisure, health, and safety.
C The onset is before age 18 years.

Code based on degree of severity reflecting level of intellectual impairment

Mild ID IQ level 50-55 to approximately 70
Moderate ID IQ level 35-40 to 50-55
Severe ID IQ level 20-25 to 35-40
Profound ID IQ level below 20 or 25

18
Intellectual disability in Down syndrome
Intellectual disability33 (i.e. mental retardation according to DSM-IV) is a car-
dinal feature of DS41 and is invariably diagnosed in individuals with DS. How-
ever, there are single cases with intelligence within the lower normal variation
when tested before start of school. The developmental impairment results in a
mean IQ of about 60 and a range from 25-70 in preschool-children with DS.
For children with DS of school age a decline of IQ across time has been re-
ported.41-45
The ID in DS is mainly a consequence of functional and developmental
brain disturbances. In addition to ID many children with DS display other neu-
rodevelopmental disorders, particularly ASD46,47 and ADHD.48,49 Moreover,
children with DS have delays across different developmental domains includ-
ing language, gross motor, fine motor, cognitive, personal-social and self-help
skills.50
Intellectual development in children with DS proceeds at a slower rate than
that in typically developing children, leading to a progressively widening dis-
parity in age-related performance.41,45
Better understanding of the trajectory of cognitive development in children
with DS may lead to the design of more effective interventions.41

Autism spectrum disorder

Autism spectrum disorder is a group of neurodevelopmental/neuropsychiatric
disorders characterized by impaired social communication and restricted be-
haviours and interests. The clinical presentations are very heterogeneous, de-
pending on the severity of the ASD per se, on associated neurodevelopmen-
tal/neuropsychiatric disorders and on underlying medical disorders.51,52 In ad-
dition to the core symptoms, most individuals with ASD also display other
impairments, such as intellectual/learning problems and attention and activity
regulation deficits. Clinical presentations vary from severe multi-impairments
with ID to high-functioning individuals with IQ within the “normal distribu-
tion”.52 There is a significant overlap with other neurodevelopmental disor-
ders, such as ID, speech and language impairment, ADHD and epilepsy illus-
trating that co-existence of disorders is the rule rather than the exception.
The prevalence of ASD in children is currently reported to be around 1%
in the general population.53 In individuals with ID the prevalence of ASD has
been reported to be as high as 40%.44 Rates of ASD are generally reported to
be higher in males than in females; about 4:1 in population cohorts. The high-
est sex-ratios have been reported in so called high-functioning ASD, i.e. those
without ID. In children with ASD and ID the ratio is about 2:1.54-59
The term infantile autism60 was introduced in the DSM-III31, substituted by
autistic disorder in the following DSM-III-R and DSM-IV32, and recently, in

19
the DSM-533, changed to autism spectrum disorder. The autism criteria set in
the DSM-IV are based on the triad of symptoms concerning qualitative im-
pairment in A1) social interaction, A2) qualitative impairments in communi-
cation and A3) restricted repetitive and stereotyped patterns of behaviour, in-
terests and activities. B) Delays or abnormal functioning in at least one of
these areas should have had its onset prior to age three years. The diagnostic
criteria can be seen in Table 2.
One single umbrella term, ASD, was introduced with the publication of
DSM-5.33 The DSM-5 also requires specification of additional information
including severity level of ASD, level of adaptive functioning, and occur-
rences of intellectual disability.
The other widely used manual for ASD classification is the International
Classification of Diseases, ICD, published by the World Health Organization
(WHO). Currently the ICD-1061 is in use, with ASD subcategories resembling
those of the DSM-IV.

Autism spectrum disorder – Diagnostic assessments

The neuropaediatric assessment is supplemented with structured interviews,
developed to improve reliability and validity in the diagnostic process of au-
tism. Examples of these are the Autism diagnostic interview-revised62
(ADI-R) or the Diagnostic interview for social and communication disorders63
(DISCO), both focusing on neurodevelopmental/neuropsychiatric symptoms.
Autism diagnostic observation schedule64 (ADOS) is a frequently used obser-
vational instrument to complete the assessment. To assess the child´s adaptive
function, a structured interview according to the VABS-II or ABAS-II is often
used.65
Table 2. Definition of autistic disorder according to DSM-IV in short. Throughout
this thesis the terminology used is autism spectrum disorder.
Autism spectrum disorder
A A total of six (or more) items from (1), (2), and (3), with at least two from (1),
and one each from (2) and (3):
1. Qualitative impairment in social interaction, as manifested by at least two
of four defined symptoms
2. Qualitative impairments in communication as manifested by at least one
of four defined symptoms
3. Restricted repetitive and stereotyped patterns of behavior, interests and ac-
tivities, as manifested by at least one of four defined symptoms
B Delays or abnormal functioning in at least one of the following areas, with
onset prior to age three years: (1) social interaction, (2) language as used in
social communication, or (3) symbolic or imaginative play.
C The disturbance is not better accounted for by Rett’s disorder or Childhood
disintegrative disorder

20
Intellectual disability and autism spectrum disorder
Matson and Shoemaker (2009)46 pointed out that ID and ASD co-vary at high
rates and that a greater severity of one of these two disorders appears to have
effects on the other disorder. In the 1980s the percentage of ID in children
with ASD was estimated to be 70-90%.66 Today, considering the total ASD
spectrum, including an increasing number of “high-functioning” children with
ASD, the rate of ID in children with diagnosed ASD can be estimated to about
15-25% at school age. However, at preschool age the corresponding rate
would probably be about 50%.67 There is a close relation between ID and
ASD, and when one of these impairments is severe the other is likewise af-
fected.46,52 It has also been demonstrated that the severity of ASD and chal-
lenging behaviours escalates when IQ decreases.46

Autism spectrum disorder in Down syndrome

It has often been claimed that individuals with DS display an affectionate and
social personality. Even so, when screening to identify ASD it has been re-
ported that ASD is more common in individuals with DS, with varying rates
up to over 30%.12,68-72 Two population-based studies have been performed us-
ing screening-instruments and interviews reporting a prevalence 10-20%.42,73
It has been suggested that the increased frequency of ASD in DS should mo-
tivate larger epidemiological studies.73-75
Rasmussen et al72 studied several medical factors in a clinically based sam-
ple including 25 individuals, age range 4 to 33 years, with DS and ASD. The
subjects had been referred for assessment due to suspected ASD and all met
the criteria according to DSM-III-R31 or DSM-IV32. It was pointed out that
ASD should always be considered as a comorbid disorder in patients with DS
and that the diagnosis of ASD was delayed when compared to children with-
out DS.
Moss et al74 studied individuals with DS and found that 19% met criteria
for ASD. They concluded that individuals with DS and ASD had broad simi-
larities to those with idiopathic ASD regarding autistic and behavioural char-
acteristics; however, subjects with DS tended to be less withdrawn.
In a report by Warner et al75 the profiles of autism symptoms in children
with DS were analysed and compared to those of children with ASD but with-
out DS. Profiles of autistic symptoms in the two groups were similar, however
children with DS and ASD tended to have milder social difficulties but similar
profiles of communication and repetitive behaviour.

21
Attention-Deficit/Hyperactivity Disorder
Attention-deficit/hyperactivity disorder, characterized by either inattention or
hyperactivity-impulsivity or both, has been reported to occur in 5-7% of chil-
dren in general76 and in up to 44% in children with DS48. The DSM-IV states
that there should have been a certain number of symptoms from each category
that have persisted for at least six months and to a degree that is maladaptive
as well as inconsistent with developmental level. Moreover, some symptoms
should have appeared before the age of seven years (this age level has been
changed in DSM-5 to 12 years) and present in two or more settings (such as
school, home or recreational activities). The main cognitive deficit in ADHD
is impaired executive functions. Attention-deficit/hyperactivity disorder is
categorised into three types; ADHD combined type, ADHD predominantly
inattentive type or ADHD predominantly hyperactive-impulsive type. A cor-
relation between intellectual level and executive function has been demon-
strated; when intellectual level declines, executive problems increase.77
Table 3. Definition of Attention-deficit/hyperactivity disorder according to DSM-IV
in short.
Attention-deficit/hyperactivity disorder
A Either 1 or 2, or both
1. Inattention: six (or more) defined symptoms of inattention have persisted
for at least 6 months to a degree that is maladaptive and inconsistent with
developmental level
2. Hyperactivity-Impulsivity: six (or more) defined symptoms of hyperac-
tivity-impulsivity have persisted for at least 6 months to a degree that is
maladaptive and inconsistent with developmental level.
B Some symptoms that caused impairment present before 7 years of age
C Some impairment is present in two or more settings
D Clear evidence of clinically significant impairment
E The symptoms do not occur exclusively during the course of, and are not bet-
ter accounted for by, another mental disorder

Attention-deficit/hyperactivity disorder in Down syndrome

There are reports on prevalence of ADHD in DS with results varying between
14 and 43%.48 In the assessment process of ADHD in children with DS it is
important to consider that visual and hearing impairment, obstructive sleep
apnoea syndrome and thyroid disease are associated with DS and may mimic
symptoms of ADHD.

22
Other neurodevelopmental/neuropsychiatric disorders in
Down syndrome
In addition to ID, ASD and ADHD there are also other neurodevelopmen-
tal/neuropsychiatric disorders that may occur in children with DS. Conduct
disorder appears in more than 10%; however, the prevalence is lower than that
in other groups with ID.78,79 The prevalence of depression in DS has been re-
ported to be around 11% and the most common symptom to be loss of inter-
est.79 It has been suggested that 10-22% of the individuals with DS have met
diagnostic criteria for anxiety disorder79; i.e. a rate higher than that in the gen-
eral population. The prevalence of obsessive-compulsive disorder (OCD) in
DS has been found to be comparable to that of the general population, around
3.5%.79 No increased risk of bipolar disorder has been reported in DS. Acute
regression has been reported to occur in children and adolescents with DS.
The regression occurs regardless of cognitive level and includes loss of inde-
pendence in activities of daily living, language deterioration and loss of cog-
nitive skills. In the study by Mirches et al80, all patients had experienced severe
emotional stress prior to regression.80 Catatonia in DS has also been re-
ported.79,81 A decline, termed Down syndrome disintegrative disorder, with
cognitive deterioration featuring autistic characteristics and catatonia, has re-
cently been recognized in young adults with DS. In this group, symptoms were
reported to improve after immunotherapy.82

Behavioural phenotype
The concept of behavioural phenotype was introduced by Nyhan83, in 1972
when describing the Lesch-Nyhan syndrome as an identifiable biological dis-
order with behavioural features. Flint and Yule84 proposed a definition of be-
havioural phenotype in 1994: “The behavioural phenotype is a characteristic
pattern of motor, cognitive, linguistic and social abnormalities which is con-
sistently associated with a biological disorder”. It has been suggested that
delineation of a behavioural phenotype could be the first step towards the mo-
lecular characterization of behaviour.85
Autism spectrum disorder is increasingly reported in syndromes with ge-
netic origin52,86-92 and autism symptoms in specific syndromes have been ana-
lysed in order to reveal a distinct profile, i.e. an autism phenotype.

23
Intervention

Interventions in intellectual disability in childhood

In Sweden, children with DS are assessed with a cognitive test at the age of 5
to 6 years, before they start school. When there is a clear ID the child is entitled
to attend the special school for children with ID. When test results and the
child´s adaptive functioning indicate a mild ID or borderline intellectual func-
tioning the parents may choose to let their child start off in a mainstream
school.
Communication and speech impairments are important parts in the cogni-
tive impairment in DS and a main target for intervention. Augmentative and
alternative communication (AAC) refers to the use of non-vocal communica-
tion systems. The AAC systems are recommended for individuals who either
have unintelligible or limited speech abilities, or who lack speech altogether.
Individuals with disorders that affect the functional use of speech, and there-
fore may be more likely to use AAC, include those with a variety of develop-
mental disabilities such as ID and ASD.93 The most obvious role is to provide
a way to communicate. The AAC can also be used to augment existing speech
and to replace or mitigate problem behaviours, such as screaming or hitting,
with an alternative mean of communication.94 A frequently used method for
training of communication for children without verbal language is the Picture
exchange communication system (PECS).95

Figure 5. Augmentative alternative communication with PECS

24
To adequately measure whether an intervention aimed at enhancing cogni-
tive/communicative functions in children with DS is effective, (irrespective of
whether the intervention is pharmacological or educational) the typical age-
related changes in cognitive functioning – across multiple domains – need to
be considered. In this way, the effects of treatment versus the effects of age-
related developmental changes can be differentiated. The use of specific
standardized neuropsychological tests that have a sufficiently low baseline to
eradicate floor effects would allow for more precise evaluations of the effects
of interventions.

Figure 6. Girl with Down

syndrome working with
the communication aid
together with her father

Autism intervention in childhood

It is important to identify developmental disorders, including autism, early in
order to inform parents and staff in the preschool setting about basic cognitive
problems of the child. Diagnosis and information are often major components
of good treatment. Earlier diagnosis creates opportunities for children with
autism spectrum disorder to benefit more fully from intervention. Intervention
should be performed to improve the situation of the child and family rather
than to cure the underlying disorder.52,96-99
The specific social, communicative and behavioural impairments that char-
acterize ASD require special approaches when it comes to intervention.52,100-
103
It has been recognised since the 1970s that structured educational pro-
grammes is one of the most important aspects of successful treatment of chil-
dren with ASD.104 Treatment and education of autistic and communication
related handicapped children (TEACCH) is an example of a highly structured
and visually based program developed by Schopler and colleagues105 at the
University of North Carolina. The program includes a series of cognitive, de-
velopmental, educational and behavioural strategies to create highly individ-
ualized curricula and visual work systems and has been especially valuable
for children with lower intellectual function.

25
 The techniques based on Applied behavioural analysis (ABA) was devel-
oped by Lovaas in the 1960s to systematically change non-functional behav-
iours105 and it is now often referred to as Early intensive behavioral interven-
tion106 (EIBI), to emphasize intensity. There has been a clear trend towards
merging ABA and behavioural interventions that utilize more “naturalistic”
approaches, such as the Early start Denver model100, implemented in the
child´s natural settings to teach developmentally appropriate and prerequisite
skills107-109. Applied behavioural analysis has been modified for the Swedish
habilitation organization.110,111 The main principle for ABA is to reduce neg-
ative and enhance positive behaviours as well as to achieve new skills. An
important goal is to focus not only on the child itself but also on the child in
interaction with the environment. Problematic behaviours are often under-
stood as a lack of ability to communicate. A way of reducing the negative
behaviour (e.g. head-banging, screaming) is to find adequate methods for
communication.
A higher cognitive level and acquisition of speech before five to six
years of age have been found to be associated with better outcomes in chil-
dren with ASD, for example regarding adaptive skills.67,112-114 The im-
portance of IQ for outcome has also been demonstrated in follow-up stud-
ies of preschool children.114-116 The degree of autism may not be crucial for
outcome, but coexisting conditions (i.e. ID, ADHD, epilepsy) influence
outcome.117-120
Information to parents about diagnosis, prognosis and how to help to de-
velop skills or to compensate for communicative, cognitive and behavioural
deficits, are included in almost all intervention programmes aimed for children
with ASD. Parents may also need education on how to cope with challenging
behaviour.

Autism intervention in adolescents with intellectual disability and ASD

Social skills are important for individuals with ASD across the lifespan. Wal-
ton and Ingersoll121 reviewed specific interventions with the aim to improve
social skills in adolescents with ASD combined with severe or profound ID.
They reported that studies in the field were associated with significant chal-
lenges regarding research design and methodology.121 Individuals with ASD
and ID tended to display fewer positive verbal and nonverbal social skills and
more challenging nonverbal social behaviours than those with a similar level
of ID without ASD.121 Individuals with ASD and ID also displayed higher
rates of problem behaviours than those with ID alone. The differences in chal-
lenging behaviours between individuals with ASD and ID and those with ID
only demonstrate that those with ASD and ID have unique needs. Conse-
quently, they may not be well served by existing intervention programmes
designed for individuals with ID only.121

26
 Walton et al.121 proposed a developmental framework of adapting early
childhood interventions for use with youth and adults with ASD and se-
vere/profound ID. One example would be the naturalistic behavioural inter-
ventions, successfully used to promote social skills in young children with
ASD and ID.121

27
Aim

The aim of the thesis was to investigate the neurodevelopmental/neuropsychi-

atric aspects of DS in a population-based cohort of children and adolescents,
5-17 years of age at time of inclusion.

The specific aims were

…to investigate the prevalence of ASD and ADHD in subjects with DS

…to investigate levels and profiles of ID in relation to age, gender and co-
occurring ASD and/or ADHD

…to describe the autism phenotype in children with DS and ASD

…to evaluate the effects of a psycho-educational intervention in subjects with

DS and ASD

28
Subjects and Methods

The study was performed in the county of Uppsala with around 350 000 in-
habitants. All children with DS living in the county have their medical service
at a specialized outpatient clinic at Uppsala University Children’s Hospital, in
close collaboration with the rehabilitation teams of Uppsala County. All pa-
tients with DS are followed according to the national medical guidelines for
DS in Sweden.19 These guidelines are in good agreement with those from the
United States.12
Medical records of the children who did not take part in the studies were
reviewed by the responsible neuropaediatrician. The team, consisting of one
neuropaediatrician, two neuropsychologists, one special-teacher and two pae-
diatric nurses, conducted all assessments. Paediatric records of the subjects
were reviewed regarding perinatal and neonatal data, growth, medical disor-
ders, visual and hearing status, as well as previously recognized and diagnosed
neurodevelopmental/neuropsychiatric disorders. All children had been sub-
jected to a medical work-up according to the national care programme for DS
during the year preceding the study. An overview of all subjects participating
in the studies is presented in Table 4.
Table 4. Study group and methods used in study I-IV
Study I Study II Study III Study IV

Object of Prevalences of Autism Autism

Level of ID
study ASD/ADHD phenotype intervention
Target group n=60 n=60 n=17 n=17
Study group n=41 n=60 n=17 n=14
Male:female 29 M:12 F 41 M:19 F 13 M:4 F 10 M:4 F
Methods for ADI-R WPPSI-III ADOS Goal achieve-
assessment ADOS WISC-IV ment
WPPSI-III ABAS-II Parental report
WISC-IV VABS-II FSI
ABAS-II Leiter-R*
VABS-II
SNAP-IV
SCQ
*) Leiter-R had been used for one child

29
The study cohort
A population-based cohort of 60 children and adolescents with Down syn-
drome, aged 5-17 years and living in Uppsala County, constituted the study
group. Forty-one individuals (29 M, 12 F; mean age 11 years) for whom par-
ents gave consent for participation were clinically assessed regarding ASD
and ADHD and the level of ID (Paper I). At the time of the cognitive assess-
ment, three subjects had turned 18 years. In 21 subjects (14 M, 7 F), a cogni-
tive test had been performed less than three years earlier and this group was
not re-tested. Twenty children (15 M, 5 F) were tested within the study by the
neuropsychologist in the team. The remaining 19 children (12 M, 7 F) did not
take part in the ASD-ADHD assessment. Instead, the cognitive tests per-
formed before school-start (at the age of 6 years) were reviewed (Paper II).
The children were evenly distributed across the age-span; 29 were
5-12 years old and 31 were teenagers, 13-18 years old. The M/F ratio in the
total group was 2.2:1.
All children with ASD were analysed regarding data on degree of autism-
symptoms and the results were compared to those of the children with DS but
without ASD and to those of a normative group of children with ASD from
the ADOS test manual (Paper III). Finally, of the 17 children who obtained a
diagnosis of ASD at the assessment, 14 children took part in an intervention
targeting social/communication and daily activity skills (Paper IV).

Figure 7. Flowchart demonstrating the inclusion procedure and groups of investiga-

tion for the study I–IV

30
Paper I – Prevalence study
Of the 60 subjects with DS, aged 5-17 years, 41 participated in the ASD and
ADHD prevalence study. Six children did not complete the investigation and
13 families declined participation. The prevalence´s of ASD and ADHD were
investigated, and the results were related to the level of ID and to medical
factors. The assessments included questionnaires to parents and teachers, a
structured interview with the parents as well as an observation and examina-
tion of the child. Several questionnaires and diagnostic tools were used.
Strengths and Difficulties Questionnaire (SDQ) was completed by both
parents and teachers. The psychometric properties of the SDQ parent form
have been evaluated and good internal consistency has been found.122 SDQ
has been used for children with ID123 and adults with DS.124
SNAP-IV Rating Scale125 is a screening tool for ADHD and includes the
items according to DSM-IV32 and DSM-5.33 SNAP-IV was completed by par-
ents as well as teachers.
Social Communication Questionnaire (SCQ) is a parent-report question-
naire that identifies symptoms associated with ASD.126
Autism Diagnostic Interview-Revised (ADI-R), is a semi-structured, inves-
tigator-based interview, aimed for caregivers of children for whom autism or
pervasive developmental disorders are possible diagnoses.127 The instrument
has been reported to have a good reliability.62
A structured observation of the child with a video-camera was performed.
The child’s performance was scored according to the Autism Diagnostic Ob-
servation Schedule (ADOS), which is a semi-structured observation for indi-
viduals suspected of having autism.64
All results of SDQ and SNAP-IV were analysed by a neuropaediatrician
and a paediatric nurse. Diagnosis of ADHD was based on results from SDQ,
SNAP-IV and the clinical assessment. The child’s cognitive level was taken
into account when diagnostic criteria were evaluated in accordance with
DSM-IV and DSM-5. ADI-R and ADOS assessments were performed by a
child-neuropsychologist and a special-teacher, both well-experienced in the
field. The child was also assessed by the neuropaediatrician and paediatric
nurse to include other neurodevelopmental and medical aspects. DSM-IV and
DSM-5 criteria for ASD were assessed with regard to the child´s cognitive
level. The child had to meet both ADI-R and ADOS criteria, DSM IV/DSM-
5 criteria and the team’s conjoint clinical assessment in order to be diagnosed
with ASD.

Paper II – Intellectual disability study

The assessment included all 60 children of the population-based cohort. Intel-
lectual disability was defined according to DSM-IV, which was used at study
start. Scientific reports often use the classification by the American Academy

31
of Mental Retardation128, i.e. mild ID IQ 50-70 and severe ID IQ<50 (see Ta-
ble 5). These two categories were used in the main evaluations.
The major part of the children (n=41) had their cognitive testing performed
with Wechsler Preschool and Primary Scale of Intelligence34 (WPPSI-III).
WPPSI-III is recommended for children with a mental age >2.5 years and pro-
vides a full scale IQ, verbal IQ and performance IQ. It has been established
that WPPSI-III can be used for older children with intellectual disability.129,130
Seven children were tested with Wechsler Intelligence Scales for Children-IV
(WISC-IV),35 one with Leiter-R test131 and 11 children were clinically as-
sessed by a special-teacher without formal testing due to profound ID.
Adaptive Behavior Assessment System-II (ABAS-II)37 and Vineland Adap-
tive Behavior Scales-II (VABS-II)36 were used for assessment of adaptive
functions. The psychologists at the local rehabilitation centres in the county
commonly use ABAS-II. The ABAS-II is a validated questionnaire and pro-
vides norm-referenced standard scores for three domains: conceptual domain,
social domain and practical domain and a merged score – general adaptive
composite (GAC).
Within this study ABAS-II was supplemented with VABS-II as many sub-
jects were at such a low level of functioning that it was assumed they would
be at floor level in the ABAS-II test. The Vineland Adaptive Behavior Scales
(VABS-II) yields a composite score and four domain scores: communication,
daily living skills, socialization and motor skills (younger children).
A tested IQ-value could be obtained in 33 children and in another 16, it was
only possible to decide the broader level of ID (mild, moderate, severe or pro-
found). The remaining 11 subjects had such a low level of function that it was
not possible to perform a cognitive test, but these children had been considered
to have profound ID by clinical examination. Thus, a level of ID was obtained
for all 60 children in the cohort. In the main analysis, ID was classified into
mild (IQ 50-70) or severe (IQ <50).128 In the analyses comparing two assess-
ments at different ages in the same child, the DSM-IV classification was used;
mild (IQ 50-70), moderate (IQ 35-50), severe (IQ 20-35) and profound (IQ
<20).32
Table 5. The differences in terminology regarding intellectual disability in DSM-IV
and AAMR
DSM-IV AAMR
Mild 55 to 69 Mild 51 to 75
Moderate 40 to 54 Severe <50
Severe 25 to 39
Profound <24

32
Paper III – Autism phenotype study
The autism assessment included observation according to ADOS64. There are
four major domains in ADOS Module-1; verbal and nonverbal communica-
tion (A), reciprocal social interaction (B), play (C) and stereotyped behaviour
and restricted interests (D). The diagnostic algorithm for autism includes the
domains of A, B and D which are the domains used in the study.
Forty-one subjects had been assessed within the ASD and ADHD preva-
lence study which revealed that 17 (41%) had ASD and 14 of those had se-
vere/profound ID.132 Six (25%) children among those without ASD had se-
vere/profound ID.

Figure 8. Flowchart demonstrating the subgroups and the comparisons of autism

profiles within the phenotype study

Profiles of autistic symptoms in the children assessed with ADOS Module-1

(15 children with ASD, 12 children without ASD) were compared (compari-
son A, fig 8). Furthermore, the profiles of autistic symptoms in the children
with severe/profound ID, with or without ASD, were compared (comparison
B, fig 8). Additionally, children with DS and ASD assessed with Module-1
were compared with the reference group of children with idiopathic autism
available in the ADOS manual Module-1 (comparison C, fig 8).

Paper IV – Intervention study

Parents of the 17 subjects, diagnosed with ASD after assessment within the
ASD and ADHD prevalence study were asked if they wanted to participate
with their child in the intervention study. A targeted intervention was per-
formed in which 14 of the subjects with DS and ASD from study I, (age range

33
6-18 years, median 13.0 years) participated. Three subjects could not partici-
pate; one due to severe behavioural problems for which an individualized in-
tervention had already been initiated, one family moved from the county and
the parents of the third patient did not respond to the invitation. The sex ratio
of the participating 14 children was M:F=10:4. Eleven of the 14 participants
had severe/profound, two had moderate and one had mild ID. Seven subjects
had no verbal speech and the remaining seven had major communication dif-
ficulties using picture communication aids as alternative means of expressing
themselves. All participants had very few activities outside school.
Parents of the 14 children were offered to participate with their child in a
comprehensive psychoeducational intervention programme, based on ABA
principles but modified and adapted for the group of children and teenagers
with DS, ASD and mostly severe/profound ID. Communication and leisure
activities were the main focus of the intervention. The intervention aimed to
improve social skills and communication abilities of the children and, as a
very important part, the intervention also provided an education programme
to parents and teachers.
The programme included information to parents and preschool/school staff
about the cognitive and behavioural deficits that underlie and characterize
ASD and about specific interventions for the disorder.
Table 6. The information and preparation phase comprised six steps.
Intervention programme
1 Educational programme for parents and close relatives focusing on general
information about DS and ASD and aspects on communication and leisure
activities.
2 Educational programme, as above, for preschool and school staff.
3 Work-shops for parents and staff, forming a team around each child, with
speech-therapist and special-teacher working with communication and com-
munication-aids.
4 Work-shops for parents and staff, forming a team around each subject, with
physiotherapist and youth worker finding appropriate leisure activities for
each child.
5 Medical assessment by the neuropediatrician concerning need for medical
treatment of for example sleep-disorder or obsessive/compulsive behavioural
problems.
6 Group discussions for the parents together with an experienced child-neuro-
psychologist.

In the preparation and training phase, the parents and staff chose 1-2 commu-
nication tasks and 1-2 physical tasks for their child to train. These tasks had
not been managed by the child before start of the intervention. The goals were
set with guidance from the professionals. Thereafter, the child´s training

34
started at home and in school in order to achieve the goals. After a training
period of three months, there was an evaluation of the goals.
A follow-up, 18 months after the completion of the intervention pro-
gramme, was carried out. The follow-up included questionnaires and inter-
views with the parents focusing on the child´s well-being and level of function
at home and in school as well as well-being of parents and siblings. All 14
children took part in the whole programme and they served as their own con-
trols.

35
Statistics
In paper I the statistical analyses used were Fisher´s exact test and Jonckheere-
Terpstra trend test. The p-values of Fisher´s exact test are exploratory and i.e.
calculated without adjustments for multiple testing. The Jonckheere–Terpstra
trend test was used to analyse the association between intellectual disability
and diagnosis.
In paper II the intellectual level of two age groups were compared using
odds ratios with 95% confidence intervals. The mean IQ in the verbal domain
was compared with the mean performance on the nonverbal domains using a
paired samples t-test for a subgroup.
In paper III, mean scores on the ADOS algorithm items for children with
ASD were compared with those for children without ASD, using two sample
t-tests. The means for the two groups on each item were also illustrated using
95% confidence intervals. The t-tests were supplemented with chi-square tests
due to skewed distributions. For each ADOS algorithm item, mean scores for
children with DS and ASD were compared with the mean scores for the idio-
pathic autism group, presented in the ADOS manual, using one sample t-tests,
also supplemented with chi-square tests.
In paper IV goals for children with DS and ASD were set and the mean
number of goals was computed for home and for school, respectively. A paired
sample t-test was used to compare the mean scores before and after the inter-
vention for the “Family Strain Index”. Mean scores and 95% confidence in-
tervals measuring parent’s perception of the intervention 18 months after com-
pletion were computed. An alpha level of .05 was used for all statistical tests
in all four papers.

Ethics
The Regional Ethical Review Board of Uppsala approved the studies
(Dnr 2011-365 (Study I-III) and 2014-461 (Study IV)).

36
Results

Paper I – Prevalence study

Autism Spectrum Disorder

Forty-one subjects (29 boys, 12 girls) with an age range of 5-17 years, mean
age 11 years, comprised the study group. Based on performed test data and
cognitive data in the medical records, all children had ID. There was no evi-
dence of any difference in medical conditions (preterm birth, neonatal hyper-
bilirubinemia, neonatal respiratory distress, congenital heart disease, West
syndrome, treatment with thyroxin or growth hormone) between the groups
with and without ASD.
According to ADI-R, ADOS, DSM-IV/DSM-5 criteria and the conjoint
clinical assessment of the research-team, 17 (41%) children (13 M, 4 F) met
criteria for ASD. In total, 22 (54%) children (16 M, 6 F) had ASD and/or
ADHD in addition to ID, while the remaining children (13 M, 6 F) had neither
ASD nor ADHD. When analysing the SCQ, almost all children (16/17) with
ASD had a score above 13, supporting ASD.
In the group with ASD (n=17), nine subjects (6 M, 3 F) (53%) also met the
criteria for ADHD.

Attention-deficit/hyperactivity disorder
Fourteen (34%) subjects (9 M, 5 F) met DSM-IV/DSM-5 criteria for ADHD.
The inattentive presentation was seen in seven of the 14 children and seven
children met criteria for the combined presentation.
Sixty-four percent (9/14) of the children with ADHD also had ASD. An-
other eight children met 4-5 DSM criteria, i.e., corresponding to subthreshold
ADHD. There was no evidence of any difference in the medical conditions
listed above between the groups with and without ADHD.

Comorbidity – ASD and ADHD

Nine children (22%) were diagnosed with both ASD and ADHD. All of these
had ADHD with the combined presentation and they all had profound ID.

37
There was no evidence of a difference in medical conditions between the
groups with and without ASD and/or ADHD.

Paper II – Intellectual disability study

Intellectual function
The cognitive/intellectual functions in this population-based cohort (n=60)
was studied and an ID-level was obtained for all 60 children in the cohort. In
the total group, 15 subjects (25%) had mild ID, 19 (32%) had moderate ID, 16
(27%) had severe ID and 10 (17%) had profound ID.
Of the 37 younger children (5-12 years), 13 (35%) had mild ID, 14 (38%)
had moderate, four (11%) had severe and six (16%) had profound ID. Of the
23 teenagers (13-18 years), two (9%) had mild, eight (35%) had moderate, 11
(48%) had severe and two (9%) had profound ID. Fifty-seven percent of the
teenagers (13/23) had severe or profound ID, whereas the corresponding fig-
ure in the younger age group was 27% (10/37).
Ninety-one percent of the teenagers had severe ID according to the AAMR
classification (IQ <50). This should be compared to 65% of the younger chil-
dren. Further, the most marked difference between mild and severe ID in re-
lation to age was found below and above the age of eight years (OR: 16.0,
95% CI: 3.2-81.0, p<0.001). Hence, the risk of having severe ID was markedly
increased above eight years of age.
More boys than girls had severe ID, although the difference was not signif-
icant (OR: 2.83, 95% CI: 0.82-9.76, p=0.111).
The severity of ID increased in seven of the eight children assessed twice.
Two of the children, tested prior to the study, had borderline intellectual func-
tioning with IQs between 70 and 84 at the first assessment before starting
school.
It was only possible to assess the intellectual profiles, regarding verbal and
nonverbal domains, in 20 of the 60 subjects. In 11 of these the IQ-scores in
the verbal domain were higher than those in the nonverbal domain, whereas
in six subjects the opposite was seen. The difference between the domains was
less than 13 IQ-points in all subjects. For the remaining 40 subjects no infor-
mation regarding profile could be obtained. It was not possible to evaluate the
processing speed due to a largely low level of cognitive function in this cohort
of children.

Adaptive function
A General Adaptive Composite score (GAC) from ABAS-II was obtained in
35 of the 60 children. Twenty-four, all with severe/profound ID, had a GAC

38
score corresponding to floor level. VABS-II was sent to parents of the 41 chil-
dren who took part in the ASD/ADHD/ID assessment. A complete VABS-II
was obtained from parents of 13 children.
A total of nine children had both ABAS-II and VABS-II results. In the five
children with ABAS-II at floor level, VABS-II data gave a more detailed pic-
ture. Thus, Vineland adaptive data particularly supported the classification of
ID level in the differentiation between severe and profound ID.

Level of ID in relation to ASD and ADHD

Of the 41 subjects tested; 17 had ASD, 14 had ADHD and nine had both ASD
and ADHD. The subjects with ASD had generally a more severe ID. Thus,
one child had mild ID, three moderate, seven severe and six children had pro-
found ID. The children with ADHD had varying levels of ID; four mild, four
moderate, four severe and two had profound ID. All children with combined
ASD and ADHD had severe or profound ID. There was no evident difference
in the verbal vs nonverbal results between the groups, neither for those with
ASD nor for those with ADHD.

Gender distribution
In the cohort of 60 children with DS, age 5-17 years, the M:F ratio was 2.2:1
(Paper I and II). This is a higher proportion of boys than normally reported for
children with DS for which the ratio often is found to be 1.3:1.133 The gender
distribution of the children with DS who were born in the county of Uppsala
(M:F ratio 1.6:1) was in line with national data. The major part of the children
who had moved into the county represented males (M:F ratio 3.0:1).

Paper III – Autism phenotype study

Autism phenotype
An essential finding in the present study was that, according to ADOS Mod-
ule-1, the group of children with DS and ASD differed significantly within all
autism domains, from those with DS without ASD. This was also evident
when the level of ID had been taken into consideration, i.e. when children with
DS and severe ID with and without ASD were compared. Thus, there was a
group of children with DS and severe ID who did not have ASD.
The group with DS and ASD had a relatively similar ADOS Module-1 pro-
file as the “matched autistic group” (idiopathic autism group). However, there
were some significant differences, i.e. less severe symptoms in the DS and
ASD group in the communication domain, mainly with regard to the item

39
“Stereotyped/idiosyncratic use of words or phrases”. No specific autism phe-
notype or profile was evident in the group of children with DS and ASD.
Thus, a considerable proportion of children with DS exhibited ASD in ad-
dition to severe/profound ID and their autism profile was found to be rather
similar to that of children with idiopathic autism with a level of ID correspond-
ing to “lower-functioning autism”. No specific autism phenotype or profile
could be demonstrated in this group of children with DS and ASD.

Paper IV – Intervention study

Evaluation of goals achieved, after intervention

Nine children had evaluations both from home and school, whereas for four
children, results could only be obtained from home. The parents of one child
did not complete the intervention period and this child could not be evaluated.
The number of goals set varied from 2 to 5 (M = 3.77, SD = 1.09). On average,
92.31% (SD = 18.78%) of the goals were (to some extent or completely)
achieved at home and 95.56% (SD = 13.33%) of the goals were (to some ex-
tent or completely) achieved at school. On average, over 90% of the goals
were to some extent or completely achieved, both at home and at school.

Family strain index questionnaire

Parents of 11 of the 14 children (79%) completed the “Family strain index
questionnaire” both before the intervention and at follow-up 18 months after
the intervention had been completed. Parents of three children declined this
part of the follow-up for various reasons that were unrelated to their child’s
disability. The mean scores were almost identical at the follow-up (M=10.91,
SD=4.78) to those before intervention (M=11.27, SD=5.02); t10=.48, p=.640,
Cohens’ d=.07.

Parents´ perception of the intervention

Parents of 10 of the 14 children (71%) completed the six items using the
120 mm horizontal line indicating level of satisfaction. Parents of four chil-
dren declined this part of the follow-up for various reasons, including severe
medical disorders in two children. The 95% confidence intervals for the mean
ratings on the six items are presented in the visual scale in Figure 9.

40
Figure 9. Parents perception of the intervention indicating level of satisfaction
on a horizontal line of 120 mm where the figures 0 and 120 correspond to
“No, not at all/No positive effect” and “Yes, very much/Very positive effect”,
respectively

During the interview, the parents made several comments, e.g.

”We suspected autism long ago; we are relieved to have it confirmed. Now we
can get appropriate help and support”.

“Our son is treated in another way now, we understand his behaviour better.”

“We prepare more before activities. We have a changed mind-set, we don´t

have to do things that don´t work, e.g. travel while on vacation.”

“My worries and stress concerning my child’s behaviour and my own short-
comings were reduced by the intervention.”

41
Discussion

Children with DS and co-existing neurodevelopmental/neuropsychiatric dis-

orders in addition to ID and medical disorders constitute a severely disabled
group. This thesis intends to explore neurodevelopmental/neuropsychiatric as-
pects of DS and to highlight the importance of considering the occurrence of
ASD as well as ADHD, in addition to ID in these children.
It has been increasingly recognized that neurodevelopmental/neuropsychi-
atric disorders coexist and overlap to a large extent. This broad group of dis-
orders includes intellectual disability/intellectual developmental disorder
(ID/IDD), autism spectrum disorder (ASD), attention-deficit/hyperactivity
disorder (ADHD) with and without oppositional defiant disorder and conduct
disorder, speech and language disorders, obsessive compulsive disorder, tics
and Tourette syndrome, developmental coordination disorder (DCD) as well
as eating and sleeping disorders. Today these disorders are often referred to as
ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental
Clinical Examinations), which is an umbrella term for the conditions.134 Spe-
cific underlying cognitive deficits (e.g. concerning theoretical/abstract think-
ing, executive functions, “theory of mind” and central coherence) have been
identified.52 The symptoms that define the disorders are detailed in the diag-
nostic and statistical manual of mental disorders, now the 5th edition.33 There
are also individuals with clear symptoms but not meeting full criteria for a
disorder/diagnosis who may for example present with autistic symptoms. Un-
derlying medical disorders, pre-, peri- or postnatally derived always need to
be considered in children with ESSENCE. The prevalence of neurodevelop-
mental/neuropsychiatric disorders is often considerably increased in defined
etiological diagnoses such as specific syndromes.52,135

Prevalence study
The study aimed at identifying children with DS and ASD and/or ADHD,
based on the total population of children and adolescents with DS, 5-17 years
old, in the county of Uppsala.
A high proportion of ASD was found. For the group of children, assessed
within the study, the rate was 41%. Even though there is one previous popu-
lation-based prevalence study of ASD in DS,136 this is to our knowledge the
first time such a study has been performed in which all participating children

42
had a comprehensive clinical assessment including ADI-R, ADOS and an
evaluation by an experienced clinical staff.
The proportion of children with ADHD was 34%. The results are in agree-
ment with those of a clinically based study from Israel, reporting a prevalence
of 44%.,48 Some of the children in our study group had the predominantly in-
attentive presentation. Evaluation of inattentive symptoms is difficult in a
child with severe ID and in many of these children, the inattentiveness was
not considered as an additional problem by the parents.
The prevalences of ASD and ADHD were high. The rates are in line with
the findings by Strömme and Diseth135, reporting that 42% of children with
ID, with a defined aetiology, had co-occurring psychiatric diagnoses, most
common ADHD and ASD. Even if there were no child with ASD or ADHD
in the non-participating group, the prevalences, 28% and 23%, respectively,
would still be markedly high.
In a Finnish study from 200669 of school-aged children with DS, it was
discussed that ADHD was common but neither diagnosed nor medically
treated. The authors commented that surprisingly little has been published on
attention problems in subjects with DS, and that there are no evidence-based
recommendations for treatment of such problems in this group. In accordance
to this study and to our knowledge, there is no published study on pharmaco-
logical treatment for ADHD in children with DS.
A lower recognition in clinical practice of ASD, ADHD and mental health
conditions in children with genetic syndromes – compared with research stud-
ies – have been reported. The reason behind these lower rates of ASD and
ADHD, i.e. not identifying these disorders in children with intellectual disa-
bility and a genetic syndrome may be referred to the concept of ”diagnostic
overshadowing”.71
To our knowledge, there is no population-based study of children and ado-
lescents with DS in which comprehensive assessments of ASD, ADHD and
ID have been performed. Neither is there any study in children and adolescents
with DS that includes a systematic testing of intellectual levels with verbal
and nonverbal domains, related to co-occurring developmental disorders.
There are several studies on the autism phenotype in different genetic syn-
dromes but only few of these involve individuals with DS. Likewise, although
many studies report on autism intervention only a few involve children and
teenagers with DS, ASD and severe/profound ID.

Intellectual disability study

The ID in children with DS was more profound than reported earlier. Mean
IQ was lower in the older group (13-18 years) than in the younger (5-12 years).
A majority, (57%) of the teenagers had severe or profound ID. The corre-
sponding figure in the younger age group was 27%. The WPPSI-III was used

43
also in the older age group since no other cognitive test would be appropriate
for teenagers with this low level of intellectual function and it has been
claimed that WPPSI-III can be used for older children with intellectual disa-
bility.130
A more severe ID was found in subjects with ASD or combined ASD and
ADHD. Furthermore, the ID was more severe in this cohort of subjects with
DS, than that reported in earlier studies.41This could be due to the population-
based design, which made it possible to acquire cognitive/IQ results from the
total group of 60 individuals, also including children with the most profound
ID. Our results demonstrated that the severity of ID increased in children who
had two tests performed, the first at an age of 5–7 years and the second at 11–
16 years. It is not evident whether this is a sign of early intellectual decline or
if this subset differs in other aspects.
Our results demonstrate a lower level of IQ in the teenagers compared to
the younger children. A lower level of IQ was particularly prominent in chil-
dren older than eight years. It is not evident whether this is due to an early
intellectual decline or if the age-groups differ in other aspects. The results do
not confirm higher scores in nonverbal compared to verbal tests as reported
earlier.137 In fact, all children, possible to test, had even profiles in the verbal
and nonverbal domains.

Autism phenotype study

In the clinically assessed study group of 41 children with DS it was evident
that one group met criteria for ASD and one group did not. This was further
confirmed in this study when ADOS profiles were analysed in detail, both in
the total group of children with DS and ASD and in those with DS, ASD and
severe ID. Both groups diagnosed with ASD had higher scores in 12 and 10
of the 15 ADOS algorithm items, respectively.
The study also demonstrated that the group with DS and ASD basically had
a similar profile as that of the idiopathic autism group. However, there were
some differences, i.e. there were less severe symptoms in the DS and ASD
group with regard to communication problems, e.g. stereotyped/idiosyncratic
use of words or phrases. This could possibly be related to the severely im-
paired verbal abilities seen in the DS group.
No specific autism phenotype or profile was evident in the group of chil-
dren with DS and ASD. Different genetic syndromes have been investigated
regarding autism phenotype according to ADOS, e.g. 22q11 deletion syn-
drome138, fragile X syndrome139, Cornelia de Lange syndrome140 and Phelan-
McDermid syndrome91 and compared to children with idiopathic autism. Var-
ying differences, from subtle to more pronounced, between idiopathic autism
and the different syndrome groups have been identified. The presentation of

44
ASD in children with DS seems to be similar to what has been shown in other
syndromes.
An important finding in our study group was that only four of the 17 chil-
dren with DS and ASD had obtained a diagnosis of ASD before the study was
carried out. This is probably due to that children with ID, regardless of asso-
ciated neurodevelopmental disorders and regardless of aetiology are entitled
to attend special schools for children with intellectual disability and entitled
to receive measures from rehabilitation services.
Autism in children with DS cannot entirely be referred to the level of ID,
thus awareness and recognition of autism in these children are important.
However, as shown earlier, the more severe ID the more increased risk to de-
velop ASD. An important finding is that there is a group of children with DS
and severe/profound ID that does not have autism. Since the autism phenotype
in children with DS and ASD was similar to that in idiopathic autism, common
clinical methods to assess ASD should be appropriate to use in children with
DS.

Intervention study
The most important finding in the intervention study, based on modified ABA
principles, was that the children were able to achieve new goals and skills they
had not previously managed. The goal setting was individualized to the sever-
ity of ID of each child, which made it possible to address specific problems of
communication and daily activities. Most children achieved the goals that had
been set, either fully or to some extent, and the results demonstrated some
improvements in all children.
The role of intellectual level on the outcome of behaviour modification pro-
grammes in children with ASD is important to consider and children with
higher cognitive levels have been found to have better acquisition of skills and
better adaptive functioning outcome.67,96 To understand problem behaviour a
variety of factors need to be considered; medical or psychiatric conditions,
adaptive functions and environmental factors that may influence the behav-
iour.141 Since the strongest predictor of a favourable outcome is related to the
level of IQ, there is a need to consider the child´s IQ-level, not only the ASD
diagnosis per se when planning the intervention. Therefore, developmental
assessments with appropriate test instruments need to be part of any ASD as-
sessment.
The “Family Strain Index” interview demonstrated that the parents rated
the stress and burden of illness correspondingly high before intervention and
at the follow-up. Our results are in agreement with those of the study by Silva
et al.142 where no difference in parental stress before and after an intervention
could be demonstrated in children with ADHD combined with either external-
izing disorders or ASD.

45
 The parental interviews revealed that almost all parents expressed a sense
of relief when they received confirmation that their child also had ASD. Many
of the parents had experienced that their child had been misunderstood for
many years. It had been evident for the parents that their child had additional
difficulties compared to other children with DS. Many parents had experi-
enced a feeling of loneliness and insufficiency in the attempts to meet the
needs of the child. The evaluation also demonstrated that the use of strategies,
intended to facilitate activities and communication, remained to a large extent
18 months after completion of the intervention.
When planning an intervention for a child with ASD, it is important to as-
sess and consider the general cognitive functioning. Most current ASD inter-
ventions include elements of ABA, which can be applied both with an inten-
sive and a non-intensive approach. However, they must be individualised and
also include all the “non-ASD” aspects (i.e. other ESSENCE symptoms).134
The strongest predictor of favourable outcome is undoubtedly the level of
IQ, which underscores the need not to consider an ASD diagnosis in itself
“enough”. The IQ-level, not the ASD diagnosis per se, is the most important
variable in predicting outcome.
The results demonstrate that a psychoeducational programme can be
adapted for schoolchildren with DS, ASD and severe or profound ID. The goal
setting was individualized to the severity of ID of each child, which made it
possible to address specific problems of communication and daily activities.
To our knowledge, no similar intervention in schoolchildren with DS, ASD
and severe/profound ID has been reported.

Sex ratio
The cohort of 60 children had a higher proportion of boys (the M:F ratio in
the study cohort was 2.2:1) than generally seen in DS133 (1.3:1). However,
analysis of the M:F ratio for the total DS population year by year between
2005 and 2014 demonstrated similar ratios as that in the cohort.
Gender distribution in the prevalence study cohort was also analysed. The
41 children taking part in the prevalence study had a M:F ratio of 2.4:1, while
the 19 children, not participating in the study had a M:F ratio of 1.7:1.
The M:F ratio for children born in Uppsala County between 1997 and 2005
was 1.6:1, i.e. similar to that in the total population of newborn infants with
DS in Sweden. The population of Uppsala is increasing, partly due to migra-
tion, and consequently families with children with DS have also moved into
the county. The gender distribution of the children moving into Uppsala
County was skewed with a M:F ratio of 3.0:1, explaining the high M:F ratio
in the cohort.

46
Strengths and limitations
Strengths of the thesis is the population-based design and that the centralized
follow-up programme, that is applied in Uppsala County, made it possible to
include all children (5–17 years) with DS. Furthermore, the organisation with
a specialized outpatient clinic where all children with DS in the county are
cared for provides a holistic approach regarding medical, neuropsychological
and educational areas.
A strength of the prevalence study is that all participating subjects were
comprehensively, clinically assessed by a team using well-validated instru-
ments, with interviews and observations of the child, including a clinical neu-
ropaediatric evaluation. A strength of the ID severity study was that it was
based on the total population of 60 children. A limitation that should be men-
tioned relate to that only two thirds (41 of the 60 children) of the children took
part in the study regarding the ASD and ADHD assessments in the prevalence
study. An analysis of the 19 children (M:F ratio 1.7) who did not participate
in the study revealed that 13 families denied participation and 6 families were
not able to cope with the assessments. Based on the records from the outpatient
clinic; five of these children (n=19, M:F ratio 1.5:1) had suspected ASD (26%)
and two boys (11%) had an ADHD diagnosis, one of whom also had suspect
ASD.
The ID severity study was limited by the fact that some of the children who
did not take part in the ASD and ADHD assessment had their assessment of
intellectual level several years earlier, before school start. Moreover, only
eight of 60 children (13%) had been assessed twice enabling evaluation over
time. Another limitation is that the available IQ tests are not adjusted for teen-
agers with low levels of ID.
A limitation in the intervention study was the lack of controlled randomised
design. However, since the study group was small, and the study period ex-
tended over 2 years, randomization was not considered possible.

47
Conclusions and clinical implications

The thesis investigates associated neurodevelopmental/neuropsychiatric as-

pects in a population-based cohort of children with DS.

Forty-one children with DS were assessed, 41% had ASD and 34% had
ADHD in addition to ID. Nine of the 41 (22%) had both ASD and ADHD.
The coexistence of ID, ASD and ADHD in these children results in a particu-
larly difficult situation.
We suggest a screening procedure at 3–5 years of age for ASD and for
ADHD at early school years. These recommendations should be included in
guidelines for DS.

The cohort of children with DS had a more severe level of ID than previously
reported – 75% had moderate to profound ID. We found a more severe level
of ID in the teenage group compared to that of the younger children. There
was no obvious gender difference concerning level of ID. Children with ASD
had a more severe level of ID; no difference was seen concerning ADHD.
We suggest that children with DS should be re-evaluated regarding level of
ID before entering secondary school. These recommendations should also be
included in guidelines for DS.

Children with DS and diagnosed ASD, at different levels of ID, had signifi-
cantly more symptoms, within all autism domains, compared to those with DS
without ASD. Thus, there was a group of children with DS and ID who did
not have ASD. This was also evident when the comparison between those with
and without ASD also included the subjects with severe ID.
Overall, the autism phenotype in children with DS and ASD was similar to
what is seen in idiopathic autism. The commonly used interviews and obser-
vations, combined with comprehensive clinical neuropaediatric and neuropsy-
chological assessments, used to diagnose ASD in the study, seemed to be ap-
propriate in this patient group.
The results of the ASD intervention demonstrated that a psychoeducational
programme could be adapted for schoolchildren with DS, ASD and with se-
vere or profound ID. The individualized goal setting made it possible to ad-
dress specific problems of communication and daily activities. In addition, the
parents’ views on the intervention were encouraging.

48
Epilogue

During my years of clinical work, I have learnt that our medical care is appro-
priate and for most children with DS the physical health is relatively good.
In this research work, we have found that the health, in many children with
DS, is much more affected by neurodevelopmental/neuropsychiatric disorders
than by medical disorders.
In the same way as we have created a medical health care programme, I
hope that we will now focus on identifying ASD and ADHD in children with
DS and develop effective interventions for treatment, education and training.

49
Summary in Swedish

Denna avhandling undersöker associerade utvecklingsneurologiska och neu-

ropsykiatriska aspekter hos en populationsbaserad grupp av barn med Downs
syndrom (DS).
Vi har undersökt förekomst av autismspektrumtillstånd (ASD) och ADHD,
i relation till grad av intellektuell funktionsnedsättning (ID) och medicinska
tillstånd. När studien startade fanns i Uppsala län 60 barn med DS i ålders-
spannet 5 – 17 år och 41 av dessa deltog i studien. Vi fann att 17 barn hade
ASD (41%) och 14 hade ADHD (34%). Vi föreslår att alla barn med DS ska
genomgå screening för ASD i 3–5 års ålder och för ADHD i tidig skolålder.
Alla 60 barn har bedömts avseende grad av ID. De 41 barn som deltog i
studien genomgick utvecklingsbedömning inom studien eller nära i tid (<3 år
före studien). De övriga 19 barnen hade testats inför skolstart och dessa be-
dömningar granskades. I den totala gruppen av 60 barn fann vi en svårare grad
av ID än vad som tidigare rapporterats; eftersom 75% av barnen hade me-
delsvår–grav ID (IQ <50). Vi fann att tonåringar (13–18 år) hade en svårare
grad av ID än yngre barn (5–12 år). Barn med ASD hade dessutom svårare
grad av ID, detta var dock inte fallet för barnen med ADHD. Vi föreslår att
alla barn med DS bör genomgå en ny utvecklingsbedömning inför högstadiet.
Graden av autism-symtom analyserades för alla barn som inom studien ge-
nomfört en autismutredning. Även hos barnen med svår–grav ID (IQ <35)
sågs en tydlig skillnad i svårighetsgrad av autism-symtom när man jämförde
de som fick diagnosen ASD med de som inte uppfyllde diagnoskriterierna.
Autism-symtom hos barn med DS kan således inte bara hänföras till svårig-
hetsgrad av ID – det är viktigt att överväga förekomst av ASD även i gruppen
med svår ID. Profilen av autism-symtom skilde sig något från den som ses vid
idiopatisk autism (d v s autism utan säker orsak), men endast marginellt. Vi
förordar en hög medvetenhet om den ökade förekomsten av ASD hos alla barn
med DS och menar att standardutredning för ASD är möjlig också för denna
grupp.
De 17 barn som fick diagnos ASD erbjöds att delta i ett interventionspro-
gram, och 14 av dessa familjer tackade ja. Interventionen innehöll föreläs-
ningar och workshops för både föräldrar och skolpersonal, och därutöver bil-
dades en särskild föräldragrupp för att möjliggöra erfarenhetsutbyte. Indivi-
duella mål för barnen fastställdes, varefter en träningsperiod på 3 månader
genomfördes i hem och skola. Därefter följde en utvärdering som visade att

50
barnen kunde nå nya mål och hitta nya förmågor, samtidigt som föräldrarna
upplevde en positiv effekt av interventionen.
Sammanfattningsvis är ASD och ADHD vanligt hos barn med DS. Svårig-
hetsgraden av ID kan öka i tonåren. Profilen av autism-symtom är relativt lika
den hos barn med idiopatisk autism. Även äldre barn och tonåringar med svår–
grav ID kan ha nytta av individuellt anpassad autismintervention.

51
Acknowledgements

Jag känner tacksamhet gentemot de barn och tonåringar med Down syndrom
som deltagit i vår studie. Jag är också tacksam gentemot deras föräldrar som
delat med sig av sina erfarenheter och sin kunskap.
Jag vill tacka min huvudhandledare Jan Gustafsson och mina handledare
Göran Annerén, Elisabeth Fernell och Åsa Myrelid. Ni har lärt mig forskning-
ens grunder i alla avseenden. Ett särskilt tack till Elisabeth; din kunskap, ditt
stöd och din vänskap har burit mig genom detta projekt.
Jag vill tacka mina medarbetare i forskarteamet; Bodil Ekstam, Cathrine
Göransson, Agneta Holmbom, Anne Isaksson, Lotta Johansson, Marie Åberg
och Joakim Westerlund. Utan er hade projektet inte varit möjligt att genom-
föra. Ett särskilt tack till Marie, utan dig ingen intervention!
Jag vill också tacka mina kollegor i Neuroläkargruppen som gjort det möj-
ligt för mig att få tid för forskning.
Tack till Svenska Downföreningen, ert arbete har gjort det möjligt för oss
att kunna förmedla våra resultat till sjukvården, habiliteringen, och allmän-
heten. Ett särskilt tack till Isabella Kollman för värdefulla synpunkter och glö-
dande engagemang.
Tack alla ni andra – familj och vänner – som på ett eller annat sätt hjälpt
mig under de här åren.
Till slut vill jag uttrycka min tacksamhet över att leva i ett land där möjlig-
heten till utbildning på alla nivåer är fri för alla.

Stiftelsen Sävstaholm, Gillbergska Stiftelsen och forsknings-ALF medel från

Region Uppsala har finansierat studierna i avhandlingen.

52
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