Autism is a heterogeneous entity that clearly has a substantial genetic component to its cause. There is likely enough evidence to suggest that there are common genetic mechanisms that predispose to various psychiatric disorders. More recent studies have attempted to identify the specific genes involved in predisposition to autism. In general, such conditions can be subdivided into metabolic, mitochondrial, chromosomal, and monogenic (ie, caused by mutation in a single gene). This article examines what conditions should be considered in the child who does not appear to have a syndromic cause as the reason for the autistic phenotype.
Autism is defined as a behavioral disorder, characterized by the triad of impaired social skills, delayed speech, and areas of intense focus. In the past autism was thought to be relatively uncommon, with incidence figures of 1 in 2500 cited by various articles written in the 1980s. Recently, however, the incidence of autism has increased, with figures as high as 1 in 110 published. Two possible reasons, which may not necessarily be mutually exclusive, are increased exposure to environmental toxins and a broader definition of autism, so that it now comprises a spectrum (autism spectrum disorders [ASDs]) which also includes, for example, Asperger syndrome and pervasive developmental disorder.
Autism is a heterogeneous entity that clearly has a substantial genetic component to its cause. This aspect is shown by a high concordance rate in monozygous twins, with approximately a 90% concordance for both twins having one of the ASDs. However, it is not uncommon for one twin to have autism and the other to have Asperger syndrome. As a result, the heritability is one of the highest cited for a psychiatric disorder, with a figure of 90% usually cited. However, in fewer than half of the cases of autism can a cause be found, so the molecular basis of autism remains mostly unknown. Several epidemiologic studies have been done in an attempt to achieve a better understanding of potential mechanisms that might lead to autism. For example, Schendel and colleagues examined the frequency of congenital anomalies in children with autism as well as the frequency of autism in children with congenital anomalies. The investigators found that children with a diagnosis of autism had an approximately twofold increased frequency of congenital anomalies (6% compared with a frequency of 3% in controls). In most of these children the anomaly was isolated, and in no case was a syndrome diagnosed. Similarly, the frequency of autism among children with congenital anomalies was double that of a control population, with frequencies of 0.43% and 0.22%, respectively. The autism frequency was not the same across all types of anomalies, but was greater in those with either a brain and/or eye anomaly.
Although it may be tempting to suggest that there are shared prenatal environmental factors responsible for the occurrence of both the anomaly and the autism, the investigators stated that “the pattern was indicative of neither a single etiology or pathogenetic mechanism nor a specific insult.” However, they did stress that congenital anomalies could serve as indicators of central nervous system dysfunction, and thus the link to development of autism.
Another noteworthy association that has been described is the finding of a correlation between a family history of autoimmune disorders and ASDs. This group found that among a group of 3325 children with a diagnosis of autism, with 1089 of those having infantile autism, there was a significantly greater frequency of maternal rheumatoid arthritis, maternal celiac disease, and both maternal and paternal type 1 diabetes (but only in the parents of those with infantile autism). One possible mechanism is via a genetic link to HLA system genes, some of which have been implicated in causing infantile autism.
An association with increased paternal age has also been described by several groups. This link has generally been attributed to increased mutation load in the sperm of older males; however, one group that studied families with more than one affected child found that the often described male to female ratio of 4:1 diminished with increasing paternal age, so that among offspring born to men younger than 30 years, the sex ratio was 6.2:1 whereas among offspring born to men older than 45 years, the ratio was 1.2:1. Various mechanisms proposed to explain these findings included de novo copy number variant (CNV), new mutation, or chromosome anomalies, particularly involving the X chromosome.
Other studies have found a greater frequency of parental psychiatric disorders, with such frequency approaching a twofold increase. Schizophrenia in both parents, and depression or personality disorders in mothers were more common in this study. The investigators noted that other studies had also found an association between parental psychiatric disorders and childhood autism, but differences existed among the various studies. Nonetheless, there is likely enough evidence to suggest that there are common genetic mechanisms that predispose to various psychiatric disorders.
More recent studies have attempted to identify the specific genes involved in predisposition to autism. One of the tools used by these studies is exome sequencing, in which all the coding regions of the human genome are simultaneously sequenced, searching for mutations that might be causative or contributory to the cause of an individual’s disorder. O’Roak and colleagues, using exome sequencing in 20 individuals with ASDs, found 21 de novo mutations, with 11 causing alterations in the gene product (protein). Therefore, in the not too distant future this technique will be applied clinically in an attempt to identify the causes of a particular child’s autism.
Until that time, what should be done to evaluate the child for an identifiable genetic cause? Several studies have found that in a small subgroup of children with autism or ASD, there is an underlying genetic or chromosomal abnormality, with figures ranging between 10% and 41% for that proportion. Table 1 summarizes some of these studies. It should be noted that some of these studies presented only genetic causes, whereas others attempted to identify all causes. The populations examined were also varied; some data were obtained from a group of children referred to a genetics clinic, whereas other data were from autism units or were recruited for the study. Nevertheless, these data serve as starting points for providing guidelines for the evaluation of the child with autism.
| Reference Investigation | ||||||||
|---|---|---|---|---|---|---|---|---|
| Schaefer and Lutz | Kosinovsky et al | Roesser | Benvenuto et al | Shen et al | Herman et al | Battaglia and Carey | Boddaert et al | |
| Source of patients | Genetics clinic | Autism centers | Autism centers | None (review article) | Recruited patients | Genetics clinic | Autism centers | Autism centers |
| Total N | 32 | 132 | 207 | NA | 852 | 71 | 85 | 77 (8 unused) |
| Physical exam | 2 | — | 13 | 3%–4% | — | — | — | — |
| Metabolic evaluation | 0 | 0 | — | — | — | 0 | 0 | — |
| Audiogram | 1 | — | — | — | — | — | 1 | — |
| Rubella titers | 0 | — | — | — | — | — | — | — |
| Karyotype | 2 | — | 4 | — | 19 | 2 | 1 | — |
| Fragile X | 2 | 2 | 1 | 2%–5% | 2 | 0 | 1 | — |
| MRI | 1 | — | — | — | — | — | 2 | 33/69 |
| EEG | 0 | 1 | — | — | — | — | 1 | — |
| MECP2 | 2 | — | 0 | — | — | 3 | — | — |
| 22q11 FISH | 0 | — | 0 | — | — | — | — | — |
| 15 interphase FISH | 1 | — | 0 | 1%–2% | — | 0 | 2 | — |
| 17p FISH | 1 | — | — | — | — | — | — | — |
| Uric acid | 1 | — | — | — | — | 0 | — | — |
| Microarray | — | — | 1%–2% | 154 CNV, 59 pathogenic | 1 | — | — | |
| PTEN | — | — | — | — | 2 | — | — | |
| Total | 13/32 (41%) | 1.5% | 9% | 7%–13% | 9%–20% | 11% | 10.5% | 48% |
What are these genetic conditions? In general, they can be subdivided into metabolic, mitochondrial, chromosomal, and monogenic (ie, caused by mutation in a single gene). An understanding of what these conditions are is useful in understanding the recommendations of the various specialty groups. Because there are good reviews of the various conditions associated with autism, this article tries to answer the question, “what conditions should be considered in the child who does not appear to have a syndromic cause as the reason for the ASD phenotype?”
Metabolic disorders
Metabolic disorders are generally not considered to be a significant cause of autism, but because many are amenable to some form of treatment, it is important to recognize a metabolic disorder when it is present. The following is a brief review of some of these disorders that can be a cause of ASD.
Phenylketonuria
Phenylketonuria (PKU) is one of the more common disorders of amino acid metabolism, caused by homozygous or compound heterozygous mutation of the phenylalanine hydroxylase gene. PKU is one of the disorders for which newborn screening is done in the United States and several other countries; however, screening for PKU does not occur universally. In addition, if the screening is done too early (eg, first 12 hours of life), false-negative results can occur. Therefore, the physician needs to still consider PKU in the differential diagnosis in certain circumstances.
The phenotype of untreated PKU individuals includes cognitive impairment, seizures, microcephaly, decreased pigmentation, and a musty odor. Among individuals with autism, PKU has been reported to occur more frequently than expected by chance ; however, the absolute frequency is still expected to be low, as demonstrated by the finding that autism in untreated PKU patients only occurs 5% of the time. As already noted, if there is suspicion that the child may have PKU as the cause of the autism phenotype, diagnosis can easily be achieved by measurement of serum levels of phenylalanine.
Disorders of Purine Metabolism
Only one condition in this group is associated with the development of ASD, that being adenylosuccinate lyase (ADSL) deficiency. Phenotypic manifestations in this autosomal recessive condition include seizures, cognitive impairment, and hypotonia. The frequency of autism as a component manifestation is unknown, although Jaeken and Van den Berghe described autistic features in 3 of 8 children with this condition. Diagnosis is achieved by measurement of succinyladenosine and succinylamino imidazole carboxamide in cerebrospinal fluid, serum, or urine.
However, a second condition in this category deserves mention. Adenosine deaminase (ADA) deficiency can lead to severe combined immunodeficiency and, if untreated, early death. Most untreated children die soon after birth, but in those who were treated by bone marrow transplantation, Rogers and colleagues found behavioral abnormalities such as hyperactivity/attention-deficit disorder, aggressive behavior, and social problems. Autism was not described as occurring more frequently. This finding is relevant in that there are reports of children with autism having reduced levels of ADA in their sera, leading some groups to search for mutations or polymorphisms in one ADA allele. Two Italian studies did report a significantly increased relative risk for autism in patients with heterozygosity for an ADA allele (ADA2) associated with reduced catalytic activity, and suggested this variant might be associated with an increased risk of autism. Hettinger and colleagues in a North American population did replicate these findings, so it was suggested that the ADA polymorphism may play a more significant role in Italian populations than in United States populations. In summary, ADA2, a variant form of the ADA gene, may be associated with an increased predisposition to develop autism, but having two mutations (pathogenic changes) causes a condition which is not associated with an increased risk of autism.
Succinic Semialdehyde Dehydrogenase Deficiency
This condition is a relatively rare (although the true prevalence is unknown) neurometabolic, autosomal recessive disorder that can be diagnosed by determination of succinic semialdehyde dehydrogenase (SSADH) enzymatic activity in leukocytes. The finding of elevated levels of 4-hydroxybutyric acid on urine organic acid screens often raises the suspicion that this is the underlying disorder. This condition is characterized by cognitive impairment, hypotonia of childhood onset, ataxia, and seizures. Behavioral disturbances include hyperkinesis, aggression, self-injury, and sleep disturbances. Autistic features were described in 12% (4/33) of older individuals. Therefore, despite the unknown prevalence, it is likely that SSADH deficiency and autism affects fewer than 1 in several million. However, it is important to keep in mind that therapeutic decision making could be affected by knowledge that a patient has SSADH deficiency. For example, based on its pharmacologic properties, finasteride could prove to be a useful adjunctive therapy in those with SSADH deficiency.
Disorders of Creatine Transport and Metabolism
Three different disorders have been identified as falling into this category. Deficiencies of arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT) affect creatine metabolism, whereas deficiency of creatine transporter 1 (CT1) enzyme affects its transport into brain tissue. As a group, these conditions are termed the creatine deficiency syndromes (CDS). AGAT and GAMT deficiencies are thought to be extremely rare, whereas CT1 is thought to account for as much as 1% to 4% of cases of X-linked cognitive impairment. Clinical manifestations in all include developmental delay, cognitive impairment, autistic manifestations, seizures, and hypotonia. Those with CT1 deficiency may also have the additional manifestations of midface hypoplasia and short stature. In a review of CDS, Schulze noted that two-thirds of those with a CDS had autism. Diagnosis of these conditions can be achieved by detection (or lack thereof) of the creatine peak on magnetic resonance spectroscopy, and confirmed by measurement of plasma and urine levels of creatine and guanidinoacetate. The pattern of results often points to the diagnosis (eg, in AGAT deficiency, plasma creatine is low/normal, whereas plasma and urine guanidinoacetate is low; in GAMT deficiency, plasma creatine is low, whereas plasma and urine guanidinoacetate are elevated). It has been questioned whether children with autism should be screened for one of these disorders. These conditions are admittedly rare; however, because therapeutic interventions can improve manifestations and, if given early enough, can prevent cognitive impairment and neurologic symptoms in some of these conditions, consideration should be given to pursuing testing in children with consistent phenotypic manifestations. Unfortunately, treatment is less successful in the more common CT1.
Cerebral Folate Deficiency
This group of conditions is defined as any one of the neurologic entities characterized by low cerebrospinal fluid concentration of 5-methlyhydrofolate in the presence of normal serum folate levels. Cerebral folate deficiency comprises a heterogeneous group of conditions for which the molecular basis is incompletely understood, although disorders/genes identified to date include dihydrofolate reductase, α-5,10-methylene-tetrahydrofolate reductase, 3-phosphyglycerate dehydrogenase, or dihydropteridine reductase deficiencies; as well as Rett, Aicardi-Goutieres, or mitochondrial syndromes. Despite this heterogeneity, it has been suggested by some but not others that a clinical phenotype exists. This phenotype includes early normal development until approximately 4 to 6 months, with subsequent developmental delay, agitation, sleep disturbances, deceleration of head growth, ataxia, hypotonia, and seizures. However, Mangold and colleagues did not find supportive evidence for this assertion, and cautioned against viewing this group of conditions as a distinct syndrome.
The diagnosis is achieved by measurement of cerebrospinal fluid 5-methyltetrahydrofolate (5MTHF), and finding reduced levels. One group recently described 103 patients with cerebral folate deficiency, although the frequency of autism in this cohort was not noted. Ramaekers and colleagues described autism in 4 of 28 patients, whereas Moretti and colleagues reported autism in 5 of 7 patients. Therefore, it is clear that autism is not a consistent finding in what is likely a rare group of disorders. Nonetheless, in a child with autistic manifestations with some of the other findings of this group of disorders, it may be worthwhile to pursue this diagnosis because there is some evidence that treatment with folinic acid may lead to improvement of some of the symptoms.
Smith-Lemli-Opitz Syndrome
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol metabolism characterized by a distinctive phenotype of physical, cognitive, and behavioral manifestations. The clinical findings include microcephaly, ptosis, anteverted nares, micrognathia, and syndactyly between toes 2 and 3 (present in more than 90% of cases). Genital anomalies in males are also common. All have cognitive impairment, and at least 75% have autistic features. The frequency of SLOS in the population is approximately 1 in 30,000 (but may be as high as 1 in 20,000) so a reasonable estimate for the prevalence of those with SLOS and autism is that 1 in 40,000, or 1 in 267 of those with autism will have SLOS. Therefore, screening all with autism for SLOS will have a very low yield; this was also found by Tierney and colleagues, who did not find metabolic evidence for SLOS in those with autism, and suggested that the frequency of unrecognized SLOS among individuals with autism is less than 0.2%. However, targeted testing of those in whom there is clinical suspicion is worthwhile. Diagnosis is accomplished by measurement of 7-dehydrocholesterol in serum. Benefits of diagnosis include the potential for amelioration of symptoms by treating with cholesterol; however, a recent prospective trial failed to identify a true effect on behavior.
Although Tierney and colleagues did not identify individuals with SLOS in their study, they did find that abnormally low levels of cholesterol were found in almost 20% of children with autism, further supporting a role for reduced lipid levels in children with autism. This finding has potential for identification of possible interventional or preventive therapies as well as for understanding additional causes of autism.
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