Pediatric Neurology 49 (2013) 232e236

Contents lists available at ScienceDirect

Pediatric Neurology
journal homepage: www.elsevier.com/locate/pnu

Topical Review

Autism Spectrum Disorders and Inborn Errors of Metabolism: An Update

Mohammad Ghaziuddin MD *, Mohammed Al-Owain MD
University of Michigan, Ann Arbor, Michigan, and King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

abstract
BACKGROUND: Autism spectrum disorder is characterized by social communicative decits with restricted interests

occurring in about 1% of the population. Although its exact cause is not known, several factors have been implicated in its etiology, including inborn errors of metabolism. Although relatively uncommon, these disorders
frequently occur in countries with high rates of consanguinity and are often associated with behavioral problems,
such as hyperactivity and aggression. The aim of this review is to examine the association of autism with these
conditions. METHOD: A computer-assisted search was performed to identify the most common inborn errors of
metabolism associated with autism. RESULTS: The following disorders were identied: phenylketonuria, glucose-6phosphatase deciency, propionic acidemia, adenosine deaminase deciency, SmitheLemlieOpitz syndrome and
mitochondrial disorders, and the recently described branched chain ketoacid dehydrogenase kinase deciency.
CONCLUSION: The risk of autistic features is increased in children with inborn errors of metabolism, especially in the
presence of cognitive and behavioral decits. We propose that affected children should be screened for autism.
Keywords: autism, metabolic disorders, autism spectrum disorders, inborn errors of metabolism

Pediatr Neurol 2013; 49: 232-236

2013 Elsevier Inc. All rights reserved.
Introduction

Autism spectrum disorder (ASD) is a behavioral syndrome characterized by social communication decits with
rigid restricted interests, occurring in about 1% of the population.1,2 Although ASD and autism are often used interchangeably, the former more correctly refers to a group of
disorders of varying degrees of severity. At least 10% of
patients with ASD suffer from comorbid disorders, such as
tuberous sclerosis and fragile X syndrome.3
ASD can also occur with inborn errors of metabolism,
sometimes referred to as inherited metabolic disorders,
which occur in 1 in 800 live births.4 These conditions, which
have become increasingly important because of the progress made in their diagnosis and management,5 occur when
an enzyme or a transport protein deciency causes a block
in a metabolic pathway resulting either in a harmful accumulation of the substrate behind the block or in a deciency
of the product. They can be divided into acute and chronic

Article History:
Received 15 February 2013; Accepted 31 May 2013
* Communications should be addressed to: Dr. Ghaziuddin; Department of Psychiatry; University of Michigan; Ann Arbor, MI 48109-0277.
E-mail address: mghaziud@umich.edu
0887-8994/$ - see front matter 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.pediatrneurol.2013.05.013

categories. The former group usually begins in the rst 2-3

years of life and may present in metabolic crisis (intoxication), whereas the latter may come to medical attention at
any time and have a more insidious course. Metabolic disorders with intoxication often present with acute encephalopathy associated with acidosis, hyperammonemia, and/
or hypoglycemia.5 Several behavioral and neuropsychiatric
abnormalities can occur in children with metabolic disorders.6 These stem from the involvement of the central
nervous system and include learning disability, social decits, hyperactivity, aggression, catatonia, psychosis, and
depression.7 Because most metabolic disorders are autosomal recessive,8 they are more common in countries with
high rates of consanguinity, where they are associated with
a signicant degree of morbidity and mortality.9
Increased awareness of both autism and of inherited
metabolic disorders has increased the focus on the comorbidity between them. Although, the exact rate of autism in
patients with inherited metabolic disorders is not known,
the rate of the latter in patients with autism is said to be
around 2%. For example, in a study of 222 Greek children
with autism, 2.7% suffered from a metabolic disorder.10
However, given that the correct diagnosis of an inborn error of metabolism requires both clinical and technological
expertise, this gure is probably closer to 5%.11

M. Ghaziuddin, M. Al-Owain / Pediatric Neurology 49 (2013) 232e236

There have been no recent reviews of the association of

autism with metabolic disorders since the last review by
Manzi and colleagues.12 Since then, several new reports
have described the occurrence of autism in patients with
inherited metabolic disorders. For example, a novel metabolic entity (branched chain ketoacid dehydrogenase kinase
deciency) was recently described in multiple consanguineous families with autism, epilepsy, and intellectual
disability.13 The aim of this review is to describe the association between the two conditions with particular reference to publications since the review by Manzi et al.12
Method
A computer-assisted PubMed search was performed with the keywords
autism, autism spectrum disorders, pervasive developmental
disorders, metabolic diseases, metabolic disorders, and inborn errors
of metabolism. Through cross-references, reviews and book chapters were
also examined. The following disorders were most commonly identied.
Aminoacidopathies
Phenylketonuria

Phenylketonuria (PKU) is a common autosomal recessive disorder of

amino acid metabolism, occurring in about 1 in 10,000 people. It is
caused by a dysfunction in the metabolism of phenylalanine resulting
either from a deciency of the enzyme phenylalanine hydroxylase or of
its essential cofactor tetrahydrobiopterin. Because phenylalanine is not
metabolized, it accumulates in the body and causes reduction of myelin
and neuronal loss.14 If PKU is not treated immediately after birth, irreversible brain damage may occur, and, one of its features may include
autism.
The exact prevalence rate of autism in PKU is not known. However,
the association between the two disorders is well-documented in single
case reports and case series. Chen and Hsaio15 described autistic features
in an adolescent who was later diagnosed with classical PKU. Treatment
with a low-phenylalanine diet started after the diagnosis of PKU did not
decrease the autistic symptoms. The authors emphasized the need for
excluding PKU as a cause of autism in those countries where neonatal
screening is not done systematically. In a relatively recent Italian study,
Baleili and colleagues16 examined the features of autism in a group of 97
patients with classical PKU. Sixty-two were diagnosed early based on
neonatal screening and were receiving treatment. None in this group
met the criteria of autism. In the remaining 35 patients, who were
diagnosed late, two patients (5.7%) met the full criteria of autism. Patients in the former group were of normal intelligence, whereas those in
the latter group were in the mentally disabled range.16
Although the exact cause of autism in untreated PKU is not clear, it
probably results from the accumulation of phenylalanine causing brain
damage. Several other neuropsychological abnormalities have been
described in persons with PKU, including those who have been treated.
Some of these include executive function decits and problems with
attention and impulsivity.17,18 Once the diagnosis of autism in children
with PKU is established, treatment should consist of incorporating
educational and behavioral interventions focusing on the social and
communication decits.
Disorders of branched-chain amino acids

Branched chain amino acids (BCAAs, leucine, isoleucine, and valine)

are essential amino acids required by the body. In a recent report,13 investigators examined three consanguineous families of Middle Eastern
origin with autism, intellectual disability, and seizure disorder (or an
abnormal electroencephalograph). They found that affected persons
with the three disorders had low levels of BCAAs, which were corrected
after the administration of the amino acids. The cause was the occurrence of mutations in the branched-chain ketoacid dehydrogenase kinase gene (BCKDH), which encodes a protein involved in inactivating the
branched-chain ketoacid dehydrogenase complex, the deciency of
which causes maple syrup urine disease. Mice with this gene knocked

233

out had low BCAA levels in plasma and in the brain and exhibited
neurological impairments typical of autism. BCKDH-knockout mice fed a
diet enriched in BCAAs showed neurological improvements. However,
the clinical signicance of this report is unclear. Even if plasma BCAAs are
normalized, patients might be beyond the critical periods for developing
social and language skills typical of autism.13
Organic acidurias
Propionic acidemia

Propionic acidemia is a common form of organic aciduria resulting

from the deciency of propionyl-Coenzyme A carboxylase. It is characterized by frequent and potentially lethal episodes of metabolic acidosis
often accompanied by hyperammonemia.19 The incidence of this disorder in countries such as Saudi Arabia is relatively high, with an estimated
frequency of 1:2000-5000 live births20 partly resulting from tribal
founder mutation.9 It is initially diagnosed by performing an acylcarnitine prole and analysis of urine organic acids. Further conrmation is
done by enzyme assay or gene testing. Psychiatric symptoms such as
visual hallucinations21 have been reported, as well as autism.22 Interestingly, recent reports have suggested that propionic acid administered
by an intracerebroventricular injection or systemically may induce an
animal model of autism.23-25 Therefore, in countries with high rates of
recessive disorders, autism should be considered in the differential
diagnosis whenever a patient with propionic acidemia presents with
behavioral symptoms.
3-methyl-crotonyl-CoA carboxylase deciency

This is a disorder of leucine metabolism. Some reports have described

the occurrence of mental retardation and developmental disorders in
children with this enzyme deciency at the time of birth and identied
by neonatal screening. One report has mentioned the presence of autism
in a child identied in a retrospective analysis of 35 patients. Another
child was said to suffer from obsessive-compulsive disorder and was
placed in a gifted program. However, details about the diagnosis were
not given. It is difcult to say to what extent this deciency contributed
to the presence of autism.26
Pyridoxine dependency

Pyridoxine dependency epilepsy is a form of organic aciduria characterized by early-onset epileptic encephalopathy responsive to large
dosages of pyridoxine. It is caused by antiquitin (a-aminoadipic-semialdehyde dehydrogenase) deciency. In addition, most patients have
intellectual disability despite good seizure control. Antiquitin is coded by
the gene ALDH7A1. Presentations include late-onset of seizures and
autism. In a large cohort with pyridoxine dependency epilepsy, Mills
et al. reported that a single patient (F19) who had both seizures and
autistic features responded to treatment with pyridoxine.27 The diagnosis is generally conrmed by measurement of a-aminoadipic semialdehyde and gene testing.28
Purine and pyrimidine disorders
Adenosine deaminase (ADA) deciency

Adenosine deaminase plays an important role in the regulation of the

neurotransmitters such as dopamine and serotonin and also in the
functioning of the immune system. Absence of the enzyme ADA leads to
the accumulation of deoxyadenosine, which is toxic to the lymphocytes
resulting in immunodeciency. The disorder can be of early or late onset,
with a range of clinical features depending on the level of deciency of
the enzyme.29 A few case reports have described autistic features in
patients with reduced levels of ADA.30,31 Stubbs and colleagues found
that the level of ADA was decreased in children with autism compared
with normal, intellectually disabled and children with cerebral palsy.32
In an Italian study, Bottini et al.33 compared 118 autistic children with
126 controls. The autistic group had increased levels of the variants of
the enzyme that are associated with reduced activity. However, Hettinger et al.34 could not nd evidence of disturbed enzyme activity in a
study of 126 families in a North American sample. There is no evidence to
suggest that treatment of ADA deciency can lead to improvement of
autistic features.

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Adenylosuccinate lyase deciency

Adenylosuccinate lyase deciency is an autosomal recessive disorder

of purine synthesis characterized by increased levels of succinylaminoimidazole carboxamide riboside and succinyladenosine. Clinical features include autistic symptoms, seizures, and mental retardation.35 The
cause of autism in this syndrome is not known, but is probably mediated
through the presence of mental retardation.
Dihydropyrimidine dehydrogenase and dihydropyrimidinase deciencies

These two enzymes in the pyrimidine metabolic pathway are

required sequentially to catalyze the conversion of uracil/thymine to
dihydrouracil/dihydrothymine followed by -ureidopropionate and ureido isobutyrate. Symptoms may include psychomotor retardation and
epileptic encephalopathy.36 Autistic features can be seen in both the
disorders.37 Diagnosis relies on measurement of uracil/thymine and
dihydrouracil/dihydrothymine in the body uids.
Disorders of vitamins and cofactors
Biotinidase deciency

Biotin is a cofactor for all carboxylases in the body including

propionyl-CoA carboxylase, pyruvate carboxylase, and 3-methyl-crotonyl-CoA carboxylase. The urine organic acid analysis and acylcarnitine
prole may suggest the diagnosis; however conrmation requires biotinidase enzyme assay and/or gene testing. Besides a skin rash, the
enzyme deciency causes a neurological disease (poor hearing and
vision, seizures, and developmental and behavioral disturbances).38 A
single patient with partial biotinidase deciency with autism has been
reported.39
Cerebral folate deciency

Characterized by low cerebrospinal uid folates (especially 5methyltetrahydrofolate) and normal peripheral folate metabolism, cerebral folate deciency is increasingly being recognized in various
neurological disorders. It is associated with folate receptor autoimmunity and the deciency of one of several enzymes involved in folate
metabolism.40,41 Patients may exhibit autistic features in addition to
psychomotor retardation, seizures, movement disorder, and visual and
hearing impairment. If treated early, patients may show a favorable
response to folinic acid.42 Diagnosis may be challenging and requires the
assay of cerebrospinal uid neurotransmitters and specic enzymes.
Disorders of mitochondrial energy metabolism
Disorders of creatine metabolism

The hallmark of these disorders is the deciency of creatine in the

brain. Collectively called creatine deciency syndrome, they include Larginine:glycine amidinotransferase deciency, guanidinoacetate
methyltransferase deciency, and X-linked creatine transporter defect.
Autism is seen in all of these disorders. Cerebral creatine deciency by
magnetic resonance spectroscopy of the brain is the characteristic
feature of all of these disorders. Measurement of guanidinoacetate,
creatine, and creatinine in body uids (urine, serum, and cerebrospinal
uid) is also useful as a screening test. Enzymatic assay and/or gene
testing are required for conrmation.43,44
Mitochondrial disorders

Mitochondria are intracellular structures that play an important role

in protein and lipid metabolism. They participate in the production of
cell energy and modulate other functions such as signaling, cellular
differentiation, and cellular death. Monoamine oxidase enzymes A and B,
which have been implicated in a variety of psychiatric disorders, are
localized in the outer mitochondrial membrane.45 Mitochondrial disorders have been reported predominantly with depression but also with
other psychiatric disorders. In a review of the literature, Fattal and colleagues46,47 found 19 patients with mitochondrial disorders and associated psychiatric abnormalities such as bipolar disorder, anxiety
disorders, and schizophrenia. For example, electron microscopic studies
have revealed abnormalities in the size and density of mitochondria in
the postmortem brains of patients with schizophrenia. Positron emission
tomography studies have shown altered brain metabolism resulting
from mitochondrial dysfunction in schizophrenia and bipolar disorder.

Altered mitochondrial gene expression has been reported in some

psychiatric disorders using array-based technology. A few case
reports have also described the occurrence of autism in mitochondrial
disorders. In a study of 12 children with hypotonia, epilepsy, autism, and
developmental delay, Fillano et al.48 found evidence of mitochondrial
abnormalities in a signicant number of children. These included
abnormal appearance of mitochondrial organelles and mitochondrial
DNA deletions. Ezuga et al.49 described a 12-year-old boy with autism,
mental retardation, leg weakness, and dysmorphic features. A buccal
swab electron transport chain analysis revealed a reduction in complex
IV and complex I activities, whereas a molecular cytogenetic study
showed a small deletion involving the 5q14.3 region. Because most of the
reports describing autism in mitochondrial disorders were based on
small numbers, they can only be regarded as preliminary.
Other disorders
Glucose 6-phosphate dehydrogenase (G6PD) deciency

G6PD converts glucose-6-phosphate to ribose-5-phosphate, which is

a precursor of molecules such as RNA and DNA. The enzyme deciency
increases the risk of the red blood cells to oxidative stress. It is the most
common human enzyme defect, being present in more than 400 million
people around the world. Symptoms include acute hemolytic anemia,
chronic hemolytic anemia, and neonatal hyperbilirubinemia. G6PD
deciency is particularly common in people of African and Mediterranean origin, especially in areas endemic to malaria against which it
provides some protection.50 Al-Salehi and Ghaziuddin51 described two
boys with autism and G6PD deciency from a case series in Saudi Arabia.
Both patients had severe language delay with mental retardation, and
one also had a seizure disorder. The authors postulated that the one
factor leading to autism in patients with this enzyme deciency might be
the development of kernicterus resulting from hyperbilirubinemia. Thus,
a subgroup of children with kernicterus may be vulnerable to developing
autism, especially in developing countries, where a contributing factor is
G6PD deciency.
SmitheLemlieOpitz syndrome

This is a recessive disorder in which the body does not metabolize

cholesterol properly, leading to increased serum levels of 7dehydrocholesterol. The symptoms range from isolated intellectual
disability to severe physical and mental decits incompatible with life.
Some of the physical features include microcephaly, ptosis, short stature,
and abnormalities of the second and third toes.52 Neurodevelopmental
symptoms may consist of hyperactivity and autistic symptoms with
stereotyped behaviors that may be specic to the syndrome. Among
stereotyped behaviors of SmitheLemlieOpitz patients, two may be
relatively specic: a characteristic upper body movement (opisthokinesis) and stereotypic stretching motion of the upper body accompanied
by hand icking.53 Treatment of the autistic features is symptomatic
although some patients seem to respond to a supplementary diet of
cholesterol.53
Succinic semialdehyde dehydrogenase deciency

Succinic semialdehyde dehydrogenase deciency (4-hydroxybutyric

aciduria) is caused by a defect in the catabolic pathway of the inhibitory neurotransmitter g-aminobutyric acid. Urine organic acid analysis
reveals the elevations of g-hydroxybutyric acid. Clinically, the disorder is
characterized by psychomotor retardation, hypotonia, ataxia, ASD, and
seizures. Other behavioral manifestations (hyperkinetic behavior,
aggression, self-injurious behaviors, hallucinations, and sleep disturbances) are seen in nearly half of all patients, more commonly in
older individuals. Patients with this disorder are treated with vigabatrin,
an anticonvulsant that irreversibly blocks g-aminobutyric acid transaminase.54
Sanlippo syndrome (mucopolysaccharidosis type III)

The deciencies of four enzymes involved in the degradation of

heparan sulfate cause Sanlippo syndrome, a lysosomal storage disease
characterized by severe neurodegenerative course with minimal somatic

M. Ghaziuddin, M. Al-Owain / Pediatric Neurology 49 (2013) 232e236

features.55 Several behavioral disturbances, including autism, have been
reported in Sanlippo syndrome.56

Assessment and treatment

Clinicians working in countries with a high prevalence of

recessive conditions should rule out autism in patients with
inborn errors of metabolism, especially in children with
behavioral problems. Common behavioral problems that
suggest a need for screening for autism include speech and
language abnormalities, hyperactivity and impulsivity, difculty in interacting with peers, suggestion of intellectual
disability, and presence of excessive interests and ritualistic
behaviors. There is a general consensus that the earlier the
diagnosis of autism, the better the long-term outcome. In
addition, a timely diagnosis is also necessary for accessing
the right kind of educational and psychological services and
also for educating the parents about autism and its likely
outcome.
Screening measures and rating scales for autism should
be used, and complex cases should be referred to a
specialist. Conversely, clinicians working in autism assessment centers should rule out comorbid metabolic disorders,
especially in patients with mental retardation/intellectual
disability, seizure disorder, and dysmorphic features and in
those with a family history of these conditions. In consultation with an expert in metabolic disorders, screening
should be done for serum amino acids, lactate, ammonia,
acylcarnitine, urine mucopolysaccharides, and organic
acids. An amino acid analysis, a urine organic acid screen,
and an acylcarnitine prole are the most widely used
screening tests for the evaluation of suspected metabolic
disorders. These tests collectively have a high detection rate
of many aminoacidopathies (e.g., phenylketonuria), organic
acidurias (e.g., propionic acidemia), and urea cycle defects.
Conrmation of the diagnosis usually requires an enzyme
assay and/or gene testing. However, routine testing for
metabolic disorders in all patients with autism is not indicated.57 This is partly because the yield of metabolic disorders in children with ASD is less than 5%.11 At this stage,
therefore, as recommended by the American College of
Medical Genetics, selective metabolic screening/consultation should be considered only on the basis of clinical
ndings.57 Possible clinical indications include a history of
lethargy, cyclic vomiting, early seizures, dysmorphic features, intellectual disability, concerns about newborn
screening, or birth outside the United States, suggesting
problems with maternal public health measures.58
Depending on the age of the child, dietary treatment for
the metabolic disorder should be considered in addition to
autism-specic interventions such as social skills training,
speech therapy, and educational placement.
Conclusion

Autistic symptoms occur in a variety of inborn errors of

metabolism. These are more likely to occur in certain
countries, such as in the Middle East, where recessive
conditions are common because of consanguinity. The association of autism with metabolic disorders underscores
that autism can be the end result of a variety of insults and
injuries. The severity of the autistic symptoms varies with
the timing of the diagnosis and the subsequent treatment,

235

as in the case of phenylketonuria. Screening for autism

should be done when metabolic disorders occur with
cognitive and behavioral problems. Treatment should
address the symptoms resulting from both the inborn
errors of metabolism and the autism spectrum disorder.
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