syndromes

1. American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 160C:295–300 (2012)
A R T I C L E
Cognitive and Behavioral Aspects of
Smith–Lemli–Opitz Syndrome
ANDREA DIAZ-STRANSKY AND ELAINE TIERNEY*
The brain’s high concentrations of cholesterol make it especially vulnerable to the cholesterol biosynthetic defect
that characterizes Smith–Lemli–Opitz syndrome (SLOS). An attempt to characterize the cognitive and behavioral
phenotype of SLOS has identified increased rates of intellectual disability, language and motor developmental
delay, repeated self-injury behaviors, sensory hyperreactivity, hyperactivity, affect dysregulation, and sleep
disturbances. Some research has suggested that carriers of the gene mutation that results in SLOS display
increased risk of suicidal behavior. Cholesterol dysregulation impairs neuroplasticity, which may be a mechanism
underlying some of the mentioned abnormalities. Discrete positive effects have been reported with the use of
cholesterol supplementation in the treatment of SLOS. Research has been limited by the small number of subjects
available, and a limited understanding of lipid metabolism in the brain. Hopefully future research will help clarify
the role that cholesterol plays in cognitive and behavioral abnormalities like the ones associated with SLOS. This
would accelerate the development of treatments for SLOS, and perhaps also further understanding of non-
syndromic psychiatric disorders such as autism and attention deficit hyperactivity disorder.
ß 2012 Wiley Periodicals, Inc.
KEY WORDS: intellectual disability; language deficits; motor deficits; opisthokinesis; self-injury behavior; autism; hyperactivity; sensory
hypersensitivity; affect dysregulation; sleep disturbances; suicidal risk; behavioral response to cholesterol supplementation
How to cite this article: Diaz-Stransky A, Tierney E. 2012. Cognitive and behavioral aspects of
Smith–Lemli–Opitz syndrome. Am J Med Genet Part C Semin Med Genet 160C:295–300.
INTRODUCTION
Smith–Lemli–Opitz syndrome (SLOS)
exposes the essential role that cholesterol
plays in the central nervous system.
Beyond the somatic malformations
that characterize SLOS, altered sterol
biosynthesis disrupts cognitive and
behavioral functions. If nearly 25% of
the body’s cholesterol is concentrated
in the brain [Benarroch, 2008], neuro-
logical development and physiology
would likely be affected by this sterol’s
abnormal homeostasis. Neurobehavio-
ral alterations reported in SLOS include
increased rates of intellectual disability,
autism, attention deficits, anxiety symp-
toms such as sleep-cycle disturbances,
and self-injurious behaviors [Tierney
et al., 2000]. The severity of cholesterol
deficiency correlates with the severity of
physical alteration [Tint et al., 1995;
Witsch-Baumgartner et al., 2000].
However, behavioral manifestations
may vary widely regardless of cholesterol
levels. Thus, the influence of sterol syn-
thesis and homeostasis alterations in
SLOS neurobehavioral traits remains
unclear. Nevertheless, outlining cogni-
tive and behavioral traits that are com-
mon in this monogenic syndrome may
increase current understanding of the
influence that genetic interactions may
have on physiology, cognition and be-
havior. In cases of mild SLOS physical
phenotypes, the cognitive and behavior-
al alterations associated with SLOS can
suggest the diagnosis. Furthermore,
identifying the deficits that accompany
the syndrome may guide pharmacologic
management and other therapeutic
interventions. Following is a review of
the cognitive and behavioral traits of
SLOS, and a discussion of potential un-
derlying mechanisms.
COGNITIVE IMPAIRMENT
Cognitive deficits are commonly associ-
ated with SLOS. Ever since SLOS
Andrea Diaz-Stransky, M.D. is a Psychiatry and Behavioral Neuroscience Trainee at Johns
Hopkins University School of Medicine. She has a special interest in the field of Child Psychiatry,
and focuses on characterizing behavioral phenotypes of genetic, metabolic and neurologic dis-
orders. She is a member of the American Academy of Child and Adolescent Psychiatry and the
American Psychiatric Association.
Elaine Tierney, M.D. is Director of Psychiatry at Kennedy Krieger Institute, and Associate
Professor in the Department of Psychiatry and Behavioral Sciences at Johns Hopkins University
School of Medicine. As a pediatric and adult psychiatrist, Dr. Tierney’s special research interest has
been in autism, genetic, metabolic and neurological disorders that cause behavioral disturbances.
She is a member of the American Academy of Child and Adolescent Psychiatry, the American
Psychiatric Association, the Maryland Psychiatric Society, and the Maryland Regional Council of
Child and Adolescent Psychiatry.
*Correspondence to: Elaine Tierney, KKI Psychiatry, Rm. 227A, 716 North Broadway, Baltimore,
MD 21205., E-mail: tierney@kennedykrieger.org
DOI 10.1002/ajmc.31342
Article first published online in Wiley Online Library (wileyonlinelibrary.com): 5 October 2012
ß 2012 Wiley Periodicals, Inc.

2. was first characterized in 1964, micro-
cephaly and intellectual disability were
identified as part of the constellation of
congenital anomalies [Smith et al.,
1964]. Nonetheless, the phenotypic het-
erogeneity of the syndrome is also evi-
dent in the wide ranging cognitive
abilities of individuals with SLOS,
from borderline normal intelligence
[Mueller et al., 2003] to profound intel-
lectual disability (ID) [Opitz et al., 1969;
Lowry and Yong, 1980; Kelley et al.,
1996]. Nearly 1 in 10 children with
SLOS have mild ID, falling in the IQ
range of 50–70 [Lowry and Yong, 1980;
Ryan et al., 1998; Kelley and Herman,
2001]. The underlying pathophysiology
of the cognitive deficits found in SLOS
remains unclear. It is possible that certain
The underlying
pathophysiology of the
cognitive deficits found in
SLOS remains unclear. It is
possible that certain
developmental processes that
depend on cholesterol
biosynthesis such as
dendritogenesis,
synaptogenesis, and
myelination, may be altered
in SLOS. Impairment of
these processes during
organogenesis could then lead
to learning and memory
deficits.
developmental processes that depend on
cholesterol biosynthesis such as dendri-
togenesis [Takemoto-Kimura et al.,
2007], synaptogenesis [Mauch et al.,
2001], and myelination [Saher et al.,
2005], may be altered in SLOS.
Impairment of these processes during
organogenesis could then lead to learn-
ing and memory deficits. This is evident
in SLOS rodent models, in which the
gene for 7-dehydrocholesterol reductase
(DHCR7) inhibition was associated
with poor performance in learning
and memory tasks [Xu et al., 1998].
Language and motor development have
been examined in children with SLOS.
Consistent findings have been severe
language impairment [Tint et al.,
1994; Kelley et al., 1996; Nwokoro
and Mulvihill, 1997] with a greater
impairment of expressive abilities as
opposed to receptive abilities [Kelley
and Herman, 2001]. In terms of motor
development, gross motor skills appear
more impaired than fine motor skills
[Kelley and Herman, 2001]. In a review
of different studies with 55 individuals
with SLOS, 100% reported psychomo-
tor delay [Johnson, 1975]. Nonetheless,
most individuals learn how towalk [Kel-
ley and Herman, 2001].
Other genetically inherited syn-
dromes have been noted for pathogno-
monic movements such as hand-
wringing in Rett’s syndrome [Hagberg
et al., 1983]. However, such syndrome-
specific movements are not as penetrant
in most genetic disorders. In the case of
SLOS, parental reports have revealed
that nearly 50% of individuals with
this syndrome present a similar motor
movement pattern referred to as ‘‘opis-
thokinesis.’’ It consists of a ‘‘forceful and
rapid backward head and trunk arching
and backward thrusting’’ [Tierney
et al., 2000, p.132]. This movement
was more commonly observed in infan-
cy, and lessened with age. The clinical
relevance of this movement is that it
may often result in head-banging against
nearby objects, and may require the
use of protective head devices as well
as adaptations in the child’s living
environment. In the same study of
SLOS individuals, a smaller portion
of children who do not display
opisthokinesis showed sporadic back-
ward neck-arching [Tierney et al.,
2001]. Another movement pattern ob-
served less often in this population is
upward arm stretching accompanied
by rapid flapping of both hands with
stretched fingers. Other upper limb
movements reported have been myo-
clonic movements in two individuals
with SLOS. The mechanisms that
underlie these behavioral patterns re-
main elusive.
BEHAVIORAL
ABNORMALITIES
Repeated self-injury has been noted as a
prominent stereotypical behavior in
SLOS. Ryan et al. [1998] reported
that 35% of their study population
(n ¼ 23) displayed self-injury behavior.
The life-time prevalence of self-injury
reported for SLOS subjects ranges be-
tween 71% and 89% [Tierney et al.,
2000, 2001]. It includes head-banging
with hands or against other objects, as
well as self-biting.
Sensory hyperreactivity has been fre-
quently noted in individuals with SLOS
including tactile [Nwokoro and Mulvi-
hill, 1997; Ryan et al., 1998] and audi-
tory hypersensitivity [Nwokoro and
Mulvihill, 1997]. These observations
were consistent with a later study by
Tierney et al. [2000] using the Sensory
Profile [Dunn and Westman, 1997;
Dunn, 1999] that reported significantly
greater sensory hyperreactivity in SLOS
individuals compared to other subjects
who were either typically developing or
had attention deficit hyperactivity disor-
der, Asperger disorder, idiopathic au-
tism, or other developmental disorders
[Dunn and Westman, 1997; Kientz and
Dunn, 1997; Ermer and Dunn, 1998;
Dunn, 1999].
Autism spectrum disorders are one of
the most prominent behavioral traits as-
sociated with SLOS. ‘‘Ritualistic and
repetitive behaviors’’ in more than near-
ly half of SLOS individuals were first
noted by Ryan et al. [1998]. Besides
the stereotypic movements described
before, other repetitive behaviors in
SLOS can include compulsions such as
playing the same cassette repeatedly, ab-
normal obsessions such as the specific
placement of an object [Ryan et al.,
1998], pulling on one’s own hair
[Nwokoro and Mulvihill, 1997], rigidity
of daily routine, and need for persistence
[Tierney et al., 2001]. Opitz [1999] de-
scribed the presence of autism character-
istics in SLOS. A study of 13 subjects
noted that between ages 4.0 and 5.0
years, 46% met clinical diagnostic
296 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

3. criteria for autism using ADI-R algo-
rithm retrospective questions and the
DSM-IV criteria for autism [Tierney
et al., 2001]. Furthermore, Sikora
et al. [2006] reported an autism spectrum
disorder (ASD) prevalence of nearly 75%
in SLOS individuals. SLOS is one of the
monogenic syndromes with the highest
rates of ASD [Sikora et al., 2006]. Thus,
it has been hypothesized that a potential
pathophysiologic mechanism of ASD
is related to abnormalities in the choles-
terol biosynthesis pathway [Lee and
Tierney, 2011].
Hyperactivity has been often noted
in SLOS individuals [Elias and Irons,
1995; Opitz, 1999]. A case report of
a child diagnosed with attention
deficit hyperactivity disorder (ADHD)
noted clinical improvement with
methylphenidate treatment [Nowaczyk
et al., 1998]. Nevertheless, other cases
have been described in which ADHD
symptoms are refractory to methylphe-
nidate and dextroamphetamine [Bukelis
et al., 2007]. Further studies are neces-
sary to ascertain the prevalence and ef-
fective management of ADHD in
individuals with SLOS.
Affect dysregulation has been noted in
SLOS starting in infancy as marked irri-
tability [Kelley et al., 1996; Nwokoro
and Mulvihill, 1997]. Johnson [1975]
described a high-pitch cry that accord-
ing to parent reports can last hours or
even entire nights for 2–3 weeks at a
time. SLOS infants have been described
as inconsolable [Opitz, 1999] and hyper-
sensitive to stimulation [Porter and Her-
man, 2011]. This irritability is expressed
at later stages as sad affect, impatience,
low frustration tolerance, inappropriate
screaming, anxiety and fast mood
changes [Tierney et al., 2000]. Abnor-
mal aggression is a commonly reported
symptom among children [Ryan et al.,
1998] and adults [Pauli et al., 1997],
and was described as a current or past
observation in 52–63% of individuals
with SLOS [Ryan et al., 1998; Tierney
et al., 2001].
Sleep disturbance prevalence in indi-
viduals with developmental delay ranges
between 13% and 86%, and is possibly
influenced by age, genetic disorder,
medical comorbidities, breathing-relat-
ed problems, and physical and sensory
handicaps [Didde and Sigafoos, 2001].
Severe sleep cycle disturbances have
been reported in individuals with
SLOS. Ryan et al. [1998] surveyed the
parents of 23 children with SLOS and
found that 70% reported abnormal
sleeping patterns. Prominent complaints
were difficulty settling and awakenings
through the night, which were mostly
refractory to sedatives.
When parents of SLOS individuals
were asked to complete questionnaires
regarding sleeping disturbances, Zarow-
ski et al. [2011] found that snoring
and mouth breathing was reported for
50% and 66.7% of the subjects, respec-
tively. This may be exacerbated by facial
anomalies characteristic of SLOS indi-
viduals including oral abnormalities
and hypotonia [Ryan et al., 1998; Kelley
and Hennekam, 2000; Porter, 2008].
Reported sleep onset symptoms includ-
ed difficulty falling asleep (61.1%),
and sleep onset time >30 min (62%).
Sleep maintenance symptoms were
also marked, including multiple awak-
enings, difficulty falling back to sleep,
early morning awakening, and ‘‘restless
sleep.’’ Furthermore, sleep-time associ-
ated rituals and anxiety were common
among SLOS individuals. It is not sur-
prising that most parents reported exces-
sive daytime-sleepiness in their children.
The study overall indicates that subjec-
tive sleep disturbances are common
among SLOS individuals. However,
parental oversensitivity has been attrib-
uted to the increased rate of perceived
sleep disturbances in other populations
of developmentally delayed children
[Hering et al., 1999]. Thus, objective
measures including polysomnography
evaluations are necessary in individuals
with SLOS.
SUICIDALITY IN GENE
MUTATION CARRIERS
Based on the reported association
between low serum cholesterol and sui-
cidal behavior [Ellison and Morrison,
2001], Lalovic et al. [2004a] hypothe-
sized that carriers of the SLOS gene,
DHCR7, might be similarly affected.
A potential mechanism in carriers of
this mutation would be a partial enzy-
matic deficit in the cholesterol biosyn-
thesis pathway. Detrimental effects on
behavior in carriers of gene mutations
have also been found in individuals
with mutations in other cholesterol bio-
synthesis related genes, suggesting that
carrier status may indeed influence be-
havioral traits. Such is the case of carriers
of NAD (P) dependent steroid dehydro-
genase-like (NSDHL) gene mutations,
who have been reported to display
higher rates of callousness and antisocial
behavior [Du Souich et al., 2012].
In the case of SLOS, Lalovic et al.
[2004a] studied parents of SLOS
individuals who were DHCR7 carriers
and found that 30% of them had a bio-
logical relative who had attempted or
committed suicide. This is more than
Opitz described the presence
of autism characteristics in
SLOS. A study of 13 subjects
noted that between ages 4.0
and 5.0 years, 46% met
clinical diagnostic criteria for
autism using ADI-R
algorithm retrospective
questions and the DSM-IV
criteria for autism.
Furthermore, Sikora et al.
reported an autism spectrum
disorder (ASD) prevalence of
nearly 75% in SLOS
individuals. SLOS is one of
the monogenic syndromes with
the highest rates of ASD.
Thus, it has been
hypothesized that a potential
pathophysiologic mechanism
of ASD is related to
abnormalities in the
cholesterol biosynthesis
pathway.
ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 297

4. three times the rate recorded in control
subjects, who were healthy parents of
autistic children. Five suicide attempts
were reported in the study population,
while only one was reported among
comparison subjects. It is important to
note that cholesterol levels were not
measured in the study, and thus, the
nature of the increased suicidal risk
reported is unclear. Another study con-
ducted by the same group did not find an
association between DHCR7 status and
other cholesterol-related genes and in-
creased risk of suicide [Lalovic et al.,
2004b]. Furthermore, the lipid profile
of parents of SLOS individuals has not
been thoroughly studied to the best of
our knowledge. Although individuals
with SLOS have self-injury behaviors,
they generally do not attempt to kill
themselves. However, the degree of in-
tellectual disability that is typical in
SLOS individuals may preclude suicidal
ideation and attempts. Future research
will require lipid and genetic testing of
both parents in each family, and perhaps
even animal models to understand the
role that partial DHCR7 enzyme defi-
ciency plays in brain physiology and
psychopathology.
POTENTIAL
PATHOPHYSIOLOGY
OF COGNITIVE AND
BEHAVIORAL ANOMALIES
IN SLOS
A better understanding of the pathophys-
iologic mechanisms that underlie abnor-
mal cognition and behavior in SLOS
could guide effective management in
SLOS individuals and moreover, eluci-
date the pathophysiology that underlies
other cases of autism. As discussed previ-
ously, mood disturbances such as anxiety
and affect dysregulation [Tierney et al.,
2001], ADHD symptoms [Bukelis et al.,
2007], and learning difficulties are com-
mon in SLOS individuals. All of these
alterations have been related to sleep
disturbances in typically developing
children [Drummond and Brown,
2001; Huang et al., 2007; Chorney
et al., 2008; Owens, 2009; Walker,
2009; Mander et al., 2011]. An essential
role for cholesterol in synaptic plasticity
has been examined by Koudinov and
Koudinova [2001]. It is possible that
neuroplasticity is altered in individuals
with SLOS, and that this alteration is
exacerbated by sleep disturbances, which
in turn exacerbates mood disorders,
learning and memory impairment.
Altered plasticity is also thought to
underlie the pathophysiology of ASD
in some individuals [Polsek et al.,
2011], a population that is also burdened
bycognitive,adaptivebehavior problems,
and poor sleep [Vriend et al., 2011].
Figure 1 summarizes the potential rela-
tion that altered neuroplasticity may have
with various neurobehavioral alterations.
Based on the role that cholesterol may
play in the physiologic and neurobeha-
vioral pathology of SLOS, approaches to
treatment have explored the effects of
cholesterol supplementation.
COGNITIVE AND
BEHAVIORAL RESPONSE
TO CHOLESTEROL
SUPPLEMENTATION
Although symptomatic management
was the only treatment available for
SLOS for decades, the discovery of the
cholesterol biosynthesis deficit that
underlies this syndrome led to the use
of dietary cholesterol interventions as a
main line of treatment [Irons et al., 1993;
Tint et al., 1994]. Cholesterol supple-
mentation has been associated with im-
proved growth patterns [Nwokoro and
Mulvihill, 1997] and gastrointestinal
function [Kelley and Herman, 2001].
Its effect on cognitive and behavioral
functions is less clear. In 1998, a study
by Ryan and coworkers did not find a
significant improvement in develop-
mental abilities after a short period of
cholesterol supplementation. However,
parent reports recurrently note im-
proved alertness [Ryan et al., 1998]
and attention [Elias and Irons, 1995],
better sleeping patterns [Ryan et al.,
1998], decreased irritability [Elias and
Irons, 1995; Nwokoro and Mulvihill,
1997], decreased aggression, [Nwokoro
and Mulvihill, 1997; Ryan et al., 1998],
less self-injury [Irons et al., 1995; Ryan
et al., 1998] as well as less temper out-
bursts, trichotillomania, and tactile de-
fensiveness [Nwokoro and Mulvihill,
1997].
Figure 1. Potential influence of altered neuroplasticity on Smith–Lemli–Opitz
syndrome neurobehavioral alterations. Processes that disrupt synaptic neuroplasticity
such as altered cholesterol homeostasis or sleep disturbances are thought to influence
cognitive and behavioral function. Altered neuroplasticity may be an underlying mech-
anism in SLOS, increasing symptoms of attention-deficit hyperactivity disorder
(ADHD), mood disorders, learning and memory impairment, and obsessive–compulsive
symptoms.
298 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

5. In 1998, a study by Ryan
coworkers did not find a
significant improvement in
developmental abilities after a
short period of cholesterol
supplementation. However,
parent reports recurrently note
improved alertness and
attention, better sleeping
patterns, decreased irritability,
decreased aggression, less
self-injury as well as less
temper outbursts,
trichotillomania, and tactile
defensiveness.
Furthermore, parents observe happier
affect [Irons et al., 1995; Nwokoro
and Mulvihill, 1997; Pauli et al., 1997;
Opitz, 1999], and in subjects who were
abnormally passive, they observe in-
creased alertness, activity [Irons et al.,
1995; Ryan et al., 1998], vocalization
[Pauli et al., 1997; Opitz, 1999] and
sociability during periods of cholesterol
supplementation. Following the hy-
pothesis that increased 7-dehydrocho-
lesterol (7-DHC) production may
contribute to the pathophysiology of
SLOS, the use of simvastatin has been
explored recently. A study of simvastatin
and cholesterol supplementation de-
scribed parent reports of decreased
irritability and self-injury, improved ap-
petite and sleeping patterns. However,
no change was observed in the subject’s
developmental quotient score [Szabo´
et al., 2010]. It is important to note
that not all individuals with SLOS re-
spond to treatment in the same way.
This may be related to varying levels
of residual DHCR7 enzyme activity
that they may have [Kelley and Herman,
2001].
Baseline cholesterol and 7-DHC
levels have been correlated to devel-
opmental quotient [Sikora et al.,
2004]. However, the relation between
cholesterol biosynthesis defects and neu-
robehavioral abnormalities is not well
understood. Cholesterol turnover is
necessary for the formation of axons,
dendrites and synaptogenesis, playing a
vital role in brain organogenesis [Lund
et al., 2003]. The effect of cholesterol on
signaling of neurotransmitters like sero-
tonin, dopamine, and gamma-amino
butyric acid (GABA) and their pro-
tein-bound receptors could play a role
in the developmental alterations ob-
served in SLOS. Attempts have been
made to study SLOS behavior using
mouse models with limited success
[Moy et al., 2009]. A caveat in the use
of cholesterol supplementation for
SLOS cognitive and behavioral func-
tions is that the passage of serum choles-
terol through the blood–brain barrier is
extremely limited. Most of the brain’s
cholesterol is produced locally. Thus,
if cholesterol intake indeed affects neu-
robehavioral functions, its benefit could
be related to indirect influences on
hormone metabolism and other periph-
eral changes effects [Kelleyand Herman,
2001]. On the other hand, variations
in blood–brain barrier permeability
between individuals may modulate
the effect that cholesterol supplementa-
tion can have on brain physiology.
CONCLUSION
Overall, higher rates of mood disturban-
ces [Tierney et al., 2001], ADHD symp-
toms [Bukelis et al., 2007], learning
difficulties, and sleep disturbances have
been reported in individuals with SLOS.
The nature of the association between
such cognitive and behavioral abnor-
malities, and SLOS neurobehavioral
manifestations remains unclear. Quanti-
tative clinical research and animal
models may help elucidate underlying
mechanism and may help identify clini-
cal approaches adapted to individuals
with SLOS.
ACKNOWLEDGMENTS
The authorswould like to thank Andrew
J. Stonesifer for his assistance designing
the figure in this text.
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