Disorders Associated with Intellectual Disabilities

Nancy C. Brahm, Jerry R. McKee, and Douglas W. Stewart

INTRODUCTION

Intellectual disabilities (IDs) can be identified in childhood or adolescence. Current criteria for diagnosis are based on deficiencies in intellectual and adaptive functioning with an onset prior to 18 years of age.¹ This diagnosis is made regardless of the presence or absence of concomitant medical or psychiatric disorders. In the case of mild ID, deficiencies may not be apparent in early life. Problems can be noted when the chronologic age of the child and the developmental milestones achieved by peers with similar backgrounds, cultures, socioeconomic status, and psychosocial settings differ significantly.¹ These gaps between developmental advances widen as the individual ages. Adaptive functioning deficits pose a number of challenges in treating those with an ID.

Whereas it has been estimated that a psychiatric disorder may beset approximately one-fifth of the general population in the United States, the prevalence may be double for persons with an ID.² Underrecognition of the need for mental health services may be due to a lack of caregiver awareness regarding psychiatric disorders in persons with IDs and/or insufficient provider training and clinical experience with this population.² Additional barriers to accurate diagnosis may arise from deficits in adaptive functioning, a mechanism by which individuals effectively manage commonly encountered life demands and independence compared with nondevelopmentally disabled peers.¹ Communication deficits are a barrier specific to this population. Furthermore, those with an ID often have few social interactions and limited integration into the community. Stimulation and interaction with peers typically shapes behaviors in the general population. A different set of coping skills can develop in their absence. Self-talk is an example of a coping mechanism that can be misinterpreted as a sign of psychosis. Inadequate coping skills may result in a higher risk for the development of adjustment problems.³ Another potential problem for the clinician assessing persons with an ID is a significant gap between receptive and expressive language skills. If not readily recognized, intellectual capabilities can be overestimated, resulting in incongruent expectations and/or abilities. In the general population, features of psychiatric illnesses are more readily identifiable, and the clinician is able to effectively interview and evaluate the patient. The term “diagnostic overshadowing” has been used to refer to clinician perceptions that behavioral problems are secondary to an ID and not the result of a psychiatric comorbidity.⁴

The term “mental retardation” (MR) is now generally used only with respect to the diagnostic criteria found in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR).¹ The currently accepted designation is “ID.” The American Association on Intellectual and Developmental Disabilities (AAIDD) supports this designation and has a definition on their website.⁵ For this chapter, the designation “ID” will be applied to the population of individuals who scored 70 or less on standardized intelligence tests, indicative of some limitations in intellectual functioning and adaptive behavior(s) with onset before 18 years of age. The term MR will be applied sparingly. This chapter focuses on Down syndrome (DS), autistic disorder, and Rett syndrome (RTT).

CLINICAL PRESENTATION Mental Retardation

DOWN SYNDROME

DS is associated with common dysmorphic features and a wide range of medical and psychiatric concerns, including a number of developmental abnormalities. Congenital heart defects, seizures, orthopedic abnormalities, sensory defects, and disorders of the eye (e.g., cataracts, glaucoma), GI tract, immune system, skin, and thyroid gland are all associated with DS. Persons diagnosed with DS also have a high probability of early onset Alzheimer’s disease (AD).⁶ This section will focus on DS and the comorbidities of AD and leukemia.

Epidemiology

DS is the most frequently occurring genetically based syndrome associated with an ID.⁷ In the United States, the incidence is estimated to be 1 in 732 births, although prevalence rates may be different for specific racial/ethnic populations.⁷

Etiology and Pathophysiology

Chromosomal analysis identified the etiology of DS as the presence of an extra chromosome 21. DS, also referred to as trisomy 21, represents one of the most studied abnormal chromosomal conditions. Nondisjunction of chromosome 21 accounts for the majority of the errors. Chromosomes divide and separate in a process known as disjunction during meiotic division. Failure to fully separate at this stage can result in both chromosomes remaining in the same cell, creating an abnormal number of chromosomes on each strand. The nondisjunction at chromosome 21 is strongly linked to increased maternal age.

For many years, advanced maternal age has been recognized to positively correlate with an increased risk for DS. Consideration has been given to paternal age as a potential risk factor for DS. The possibility of paternally mediated nondisjunction has not been eliminated, but evidence of a link has been inconclusive.⁸

Those with DS are more at risk for congenital heart defects. A retrospective, case–control study that included maternal questionnaire completion and medical records review sought to evaluate use of folic acid supplementation during the periconceptual period and any association between congenital heart defects and DS. Controlling for substance use during pregnancy and demographics, including maternal age at conception, supplementation use was compared between two groups. In the cohort with DS and congenital defects, specifically atrioventricular septal defects, supplement use was less compared with those with DS and no defects.⁹

Clinical Presentation and Diagnosis

The consequences of this chromosomal variance include characteristic facial features, some degree of ID, hypotonia, an increased risk for congenital heart disease, and early onset AD.⁶ The characteristic facial features make children with DS more readily identifiable at birth.¹⁰ IDs range from mild to severe.¹⁰

For the purpose of this chapter, the term dual diagnosis refers to an intellectually disabled person with a comorbid psychiatric disorder.² The most prevalent psychiatric and/or behavioral disorders in persons with an ID involve attention, mood, personality, and cognitive processing.¹¹ One population-based study of persons with ID (n = 1,023) sought to determine the prevalence of psychiatric disorders. Using regression analysis in conjunction with comprehensive individual evaluations, approximately 40% met criteria for needing mental health services.¹² In persons with DS, depression prevalence rates ranged from zero to slightly over 11%.¹³ The risk for depression is increased by a number of factors, such as decreased total brain volume; reduced levels of the neurotransmitters, specifically serotonin, γ-aminobutyric acid (GABA), taurine, and dopamine, critical in mood regulation; and decreased cognitive function.¹³

The differential diagnosis for mood disorders in all patients should include an evaluation of thyroid function. The lifetime risk of thyroid disorder as a comorbidity in people with DS is estimated at 3% to 5%.¹⁰ Because clinical signs and symptoms of hypothyroidism can mimic some of the features of depression, thyroid function should be evaluated in patients with DS.

TREATMENT

Desired Outcomes

Treatment goals in DS are to identify medical and psychiatric comorbidities, set realistic goals, and provide effective nonpharmacologic and pharmacologic interventions to improve the quality and length of life.

CLINICAL PRESENTATION Down Syndrome

General Approach to Treatment

Medical screenings should assess for hypothyroidism, cardiac problems, sensory impairments (including hearing loss secondary to chronic otitis media with effusion or vision defects due to congenital cataracts or glaucoma), and GI problems (including constipation and celiac disease).¹⁰ Guidelines for health supervision and anticipatory guidance in infants, children, and adolescents with DS are available through the American Academy of Pediatrics (AAP).¹⁰ Routine screenings are also recommended throughout the course of life to address psychosocial changes, potential residential or vocational stressors, and the consequences of aging.¹⁰

Nonpharmacologic Treatments

The use of social supports for both individuals with DS and their family is known to help develop functional adaptive skills and therefore the fulfillment of the potential of the person with DS.¹⁰ Family education and support network development assist caregivers by providing tools and resources necessary to more effectively manage persons with DS, allowing these persons to achieve their full potential. In the treatment of psychiatric disorders, treatment modalities available to the general population also apply to those with DS. Nonpharmacologic options for depression include psychotherapy and electroconvulsive therapy (ECT).¹³ Information on the effectiveness of ECT in the DS population is limited to case reports. If communication skills are adequate, psychotherapy may also be an option. Treatment strategies include psychodynamic and cognitive behavior therapy (CBT). A review of the literature found that psychotherapy applicability results can vary with the level of ID. For persons with mild intellectual impairment and depression, this treatment modality may be beneficial. The current behavioral therapy models are more effective in addressing specific problematic behaviors rather than the underlying emotional problems of persons with ID. The extent to which these strategies translate to persons with DS and moderate to severe ID is not known.¹³

Pharmacologic Treatments

Pharmacotherapy for the treatment of depression in patients with DS follows guidelines used in the general population. For more information on the treatment of depression, see Chapter 51.

Features of depression commonly seen in persons with DS, in order of frequency, include apathy, disordered sleep, and changes in weight. Difficulty identifying depression in this population is impacted by the level of cognitive impairment, the ability to express abstract concepts (such as helplessness or hopelessness), and the level of adaptive functioning.¹³ Clinical trials focused specifically on this population are few, and most information has been based on small studies or case reports. Efficacy of selective serotonin reuptake inhibitors (SSRIs) and amitriptyline is reported. If psychotic features (e.g., delusions, hallucinations) are present, low-dose antipsychotic augmentation is recommended. In the studies reviewed, treatment duration was 2 to 3 years.¹³

As with treatment of depression in the general population, it is essential to ensure that the medication trial is of appropriate dose and duration of antidepressant or combination antidepressant/antipsychotic. Ruling out comorbid medical conditions that could contribute to depression is essential.

Personalized Pharmacotherapy

In addition to the chromosomal aberration and dysmorphic features associated with DS, certain hematologic malignancies are more common in children with DS, with acute lymphoblastic leukemia (ALL) and the megakaryoblastic form of acute myelogenous leukemia (AML) seen much more frequently than other cancers. Children with DS have anecdotally been observed to have higher rates of methotrexate toxicity during treatment for cancers compared with other children. Speculation concerning causality has focused on alterations in methotrexate metabolism controlled by genes on chromosome 21. Even though mouth ulcers and bone marrow suppression are seen more frequently in children with DS receiving methotrexate, differences in pharmacokinetics do not appear to explain the higher rate of toxicity in patients with DS.¹⁵

Down Syndrome with Alzheimer’s Disease

Persons with IDs, including DS, are at greater risk for AD. In adults with DS, more than 25% experience neuropsychiatric symptoms,¹⁶ including aggression, inattention, impulsivity, and stereotypies. In adults with DS evaluated for AD, it was reported that depressed adults with no discernible reason for sadness were more likely to be positive for dementia.¹⁶

Assessing changes in functionality and cognition are problematic in this population, particularly in those with greater intellectual impairments. Early studies in this population did not specify the diagnostic criteria used for identification of dementia of Alzheimer’s type. A well-delineated diagnosis of AD or dementia, Alzheimer’s type, requires a documented decline from baseline cognitive functioning. To meet the diagnostic criteria, the following are needed: baseline functioning data, functionality changes not explained by general aging, and progressive decline.¹ Identification of appropriate assessment scales for use in those with DS has also been problematic. The Dementia Scale for Mentally Retarded Persons (DMR) was used as the primary outcome measure in a medication efficacy trial. It also provided secondary outcome measurement and assessment of cognition, neuropsychiatric features, adaptive behavior, and a global impression.¹⁷

In persons older than 40 with DS, behavior changes are the primary features of the early stages of dementia. For this older cohort, higher frequencies of irritability, fear, sadness, and suspicion are seen than in a younger population. Violent outbursts have not been identified as a reliable indicator of dementia, but methodologic shortcomings preclude firm conclusions.¹⁶ Furthermore, there is a fivefold greater prevalence of comorbid DS and dementia compared with other IDs and dementia. Gender also is important, as the male-to-female ratio is 3:1 for DS and AD.¹⁸ Selected task skills were found to decline 2 years prior to a diagnosis of AD.¹⁹ In the absence of documentation of change, specific criteria needed for a diagnosis of AD may not be met. Diagnostic criteria for AD include changes in memory, language skills, and activities of daily living (ADLs).¹ Information on the natural progression of cognitive changes in those with DS and AD is limited.

Pathophysiology

Neuritic plaques and neurofibrillary tangles are the hallmarks of AD. A gene for amyloid-β precursor protein is located on chromosome 21.²⁰ Neuropathic changes associated with AD are typically found in those with DS by middle age.¹⁶ The severity of ID has been theorized to significantly impact the incidence of AD, but study results are inconclusive, and the level of ID may limit evaluation. A study of DS (n = 405) with and without dementia identified specific amyloid-β precursor proteins that might be predictors of dementia in DS regardless of age, gender, and level of ID.²⁰ A more extensive discussion of the pathophysiology of AD is beyond the scope of this chapter. For more information about AD, see Chapter 38.

TREATMENT

The therapeutic goal is to maintain functioning and quality of life as close to baseline as possible for as long as possible. Approaches to therapy for persons with DS combined with AD include nonpharmacologic and pharmacologic interventions. As with the general population with AD, treatment of AD for those with DS is multimodal and includes currently available treatments and supports in order to maintain functionality as long as possible.²¹

Nonpharmacologic Treatments

Traditionally, this population receives some level of residential living supports in either the family home or a residential facility. Depending on the level of ID, a family member, other caregiver, or residential facility staff may provide information to the clinician regarding functional status.

Pharmacologic Treatments

Pharmacologic treatments neither cure nor stop the pathologic changes associated with AD. The goals of pharmacotherapy in persons with DS and AD, as in the general population of AD patients, are to slow the decline in cognitive function and help preserve ADLs to the greatest extent possible. The use of cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA) receptor antagonist in the DS population is being studied.

There is evidence to support the use of cholinesterase inhibitors to enhance learning and memory in persons with DS. The majority of the research in this area has been with donepezil. In a review of the literature, a 24-week, double-blind, placebo-controlled, parallel-group trial (n = 30, 27 completed) used the DMR as the primary outcome measure and the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), and Adaptive Behavior Scale (ABS) as secondary measures. Findings with the DMR, SIB, and ABS indicated less deterioration for the treatment group versus the control group. The results for the NPI were reversed: the placebo group demonstrated more improvement compared with the treatment group. Dosing was 5 mg daily for the first 4 weeks, and 10 mg daily thereafter. Side effects included diarrhea, insomnia, fatigue, and nausea.²²

Use of rivastigmine, galantamine, or memantine in those with an ID has not been studied as extensively as donepezil. An assessment of the efficacy of rivastigmine for dementia in AD in the DS population was not statistically significant compared with that in a placebo group from a previous study. Rating scales used were the DMR, NPI, and ABS.²³ Rivastigmine-associated adverse effects included GI upset (e.g., diarrhea, nausea, vomiting), fatigue, and insomnia.²³ For more information about pharmacotherapy treatment guidelines in AD, see Chapter 38.

Preexisting medical comorbidities, such as congenital heart defects, or concomitant pharmacotherapy may limit use of cholinesterase inhibitors in persons with DS. Clinicians are encouraged to monitor patients receiving cholinesterase inhibitors for bradycardia²⁴ and the potential for drug interactions.

A potential neurologic comorbidity of concern in this population is seizures. Overall, approximately 8% of the DS population has a seizure disorder, and seizure activity increases with age.²⁵ Distribution of seizure onset is bimodal, with the first peak incidence appearing before 1 year of age. This first peak is predominantly composed of infantile spasms. Seizure patterns in the DS population, in order of prevalence, are partial (47%), infantile spasms (32%), and generalized tonic–clonic (21%).²⁵ Advanced AD is an independent risk factor for new-onset seizures.²⁵ Monitoring for new-onset seizure activity and medicating with anticonvulsants as appropriate are essential. For more information about epilepsy and seizure disorders, see Chapter 40.

Evaluation of Therapeutic Outcomes

Baseline functioning must be established early in adult life prior to the onset of AD, which generally occurs during the third or fourth decade of life. This can be particularly crucial in individuals without expressive language skills. Followup evaluations should be performed annually. If cholinesterase inhibitors are used, evaluations every 2 to 4 months (after achieving a maintenance dose) are recommended to monitor for effectiveness if the anticipated gains have not been observed. Monitoring for potential medication-related side effects, including diarrhea, nausea, vomiting, insomnia, and headache, is also essential.²¹

Clinical Controversy…

Down Syndrome and the Immune System

Leukemia is frequently diagnosed in DS children. The relative risk for leukemia is 10 to 20 times greater in persons with DS than in the general population.²⁷ The two forms more commonly encountered in DS children are ALL and AML. While ALL is the most common form of leukemia in all children, the rate of DS-AML is about equal to DS-ALL in children who are younger than 5 years of age (this ratio is about 1:4 in children without DS). The most commonly identified form of DS-AML is acute megakaryoblastic leukemia (AMKL). The incidence of this disorder in DS has been identified as high as 500 times greater than in the non-DS pediatric population.²⁸ Another myelodysplastic disorder almost unique to children with DS is transient myeloproliferative disorder (TMD). For TMD, the period prevalence in infants with DS has been estimated to be 10% to 20%.²⁷ It can spontaneously remit and cannot be clinically differentiated from AML. However, within 4 years following spontaneous remission of TMD, 20% of this population will develop AMKL.²⁸

In the DS population, ALL survival rates are lower than in the non-ID pediatric population.²⁷ Children with DS also experience more chemotherapy-related toxicities (specifically mucositis and infection) compared with non-DS children with ALL.²⁷

Chemotherapy-induced cardiotoxicity is of particular concern in children with DS, as 50% may have a congenital heart defect.¹⁰ High rates of cardiomyopathy (17.5%) are reported with treatment with anthracyclines.²⁷ Children with DS and newly diagnosed with AML (n = 54) were enrolled into a standard protocol with daunorubicin and mitoxantrone to evaluate treatment efficacy and toxicities. Researchers reported the treatment protocol effective for remission and survival for the children in the DS-AML arm, but 17.5% of this group developed cardiomyopathy during or shortly after treatment completion, supporting the current practice of dosage reductions.²⁹ In addition, higher levels of the methotrexate metabolite were found, supporting the link between DS and drug metabolism alterations secondary to alterations on chromosome 21.²⁷

Evaluation of Therapeutic Outcomes

Assessment of therapeutic outcomes for those with DS starts with a thorough multidisciplinary evaluation to establish a baseline problem list, identification of clear therapeutic goals, and using valid pharmacotherapeutic rationale to guide medication dosing and adverse drug effect monitoring.

An in-depth list of treatment targets, both subjective and objective, is important in persons with DS to assist in evaluation of medication response. Careful monitoring for emergence of potential side effects should be regularly conducted and documented as part of ongoing assessment of medication effectiveness and to ensure that side effects are not a contributing factor to behavioral changes.

AUTISM

Autistic disorder is one of five behaviorally defined pervasive developmental disorders (PDDs). Others include RTT, Asperger’s disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS).¹ These disorders are grouped together and referred to as autism, or autism spectrum disorders (ASDs), by the DSM-IV-TR. RTT and childhood disintegrative disorder are rarer, typically more severe in manifestations, and are generally considered separately. This section will focus specifically on autism, which is characterized by severe and sustained impairments in three behavioral domains: (a) reciprocal social interaction (withdrawal or lack of interest in peers), (b) language and communication skills (limitations in the use of speech and nonverbal skills), and (c) range of interests and activities (repetitive, restricted behaviors, stereotyped mannerisms).^1,30 Autism is not a disease but a neurodevelopmental disorder with multiple possible etiologies.³¹ The onset is typically younger than 3 years of age and is usually, but not always, associated with some degree of ID.¹ Autism was first described by Leo Kanner in 1943 and has been historically described as early infantile autism, childhood autism, and Kanner’s autism.¹

Epidemiology

There has been a recent sharp increase in the reported prevalence of autism. Newer surveys estimate the prevalence to be 1:88.³² It is suggested that the reported increased prevalence is primarily related to changing and broadening diagnostic criteria, along with an increased index of suspicion, rather than by an actual increased incidence, as autism is behaviorally identified, and the diagnostic boundaries are not always clear.^33,34 In addition, inclusion of individuals with diagnoses of Asperger’s disorder and PDD-NOS in newer studies may contribute to the increase.³⁴ Some behaviors (e.g., stereotypies) seen in persons with autism can also be seen in nonautistic individuals. One study found children with a history of early institutionalization demonstrated more stereotypical behaviors that markedly decreased following increased interactions postplacement.³⁵ There is a significant impact of intellectual ability on the expression of symptoms of autism,³⁶ resulting in a lack of homogeneity in clinical expression of the condition. Autism is between four and five times more prevalent in males.³¹ When present, ID ranges from mild to severe. The heterogeneity and early onset represent two methodologic problems for large-scale research studies.³¹

Etiology and Pathophysiology

The etiology of autism is attributed to multiple causal factors, including gene mutations, abnormalities in brain development, and genetic–environment interactions.³⁰ Autism frequently occurs concomitantly with other developmental disorders that have a known genetic basis such as RTT and fragile X syndrome.³⁴ Current research primarily focuses on genetics and neuropathology. Although a single genetic mutation or variant leading to autism has yet to be identified, research findings indicate that structural alterations in the genome DNA, known as copy number variations (CNVs), may be involved in ASD. Research identified a number of CNVs associated with ASDs, as this appears to be a highly heritable disorder.³⁷

These findings provide support for the heterogeneity of neurodevelopmental disorders, whereby disruption represents a critical period in the development of excitatory and inhibitory neuron development. A combination of genetic and/or environmental factors, in the absence of any compensatory mechanism, may interfere with brain plasticity.³⁶ A meta-analysis provided some support for the theory that ASD may arise from interference in the excitatory and inhibitory balance expression and/or timing during critical periods.³⁸ A review of the literature found persons with autism demonstrated what was termed “unusual sensory processing.” Additional findings included (a) a diagnosis of autism was associated with greater sensory symptoms than in other developmental disorders, (b) increased age was associated with decreased symptoms, and (c) for children there was a positive correlation between social impairment and sensory symptoms.³⁹

Siblings of affected children have a significantly greater risk of having autism (3% to 18.7%) than those in the general population.⁴⁰ Results from a national volunteer registry (n = 2,920 children, 1,235 families, a minimum of 1 child meeting ASD diagnostic criteria, and a minimum of 1 full sibling) found that the sibling concordance rate was 10.9%. Overall an additional 8.9% of the siblings demonstrated language delay with autistic-like speech quality.⁴¹

Further support for the high heritability of the disorder was shown by additional research in this area. Sibling risk varies based on the gender of the index child: 4% versus 7% for female compared with male. If a second child is diagnosed, the risk for concordance in subsequent siblings increases to between 25% and 30%, higher than previously reported. The risk for a monozygotic twin with autism ranges from 60% to 95% that both twins will be diagnosed with autism.⁴²

Parental age has been investigated as a potential risk factor for autism. While results are thus far inconclusive, a number of intriguing results have been found. A case–control study design of a cohort of age- and sex-matched pairs (n = 68) found a significant effect linking the age of both parents and a child with a diagnosis of autism. Unadjusted parental ages were higher for both parents (paternal 4 years higher, maternal 4.8 years higher) compared with controls. After adjusting for variables such as educational level and gestational age, the differences widened to 5.9 and 6.5 years, respectively.⁴³ Shelton et al. found parental age was a risk factor if the mother was less than 30 years old.⁴⁴

Environmental exposures including toxic chemical exposure, teratogens, perinatal insults, prenatal infections,³⁴ and copper and zinc levels⁴⁵ are under investigation. Immunization with measles/mumps/rubella vaccine has been investigated, and no causal association identified.⁴⁶

Autism frequently occurs concomitantly with epilepsy⁴⁷ and may be associated with microdeletion gene defects that are also risk factors for schizophrenia and attention-deficit/hyperactivity disorder (ADHD). Examples include the association between autism, ID, schizophrenia, and seizures with microdeletions on the 15q13.3 and 1q21.1 regions.⁴⁸ Other sites also may be implicated. The two most common single gene abnormalities associated with autism are fragile X syndrome and tuberous sclerosis.⁴²

The neurodevelopmental foundation of autism has sparked significant interest in early morphologic changes in brain development, particularly findings of early brain overgrowth. Head circumference at birth ranges from slightly below normal to within normal limits. This finding changes by 2 to 3 months of age when accelerated head growth occurs. The rate of growth may exceed 2 standard deviations above the average. Approximately 60% of infants diagnosed with autism compared with 6% of normal infants have this rate of accelerated head growth. The increase positively correlates to the increase in ID severity. Following this period of accelerated head growth, during which time the infant brain may achieve the size of the adult brain, deceleration or a complete cessation of head growth is noted.³¹

Accelerated brain growth may predispose the developing brain to increased vulnerability. This is consistent with the concept of plasticity, whereby development of cortical circuitry is established during critical postnatal periods. During this period of development, a balance of excitatory and inhibitory neurofunctionality occurs. It has been theorized that during this critical period if an imbalance occurs, this results in neurodevelopmental disorders, such as autism.³⁶ This theory is consistent with the diagnostic criteria of onset within the first 3 years, abnormalities in three major areas (socialization, communication, and repetitive behaviors¹), and disruption in neurocircuitry development.

Dysfunction of virtually all neural systems in the brain has been proposed at some point as a potential basis of autism.⁴⁹ The neuropathologic changes noted in persons with autism are suggested to be of prenatal origin, primarily in the first 6 months of gestation.³¹ Evidence has been published that suggests that autism affects a functionally diverse and widely distributed set of neural systems, making the disorder far broader in scope than a simple social interaction disorder.⁴⁹ Despite these findings, the pattern of brain abnormality appears somewhat discrete. Autism spares many perceptual and cognitive systems. A localized neural deficit can have more widespread neurofunctional implications through its influence on brain development.⁴⁹

There is research to support abnormalities in cholinergic receptors and decreases in the nicotinic receptor binding in the cholinergic system as well as dysfunction in the GABAergic system⁴⁷ in persons with autism. Nicotinic receptors enhance cognitive processing (i.e., memory and attention) and open the possibility of therapeutic intervention via cholinergic receptor modulation.⁵⁰ Approximately 25% to 60% of children with autism have elevated peripheral platelet concentrations of the neurotransmitter serotonin.⁵¹ Studies of dopamine and catecholamine metabolites have failed to consistently show abnormalities.