03 - 31.3 Intellectual Disability

31.3 Intellectual Disability

sample. Appl Neuropsychol Child. 2013 [Epub ahead of print]. Kestenbaum CJ. The clinical interview of the child. In: Wiener JM, Dulcan MK, eds. The American Psychiatric Publishing Textbook of Child and Adolescent Psychiatry. 3rd ed. Washington, DC: American Psychiatric Publishing, Inc.; 2004:103– 111. King RA, Schwab-Stone ME, Thies AP, Peterson BS, Fisher PW. Psychiatric examination of the infant, child, and adolescent. In: Sadock BJ, Sadock VA, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th ed. Vol. II. Philadelphia: Lippincott Williams & Wilkins; 2009:3366. Lyneham HJ, Rapee RM. Evaluation and treatment of anxiety disorders in the general pediatric population: A clinician’s guide. Child Adolesc Psychiatr Clin N Am. 2005;14(4):845. Pataki CS. Child psychiatry: Introduction and overview. In: Sadock BJ, Sadock VA, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2009:3335. Puig-Antich J, Orraschel H, Tabrizi MA, Chambers W. Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic Version. New York: New York State Psychiatric Institute and Yale School of Medicine; 1980. Staller JA. Diagnostic profiles in outpatient child psychiatry. Am J Orthopsychiatry. 2006;76(1):98. Weeks M, Wild TC, Poubidis GB, Naiker K, Cairney J, North CR, Colman I. Childhood cognitive ability and its relationship with anxiety and depression in adolescence. J Affect Disord. 2013 http://dx.doi.org/10.1016/j/jad.2013.08.019. Winters NC, Collett BR, Myers KM. Ten-year review of rating scales, VII: Scales assessing functional impairment. J Am Acad Child Adolesc Psychiatry. 2005;44:309. Youngstrom EA, Duax J. Evidence-based assessment of pediatric bipolar disorder. Part 1: Base rate and family history. J Am Acad Child Adolesc Psychiatry. 2005;44:712. 31.3 Intellectual Disability Intellectual disability, formerly known as mental retardation, can be caused by a range of environmental and genetic factors that lead to a combination of cognitive and social impairments. The American Association on Intellectual and Developmental Disability (AAIDD) defines intellectual disability as a disability characterized by significant limitations in both intellectual functioning (reasoning, learning, and problem solving) and in adaptive behavior (conceptual, social, and practical skills) that emerges before the age of 18 years. Wide acceptance of this definition has led to the international consensus that an assessment of both social adaptation and intelligence quotient (IQ) are necessary to determine the level of intellectual disability. Measures of adaptive function assess competency in social functioning, understanding of societal norms, and performance of everyday tasks, whereas measures of intellectual function focus on cognitive abilities. Although individuals with a given intellectual level do not all have identical levels of adaptive function, epidemiologic data suggest that prevalence of intellectual disability is largely determined by intellectual level and a level of adaptive function, which typically corresponds closely with cognitive ability. In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), various levels of severity of intellectual disability are determined on the basis of adaptive functioning, not on IQ scores. This change in emphasis from prior diagnostic manuals has been adopted by DSM-5 because adaptive functioning determines the level

of support that is required. Furthermore, IQ scores are less valid in the lower portions of the IQ range. Making a determination of severity level of intellectual disability, according to DSM-5, includes assessment of functioning in a conceptual domain (e.g., academic skills), a social domain (e.g., relationships), and a practical domain (e.g., personal hygiene). Societal approaches to children with intellectual disability have shifted significantly over time. Historically, in the mid-1800s many children with intellectual disability were placed in residential educational facilities based on the belief that with sufficient intensive training, these children would be able to return to their families and function in society at a higher level. However, the expectation of educating these children in order to overcome their disabilities was not realized. Gradually, many residential programs increased in size, and eventually the focus began to shift from intensive education to more custodial care. Residential settings for children with intellectual disability received their maximal use in the mid-1900s, until public awareness of the crowded, unsanitary, and, in some cases, abusive conditions sparked the movement toward “deinstitutionalization.” An important force in the deinstitutionalization of children with intellectual disability was the philosophy of “normalization” in living situations, and “inclusion” in educational settings. Since the late 1960s, few children with intellectual disability have been placed in residences, and the concepts of normalization and inclusion remain prominent among advocacy groups and parents. The passage of Public Law 94–142 (the Education for all Handicapped Children Act) in 1975 mandates that the public school system provide appropriate educational service to all children with disabilities. The Individuals with Disabilities Act in 1990 extended and modified the above legislation. Currently, provision of public education for all children, including those with disabilities, “within the least restrictive environment” is mandated by law. In addition to the educational system, advocacy groups, including the Council for Exceptional Children (CEC) and the National Association for Retarded Citizens (NARC) are well known parental lobbying organizations for children with intellectual disability and were instrumental in advocating for Public Law 94–142. The American Association on Intellectual and Developmental Disabilities, formerly known as The American Association on Intellectual disability (AAMR), is the most prominent advocacy organization in this field. It has been very influential in educating the public about, and in supporting research and legislation relating to, intellectual disability. The AAIDD promotes a view of intellectual disability as a functional interaction between an individual and the environment, rather than a static designation of a person’s limitations. Within this conceptual framework, a child or adolescent with intellectual disability is determined to need intermittent, limited, extensive, or pervasive “environmental support” with respect to a specific set of adaptive function domains. These include communication, self-care, home living, social or interpersonal skills, use of community resources, self-direction, functional academic skills, work, leisure, health, and safety. The United Nations Convention on the Rights of Persons with Disabilities (2006) has

created a forum to promote the full social inclusion of people with intellectual disability. Through its recognition and focus on social barriers, this international forum aims to provide protections for individuals with intellectual disability, and to seek more inclusion of those with intellectual disability in social, civic, and educational activities. NOMENCLATURE The accurate definition of intellectual disability has been a challenge for clinicians over the centuries. All current classification systems underscore that intellectual disability is based on more than cognitive deficits, that is, it also includes impaired social adaptive function. According to DSM-5, a diagnosis of intellectual disability should be made only when there are deficits in intellectual functioning and deficits in adaptive functioning (Table 31.3-1). Once intellectual disability is recognized, the level of severity is determined by the level of adaptive functional impairment. Table 31.3-1 DSM-5 Diagnostic Criteria for Intellectual Disability CLASSIFICATION DSM-5 criteria for intellectual disability include significantly subaverage general intellectual functioning associated with concurrent impairment in adaptive behavior, manifested before the age of 18. The diagnosis is made independent of coexisting physical or mental disorders. Table 31.3-2 presents an overview of developmental levels in communication, academic functioning, and vocational skills expected of persons with various degrees of intellectual disability. Table 31.3-2 Developmental Characteristics of Intellectual Disability

If the clinician chooses to use a standardized test of intelligence—which is still common practice—the term significantly subaverage is defined as an IQ of approximately 70 or below or two standard deviations below the mean for the particular test. Adaptive functioning can be measured by using a standardized scale, such as the Vineland Adaptive Behavior Scale. This scale scores communications, daily living skills, socialization, and motor skills (up to 4 years, 11 months) and generates an adaptive behavior composite that is correlated with the expected skills at a given age. Approximately 85 percent of individuals who have intellectual disability fall within the DSM-5 mild intellectual disability category. This is typically defined by a Full Scale IQ between 50 and 70 and an adaptive function severity in the mild range. Adaptive function includes skills such as communication, self-care, social skills, work, leisure, and understanding of safety. Intellectual disability is influenced by genetic, environmental, and psychosocial factors. A host of subtle environmental and developmental factors, including subclinical lead intoxication and prenatal exposure to drugs, alcohol, and other toxins have been implicated as contributors to intellectual disability. Certain genetic syndromes associated with intellectual disability such as fragile X syndrome, Down syndrome, and Prader-Willi syndrome, have characteristic patterns of social, linguistic, and cognitive development and typical behavioral manifestations. DEGREES OF SEVERITY OF INTELLECTUAL DISABILITY The severity levels of intellectual disability are expressed in DSM-5 as mild, moderate, severe, and profound. “Borderline intellectual functioning,” a term previously used to describe individuals with a full scale IQ in the range of 70 to 80, is no longer described as a diagnosis in DSM-5. The term is used in DSM-5 as a condition that may be the focus of clinical attention; however, no criteria are given.

Mild intellectual disability represents approximately 85 percent of persons with intellectual disability. Children with mild intellectual disability often are not identified until the first or second grade, when academic demands increase. By late adolescence, they often acquire academic skills at approximately a sixth-grade level. Specific causes for the intellectual disability are often unidentified in this group. Many adults with mild intellectual disability can live independently with appropriate support and raise their own families. IQ for this level of adaptive function may typically range from 50 to 70. Moderate intellectual disability represents about 10 percent of persons with intellectual disability. Most children with moderate intellectual disability acquire language and can communicate adequately during early childhood. They are challenged academically and often are not able to achieve above a second to third grade level. During adolescence, socialization difficulties often set these persons apart, and a great deal of social and vocational support is beneficial. As adults, individuals with moderate intellectual disability may be able to perform semiskilled work under appropriate supervision. IQ for this level of adaptive function may typically range from 35 to 50. Severe intellectual disability represents about 4 percent of individuals with intellectual disability. They may be able to develop communication skills in childhood and often can learn to count as well as recognize words that are critical to functioning. In this group, the cause for the intellectual disability is more likely to be identified than in milder forms of intellectual disability. In adulthood, persons with severe intellectual disability may adapt well to supervised living situations, such as group homes, and may be able to perform work-related tasks under supervision. IQ in individuals with this level of adaptive function may typically range from 20 to 35. Profound intellectual disability constitutes approximately 1 to 2 percent of individuals with intellectual disability. Most individuals with profound intellectual disability have identifiable causes for their condition. Children with profound intellectual disability may be taught some self-care skills and learn to communicate their needs given the appropriate training. IQ in individuals with this level of adaptive function may typically be less than 20. The DSM-5 also includes a disorder called “Unspecified Intellectual Disability” (Intellectual Developmental Disorder), reserved for individuals over the age of 5 years who are difficult to evaluate but are strongly suspected of having intellectual disability. Individuals with this diagnosis may have sensory or physical impairments such as blindness or deafness, or concurrent mental disorders, making it difficult to administer typical assessment tools. (e.g., Bayley Scales of Infant Development and Cattell Infant Scale) to aid in determining adaptive functional impairment. EPIDEMIOLOGY The majority of population-based prevalence estimates for intellectual disability in developing countries range from 10 to 15 per 1,000 children. The prevalence of intellectual disability at any one time is estimated to range from 1 to 3 percent of the population in Western societies. The incidence of intellectual disability is difficult to

accurately calculate because mild disabilities may be unrecognized until middle childhood. In some cases, even when intellectual function is limited, social adaptive skills may not be challenged until late childhood or early adolescence, and the diagnosis is not made until that time. The highest incidence of intellectual disability is reported in school-age children, with the peak at ages 10 to 14 years. Intellectual disability is about 1.5 times more common among males than females.

COMORBIDITY Prevalence Epidemiological surveys indicate that up to two thirds of children and adults with intellectual disability have comorbid psychiatric disorders; and this rate is several times higher than that in community samples without intellectual disability. The prevalence of psychopathology appears to be correlated with the severity of intellectual disability; the more severe the intellectual disability, the higher the risk for coexisting psychiatric disorders. An epidemiological study found that 40.7 percent of intellectually disabled children between 4 and 18 years of age met criteria for at least one additional psychiatric disorder. The severity of intellectual disability influenced the risk for particular comorbid psychiatric disorders. Disruptive and conduct-disorder behaviors occurred more frequently in those diagnosed with mild intellectual disability, whereas those with more severe intellectual disability were more likely to meet criteria for autism spectrum disorder and exhibited symptoms such as self-stimulation and selfmutilation. Comorbidity of psychiatric disorders with intellectual disability in children in this study was not correlated with age or gender. Children diagnosed with profound intellectual disability were less likely to exhibit comorbid psychiatric disorders. Psychiatric disorders among persons with intellectual disability are varied, and include mood disorders, schizophrenia, attention-deficit/hyperactivity disorder (ADHD), and conduct disorder. Children diagnosed with severe intellectual disability have a particularly high rate of comorbid autism spectrum disorder. Approximately 2 to 3 percent of those with intellectual disability meet diagnostic criteria for schizophrenia, which is several times higher than the rate for the general population. Up to 50 percent of children and adults with intellectual disability are found to meet criteria for a mood disorder when instruments such as the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS), the Beck Depression Inventory, and the Children’s Depression Inventory were used in studies. However, a limitation of these studies is that these instruments have not been standardized within intellectual disability populations. Frequent psychiatric symptoms that occur in children with intellectual disability, outside the context of a full psychiatric disorder, include hyperactivity and short attention span, self-injurious behaviors (e.g., head-banging and self-biting), and repetitive stereotypical behaviors (hand-flapping and toe-walking). In children and adults with milder forms of intellectual disability, negative self-image, low self-esteem, poor frustration tolerance, interpersonal dependence, and a rigid problem-solving style are frequent. Neurological Disorders Seizure disorders occur more frequently in individuals with intellectual disability than in the general population, and prevalence rates for seizures increase proportionally to severity level of intellectual disability. A review of psychiatric disorders in children and adolescents with intellectual disability and epilepsy, found that approximately one third

had comorbid autism spectrum disorder. The combination of intellectual disability, epilepsy, and autism spectrum disorder has been estimated to occur in 0.07 percent of the general population. Psychosocial Features A negative self-image and poor self-esteem are common features of mildly and moderately intellectually disabled persons who are aware of their social and academic differences from others. Given their experience of repeated failure and disappointment in being unable to meet their parents’ and society’s expectations, they may also be faced with falling progressively behind younger siblings. Communication difficulties further increase their vulnerability to feelings of ineptness and frustration. Inappropriate behaviors, such as withdrawal, are common. The perpetual sense of isolation and inadequacy has been linked to feelings of anxiety, anger, dysphoria, and depression. ETIOLOGY Etiological factors in intellectual disability can be genetic, developmental, environmental, or a combination. Genetic causes include chromosomal and inherited conditions; developmental and environmental factors include prenatal exposure to infections and toxins; and environmental or acquired factors include prenatal trauma (e.g., prematurity) and sociocultural factors. The severity of intellectual disability may be related to the timing and duration of a given trauma as well as to the degree of exposure to the central nervous system (CNS). In about three fourths of persons diagnosed with severe intellectual disability, the etiology is known, whereas the etiology is apparent in up to half of those diagnosed with mild intellectual disability. A study of 100 consecutive children diagnosed with intellectual disability admitted to a clinical genetics unit of a university pediatric hospital reported that in 41 percent of cases, a causative diagnosis was made. No cause is known for three fourths of persons with IQ ranging from 70 to 80 and variable adaptive functioning. Among chromosomal disorders, Down syndrome and fragile X syndrome are the most common disorders that usually produce at least moderate intellectual disability. A prototype of a metabolic disorder associated with intellectual disability is phenylketonuria (PKU). Deprivation of nutrition, nurturance, and social stimulation can potentially contribute to the development of at least mild forms of intellectual disability. Current knowledge suggests that genetic, environmental, biological, and psychosocial factors work additively in the emergence of intellectual disability. Genetic Etiological Factors in Intellectual Disability Single-Gene Causes. One of the most well-known single gene causes of intellectually disability is found in the FMR1 gene whose mutations cause fragile X syndrome. It is the most common and first X-linked gene to be identified as a direct cause of intellectual disability. Abnormalities in autosomal chromosomes are frequently

associated with intellectual disability, whereas aberrations in sex chromosomes can result in characteristic physical syndromes that do not include intellectual disability (e.g., Turner’s syndrome with XO and Klinefelter’s syndrome with XXY, XXXY, and XXYY variations). Some children with Turner’s syndrome have normal to superior intelligence. Agreement exists on a few predisposing factors for chromosomal disorders —among them, advanced maternal age, increased age of the father, and X-ray radiation. Visible and Submicroscopic Chromosomal Causes of Intellectual Disability. Trisomy 21 (Down syndrome) is a prototype of a cytogenetically visible abnormality that accounts for about two-thirds of the 15 percent of intellectual disability attributable to visible abnormal cytogenetics. Other microscopically visible chromosomal abnormalities associated with intellectual disability include deletions, translocations, and supernumerary marker chromosomes. Typically, microscopic chromosome analysis is able to identify abnormalities of 5 to 10 million base pairs or greater. Submicroscopic identification requires the use of microarrays that can identify losses of chromosomal segments too small to be picked up by light microscopy. The altered copy number variants (CNVs) in submicroscopic segments of the chromosome have been identified to be associated with up to 13 to 20 percent of cases of intellectual disability. That is, the genes associated with a particular developmental abnormality have been identified to be located in the critical regions of the pathogenic copy number variants. Genetic Intellectual Disability and Behavioral Phenotype Specific and predictable behaviors have been found to be associated with certain genetically based cases of intellectual disability. These behavioral phenotypes are defined as a syndrome of observable behaviors that occur with a significantly greater probability than expected among those individuals with a specific genetic abnormality. Examples of behavioral phenotypes occur in genetically determined syndromes such as fragile X syndrome, Prader-Willi syndrome, and Down syndrome in which specific behavioral manifestations can be expected. Persons with fragile X syndrome have extremely high rates (up to three fourths of those studied) of ADHD. High rates of aberrant interpersonal behavior and language function often meet the criteria for autistic disorder and avoidant personality disorder. Prader-Willi syndrome is almost always associated with compulsive eating disturbances, hyperphagia, and obesity. Socialization is an area of weakness, especially in coping skills. Externalizing behavior problems—such as temper tantrums, irritability, and arguing—seem to be heightened in adolescence. Down Syndrome. The etiology of Down syndrome, known to be caused by an extra copy of the entire chromosome 21, makes it one of the more complex disorders. The original description of Down syndrome, first made by the English physician Langdon Down in 1866, was based on physical characteristics associated with subnormal mental functioning. Since then, Down syndrome has been the most

investigated, and most discussed, syndrome in intellectual disability. Recent data have suggested that Down syndrome may be more amenable to postnatal interventions to address the cognitive deficits that it produces than was previously thought. Although still in the early stages of animal research, data from experiments with one mouse model, the Ts65Dn, indicates that pharmacologic interventions may influence learning and memory deficits known to occur in Down syndrome. Phenotypically, children with Down syndrome are observed to have characteristic physical attributes, including slanted eyes, epicanthal folds, and a flat nose. The etiology of Down syndrome is complicated by the recognition of three types of chromosomal aberrations in Down syndrome:

1. Patients with trisomy 21 (three chromosomes 21, instead of the usual two) represent the overwhelming majority; they have 47 chromosomes, with an extra chromosome
2. The mothers’ karyotypes are normal. A nondisjunction during meiosis, occurring for unknown reasons, is held responsible for the disorder.
3. Nondisjunction occurring after fertilization in any cell division results in mosaicism, a condition in which both normal and trisomic cells are found in various tissues.
4. In translocation, a fusion occurs of two chromosomes, usually 21 and 15, resulting in a total of 46 chromosomes, despite the presence of an extra chromosome 21. The disorder, unlike trisomy 21, is usually inherited, and the translocated chromosome may be found in unaffected parents and siblings. The asymptomatic carriers have only 45 chromosomes. Approximately 6,000 babies are affected with Down syndrome in the United States, which makes the incidence of Down syndrome 1 in every 700 births, or 15 per 10,000 live births. For women older than 32 years of age, the risk of having a child with Down syndrome (trisomy 21) is about 1 in 100 births, but when translocation is present, the risk is about 1 in
5. Most children with Down syndrome are mildly to moderately intellectually disabled, with a minority having an IQ above
6. Cognitive development appears to progress normally from birth to 6 months of age; IQ scores gradually decrease from near normal at 1 year of age to about 30 to 50 as development proceeds. The decline in intellectual function may not be readily apparent. Infant tests may not reveal the full extent of the deficits. According to anecdotal clinical reports, children with Down syndrome are typically placid, cheerful, and cooperative and adapt easily at home. With adolescence, the picture changes: youth with Down syndrome may experience more social and emotional difficulties and behavior disorders, and there is an increased risk for psychotic disorders. In Down syndrome, language function is a relative weakness, whereas sociability and social skills, such as interpersonal cooperation and conformity with social conventions, are relative strengths. Children with Down syndrome typically manifest deficits in scanning the environment; they are more likely to focus on a single stimulus, leading to difficulty noticing environmental changes. A variety of comorbid psychiatric disorders emerge in persons with Down syndrome; however, the rates appear to be lower than in children with intellectual disability and autism spectrum disorder. The diagnosis of Down syndrome is made with relative ease in an older child, but it is often difficult in newborn infants. The most important signs in a newborn include

general hypotonia; oblique palpebral fissures; abundant neck skin; a small, flattened skull; high cheekbones; and a protruding tongue. The hands are broad and thick, with a single palmar transversal crease, and the little fingers are short and curved inward. Moro reflex is weak or absent. More than 100 signs or stigmata are described in Down syndrome, but rarely are all found in one person. Commonly occurring physical problems in Down syndrome include cardiac defects, thyroid abnormalities, and gastrointestinal problems. Life expectancy was once drastically limited to about the age of 40; however, currently it is vastly increased, although still not as long as those without intellectual disability. Down syndrome is characterized by deterioration in language, memory, self-care skills, and problem-solving by the third decade of life. Postmortem studies of individuals with Down syndrome older than age 40 have shown a high incidence of senile plaques and neurofibrillary tangles, similar to those seen in Alzheimer’s disease. Neurofibrillary tangles are known to occur in a variety of degenerative diseases, whereas senile plaques seem to be found most often in Alzheimer’s disease and in Down syndrome. Fragile X Syndrome. Fragile X syndrome is the second most common single cause of intellectual disability. The syndrome results from a mutation on the X chromosome at what is known as the fragile site (Xq27.3). The fragile site is expressed in only some cells, and it may be absent in asymptomatic males and female carriers. Much variability is present in both genetic and phenotypic expression. Fragile X syndrome is believed to occur in about 1 of every 1,000 males and 1 of every 2,000 females. The typical phenotype includes a large, long head and ears, short stature, hyperextensible joints, and postpubertal macroorchidism. Associated intellectual disability ranges from mild to severe. The behavioral profile of persons with the syndrome includes a high rate of ADHD, learning disorders, and autism spectrum disorder. Deficits in language function include rapid perseverative speech with abnormalities in combining words into phrases and sentences. Persons with fragile X syndrome seem to have relatively strong skills in communication and socialization; their intellectual functions seem to decline in the pubertal period. Female carriers are often less impaired than males with fragile X syndrome, but females can also manifest the typical physical characteristics and may have mild intellectual disability. Prader-Willi Syndrome. Prader-Willi syndrome is believed to result from a small deletion involving chromosome 15, occurring sporadically. Its prevalence is less than 1 in 10,000. Persons with the syndrome exhibit compulsive eating behavior and often obesity, intellectual disability, hypogonadism, small stature, hypotonia, and small hands and feet. Cat’s Cry (Cri-du-Chat) Syndrome. Children with cat’s cry syndrome have a deletion in chromosome 5. They are typically severely intellectually disabled and show many signs often associated with chromosomal aberrations, such as microcephaly, lowset ears, oblique palpebral fissures, hypertelorism, and micrognathia. The characteristic

cat-like cry that gave the syndrome its name is caused by laryngeal abnormalities that gradually change and disappear with increasing age. Phenylketonuria. PKU was first described by Ivar Asbjörn Fölling in 1934 as an inborn error of metabolism. PKU is transmitted as a simple recessive autosomal Mendelian trait and occurs in about 1 of every 10,000 to 15,000 live births. For parents who have already had a child with PKU, the chance of having another child with PKU is 20 to 25 percent of successive pregnancies. PKU is reported predominantly in persons of North European origin; a few cases have been described in blacks, Yemenite Jews, and Asians. The basic metabolic defect in PKU is an inability to convert phenylalanine, an essential amino acid, to paratyrosine because of the absence or inactivity of the liver enzyme phenylalanine hydroxylase, which catalyzes the conversion. Therefore, PKU is largely preventable with a screening for it, which, if positive, should be followed with a low phenylalanine diet. Two other types of hyperphenylalaninemia have recently been described. One is caused by a deficiency of the enzyme dihydropteridine reductase, and the other to a deficiency of a cofactor, biopterin. The first defect can be detected in fibroblasts, and biopterin can be measured in body fluids. Both these rare disorders carry a high risk of fatality. Most patients with PKU are severely intellectually disabled, but some are reported to have borderline or normal intelligence. Eczema, vomiting, and convulsions occur in about one third of all patients. Although the clinical picture varies, typically, children with PKU are reported to be hyperactive and irritable. They frequently exhibit temper tantrums and often display bizarre movements of their bodies and upper extremities, including twisting hand mannerisms. Verbal and nonverbal communication is commonly severely impaired or nonexistent. The children’s coordination is poor, and they have many perceptual difficulties. Currently, the Guthrie inhibition assay is a widely applied screening test using a bacteriological procedure to detect phenylalanine in the blood. In the United States, newborn infants are routinely screened for PKU. Early diagnosis is important, because a low-phenylalanine diet, in use since 1955, significantly improves both behavior and developmental progress. The best results seem to be obtained with early diagnosis and the start of dietary treatment before the child is 6 months of age. Dietary treatment, however, is not without risk. Phenylalanine is an essential amino acid, and its omission from the diet can lead to such severe complications as anemia, hypoglycemia, or edema. Dietary treatment of PKU should be continued indefinitely. Children who receive a diagnosis before the age of 3 months and are placed on an optimal dietary regimen may have normal intelligence. A low-phenylalanine diet does not reverse intellectual disability in untreated older children and adolescents with PKU, but the diet does decrease irritability and abnormal electroencephalography (EEG) changes and does increase social responsiveness and attention span. The parents of children with PKU and some of the children’s normal siblings are heterozygous carriers. Rett syndrome. Rett syndrome, now diagnosed in the DSM-5 as a form of autism

spectrum disorder, is believed to be caused by a dominant X-linked gene. It is degenerative and affects only females. In 1966, Andreas Rett reported on 22 girls with a serious progressive neurological disability. Deterioration in communications skills, motor behavior, and social functioning starts at about 1 year of age. Symptoms include ataxia, facial grimacing, teeth-grinding, and loss of speech. Intermittent hyperventilation and a disorganized breathing pattern are characteristic while the child is awake. Stereotypical hand movements, including hand-wringing, are typical. Progressive gait disturbance, scoliosis, and seizures occur. Severe spasticity is usually present by middle childhood. Cerebral atrophy occurs with decreased pigmentation of the substantia nigra, which suggests abnormalities of the dopaminergic nigrostriatal system. Neurofibromatosis. Also called von Recklinghausen’s, neurofibromatosis is the most common of the neurocutaneous syndromes caused by a single dominant gene, which may be inherited or occur as a new mutation. The disorder occurs in about 1 of 5,000 births and is characterized by café au lait spots on the skin and by neurofibromas, including optic gliomas and acoustic neuromas, caused by abnormal cell migration. Mild intellectual disability occurs in up to one third of those with the disease. Tuberous Sclerosis. Tuberous sclerosis is the second most common of the neurocutaneous syndromes; a progressive intellectual disability occurs in up to two thirds of all affected persons. It occurs in about 1 of 15,000 persons and is inherited by autosomal dominant transmission. Seizures are present in all those with intellectual disability, and in two thirds of those who are not. Infantile spasms may occur as early as 6 months of age. The phenotypic presentation includes adenoma sebaceum and ash-leaf spots that can be identified with a slit lamp. Lesch-Nyhan Syndrome. Lesch-Nyhan syndrome is a rare disorder caused by a deficiency of an enzyme involved in purine metabolism. The disorder is X-linked; patients have intellectual disability, microcephaly, seizures, choreoathetosis, and spasticity. The syndrome is also associated with severe compulsive self-mutilation by biting the mouth and fingers. Lesch-Nyhan syndrome is another example of a genetically determined syndrome with a specific, predictable behavioral pattern. Adrenoleukodystrophy The most common of several disorders of sudanophilic cerebral sclerosis, adrenoleukodystrophy is characterized by diffuse demyelination of the cerebral white matter resulting in visual and intellectual impairment, seizures, spasticity, and progression to death. The cerebral degeneration in adrenoleukodystrophy is accompanied by adrenocortical insufficiency. The disorder is transmitted by a sex-linked gene located on the distal end of the long arm of the X chromosome. The clinical onset is generally between 5 and 8 years of age, with early seizures, disturbances in gait, and

mild intellectual impairment. Abnormal pigmentation reflecting adrenal insufficiency sometimes precedes the neurological symptoms, and attacks of crying are common. Spastic contractures, ataxia, and swallowing disturbances are also frequent. Although the course is often rapidly progressive, some patients may have a relapsing and remitting course. Maple Syrup Urine Disease. The clinical symptoms of maple syrup urine disease appear during the first week of life. The infant deteriorates rapidly and has decerebrate rigidity, seizures, respiratory irregularity, and hypoglycemia. If untreated, maple syrup urine disease is usually fatal in the first months of life, and the survivors have severe intellectual disability. Some variants have been reported with transient ataxia and only mild intellectual disability. Treatment follows the general principles established for PKU and consists of a diet very low in the three involved amino acids—leucine, isoleucine, and valine. Other Enzyme Deficiency Disorders. Several enzyme deficiency disorders associated with intellectual disability have been identified, and still more diseases are being added as new discoveries are made, including Hartnup disease, galactosemia, and glycogen-storage disease. Table 31.3-3 lists 30 important disorders with inborn errors of metabolism, hereditary transmission patterns, defective enzymes, clinical signs, and relation to intellectual disability. Table 31.3-3 Impairment in Disorders with Inborn Errors of Metabolism

Acquired and Developmental Factors Prenatal Period. Important prerequisites for the overall development of the fetus include the mother’s physical, psychological, and nutritional health during pregnancy. Maternal chronic illnesses and conditions affecting the normal development of the fetus’s CNS include uncontrolled diabetes, anemia, emphysema, hypertension, and longterm use of alcohol and narcotic substances. Maternal infections during pregnancy, especially viral infections, have been known to cause fetal damage and intellectual disability. The extent of fetal damage depends on such variables as the type of viral infection, the gestational age of the fetus, and the severity of the illness. Although numerous infectious diseases have been reported to affect the fetus’s CNS, the following maternal illnesses have been identified to increase risk of intellectual disability in the newborn. Rubella (German measles). Rubella has replaced syphilis as the major cause of congenital malformations and intellectual disability caused by maternal infection. The

children of affected mothers may show several abnormalities, including congenital heart disease, intellectual disability, cataracts, deafness, microcephaly, and microphthalmia. Timing is crucial, because the extent and frequency of the complications are inversely related to the duration of the pregnancy at the time of maternal infection. When mothers are infected in the first trimester of pregnancy, 10 to 15 percent of the children are affected, but the incidence rises to almost 50 percent when the infection occurs in the first month of pregnancy. The situation is often complicated by subclinical forms of maternal infection that go undetected. Maternal rubella can be prevented by immunization. Cytomegalic Inclusion Disease. In many cases, cytomegalic inclusion disease remains dormant in the mother. Some children are stillborn, and others have jaundice, microcephaly, hepatosplenomegaly, and radiographic findings of intracerebral calcification. Children with intellectual disability from the disease frequently have cerebral calcification, microcephaly, or hydrocephalus. The diagnosis is confirmed by positive findings of the virus in throat and urine cultures and the recovery of inclusionbearing cells in the urine. Syphilis. Syphilis in pregnant women was once the main cause of various neuropathological changes in their offspring, including intellectual disability. Today, the incidence of syphilitic complications of pregnancy fluctuates with the incidence of syphilis in the general population. Some recent alarming statistics from several major cities in the United States indicate that there is still no room for complacency. Toxoplasmosis. Toxoplasmosis can be transmitted by the mother to the fetus. It causes mild or severe intellectual disability and, in severe cases, hydrocephalus, seizures, microcephaly, and chorioretinitis. Herpes Simplex. The herpes simplex virus can be transmitted transplacentally, although the most common mode of infection is during birth. Microcephaly, intellectual disability, intracranial calcification, and ocular abnormalities may result. Human Immunodeficiency Virus (HIV). Cognitive impairments are well known to be associated with transmission of HIV from mothers to their babies. HIV may have both direct and indirect influences on the developing brain. A subset of infants born infected with HIV may develop progressive encephalopathy, intellectual disabilities, and seizures within the first year of life. Fortunately, over the last two decades, there has been a dramatic decrease in perinatal HIV transmission due to a combination of antiviral agents provided to mothers during pregnancy and delivery, obstetric interventions that reduce risk, and administration of zidovudine (ZDV) as a prophylaxis for six weeks to newborns exposed to HIV. In the United States, the highest rate of reported pediatric acquired immunodeficiency disease (AIDS) occurred in 1992, with 1,700 cases reported compared to less than 50 cases reported annually now. In the

United States, fewer than 300 cases of HIV transmission from mother to child were reported in 2005. However, vertical transmission of HIV from mother to child around the world, especially in Africa, is considerable. Most babies born to HIV-infected mothers in the United States are not infected with the virus. Fetal Alcohol Syndrome. Fetal alcohol syndrome (FAS) results from prenatal alcohol exposure and can lead to a wide range of problems in the newborn. According to the Centers for Disease Control and Prevention, FAS in the United States occurs at a rate ranging from 0.2 to 1.5 per 1,000 live births. FAS is one of the leading preventable causes of intellectual disability and physical disabilities. The typical phenotypic picture of a child with FAS includes facial dysmorphism comprising hypertelorism, microcephaly, short palpebral fissures, inner epicanthal folds, and a short, turned-up nose. Often, the affected children have learning disorders and ADHD, and in some cases intellectual disability. Cardiac defects are also frequent. The entire syndrome occurs in up to 15 percent of babies born to women who regularly ingest large amounts of alcohol. Babies born to women who consume alcohol regularly during pregnancy have a high incidence of ADHD, learning disorders, and intellectual disability without the facial dysmorphism. Prenatal Drug Exposure. Prenatal exposure to opioids, such as heroin, often results in infants who are small for their gestational age, with a head circumference below the tenth percentile and withdrawal symptoms that appear within the first 2 days of life. The withdrawal symptoms of infants include irritability, hypertonia, tremor, vomiting, a high-pitched cry, and an abnormal sleep pattern. Seizures are unusual, but the withdrawal syndrome can be life-threatening to infants if it is untreated. Diazepam (Valium), phenobarbital (Luminal), chlorpromazine (Thorazine), and paregoric have been used to treat neonatal opioid withdrawal. The long-term sequelae of prenatal opioid exposure are not fully known; the children’s developmental milestones and intellectual functions may be within the normal range, but they have an increased risk for impulsivity and behavioral problems. Infants prenatally exposed to cocaine are at high risk for low birth weight and premature delivery. In the early neonatal period, they may have transient neurological and behavioral abnormalities, including abnormal results on EEG studies, tachycardia, poor feeding patterns, irritability, and excessive drowsiness. Rather than a withdrawal reaction, the physiological and behavioral abnormalities are a response to the cocaine, which may be excreted for up to a week postnatally. Complications of Pregnancy. Toxemia of pregnancy and uncontrolled maternal diabetes present hazards to the fetus and can potentially result in intellectual disability. Maternal malnutrition during pregnancy often results in prematurity and other obstetrical complications. Vaginal hemorrhage, placenta previa, premature separation of the placenta, and prolapse of the cord can damage the fetal brain by causing anoxia. The use of lithium during pregnancy was recently implicated in some congenital

malformations, especially of the cardiovascular system (e.g., Ebstein’s anomaly). Perinatal Period. Some evidence indicates that premature infants and infants with low birth weight are at high risk for neurological and subtle intellectual impairments that may not be apparent until their school years. Infants who sustain intracranial hemorrhages or show evidence of cerebral ischemia are especially vulnerable to cognitive abnormalities. The degree of neurodevelopmental impairment generally correlates with the severity of the intracranial hemorrhage. Recent studies have documented that, among children with very low birth weight (less than 1,000 g), 20 percent had significant disabilities, including cerebral palsy, intellectual disability, autism, and low intelligence with severe learning problems. Very premature children and those who had intrauterine growth retardation were found to be at high risk for developing both social problems and academic difficulties. Socioeconomic deprivation can also affect the adaptive function of these vulnerable infants. Early intervention may improve their cognitive, language, and perceptual abilities. Acquired Childhood Disorders Infection. The most serious infections affecting cerebral integrity are encephalitis and meningitis. Measles encephalitis has been virtually eliminated by the universal use of measles vaccine, and the incidence of other bacterial infections of the CNS has been markedly reduced with antibacterial agents. Most episodes of encephalitis are caused by viruses. Sometimes a clinician must retrospectively consider a probable encephalitic component in a previous obscure illness with high fever. Meningitis that was diagnosed late, even when followed by antibiotic treatment, can seriously affect a child’s cognitive development. Thrombotic and purulent intracranial phenomena secondary to septicemia are rarely seen today except in small infants. Head Trauma. The best-known causes of head injury in children that produces developmental handicaps, including seizures, are motor vehicle accidents, but more head injuries are caused by household accidents, such as falls from tables, open windows, and on stairways. Child maltreatment is not infrequently implicated in head traumas or intracranial trauma such as bleeding due “shaken baby” syndrome. Asphyxia. Brain damage due to asphyxia associated with near drowning is not an uncommon cause of intellectual disability. Long-term Exposures. Long-term exposure to lead is a well-established cause of compromised intelligence and learning skills. Intracranial tumors of various types and origins, surgery, and chemotherapy can also adversely affect brain function. Environmental and Sociocultural Factors Mild intellectual disability has been associated with significant deprivation of nutrition

and nurturance. Children who have endured these conditions are at risk for a host of psychiatric disorders including mood disorders, posttraumatic stress disorder, and attentional and anxiety disorders. Prenatal environment compromised by poor medical care and poor maternal nutrition may be contributing factors in the development of mild intellectual disability. Teenage pregnancies are at risk for mild intellectual disability in the baby due to the increased risk of obstetrical complications, prematurity, and low birth weight. Poor postnatal medical care, malnutrition, exposure to toxic substances such as lead, and potential physical trauma are additional risk factors for mild intellectual disabilities. Child neglect and inadequate caretaking may deprive an infant of both physical and emotional nurturances, leading to failure to thrive syndromes. DIAGNOSIS The diagnosis of intellectual disability can be made after the history is obtained, using information from a standardized intellectual assessment, and a standardized measure of adaptive function indicating that a child is significantly below the expected level in both areas. The severity of the intellectual disability will be determined on the basis of the level of adaptive function. A history and psychiatric interview are useful in obtaining a longitudinal picture of the child’s development and functioning. Examination of physical signs, neurological abnormalities, and in some cases, laboratory tests can be used to ascertain the cause and prognosis. History The clinician taking the history, which may elucidate pathways to intellectual disability, should pay particular attention to the mother’s pregnancy, labor, and delivery; the presence of a family history of intellectual disability; consanguinity of the parents; and known familial hereditary disorders. Psychiatric Interview A psychiatric interview of a child or adolescent with intellectual disability requires a high level of sensitivity in order to elicit information at the appropriate intellectual level while remaining respectful of the patient’s age and emotional development. The patient’s verbal abilities, including receptive and expressive language, can be initially screened by observing the communication between the caretakers and patient. If the patient communicates largely through gestures or sign language, the parents may serve as interpreters. Patients with milder forms of intellectual disability are often well aware of their differences from others and their failures, and may be anxious and ashamed during the interview. Approaching patients with a clear, supportive, concrete explanation of the diagnostic process, particularly patients with sufficiently receptive language ability, may allay anxiety and fears. Providing support and praise in language appropriate to the patient’s age and understanding is beneficial. Subtle direction,

structure, and reinforcement may be necessary to keep patients focused on the task or topic. In general, the psychiatric examination of an intellectually disabled child or adolescent should reveal how the patient has coped with stages of development. Frustration tolerance, impulse control, and over-aggressive motor and sexual behavior are important areas of attention in the interview. It is equally important to elicit the patient’s self-image, areas of self-confidence, and an assessment of tenacity, persistence, curiosity, and willingness to explore the environment. Structured Instruments, Rating Scales and Psychological Assessment In children and adolescents who have acquired language, one of several standardized instruments that include numerous domains of cognitive function are used. For children ages 6 to 16 years, the Wechsler Intelligence Test for Children is typically administered, and for children ages 3 to 6 years, the Wechsler Preschool and Primary Scale of Intelligence-Revised is commonly used. The Stanford-Binet Intelligence Scale, Fourth Edition, has the advantage that it can be administered to children even younger, starting at age 2 years. The Kaufman Assessment Battery for Children can be used in children ages 2½ to 12½ years, whereas the Kaufman Adolescent and Adult Intelligence Test is applicable to a wide range of ages, from 11 to 85 years. All of the above standardized instruments evaluate cognitive abilities across multiple domains including verbal, performance, memory, and problem solving. Standardized instruments measuring adaptive function (functions of “everyday” life) are based on the construct that adaptive skills increase with age, and that adaptation may vary across different settings such as school, peer relationships, and family life. The Vineland Adaptive Behavior Scales can be used in infants through youth 18 years of age and includes four basic domains including Communication (Receptive, Expressive, and Written); Daily Living Skills (Personal, Domestic, and Community); Socialization (Interpersonal Relations, Play and Leisure, and Coping Skills); Motor Skills (Fine and Gross). Several behavioral rating scales have been developed for the population with intellectual disability. General behavioral ratings scales include the Aberrant Behavior Checklist (ABC) and the Developmental Behavior Checklist (DBC). The Behavior Problem Inventory (BPI) is a good screening instrument for self-injurious, aggressive, and stereotyped behaviors. The Psychopathology Inventory for Mentally Retarded Adults (PIMRA) is utilized to identify the presence of comorbid psychiatric symptoms and disorders. Examining clinicians can use several screening instruments for developmental and intellectual delay or disability in infants and toddlers. However, controversy over the predictive value of infant psychological tests is heated. Some report the correlation of abnormalities during infancy with later abnormal functioning as very low, and others report it to be very high. The correlation rises in direct proportion to the age of the child at the time of the developmental examination. Some exercises such as copying geometric figures, the Goodenough Draw-a-Person Test, the Kohs Block Test, and geometric puzzles

all may be used as quick screening tests of visual-motor coordination. The Gesell and Bayley scales and the Cattell Infant Intelligence Scale are most commonly used with infants. The Peabody Vocabulary Test is the most widely used vocabulary test solely based on pictures. Other tests often found useful in detecting intellectual disability are the Bender Gestalt Test and the Benton Visual Retention Test. The psychological evaluation should assess perceptual, motor, linguistic, and cognitive abilities. Physical Examination Various parts of the body may demonstrate identifying characteristics of specific perinatal and prenatal events or conditions associated with intellectual disabilities. For example, the configuration and the size of the head may offer clues to a variety of conditions, such as microcephaly, hydrocephalus, or Down syndrome. A patient’s facial characteristics, for example, hypertelorism, a flat nasal bridge, prominent eyebrows, epicanthal folds may provide clues to a recognizable syndrome such as FAS. Additional facial characteristics including corneal opacities, retinal changes, low-set and small or misshapen ears, a protruding tongue, and disturbance in dentition may be stigmata of a variety of known syndromes. Facial expression, color and texture of the skin and hair, a high-arched palate, the size of the thyroid gland, and the proportions of a child’s trunk and extremities may offer clues for particular syndromes. The circumference of the head should be measured as part of the clinical investigation. Dermatoglyphics may offer another diagnostic tool, because uncommon ridge patterns and flexion creases on the hand are often found in persons who are intellectually disabled. Abnormal dermatoglyphics occur in chromosomal disorders and in persons who were prenatally infected with rubella. Table 31.3-4 lists syndromes with intellectual disability and their behavioral phenotypes. Table 31.3-4 Syndromes with Intellectual Disability and Behavioral Phenotypes

Neurological Examination Sensory impairments occur frequently among persons with intellectual disabilities. For example, hearing impairment occurs in 10 percent of persons with intellectual disability, a rate that is four times that of the general population. Visual disturbances can range from blindness to disturbances of spatial concepts, design recognition, and concepts of body image. Seizure disorders occur in about 10 percent of intellectually disabled populations and in one third of those with severe intellectual disability. Neurological abnormalities increase in incidence and severity in direct proportion to the degree of intellectual disability. Disturbances in motor areas are manifested in abnormalities of muscle tone (spasticity or hypotonia), reflexes (hyperreflexia), and involuntary movements (choreoathetosis). Less disability may also be associated with

clumsiness and poor coordination. CLINICAL FEATURES Mild intellectual disability may not be recognized or diagnosed in a child until school challenges the child’s social and communication skills. Cognitive deficits include poor ability to abstract and egocentric thinking, both of which become more easily evident as a child reaches middle childhood. Children with milder intellectual disabilities may function academically at the high elementary level and may acquire vocational skills sufficient to support themselves in some cases; however, social assimilation may be problematic. Communication deficits, poor self-esteem, and dependence may further contribute to a relative lack of social spontaneity. Moderate levels of intellectual disability are significantly more likely to be observed at a younger age, since communication skills develop more slowly and social isolation may ensue in the elementary school years. Academic achievement is usually limited to the middle-elementary level. Children with moderate intellectual deficits benefit from individual attention focused on the development of self-help skills. However, these children are aware of their deficits and often feel alienated from their peers and frustrated by their limitations. They continue to require a relatively high level of supervision but can become competent at occupational tasks in supportive settings. Severe intellectual disability is typically obvious in the preschool years; affected children have minimal speech and impaired motor development. Some language development may occur in the school-age years. By adolescence, if language has not improved significantly, poor, nonverbal forms of communication may have evolved. Behavioral approaches are useful means to promote some self-care, although those with severe intellectual disability generally need extensive supervision. Children with profound intellectual disability require constant supervision and are severely limited in both communication and motor skills. By adulthood, some speech development may be present, and simple self-help skills may be acquired. Clinical features frequently observed in populations with intellectual disability either in isolation or as part of a mental disorder, include hyperactivity, low frustration tolerance, aggression, affective instability, repetitive and stereotypic motor behaviors, and selfinjurious behaviors. Self-injurious behaviors occur more frequently and with greater intensity in more severe intellectual disability. Dylan was a full-term infant, the second child born to his 42-year-old mother, a medical technician, and 48-year-old father, a high school basketball coach. The pregnancy was unremarkable, and Dylan’s sister, who was two years older, was healthy and developing normally. The family lived in a rural town in the Midwest. Dylan was an extremely fussy, active newborn with extended periods of crying that the pediatrician labeled classic colic. As a newborn, it was noticed that Dylan seemed to have large ears and strabismus, which the pediatrician said would probably resolve

spontaneously. At 2 months of age, at a regular pediatric visit, a systolic heart murmur was heard and electrocardiography (ECG) revealed a mitral valve prolapse. Because Dylan was not cyanotic and had no other cardiac symptoms, no treatment was recommended except monitoring. Although Dylan became less fussy over time, he remained very active, did not sleep through the night, and was a picky eater, refusing solid foods. Milestones were slightly delayed, with Dylan sitting unassisted at 10 months and walking at 18 months. Language was also delayed, and, although his first words appeared at 20 months, Dylan had always made his wants and needs known. Dylan’s parents were concerned about his activity level and his developmental delays compared with his sister; however, they were reassured by the pediatrician’s sense that boys often develop more slowly than girls in the first two years. When Dylan was 3 years of age, his preschool teacher noted that he was unable to pay attention and he was hyperactive compared to his classmates, prompting his parents to obtain a developmental evaluation. Results showed modest delays in cognitive, linguistic, and motor functioning, with a developmental quotient (DQ) of 74. Dylan was described as inattentive, shy, and anxious, and he had poor eye contact. Enrolled in a special kindergarten, Dylan remained in a combination of special education and mainstreamed classes throughout his academic life. At 7 years of age, the school psychologist evaluated Dylan and results indicated that he met criteria for a “learning disability” profile. Dylan had an overall IQ of 66, with close to average functioning in short-term memory and pronounced deficits in longterm memory, expressive language, and visual-spatial functioning. Dylan struggled with writing tasks and arithmetic, but loved science. Due to his significant problems with inattention and hyperactivity, Dylan was placed on Concerta, which was beneficial, and titrated up to 54 mg per day. He displayed transient, intense interests in unusual items, such as vacuum cleaners. When Dylan reached the older elementary grades, he began to have more difficulty socially, and he was bullied about being in special education, and teased for his long head and big ears. As he entered adolescence, Dylan became increasingly anxious, so much so that he occasionally rubbed his hands or rocked, and he “fretted” about day-to-day issues and what would happen next. His long-term sensitivities to loud sounds seemed to wane slightly, but he developed fears of storm clouds and dogs and refused to ride on elevators. He became tearful and upset after his older sister left for a party, and worried that she might have a car accident. Dylan was very shy and would occasionally pace with worry and complain of stomachaches, but he attended school and had a small group of acquaintances in the Special Olympics bowling league. He enjoyed activities that did not involve much talking or sustained attention. When Dylan was 17 years of age, his parents happened to watch a television documentary on genetic causes of intellectual disability. They were overwhelmed by the similarities between Dylan and some of the people described in the program. They later described the experience as a “jolt.” They had always accepted Dylan, quirks and all, and had stopped pushing their doctors for reasons “why” when Dylan was a

preschooler. Nevertheless, they immediately called the informational number offered in the show, and within 2 months, they had the genetic tests done that confirmed a diagnosis of fragile X syndrome. Although Dylan’s day-to-day life did not change dramatically after the diagnosis, his parents reported a big difference in their approach to his shyness, restricted interests, and inattention. Dylan was later treated for anxiety with a selective serotonin reuptake inhibitor (SSRI) antidepressant, which decreased his social anxiety and facilitated activities with a few peers. Dylan’s parents reported a mixture of feelings at having such a late diagnosis—disappointment in their doctors, relief in finally knowing, and twinges of guilt. They were energized by Dylan’s positive responses to treatments for his attentional and anxiety symptoms and were pleased with Dylan’s recent increased interest in sharing activities with classmates and peers. LABORATORY EXAMINATION Laboratory tests that may elucidate the causes of intellectual disability include chromosomal analysis, urine and blood testing for metabolic disorders, and neuroimaging. Chromosomal abnormalities are the single most known common cause of intellectual disability. Chromosome Studies Chromosome analysis is commonly obtained when multiple physical anomalies, developmental delays, and intellectual disability present together. Current techniques are able to chromosomal regions with specific fluorescent in situ hybridization (FISH) markers, leading to microscopic deletions being identified in up to 7% of persons with moderate to severe intellectual disability. A history of growth retardation, the presence of microcephaly, a family history of intellectual disability, short stature, hypertelorism, and other facial abnormalities increase the risk for finding subtelomeric defects. Amniocentesis, in which a small amount of amniotic fluid is removed from the amniotic cavity transabdominally at about the 15 weeks of gestation, has been useful in diagnosing prenatal chromosomal abnormalities. Its use is considered when an increased fetal risk exists, such as with increased maternal age. Amniotic fluid cells, mostly fetal in origin, are cultured for cytogenetic and biochemical studies. Chronic villi sampling (CVS) is a screening technique to determine fetal chromosomal abnormalities. It is done at 8 to 10 weeks of gestation, 6 weeks earlier than amniocentesis is done. The results are available in a short time (hours or days) and, if the result is abnormal, the decision to terminate the pregnancy can be made within the first trimester. The procedure has a miscarriage risk between 2 and 5 percent; the risk in amniocentesis is lower (1 in 200). A non-invasive blood test called materniT21 is a proprietary prenatal test that detects abnormalities of chromosomes 21,18,13, X and Y. It is highly specific for Down syndrome (Figure 31.3-1). There is no risk of miscarriage.

FIGURE 31.3-1 A. young child with Down syndrome. B. A young adult with fragile X syndrome. (Courtesy of L.S. Syzmanski, M.D., and A.C. Crocker, M.D.) Urine and Blood Analysis Lesch-Nyhan syndrome, galactosemia, PKU, Hurler’s syndrome (Figure 31.3-2), and Hunter’s syndrome (Figure 31.3-3) are examples of disorders characterized by intellectual disability that can be identified through assays of the appropriate enzyme or organic or amino acids. Enzymatic abnormalities in chromosomal disorders, particularly Down syndrome, promise to become useful diagnostic tools. FIGURE 31.3-3 Two brothers, age 6 and 8 years, with Hunter’s syndrome, shown with their normal older sister. They have had significant developmental delay, trouble with recurrent respiratory infection, and behavioral abnormalities. (Courtesy of L.S. Syzmanski, M.D., and A.C. Crocker, M.D.)

FIGURE 31.3-2 A 6-year-old girl with Hurler’s syndrome. Her care has involved a class for seriously multihandicapped children, attention to cardiac problems, and special counseling for patients. (Courtesy of L.S. Syzmanski, M.D., and A.C. Crocker, M.D.) Electroencephalography Electroencephalography is indicated whenever a seizure disorder is considered. “Nonspecific” EEG changes, characterized by slow frequencies with bursts of spikes and sharp or blunt wave complexes are found with greater frequency among populations with intellectual disability than in the general population; however, these findings do not elucidate specific diagnoses. Neuroimaging Neuroimaging studies with populations of intellectually disabled patients using either computerized tomography (CT) or magnetic resonance imaging (MRI) have found high rates of abnormalities in those patients with microcephaly, significant delay, cerebral palsy, and profound disability. Among patients with intellectual disability, neuroimaging is indicated, accompanying findings that suggest seizures, microcephaly or macrocephaly, loss of previously acquired skills, or neurologic signs such as dystonia, spasticity, or altered reflexes. Although clinically not diagnostic, neuroimaging studies are currently also utilized to gather data that may eventually uncover biological mechanisms contributing to intellectual disability. Structural MRI, functional MRI (fMRI), and diffusion tensor imaging (DTI) are utilized in current research. For example, current data suggest that individuals with fragile X syndrome and concurrent attentional deficits are also more

likely to show aberrant frontal-striatal pathways on MRI than those patients without attentional problems. MRI is also useful to elucidate myelination patterns. MRI studies can also provide a baseline for comparison of a later, potentially degenerative process in the brain. Hearing and Speech Evaluations Hearing and speech should be evaluated routinely. Speech development may be the most reliable criterion in investigating intellectual disability. Various hearing impairments often occur in persons who are intellectually disabled, but in some instances hearing impairments can simulate intellectual disability. The commonly used methods of hearing and speech evaluation, however, require the patient’s cooperation and, thus, are often unreliable in severely disabled persons. COURSE AND PROGNOSIS Although the underlying intellectual impairment does not improve, in most cases of intellectual disability, level of adaptation increases with age and can be influenced positively by an enriched and supportive environment. In general, persons with mild and moderate mental intellectual disabilities have the most flexibility in adapting to various environmental conditions. Comorbid psychiatric disorders negatively impact overall prognosis. When psychiatric disorders are superimposed on intellectual disability, standard treatments for the comorbid mental disorders are often beneficial; however, less robust responses and increased vulnerability to side effects of psychopharmacologic agents are often the case. DIFFERENTIAL DIAGNOSIS By definition, intellectual disability must begin before the age of 18. In some cases, severe child maltreatment in the form of neglect or abuse may contribute to delays in development, which can appear to be intellectual disability. However these damages are partially reversible when a corrective, enriched, and stimulating environment is provided in early childhood. Sensory disabilities, especially deafness and blindness, can be mistaken for intellectual disability when a lack of awareness of the sensory deficit leads to inappropriate testing. Expressive and receptive speech disorders may give the impression of intellectual disability in a child of average intelligence, and cerebral palsy may be mistaken for intellectual disability. Chronic, debilitating medical diseases may depress and delay a child’s functioning and achievement, despite normal intelligence. Seizure disorders, especially those that are poorly controlled, may contribute to persisting intellectual disability. Specific organic syndromes leading to isolated handicaps such as failure to read (alexia), failure to write (agraphia), or failure to communicate (aphasia), may occur in a child of normal and even superior intelligence. Children with learning disorders (which can coexist with intellectual disability) experience a delay or failure of development in a specific area, such as reading or

mathematics, but they develop normally in other areas. In contrast, children with intellectual disability show general delays in most areas of development. Intellectual disability and autism spectrum disorder (ASD) often coexist; 70 to 75 percent of those with ASD have an IQ below 70. In addition, epidemiologic data indicate that ASD occurs in approximately 19.8% of persons with intellectual disability. Children with ASD have relatively more severe impairment in social relatedness and language than other children with the same level of intellectual disability. A child younger than the age of 18 years with significant adaptive functional impairment, with an IQ less than 70, who also meets diagnostic criteria for dementia, will receive both a diagnosis of dementia and intellectual disability. However, a child whose IQ drops below 70 after the age of 18 years with newly acquired cognitive impairment will receive only the diagnosis of dementia. TREATMENT Interventions for children and adolescents with intellectual disability are based on an assessment of social, educational, psychiatric, and environmental needs. Intellectual disability is associated with a variety of comorbid psychiatric disorders that often require specific treatment, in addition to psychosocial support. Of course, when preventive measures are available, the optimal approach includes primary, secondary, and tertiary interventions. Primary Prevention Primary prevention comprises actions taken to eliminate or reduce the conditions that lead to development of intellectual disability, as well as associated disorders. For example, screening babies for PKU, and administrating a low phenylalanine diet when PKU is present, significantly alters the emergence of intellectual disability in those affected children. Additional primary prevention steps include education of the general public about strategies to prevent intellectual disability, such as abstinence from alcohol during pregnancy; continuing efforts of health professionals to ensure and upgrade public health policies; and legislation to provide optimal maternal and child health care. Family and genetic counseling helps reduce the incidence of intellectual disability in a family with a history of a genetic disorder. Secondary and Tertiary Prevention Prompt attention to medical and psychiatric complications of intellectual disability can diminish their course (secondary prevention) and minimize the sequelae or consequent disabilities (tertiary prevention). Hereditary metabolic and endocrine disorders, such as PKU and hypothyroidism, can be treated effectively in an early stage by dietary control or hormone replacement therapy. Educational Interventions. Educational settings for children with intellectual

disability should include a comprehensive program that addresses academics and training in adaptive skills, social skills, and vocational skills. Particular attention should focus on communication and efforts to improve the quality of life. Behavioral and Cognitive-Behavioral Interventions. The difficulties in adaptation among the intellectual disability populations are widespread and so varied that several interventions alone or in combination may be beneficial. Behavior therapy has been used for many years to shape and enhance social behaviors and to control and minimize aggressive and destructive behaviors. Positive reinforcement for desired behaviors and benign punishment (e.g., loss of privileges) for objectionable behaviors has been helpful. Cognitive therapy, such as dispelling false beliefs and relaxation exercises with self-instruction, has also been recommended for intellectually disabled persons who can follow the instructions. Psychodynamic therapy has been used with patients and their families to decrease conflicts about expectations that result in persistent anxiety, rage, and depression. Psychiatric treatment modalities require modifications that take into consideration the patient’s level of intelligence. Family Education. One of the most important areas that a clinician can address is educating the family of a child or adolescent with intellectual disability about ways to enhance competence and self-esteem while maintaining realistic expectations for the patient. The family often finds it difficult to balance the fostering of independence and the providing of a nurturing and supportive environment for an intellectually disabled child, who is likely to experience some rejection and failure outside the family context. The parents may benefit from continuous counseling or family therapy and should be allowed opportunities to express their feelings of guilt, despair, anguish, recurring denial, and anger about their child’s disorder and future. The psychiatrist should be prepared to give the parents all the basic and current medical information regarding causes, treatment, and other pertinent areas (e.g., special training and the correction of sensory defects). Social Intervention. One of the most prevalent problems among persons with intellectual disability is a sense of social isolation and social skills deficits. Thus, improving the quantity and quality of social competence is a critical part of their care. Special Olympics International is the largest recreational sports program geared for this population. In addition to providing a forum to develop physical fitness, Special Olympics also enhances social interactions, friendships, and (it is hoped) general selfesteem. A recent study confirmed positive effects of the Special Olympics on the social competence of the intellectually disabled adults who participated. Psychopharmacologic Interventions. Pharmacological approaches to the treatment of behavioral and psychological symptoms in children with intellectual disability follow the paradigms of the evidence-based literature on treatment for all children with psychiatric disorders. However, given the paucity of randomized trials in

the childhood intellectual disability population, an empirical approach must also be taken. COMMON COMORBID PSYCHIATRIC SYMPTOMS AND DISORDERS Aggression, Irritability, and Self-injurious Behavior. Risperidone has been well documented as an efficacious treatment for irritability (aggression, self-injury, and severe tantrums) in children with ASD by the Research Units on Pediatric Psychopharmacology (RUPP, Autism Network 2002). Risperidone is helpful in treating disruptive behaviors in children with below-average intelligence, and has a good overall safety and tolerability profile. Cognitive testing has demonstrated small but significant improvement in cognitive ability with risperidone use. Children and adolescents with intellectual disability appear to be at higher risk for the development of tardive dyskinesia after use of antipsychotic medications; however, the atypical antipsychotics, including risperidone and clozapine (Clozaril), may provide some relief with a decreased risk of tardive dyskinesia. There is evidence to support the use of antipsychotic agents in the management of self-injurious behavior (SIB). Although data exist on the efficacy of thioridazine in improving SIB, a “black box” warning regarding QT prolongation with thioridazine has drastically diminished use of this drug, and atypical antipsychotic agents are currently preferred. Attention-Deficit/Hyperactivity Disorder. Estimates of attention deficit/hyperactivity (ADHD) and ADHD-like symptoms among children with sub average intelligence, genetic disorders, and developmental delay is estimated to be significantly higher than rates in the community. Randomized clinical trials of several psychopharmacologic agents have been done in children with sub-average intelligence. These include trials with methylphenidate, clonidine, and risperidone. The existing data for the treatment of ADHD and ADHD-like symptoms in youth with sub-average intelligence and developmental disorders suggest that agents, particularly stimulants used to treat ADHD in typically developing children, provide some degree of benefit to children with intellectual disability and ADHD. However, the occurrence of side effects within this population appears to be greater than in children with ADHD in the community. Thus, recommendations regarding treatment of ADHD in children and adolescents with comorbid ADHD include close monitoring for side effects. Studies of methylphenidate (Ritalin) treatment in those mildly intellectually disabled with ADHD have shown significant improvement in the ability to maintain attention and to stay focused on tasks. Methylphenidate treatment studies have not shown evidence of long-term improvement in social skills or learning. Risperidone also has been found to be beneficial in reducing symptoms of ADHD in this population; however, it may produce an increase in serum prolactin level. It is prudent to begin with a trial of a stimulant medication before the use of antipsychotic agents for the treatment of ADHD symptoms in intellectual disorder. A new extended release methylphenidate oral suspension (Quillivant XR, 2013) is currently available in 25 mg/5 ml preparation, and is taken

once daily for the treatment of ADHD in children 6 to 12 years of age. Amphetamine-based preparations have been shown to be efficacious in treating ADHD in typically developing children; however, it does not appear that these stimulant preparations have been specifically studied in children with intellectual disability. Clonidine has been used clinically in this population, especially to ameliorate hyperactivity and impulsivity. Although there are scant data, clinical ratings by parents and clinicians suggest its efficacy. Atomoxetine has been shown to be efficacious in children diagnosed with ASD and prominent ADHD features, and it is used clinically in the intellectually disabled population. Depressive Disorders. The identification of depressive disorders among individuals with intellectual disability requires careful evaluation, since it may be inadvertently overlooked when behavioral problems are prominent. There have been anecdotal reports of disinhibition in response to SSRIs (e.g., fluoxetine [Prozac], paroxetine [Paxil], and sertraline [Zoloft]) in intellectually disabled individuals with ASD. Given the relative safety of SSRI antidepressants, a trial is indicated when a depressive disorder is diagnosed in a child or adolescent with intellectual disability. Stereotypical Motor Movements. Antipsychotic medications—historically, haloperidol (Haldol) and chlorpromazine, and currently, the atypical antipsychotics—are used in the treatment of repetitive self-stimulatory behaviors in children with intellectual disability when these behaviors are either harmful to the child or disruptive. Anecdotal reports indicate that these agents may diminish self-stimulatory behaviors; however, there is no improvement seen in adaptive behavior. Obsessive-compulsive symptoms often overlap with the repetitive stereotypical behaviors seen in children and adolescents with intellectual disability, particularly in those with comorbid ASD. SSRIs such as fluoxetine, fluvoxamine (Luvox), paroxetine, and sertraline have been shown to have efficacy in treating obsessive-compulsive symptoms in children and adolescents and may have some efficacy for stereotyped motor movements. Explosive Rage Behavior. Antipsychotic medications, particularly risperidone, have been shown to be efficacious for the treatment of explosive rage. Systematic controlled studies are indicated to confirm the efficacy of these drugs in the treatment of rage outbursts. βAdrenergic receptor antagonists (beta-blockers), such as propranolol (Inderal), have been reportedly anecdotally to result in fewer explosive rages in some children with intellectual disability and ASD. SERVICES AND SUPPORT FOR CHILDREN WITH INTELLECTUAL DISABILITY Early Intervention Early intervention programs serve individuals for the first 3 years of life. Such services are generally provided by the state and begin with a specialist visiting the home for

several hours per week. Since the passage of Public Law 99–447, the Education of the Handicapped Amendments of 1986, early intervention services for the entire family are emphasized. Agencies are required to develop an Individualized Family Service Plan (IFSP) for each family, which identifies specific interventions to best help the family and child. School From ages 3 to 21 years, school is responsible by law to provide appropriate educational services to children and adolescents with intellectual disability in the United States. These mandates were created by the passage of Public Law 94–142, the Education for all Handicapped Children Act of 1975, and expanded with the addition of the Individuals with Disabilities Act (IDEA) of 1990. Through these laws, public schools must develop and provide an individualized educational program for each student with intellectual disability, determined at a meeting designated as the Individualized Education Plan (IEP) with school personnel and the family. The education must be provided for the child in the “least restrictive environment” that will allow the child to learn. Supports A wide variety of organized groups and services are available for children with intellectual disability and their families. These include short-term respite care, which allow families a break and is generally set up by state agencies. Other programs include the Special Olympics, which allows children with intellectual disability to participate in team sports and in sports competitions. Many organizations also exist for families who wish to connect with others who have children with intellectual disability. REFERENCES American Association on Intellectual and Developmental Disabilities. Overview of intellectual disability: Definition, classifications and systems of support. 2010. Arnold LE, Farmer C, Kraemer HC, Davies M, Witwer A, Chuang S, DiSilvestro R, McDougle CJ, McCracken J, Vitello B, Aman M, Scahill L, Posey DJ, Swiezy NB. Moderators, mediators, and other predictors of risperidone response in children with autistic disorder and irritability. J Child Adolesc Psychopharmacol. 2010;20:83–93,196–1205. Boulet S, Boyle C, Schieve L. Trends in health care utilization and health impact of developmental disabilities, 1997–2005. Arch Pediatr Adolesc Med. 2009;163:19–26. Correia Filho AG, Bodanase R, Silva TL, Alvarez JP, Aman M, Rohde LA. Comparison of risperidone and methylphenidate for reducing ADHD symptoms in children and adolescents with moderate intellectual disability. J Am Acad Child Adolesc Psychiatry. 2005;44:748. Ellison JW, Rosengeld JA, Shaffer LG. Genetic basis of intellectual disability. Annu Rev Med. 2013 Fowler MG, Gable AR, Lampe MA, Etima M Owor M. Perinatal HIV and its prevention: Progress toward an HIV-free generation. Clin Perinatol. 2010;37:699–719. Gothelf D, Furfaro JA, Penniman LC, Glover GH, Reiss AL. The contribution of novel brain imaging techniques to understanding the neurobiology of intellectual disability and developmental disabilities. Ment Retard Dev Disabil Res Rev.