Specific Genetic Disorders and Autism: Clinical Contribution
Towards their Identification
David Cohen,1,7Nade ` ge Pichard,2Sylvie Tordjman,2Clarisse Baumann,3Lydie Burglen,4
Elsa Excoffier,5Gabriela Lazar,1Philippe Mazet,1Cle ´ ment Pinquier,1
Alain Verloes,3and Delphine He ´ ron6
Autism is a heterogeneous disorder that can reveal a specific genetic disease. This paper
describes several genetic diseases consistently associated with autism (fragile X, tuberous
sclerosis, Angelman syndrome, duplication of 15q11-q13, Down syndrome, San Filippo
syndrome, MECP2 related disorders, phenylketonuria, Smith–Magenis syndrome, 22q13
deletion, adenylosuccinate lyase deficiency, Cohen syndrome, and Smith–Lemli–Opitz
syndrome) and proposes a consensual and economic diagnostic strategy to help practitioners
to identify them. A rigorous initial clinical screening is presented to avoid unnecessary
laboratory and imaging studies. Regarding psychiatric nosography, the concept of ‘‘syndro-
mal autism’’—autism associated with other clinical signs—should be promoted because it may
help to distinguish patients who warrant a multidisciplinary approach and further investi-
KEY WORDS: Autism; specific genetic disease; multidisciplinary approach.
Autism, defined in DSM-IV as a pervasive
developmental disorder involving profound deficits in
repetitive behaviors and restricted interests, with
onset prior to 3 years old, is a syndrome associated
with genetic factors (Bailey, Phillips, & Rutter, 1996).
On average, the concordance rate among mono-
zygotic twins was 64%, whereas it was 9% among
dizygotic twins (Smalley, Asarnov, & Spence, 1988).
In fact, these rates depend on the diagnosis and
subtype of autism considered, and are not sufficient
to explain by themselves the autistic syndrome. De-
spite numerous studies, to date, very few single gene
have been identified for which there is a certainty of
its involvement in autism (Jamain et al., 2003). In-
deed, it is assumed that autism is a heterogeneous
disorder that can be associated with various causes,
including genetic ones (Bailey, et al., 1996; Cook,
2001; Petit et al., 1996).
From several clinical studies, it appears that or-
ganic causes are involved in 11–37% of autistic cases
(Gillberg & Coleman, 1996). The incidence rate is
more likely to be 10–11% as it was obtained from
epidemiological studies in large settings (Ritvo et al.,
1990; Fombonne, Du Mazaubrun, Cans, & Grand-
jean, 1997). In these studies, the authors found a spe-
1Service de Psychiatrie de l’Enfant et de l’Adolescent, Groupe
Hospitalier Pitie ´ -Salpe ´ trie ` re, Paris.
2CNRS UMR 7593, Vulne ´ rabilite ´ , Adaptation et Psychopathol-
ogie, Groupe Hospitalier Pitie ´ -Salpe ´ trie ` re, Paris.
3Unite ´ de Ge ´ ne ´ tique Clinique, Groupe Hospitalier Robert Debre ´
4Service de Neurope ´ diatrie, Groupe Hospitalier Armand Trous-
5Service de Pe ´ dopsychiatrie, Groupe Hospitalier Robert Debre ´ ,
6Fe ´ de ´ ration de Ge ´ ne ´ tique, Groupe Hospitalier Pitie ´ -Salpe ´ trie ` re,
7Correspondence should be addressed to: David Cohen, Depart-
ment of Child and Adolescent Psychiatry, Groupe Hospitalier
Pitie ´ -Salpe ´ trie ` re, AP-HP, 47 bd de l’Ho ˆ pital, 75013, Paris,
France; E-mail: email@example.com
0162-3257/05/0200-0103/0 ? 2005 Springer ScienceþBusiness Media, Inc.
Journal of Autism and Developmental Disorders, Vol. 35, No. 1, February 2005 (? 2005)
casesofautism. The most frequent singlegeneticcause
of autism is still debated: some authors report tuber-
ous sclerosis or fragile X (Fombonne, et al., 1997;
Gillberg & Colleman, 1996) whereas others suggest
15q11-q13 duplications (Cook, 2001; Schroer et al.,
1998). Other specific disorders have been described in
association with autism, but the demonstration of a
strong association remains difficult (Bailey et al.,
1996). The prevalence rate of such diseases is low
which does not facilitate epidemiological studies.
Furthermore, most of the genetic causes associated
known to be associated with autism in general (Tol-
mie, 1998; Towbin, 1997). It is difficult to speculate
whether the association of one specific genetic disease
with autism is due to a specific association, to media-
tion via mental retardation, or both. Furthermore,
when a specific genetic cause is discovered, the defin-
itive phenotype is established sometimes years after
the molecular disturbance is described, because it re-
quires large clinical samples or series.
An autistic presentation can reveal a specific
genetic disease that clinicians need to identify.
Defining which phenotypic features may contribute
to the suspicion of a genetic cause or vulnerability is a
crucial task (Skuse, 1998). Geneticists have promoted
the concept of behavioral phenotype to assess this
issue (Flint, 1998). The behavioral phenotype is not
similar to the behavioral disorder or the psychiatric
diagnosis. Thus, autism is not a behavioral phenotype
per se, but may be partly a sign in the behavioral
phenotype of a specific genetic syndrome. The aims of
the present review are to evaluate the available liter-
ature on the topic, and to formulate a consensual and
pragmatic proposal to identify specific genetic disor-
ders in autism. We suggest that the concept of
‘‘syndromal autism’’—autism associated with one or
more morphological signs—be promoted because it
may help to distinguish patients who warrant a
multidisciplinary approach and further investigation.
We conducted a literature search in the Medline
data base (1980–2001) for all reports associating two
of the following key-words : autism or autistic or
pervasive developmental disorder and genetics, cyto-
genetics, chromosome, deletion, mutation, excluding
family studies and genetic association or linkage
studies (for review see Cook, 2001). Based on this
literature review, a multidisciplinary group including
child psychiatrists (DC, ST, PM, EE, CP, GL), clin-
ical geneticists (AV, DH, LB, CB), and molecular
biologist (NP) all involved in autism research, iden-
tified a list of specific diseases that should be known
by child psychiatrists. Criteria for inclusion of a dis-
ease in the list included threshold population inci-
dence, prevalence of autistic features within a specific
disease, ease of diagnosis (e.g., recognizable dys-
morphic signs; standardized molecular screening),
availability of specific treatment and consensual data
regarding the association of autism and the specific
disease. This selection appeared necessary due to the
number of genetic anomalies reported in association
with autism, most frequently as a single case report
(for review of non X-linked disturbances see Lauris-
ten, Mors, Mortensen, & Ewarld, 1999). From this
list, we formulated a clinical work-up in order to help
practitioners diagnose a specific genetic cause when
examining an autistic patient, keeping in mind as
background the need to be efficient and cautious.
PRINCIPAL GENETIC SYNDROMES WHOSE
PHENOTYPE INCLUDES AUTISM OR
We decided to limit the review of the literature to
13 genetic disorders (fragile X, tuberous sclerosis,
Angelman syndrome, duplication of 15q11-q13,
Down syndrome, San Filippo syndrome, MECP2
mutations, phenylketonuria, Smith–Magenis syn-
drome, 22q13 deletion, adenylosuccinate lyase defi-
ciency, Cohen syndrome, and Smith–Lemli–Opitz
syndrome). The present descriptions focus on (i)
autistic traits encountered in each disorder, (ii) other
symptoms that may be helpful for diagnosis. Table I
summarizes clinical data, and indicates the estimated
frequency of each disease in autism and the frequency
of autistic traits in each genetic disorder (when
They are many anecdotal reports of autism with
chromosomal anomalies (Lauristen et al., 1999). In
most cases, epidemiological data are lacking. Nev-
ertheless with the growing use of FISH (Fluorescence
In Situ Hybridation) techniques and psychiatric
interests in clinical genetics, we may expect valida-
tion of new true associations, for instance as the 2q37
microdeletion (Ghaziuddin & Burmeister, 1999), or
104 Cohen et al.
Table I. Principal Genetic Syndromes Associated with Autistic Spectrum Disorders
Specific genetic disorder
(%) of autism
in the disease
Other behavioral traits
No language, stereotyped
Hyperactivity with attention
deficit, paroxysmal laughter,
(>1 year), ataxy, walking
Duplication of 15q11-q13
Severe autistic syndrome
Severe autistic syndrome
Heart and intestinemalformations
Temper tantrums, possible
social contact, sleep disturbance
Severe autistic syndrome
with no language
Tolerance to pain
Single gene disorders
Fragile X (FRAXA)
Poor eye contact, social
Hyperactivity with attention
deficit, sensory hyper-reactivity
Severe autistic syndrome
renal lesions, seizures
San Filippo syndrome
impulsivity, language impairment, inappropriate
Progressive loss of
disturbance in social relatedness,
loss of eye contact
(6–18 months) in girls then
regression (12–36 months)
(apraxia, ataxia, trembling)
lack of social responsiveness
Severe autistic syndrome
irritability, sleep disturbance
Facial dysmorphism, cleft
palate, congenital heartdisease, hypospadias,
2–3 toe syndactyly
marked during childhood
Facial dysmorphism obesity,
Specific Genetic Disorders and Autism105
the Lujan–Fryns syndrome. This X-linked recessive
disorder can be distinguished by a specific marfanoid
habitus, and normal adult height. Long narrow face
large forehead, long nose, maxillary hypoplasia,
highly arched palate, hypotonia and hypernasal
voice are usually present. Most patients show
mild-to-moderate mental handicap, difficult social
integration and, over 80% of cases, difficulties in
social integration due to emotional instability, shy-
ness, and hyperkinetic
involvement is common and includes usually mild
signs of autistic spectrum disorder. Hallucinations and
other acute psychotic breakdown have been reported
(De Hert et al., 1996; Fryns, 1991; Lujan, Carlin, &
Angelman syndrome is due to the lack of
maternal UBE3A (A ubiquitin–protein ligase) gene
transcription. The gene is located in the 15q11-q13
region and subject to imprinting. In two-thirds of the
cases, the structural rearrangement is a de novo
deletion. Other ethiopathogenic mechanisms include
disomy, and mutations of the imprinting center or
point mutations of the UBE3A gene (Kishino,
Lalande, & Wasgstaff, 1997). In approximately 15%
of cases, no cytogenetic or molecular anomalies can
be demonstrated. The syndrome is likely to be asso-
ciated with autism although two studies only
reported the comorbidity. The first one concerned a
sample of patients with severe mental retardation and
seizures (Steffenburg, Gillberg, Seffenburg, & Kyl-
lerman, 1996). It is therefore difficult to assess the
specificity of the association as mental retardation
and seizures are associated with autism, as well. The
second study reported one case of Angelman syn-
drome in a clinical sample of 90 autistic subjects
(estimated prevalence of Angelman syndrome in
autism = 1%) (Petit et al., 1996). Of note, Prader–
Willi syndrome that results from lack of paternal
contribution at the same locus does not share the
same phenotype (Dykens & Cassidy, 1995). To our
knowledge, very few cases were reported in the lit-
erature describing the association of autism and
Prader–Willi syndrome (Demb & Papola, 1995;
Dykens, Cassidy, & King, 1995).
Cognitive and behavioral profiles of children
with Angelman syndrome (AS) share numerous fea-
tures with autism. Children with AS have moderate
to severe mental retardation and no language. Also,
they exhibit stereotyped behaviors (hand flapping,
mouthing of objects). Walking is unstable and fre-
quently ataxic (toe tip walking). Children with AS are
excitable and appear to be always moving. The motor
hyperactivity is often associated with attention defi-
cit, which worsens social interactions, in particular in
terms of eye contact. Geneticists consider that two
behavioral signs may help the diagnosis: paroxysmal
and excessive laughter (Clayton-Smith, 1993) and
temper tantrums (Summers, Allison, Lynch, &
Sandler, 1995). However, both paroxysmal laughter
and temper tantrums may be qualified as autistic
when they happen inappropriately with regard to
context. The Angelman phenotype includes other
features that are encountered in autistic syndrome: (i)
some kind of immutability with intolerance to
change, temper tantrums and self-mutilations, (ii)
fascination with water, (iii) sleep disturbances and
insomnia, and (iv) seizures. A genetic description was
made in recent years. More studies are necessary to
specify the frequency of Angelman as a cause of
autism, and more generally in mental retardation
(estimated prevalence of Angelman syndrome within
moderate to severe mental retardation = 1.4% (Jac-
obsen et al., 1998)).
Duplication of the Proximal Part of the Long Arm of
Duplications of chromosome 15 involved in
autistic syndrome are located in the Angelman–
Prader–Willi region (15q11-q13). Duplications may
result from partial trisomy 15 (presenting an extra
marker chromosome visible with conventional cyto-
genetics to be confirmed as 15q11-q13 derivative by
FISH), or from intrachromosomal duplications. In
many cases, the duplication is tiny, and only detected
when specifically sought using the Prader–Willi locus
FISH probe. Practically, tiny duplications of 15q11-
q13 may be difficult to demonstrate by FISH on
metaphasic chromosomes. Examination of interpha-
sic nuclei with 15q11-q13 FISH probes may be rec-
ommended to increase diagnostic power (Xu & Chen,
2003). Interestingly, an imprinting phenomenon is
probably involved, as most of the reported cases with
autism exhibited duplications inherited from the
mother (Cook et al., 1997; Mao & Jalal, 2000;
Wandstrat, Leana-Cox, Jenkins, & Schwartz, 1998).
The molecular genetic aspects were recently reviewed
by Sutcliffe and Nurmi (2003).
The clinical phenotype includes usually severe
mental retardation, seizures, language disorders and
Kanner-type autism. Frequently, patients exhibit
106Cohen et al.
hypotonia (Rineer, Finucane, & Simon, 1998; Wol-
pert et al., 2000). In a literature review, Wandstrat
et al., (1998) reported 17 cases of 15q duplications.
Among the nine cases with clinical data, eight
exhibited autism. However, Bolton et al., series
(2001) showed that the interstitial duplications of 15q
includes also much milder cases with less prominent
language delay and clumsiness than the full syndrome
of autism. For some authors (Schroer et al., 1998;
Cook, 2001), this genetic abnormality maybe one
of the most common single genetic causes of
autism, besides Fragile X. It is also the most frequent
(Lauristen et al., 1999).
in the literature
Association between Down syndrome and aut-
ism has not reached a consensus as most of the pa-
tients with trisomy 21 do not exhibit autistic features.
However, epidemiological studies usually report the
association, with rates ranging from 1.7 to 2.5% in
autistic samples (Ritvo et al., 1990; Fombonne et al.,
1997). In the literature, we retrieved seven reports of
autism in patients with Down syndrome, including
one boy with mosaic trisomy (Wakabayashi, 1979; Li,
Chen, Lai, Hsu, & Wang, 1993; Ghaziuddin, 1997;
Bregmen & Volkmar, 1998). For other authors, the
association is not specific (Bailey et al., 1996). We
include Down syndrome in the present report because
of (i) its frequency in general, (ii) the possible absence
of typical signs, as facial, cardiac, and hand ab-
normalities may be less obvious in mosaic, partial
trisomies or in complex translocations (Williams,
Frias, Mccormick, Antonarakis, & Cantu, 1990).
Smith–Magenis syndrome is due to an interstitial
microdeletion of chromosome 17p11.2 (Smith et al.,
1986) which is usually undetectable with conventional
banding, but easily picked up by a specific FISH
probe. Mental retardation is variable but usually mild
to moderate, yet speech impairment is often severe.
Infants with Smith–Magenis syndrome are easy,
do not cry, and need to be awakened for feeding.
Behavioral symptoms are similar to those of autistic
children, and include oral activities and stereotyped
behaviors. Eighty percent of patients had self-
destructive behavior including onychotillomania,
wrist-biting, head-banging, and insertion of foreign
bodies into their ears. Two types of behaviors may
be unique to the syndrome: (i) self-hugging and
hand-clasping at the chest level under the chin while
squeezing their arms tightly against their chests and
sides (Greenberg et al., 1991). Increased tolerance to
pain, fascination with electronics, and severe sleep
disturbance with abnormal circadian rhythm were
reported. Some patients exhibit a certain degree of
immutability that may result in temper tantrums.
However, these children are capable of social con-
tact. Smith–Magenis children are usually small, with
short hands and obesity that may evoke Prader–
Willi syndrome. Facial dysmorphism is discrete, and
includes short, tented philtrum and relative progna-
Autism was reported in at least four patients
exhibiting the Smith–Magenis deletion (Cabral de
Almeida, Reis, & Martins, 1989; Lockwood et al.,
1988; Mariner et al., 1986; Vostanis, Harrington,
Prendergast, & Farndon, 1994). To date, it is not
possible to estimate the absolute or relative preva-
lence of the syndrome within autism.
Chromosome 22q13.3 Deletion
Psychiatrists are familiar to chromosome 22q11
deletion (also known as Di George syndrome, Shr-
printzen syndrome or velocardiofacial syndrome)
because it has been associated with schizophrenia
(Pinquier et al., 2001). The 22q13.3 deletion, affecting
the most distal region of the long arm of chromosome
22, has been recently reported to be associated with
autistic disorder (Goizet et al., 2000—1 case; Prasad
et al., 2000—3 cases). Phelan et al. (2001) analyzed 51
cases. The most frequent symptoms are global
developmental delay, absent or severely delayed
speech, generalized hypotonia, increased tolerance to
pain, and normal or accelerated growth. Other minor
signs are possible (dolichocephaly, abnormal ears,
ptosis, dysplastic toenails, chewing behavior, seizures,
and relatively large hands), but for these authors
autism should not be included because of the severity
of mental retardation and absent speech. It seems
that abilities in socialization and non-verbal com-
munication are preserved in these children and simi-
lar to those of children with similar cognitive
impairment (Phelan et al., 2001). From this point of
view, Hansen et al. (1977) report may be helpful. The
reported child, who has chromosome 22q13.3 dele-
tion, exhibited an autistic phenotype at 5 years old.
Specific Genetic Disorders and Autism 107
However autistic signs disappeared at 14 years old. It
is difficult to conclude whether the positive evolution
resulted from the treatment program.
In the current state of knowledge, it is likely
that some children who have autism, carry an
anomaly of chromosome 22. Furthermore, dysmor-
phic signs are absent or discrete, and the chromo-
somal abnormality is undetectable using regular
cytogenetic techniques. Small deletions are diag-
nosed using a specific FISH probe. The prevalence,
absolute or relative, of the chromosome 22q13.3
deletion is still unknown.
Single Gene Disorders
Fragile X Syndrome (FRAXA)
Fragile X (FRAXA) is the most frequent cause
of monogenetic mental retardation (1–4 per 6000
boys) (De Vries, Halley, Oostra, & Niermeijer, 1998;
Tolmie, 1998). The molecular basis of the syndrome
is an unstable mutation due to an expansion of a
CGG triplet-stretch in the FMR1 gene located on
the X chromosome (Hagerman, 1996). Currently,
the routine diagnosis relies on DNA assay (Southern
blot followed by PCR when necessary). Nearly 5%
of autistic patients have the syndrome (Bailey et al.,
1996; Petit et al., 1996) although recent screenings
do not report such high rates (Schroer et al., 1998).
Clinical studies estimate that 10–15% of the subjects
carrying a FRAXA mutation show autistic traits
(Fish, 1993), although most of them would not be
diagnosed as autistic if strict DSM IV criteria were
used. Einfeld, Malony, and Hall (1989) suggested
that this absence of cross-validation results from a
confusion between cognitive disorders and mental
deficit, both present in autistic children as well as
children with FRAXA.
This abnormality is associated with mild to
moderate mental retardation (IQ 40–60) and behav-
ioral symptoms related to social and communication-
related difficulties. These traits associated with lan-
guage disturbance and stereotypes may mimic typical
autism. However, during the eighties, diagnosis of
autism was overestimated in fragile X. Social and
communication-related difficulties include anxiety
and hypersensitivity to touch, auditory stimuli, and
visual stimuli, which are related to difficulty in
establishing eye contact. Hyperactivity, impulsivity,
and attention deficit may enhance social relation
deficits. Communication can be disturbed by specific
language problems as well. Some are also encoun-
tered in autism (perseveration, echolaly, palilaly).
Stereotyped motor behaviors (hand flapping) and
self-injurious behaviors (hand biting and head bang-
ing) belong to both syndromes. Notable dysmorphic
signs, that typically include a long face, large ears,
prominent jaw are commonly encountered but be-
come more apparent in older children and adults.
High stature and large head circumference are com-
monly present since infancy. However, in up to one
third of young patients, subjects with fragile X and
autism may be indistinguishable from non-FRAXA
cases with autism (Rogers, Wehner, & Hagerman,
Tuberous sclerosis is a heterogeneous genetic
disorder. The estimated incidence rate is 1/8000–1/
30000 births per year. Two genes are each involved in
approximately 50% of the reported cases: TSC1
(chromosome 9q34) and TSC2 (chromosome 16p13).
TSC2 gene is located close to the adult polycystic
renal disease (APKD) gene. In several cases, a large
deletion of both genes is observed. This fact explains
the frequent association of tuberous sclerosis and
Ectodermal abnormalities are found in almost all
patients: ash leaf-shaped depigmented skin spots or
macules, often evident from birth, but sometimes
visible only with Wood lamp (60–90%), facial angio-
fibroma (sebaceous adenomas) of the nasopalpebral
folds, usually appearing in childhood (90%), rough,
atrophic skin patches—shagreen patches—usually on
the dorsal trunk (20–40%) with cafe´-au-lait spots,
periungeal fibromata that often appear only after
puberty (50%), and dental enamel pits in the perma-
nent teeth. Cardiac rhabdomyomata occur in over
50% of infants with TSC, but those tumors tend to
regress in early infancy. Renal lesions are found in
60% of patients with TSC, either angiomyolipomas or
cysts, or both. The incidence of angiomyolipomas
increases with age; they may degenerate in multifocal
renal cell carcinoma. Childhood brain tumors (mostly
astrocytomas) may affect 10% of the patients. Mental
retardation and seizures are frequent (40 and 60% of
the patients, respectively). Brain imaging may show
tubers (focal lesions usually at the gray/white matter
interface), subependymal nodules lining the third
ventricle and/or intracranial calcifications (90%)
(Fryer, Chalmers, & Osborne, 1990).
Tuberous sclerosis may be present in 1–4% of
autistic cases (Fombonne et al., 1997) but this rate is
108 Cohen et al.
not consistent in all screening studies (Shroer et al.,
1998). Conversely, autistic traits are encountered in
25–60% of patients with tuberous sclerosis (Bailey
et al., 1996; Smalley, 1998). The frequency is higher in
case of mental retardation and seizures. Of note,
some clinical manifestations of tuberous sclerosis are
discrete, and examination with Wood light is war-
ranted (Smalley, Burger, & Smith, 1994). However,
incidence of hypopigmented skin patches is over 10%
in the general population (Norio, Oksanen, &
San Filippo Syndromes (Mucopolysaccharidosis III A
to III D)
San Filippo syndromes are autosomal recessive
disorders caused by four distinct enzymatic defects
from mucopolysaccharide breakdown. The disease
was reported in only one series with an incidence of
1% within autistic patients (Ritvo et al., 1990), but
the lack of other systematic reporting tends to
suggest that the rate might be lower. Autism may
be diagnosed based on the following signs: autistic
withdrawal, motor stereotypies, behavioral disor-
ders including impulsivity, aggressivity and hyper-
activity, language disturbances including echolaly
and palilaly, inappropriate
laughter and crying), and sleep disturbance (Wraith,
1995). There is a progressive loss of acquisitions
and psychomotor regression. In most cases, onset is
between 2 and 6 years old, and the child appears
normal prior to onset (Nidiffer & Kelly, 1983). In
the nosography of pervasive developmental disor-
ders, San Filippo syndrome is associated with dis-
The MECP2 gene is located on the X chromo-
some. The vast majority of MECP2 mutations lead to
Rett syndrome, and a MECP2 mutation is found in
more than 85% of girls with this diagnosis (Amir,
Van Den Veyver, Wan, Francke, & Zoghbi, 1999).
Yet, milder phenotypes may be seen, maybe in rela-
tion with a residual activity of the mutated protein
(Cheadle et al., 2000). Despite its historical classifi-
cation within the group of pervasive developmental
disorder due to genetic causes, patients with Rett
syndrome exhibit dementia with identifiable stages.
However, the diagnosis of autism may be possible in
a 6- to 18- month-old girl during the first stage of the
disease (Table I). The dementia allows secondarily
the diagnosis of Rett syndrome (Livet, 1998). Since
the discovery of the gene, other clinical phenotypes
have been associated with MECP2 gene mutations:
(i) moderate to severe mental retardation in boys,
alone (Bienvenu et al., 2000; Orrico et al., 2000), or
associated with progressive spasticity (Meloni et al.,
2000); (ii) Angelman-like syndrome (Imessaoudene
et al., 2001) and pure autism (Orrico et al., 2000); (iii)
lethal encephalopathy in boys (Clayton-Smith, Wat-
son, Ramsden, & Black, 2000; Villard et al., 2000);
and (iv) one case of mild mental retardation, lan-
guage specific disorder, and schizophrenia during
adolescence (Cohen et al., 2002).
Clinical symptoms secondary to MECP2 gene
mutations may be classified as follows: severe cogni-
tive impairment; motor dysfunction (ataxia, apraxia,
trembling); mild dysmorphic signs (enophtalmia, ar-
ched eyebrows, prognathism): language impairment;
disturbances in social relatedness, communication
and play; developmental phases, including a normal
developmental period followed by a severe regression
around 6 months to 1 year. It is difficult to estimate
the frequency of MECP2 gene mutations that give
pure autism compared to Rett syndrome or other
phenotypes. However, within autism in general,
Vourc’h et al., (2001) and Lobo-Menendez et al.,
(2003), who conducted a systematic search of
MECP2 gene mutations on samples of 59 and 99
autistic subjects, respectively, concluded that MECP2
mutations were not a frequent cause of autism (no
case was reported in these samples).
In Western countries, symptomatic phenylke-
tonuria has almost vanished, thanks to neonatal
screening that has allowed preventive dietary treat-
ment (Baieli, Pavone, Meli, Fiumara, & Coleman,
2003). This is not true in many developing countries
including Eastern Europe, where screening is not yet
implemented, and for patients born before the gen-
eralization of the Guthrie test, in the sixties. The
phenotype of the untreated form of the disease in-
cludes self-injurious behaviors, temper tantrums,
hyperactivity and severe mental retardation with
epilepsy. Lack of social responsiveness and diagnosis
of autism are possible (Miladi, Larnaout, Kaabachi,
Helayem, & Ben Hamida, 1992).
Adenylosuccinate Lyase Deficiency
Adenylosuccinate lyase deficiency is an auto-
somal recessive inborn error of purine synthesis
Specific Genetic Disorders and Autism 109
characterized by accumulation in body fluids of suc-
cinylaminoimidazole carboxamide riboside (SAI-
CAR) and succinyladenosine. Clinical presentation
includes mental retardation, that varies in terms of
severity, marked autistic traits, and inconstant severe
seizures (Jaeken & Van den Berghe, 1984; Stone et al.,
1992). Biochemical diagnosis is easy and inexpensive,
and requires the search of the two metabolites in
urine (Bratton–Marschall test). The frequency of the
anomaly is unknown and probably underestimated as
clinical presentation is not specific and classical bio-
chemical screening tests are normal (Kohler et al.,
1999; Race, Marie, Vincent, & Van der Berghe, 2000;
Stathis, Cowley, & Broe, 2000). We found only one
study in the literature that systematically examined
adenylosuccinate lyase deficiency in a sample of 119
subjects with autism. No mutation of the gene was
detected in the sample (Fon et al., 1995). The defi-
ciency is probably a rare cause of autism.
Smith–Lemli–Opitz (SLO) syndrome is an auto-
somal recessive inborn error of cholesterol biosyn-
thesis due to loss of activity of D7-dehydrocholesterol
reductase (Tint et al., 1994) leading to increased ser-
um levels of 7-dehydrocholesterol. The incidence has
been estimated to be 1 in 20 000–1 in 40 000 in the
Caucasian population but recent studies show even
higher incidence (1/10 000) (Battaile, Battaile, Mer-
kens, Maslen, & Steiner, 2001; Nowaczyk, Mc
Caughey, Whelan & Porter, 2001). This enzyme defect
leads to a wide spectrum of intellectual impairment
extending from a severe, lethal malformation syn-
drome (so called SLO type 2 (Curry, Carey, & Hol-
land, 1987)) to the ‘‘classical’’ phenotype delineated in
the sixties and even isolated mental retardation.
The clinical phenotype of SLO syndrome in-
cludes microcephaly, facial dysmorphism (bi-tempo-
ral narrowing, ptosis, anteverted nostrils, broad nasal
tip, prominent lateral palatine ridges and microg-
nathism), multiple malformations (cleft palate, con-
genital heart disease, hypospadias,...), short stature
and mental retardation with a wide spectrum of
severity (Kelley & Hennekam, 2000; Ryan et al.,
1998). The only consistent finding is subtotal, often
Y-shaped toes 2 and 3 syndactyly. Cognitive abilities
range from borderline intellectual functioning to
profound mental retardation. Other behavioral or
psychiatric signs include sensory hyper-reactivity, ir-
ritability, language impairment, self-injurious beha-
vior, and sleep-disturbance (Tierny et al., 2000), all
symptoms related to the autistic spectrum. Among
stereotyped behaviors of Smith–Lemli–Opitz pa-
tients, two may be relatively specific: 50% throw
themselves back in a highly characteristic upper body
movement (opisthokinesis), and one third have a
stereotypic stretching motion of the upper body
accompanied by hand flicking (Tierny, Nwokoro, &
Although it is still unclear whether the ab-
normality is frequent or not in autistic patients, two
studies from the same group reported that up to 50%
of subjects with Smith–Lemli–Opitz syndrome met
criteria for autism (Tierny et al., 2000; Tierny et al.,
2001). This syndrome needs to be known by child
psychiatrists as supplementary dietary cholesterol
improves many of the autistic behaviors of affected
children (Kelley, 2000).
Cohen syndrome is an autosomal recessive dis-
order which is difficult to diagnose, in particular
during childhood. It has a higher prevalence in Finn-
ish and Jewish populations, and the disorder is defi-
nitely due to distinct genes in these two groups. The
Nordic form is localized on 8q22-23 and caused by
mutations in COH1 gene (Kolehmainen et al., 2003).
Main signs are microcephaly (50%), prominent
central incisors (2/3 of cases) that are unusually vis-
ible because of a shortened philtrum, prominent nasal
bridge, downslanted palpebral fissures, hypoplastic
malar area, thick hair, and low hairline (Kivitie-
Kallio & Norio 2001). This facial conformation cre-
ates a permanent expression of open mouth. The fa-
cial dysmorphia is associated with truncal obesity and
hyperextensibility of the joints. The fingers are char-
acteristically long and tapered. The children are
hypotonic. They have short stature. Non cyclic, mild
to moderate neutropenia is possible and usually
asymptomatic (Kivitie-Kallio, Rajantie, Juvonen, &
Norio, 1997). In one third of the cases (mainly those
from Finland), a retinochoroidal dystrophy and a
myopia are present in patients over 5 years of age,
with ERG abnormalities. Mental retardation is often
severe (60%) to profound (20%) but may vary (IQ 30–
80) and is associated with motor clumsiness. Lan-
guage is possibly lacking or severely impaired in in-
fancy. Autistic traits are found during childhood
(Fryns et al., 1996).
110 Cohen et al.
DIAGNOSTIC STEPS TOWARDS
IDENTIFICATION OF A SPECIFIC GENETIC
The first step should be clinical, and requires a
precise family history investigation, a careful report
of the child’s developmental history, and a systematic
clinical examination. The second step includes labo-
ratory and imaging studies, and depends on hypoth-
eses formulated at the clinical step. The identification
of genetic factors is important in a diagnostic per-
spective, but also in a research or therapeutic
approach. For example, a recent study indicated that
the serotonin transporter gene by itself does not
convey risk for autism, but instead modifies the
behavioral phenotypic expression of autism and the
severity of autistic behaviors in the social and com-
munication domains (Tordjman et al., 2001). In the
present paper, we will focus on the different steps of
the search and diagnosis of known genetic disorders
associated with autism.
The Clinical Step
An investigation of family history is crucial.
Questions should be simple and precise, and declared
with empathy and caution. Early signs of autism
should be sought with the family. The Autistic
Diagnostic Interview-Revised (Lord, Rutter, & Le
Couteur, 1994) is the most commonly used interview
for this purpose. The construction of the pedigree
may suggest a possible way that heredity plays a role
and can allow for discussion of specific hypotheses.
The clinician should search for consanguineous
mating, for other affected relatives, for medical and
psychiatric family history, learning and develop-
mental difficulties, deceased infants, and malforma-
Simonoff, Bolton, & Rutter, 1996). Of note, sponta-
neous abortions are rarely evoked but their repetition
is a strong argument for a familial chromosomal
anormality. Interpretation of the pedigree may be
difficult, and one should be aware of certain pitfalls.
Within the X-linked inheritance, one can encounter
symptoms in obligate female carriers that mimic an
autosomal dominant inheritance with possible lack of
penetrance. Within autosomal dominant inheritance,
lack of penetrance may render this transmission dif-
ficult to see when recording the pedigree. Recurrence
of a disease within a sibship is not only the conse-
quence of a recessive inheritance. It can be due to a
parental germinal mosaicism, to an autosomal dom-
inant inheritance with lack of penetrance, to inbal-
ance of a familial chromosomal translocation, or to a
Developmental milestones should be recorded.
They include all steps of development until the age of
examination (He ´ ron, 1999; Ponsot et al., 1998) (i)
Prenatal history: course of pregnancy (fetal move-
ments, premature birth), results of ultrasound exams.
(ii) Neonatal history: delivery, clinical status at birth
(APGAR score, weight, body length, head circum-
ference), screening tests (hypothyroidism, phenylke-
(hypotonia), feeding pattern. (iii) Postnatal history :
developmental profile and course, behavioral signs,
including neurological status, height-weight-head
circumference growth curve. Skin should be exam-
ined with Wood lamp when there is doubt to confirm
tuberous sclerosis (He ´ ron, 1999; Simonoff et al.,
1996). Specific signs of autism should be assessed, and
subtype and severity determined. Several standard-
ized procedures are now available (e.g., the Autism
Diagnostic Observation Schedule (Lord et al., 1989).
Psychological examination may be necessary to esti-
mate the cognitive profile, or to assess more specific
functioning. Clinicians should look systematically for
symptoms that may contribute to etiologic diagnosis:
ataxia, seizures, type of language impairment, unu-
sual motor or behavioral signs, paroxysmal laughter,
severe sleep disturbance, bulimic binge, head cir-
cumference.... Examination should also include a
dysmorphologic assessment by a clinical geneticist
knowledgeable in dysmorphology. When clinical
geneticists are not easily available, alternative options
are (i) to train psychiatrists to recognize dysmor-
phology to identify syndromal autism; (ii) to send
adequate patients’ pictures (face, profile, ears, and
hands) to a geneticist for a specialized opinion (our
group is testing the feasibility of such a procedure);
(iii) to preselect for genetic advice the autistic patients
presenting morphologic anomalies or a family history
of severe developmental disorder.
(Baumann& He ´ ron,
Non-syndromal Autism vs. Syndromal Autism
Most clinicians involved in autism and pervasive
developmental disorders or mental retardation are
familiar with the idea of viewing these disorders as
syndromes. However, in the field of mental retarda-
Specific Genetic Disorders and Autism111
tion, the concept of syndromal mental retardation is
widely used to qualify patients with associated con-
genital anomalies or dysmorphism, and useful as a
clinical step for etiological search. We encourage the
use of ‘‘syndromal autism’’ to refer to patients whose
autism is associated with one or more morphological
signs, whereas ‘‘pure autism’’ should be limited to
those autistic patients who have moderate mental
retardation to normal mental functioning and no
associated signs or symptoms (except for the presence
of seizures). Given that there might be an increased
rate of syndromal autism in the severe and profound
mental retardation subgroup, we tend to consider
autistic patients with severe and/or profound mental
retardation within the syndromal autism group.
From our review of the literature and our own
experience with etiological investigations in children
and adults bearing a diagnosis of autism, it appears
extremely important to divide the autistic patients in
thesetwo groups: ‘‘syndromal
‘‘non-syndromal autism’’ (or ‘‘pure’’ autistic patients).
This distinction is crucial for those involved in genetic
studies of autism (in order to reduce the heterogeneity
of their samples), but seems for us to have practical
clinical consequences, in term of diagnostic strategies,
early detection or prevention of comorbidity, specific
treatment and follow up, genetic counseling and, in
some instances, strategies in psychiatric treatment. In
practice, from our list of associated diseases, patients
with fragile X, tuberous sclerosis, Down syndrome,
Smith–Magenis syndrome, Cohen syndrome, Smith–
Lemli–Opitz syndrome usually belong to the syn-
dromal autism group, whereas most patients with
Angelman syndrome, duplication of 15q11-q13, San
Filippo syndrome, MECP2 mutations (except Rett
phenotype), phenylketonuria, 22q13 deletion, ade-
nylosuccinate lyase deficiency exhibit isolated autistic
Laboratory and Imaging Studies
The choice of secondary investigations should be
adapted to each case, and oriented by clinical data. A
precise clinical diagnosis may help to focus on specific
biochemical, cytogenetic or molecular studies.
When non-syndromal autism is the conclusion of
the clinical step, large scale laboratory and imaging
exams are not warranted (Rapin, 1997; AACAP,
1999). A systematic study of ‘‘high resolution loan-
ding’’ karyotype and a search of the fragile X muta-
tion by DNA assay are the minimal genetic studies
(Bailey et al., 1996), in particular when parents are
young and hope to have other children (Rapin, 1997).
We suggest that an exam of the 15q11-q13 region
should also be conducted. Milder cases associated
with interstitial 15q11-q13 duplications may only be
identified with FISH studies (Bolton et al., 2001).
Facing an isolated autistic disorder with no language,
we recommend the search of a 22q13.3 deletion (the
exam is inexpensive as several commercial kits are
available), and screening for Angelman syndrome if
there is an history of ataxic gait, of inappropriate
laughter and epilepsy. In terms of metabolic studies,
the Bratton Marshall test should be systematic to
identify adenylosuccinate lyase deficiency, as the
search of mucopolysaccharids in urine to diagnose
San Filippo disease (Table II).
For some authors, the prescription of large scale
laboratory and imaging exams is justified by the fre-
quency of organic comorbidity with autism. They
suggest practicing neuroimaging, systematic blood
and urine exams, EEG (to diagnose infraclinic sei-
zures), hearing and visual function exams, fundus
examination and CSF study (Gillberg & Colleman,
1996; Livet, 1998). We do not share this view because
cost is considerable both in financial and human
comfort terms. These exams should be discussed after
the clinical step, and we recommend them only (i)
when neurological symptoms (regression, seizures,
pyramidal tract involvement,...), may indicate pro-
gressive or fixed encephalopathy, (b) when facial
dysmorphism or malformations are present or (c)
when specific behavioral traits suggest a specific
diagnosis. Similarly, wide metabolic screening should
be reserved for those patients with severe mental
handicap or specific neurological signs (regression,
transient ataxia, hypoglycemia, lactic acidosis,...) and
screening for telomeric rearrangement should be
systematically proposed in patients with a normal
conventional karyotype when (a) mental handicap is
at least moderate and associated with some devel-
opmental anomalies, microcephaly or growth retar-
dation or (b) when family history is compatible with a
Table II. Recommended Genetic Investigations in Case of Isolated
Autism with Moderate Mental Retardation
Search for fragile X mutation
FISH studies for 15q11-q13 duplication and 22q13 deletion
Search of mucopolysaccharides in urine
112 Cohen et al.
Although understanding of autism is limited in
terms of pathogeny, etiologic studies show a grow-
ing number of cases to be secondary to specific
genetic disorders. It is necessary to systematically
assess these anomalies using a rigorous clinical
process, as it may allow etiologic understanding and
genetic counseling. Genetic studies are probably
restricted by clinical heterogeneity due to the use of
different diagnostic classifications, on the one hand,
and by the possible occurrence of clinical as well as
biological ‘‘subtypes’’ of autism, on the other. It is
thus essential to determine these subtypes before
proceeding with genetic studies. Concerning psychi-
atric nosography, the concept of ‘‘syndromal au-
tism’’—i.e., autism associated with one or more
clinical signs—should be promoted because it may
help to distinguish some of the subtypes in terms of
phenotype. Given the current stage of knowledge,
we consider that only the study of conventional
karyotype and the search of the fragile X mutation
should be systematic in any patient presenting as
isolated non-syndromal autism after a careful clini-
cal and anamnesis review. In cases of autism with
moderate to severe mental handicap, we recommend
adding the search of SAICAR in urine and specific
FISH studies for 15q11-q13 duplication and 22q13
deletion. In all patients with syndromal autism, a
multidisciplinary approach is warranted and referral
to a genetic clinic and a pediatric neurology clinic
for further investigations is strongly recommended.
Finally, it is necessary to consider the genetic factors
possibly involved in autism taking into account the
interactions between genetic and pre- and- postnatal
environmental factors (Tordjman, 1999). Further
research is required on the genetics of autistic dis-
order integrating the effects of the genotype with
those of the environment.
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