Intellectual Disabilities of Developmental Onset

Alya Reeve

I. Background and Definition

Intellectual disability (ID) is an impairment of cognitive function formerly known by many different names including mental deficiency, mental retardation (MR), developmental disability, cognitive disability, also feeblemindedness, idiocy, and many pejorative labels. It is characterized by limitations in both intellectual functioning and in adaptive function. ID is not something you have, “like blue eyes, or a bad heart” that can be compared across individuals for its own characteristic pathophysiology, nor is it an independent medical disorder (diagnosed, with known etiology). ID is not a clear independent mental disorder, though it is coded on Axis II of the Diagnostic and Statistical Manual of Mental Disorders (DSM) system. Rather, ID reflects the “fit” between the capabilities of individuals and the structure and expectations of their environment (see Table 15.1). Demands of certain settings can minimize or exacerbate the signs and symptoms of ID and affect the degree of limitations in functioning for an individual.

A variety of processes can result in or be associated with ID including:

Inherited syndromes (e.g., trisomy 21, Fragile X, etc.)
Metabolic deficiencies (e.g., mitochondrial disorders, vitamin and nutritional deficiencies, etc.)

Acquired injuries (e.g., anoxia, trauma, hemorrhage, and ischemia)

TABLE 15.1 The American Association on Mental Retardation Definition of Mental Retardation

Mental retardation is a disability characterized by significant limitations both in intellectual functioning and in adaptive behavior as expressed in conceptual, social, and practical adaptive skills. This disability originates before age 18.
Five assumptions essential to the application of the definition

Limitations in present functioning must be considered within the context of community environments typical of the individual’s age peers and culture.
Valid assessment considers cultural and linguistic diversity as well as differences in communication, sensory, motor, and behavioral factors.
Within an individual, limitations often coexist with strengths.
An important purpose of describing limitations is to develop a profile of needed supports.
With appropriate personalized supports over a sustained period, the life functioning of the person with mental retardation generally will improve.

Exposure to toxins or infection (e.g., lead, or meningitis, measles, etc.)
Environmental challenge, (e.g., inability to perform to grade-expectations in school)

Emphasis on the intelligence quotient (IQ) ratings for diagnosis has skewed the assessment of ID toward a focus on measures that require education-related skills.

It is important to point out that there is neither a reliable standardized measure (test) of social intelligence (reading person-to-person situations), nor of practical intelligence (functioning in day-to-day activities and problem solving daily living). Many individuals with borderline or low IQ scores have excellent social and practical skills; and do not require assistance to maintain employment or to live independently. In the broadest sense, they function well because the natural supports within society (from family and friends to community and religious affiliations) provide the structure and interests and means to not be limited in their independence. Conversely many individuals with borderline or low normal IQ scores are unable to function independently because of a mismatch between the demands of their environment and significant deficits in social and/or practical intelligence.

Defining ID and classifying severity of ID is done in different contexts, with differing meanings and results.
- Clinicians must pay particular attention to whether they are seeking:
  - To answer a question of etiology
  - To assist in access to support services
  - To predict future development or response to treatment intervention
- Identification of syndromes, or etiopathology, may contribute to prevention strategies and improved therapeutic measures.
- Approximately 75% of children classified with ID have no associated medical condition.
- Statistical models define ID based on having IQ two standard deviations below the mean (implies that there is a continuum of cognitive ability in the general population).
- Very frequently, individuals are labeled by the school system (a social systems model) for purposes of classroom expectations, rate of learning, and specialized instruction.
The neuropsychiatrist can provide a dynamic clinical model for understanding ID by integrating information from all other models/definitions of ID.
- Incorporating neuropsychiatric tools and skills in evaluating the developmental aspects of fluid intelligence include the following:
  - Reasoning, problem solving
  - Having areas of relative strengths and weaknesses in cognitive abilities
  - Explicit and implicit learning techniques
- Integrating psychiatric functioning, life stresses, normal aging, and activities
The bibliography lists several excellent sources for more comprehensive discussion about the issues in integrating multiple sources of clinical and historical information. The focus of this chapter is on the care of patients with ID of developmental onset—much is being learned and the clinician has to adapt relevant information into their clinical practice.

II. Prevalence

Prevalence of ID/MR is estimated at approximately 0.7% to 1.25% of the general population, with some estimates as high as 3%. This rate would estimate that approximately 2 to 3 million individuals in the United States are affected with ID or MR. (The high-end estimate would assume that the death rate for individuals with ID is the same as for the general population; that ID is reliably identified in infancy; that ID does not change with increasing age). Using the 1990 census, 1.5 million people aged 6 to 64 were diagnosed with ID. The rate of ID/MR is underestimated because not all individuals seek assistance. For example, students are often passed on from grade to grade without comprehensive assessment, and if not tracked into special education programs students often drop out of school at their first opportunity. Furthermore, people know they do not want to be labeled as having ID/MR.

There are relatively lower rates for ID reported in western and mountain states in the United States; the highest rates are reported in eastern, southern, and central United States Higher rates of ID are reported in men overall, however, there are no sex-based differences among persons with severe forms of ID.

The life expectancy is increasing for individuals with ID; yet mortality rates are higher than for the general population. Death
rates after the first year of life remain elevated for people with ID. In less severe forms of ID the death rate is about twice that of the general population, whereas in severe forms of ID the death rate may be 30-fold greater. There are probably several factors that contribute to this increased death rate including:
- Neurologic disorders and secondary medical complications in those with severe forms of ID
- Aspiration and secondary complications of aspiration related to gastroesophageal reflux disease (GERD), motor dyscontrol, muscle weakness, polypharmacy, excess sedation, seizures, and eating habits
The classification of severity of ID is commonly done based on IQ as follows:
- Mild level of ID corresponds to the range of 55 to 70.
- Moderate level of ID corresponds to the range of 40 to 55.
- Severe level of ID corresponds to the range of 25 to 40.
- Profound level of ID corresponds to <25.
The rationale for this kind of classification scheme was that it could predict life-long performance and capability, and assist in anticipating the medical needs of individuals. Unfortunately these classifications are not as helpful in clinical assessment or educational programming as it was hoped, and the overreliance on simple IQ measures (without taking into account [1] a full neuropsychological assessment, especially an inventory of frontal-executive functions and [2] the environmental supports available), can often result in a mismatch between what functional level is predicted based on IQ score, and the functional level that the person is able to actually demonstrate. Providers often erroneously attribute problematic behaviors to “MR” rather than looking for more specific or relevant diagnoses.

III. Etiology and Pathophysiology—Issues for Prevention

There are approximately 250 to 300 known causes of ID and this number is likely to increase as we learn more about the genetics of cognition. However, in the clinical arena, the cause of ID in most individuals is unknown or considered idiopathic. Some of the major categories of the causes of ID are listed in the subsequent text.

A. Birth trauma

The most common problems in birth are blunt trauma or lack of oxygen. The extent of anoxic damage is not predictably detected until several weeks or months have passed. Early motor development may be normal or may evidence signs of cerebral palsy. Often anoxic damage results in only minor motor symptoms and major cognitive delay, such as decreased speed of association, difficulty with new learning, and poor or slowed retention of novel information.

B. Disorders of development

Any disorder that affects brain development, myelination, pruning, or preservation of learning, can result in loss of abilities or prevent expected acquisition of knowledge. Onset before the age of 21 qualifies the disorder as a developmental disorder
(as opposed to a disorder acquired in adulthood). Note that this is a different age criterion from federal definition of ID/MR. Several of the more common mechanisms are described in the subsequent text.

Haemophilus influenzae type b
- Cause of bacterial meningitis
  - Meningitis is 3% to 5% fatal.
  - Of the survivors, 25% to 35% have permanent brain damage: ID, partial blindness, hearing impairment, speech disorders, hemiparesis, behavioral dyscontrol, seizures.
  - Preventable by vaccination between age 2 months to 5 years
Inborn errors of metabolism that require early detection and initiation of intervention during the neonatal period to prevent ID are:
- Phenylketonuria (PKU)
  - Autosomal recessive single gene disorder
  - Untreated, leads to severe ID and cerebral palsy (CP)
  - Treatment with dietary restriction of phenylalanine permits normal intelligence, but with increased rates of hyperactivity and learning disorders.
- Galactosemia
  - Missing enzyme for digestion of dairy products
  - Associated with ID, hepatic disorders, cataracts.
- Congenital hypothyroidism
  - Causes growth retardation of brain and bone, ID (irreversible if not treated within first 6 weeks of life), and over time all the other symptoms of insufficient thyroid hormone.
  - Requires life-long replacement therapy.
  - Thyroid levels must be monitored to adjust to periods of increased need, such as during ages 3 to 4 and adolescence.

C. Genetic disorders

A variety of genetically based syndromes have been associated with ID (e.g., Down syndrome or trisomy 21). These disorders typically have predictable physical attributes, physiology, behavior, pathology, and associated medical and neurologic complications. (see Table 15.2) Individual variations in all the syndromes occur—so extensive variation should be expected in presenting symptoms, response to medications, and complications from secondary conditions. As more children are put in the mainstream of the educational system and more intensive corrective and supportive therapies are instituted early in life, individuals with ID and known syndromes can be expected to have improved functional outcomes. These therapeutic interventions necessarily change the predictive accuracy of previously described syndromes and the developmental and health issues for the person through their lifespan. With proper supports, people with ID can be expected to contradict published prognoses.

D. Autistic spectrum disorders

Autistic spectrum syndromes are of heightened concern given the apparent increased incidence and associated disability. Most individuals with autism have some degree of ID although this is not universally true and is not true of individuals with Asperger syndrome. The hallmark of autistic spectrum disorders (except for Asperger syndrome) is delayed speech and

language, impaired social skills (“social reciprocity”), and exaggerated interest or obsessions with a limited array of topics or objects. Autisticm spectrum disorders can be diagnosed by age 3, and associated clinical symptoms include poor eye contact, resisting cuddling, ritualistic behaviors of rocking and hand waving, obsession with order, late onset of talking, rhyming, or echolalic speech.

TABLE 15.2 Recognized Genetic Syndromes Presenting with Intellectual Disabilities

Down syndrome:
Approximately 7,000 infants are born annually with DS in the United States; this is a rate of 1:800 live births; the rate is independent of race or socioeconomic status. Life expectancy is variable, with some individuals living into their seventies; congenital cardiac malformations and complications from them contribute to earlier death; dementia in the fifties is reported in approximately 50%; thyroid problems and celiac disease are common medical comorbidities; atlantoaxial instability should be screened between 3 to 5 years of age and before participation in contact sports or Special Olympics.
Behavior: Characteristically placid and good-natured; although aggression, hyperactivity, and impulsivity are seen pretty regularly. Increased sociability and decreased self-injurious behavior is typical. Some clinicians report people with DS have an increased ability for imitation, which may contribute to having better acceptance in social situations. Given the high rate of hypothyroidism, thyroid functions should be investigated whenever there has been a recent change in cognition, behavior, or mood.
Cognitive Profile: Highest developmental scores are typically in infancy, with progressive slowing of cognitive development relative to normal-aged peers. Developmental language delay is present, with expressive language more affected than receptive; language pragmatics are good, with poorer grammatical abilities. Visual processing tends to be better than auditory processing; there may be deficits in short-term memory and delayed recall on formal testing.
Fragile X syndrome (Fra-X):
This syndrome is caused by massive expansion of CGG triplet trinucleotide repeats in the 5′-untranslated region of the Fragile X mental retardation-1 gene (FMR-1). Affected subjects have more than 200 repeats; phenotypically normal carriers have 43 to 200 repeats on the X chromosome at Xq27.3. Fra-X is the most common known cause of inherited intellectual disability. The prevalence in men is about twice that in women. The frequency of the permutation and mutation may be variable in different populations because of founder effects for those populations. Although prenatal testing by chorionic villus sampling can be done, the optimum time for determination of genetic risk is before pregnancy to determine genetic risk, clarification of carrier status, and availability of prenatal testing.
Physical characteristics are present from birth: Elongated face, large protruding ears, protruding jaw, hyperextensible joints, and enlarged testes in men after puberty.
Rett syndrome:
Most common cause of profound ID in women; prevalence is 1:10,000 to 1:12,000 in girls. Inherited as X-linked dominant condition, usually a single occurrence within a family. Prenatal testing is available if the MECP2 mutation has been identified in a family member. Early development is normal, with deceleration of head growth between 5 months and 4 years of age, loss of previously acquired hand use, communication dysfunction, and social withdrawal. It is categorized as a pervasive developmental disorder in DSM-IV-TR. It is complicated by secondary medical conditions of seizures, breath-holding episodes, hyperventilation, dystonia, spasticity, scoliosis, and peripheral vasomotor problems.
Behavior: Stereotypic midline hand movements of wringing, tapping, clapping, mouthing of hand and fingers are seen, as purposeful hand movements are lost. Ataxia of the trunk and gait appears in first 4 y of life; expressive and receptive language is severely impaired; psychomotor retardation is common. By age 5 to 7 y the social withdrawal is less pronounced. Gait and motor coordination deteriorates progressively, necessitating a wheelchair. Gaze remains a vital method of communicating with the world around them; interest may be shown by increased activity of the purposeless midline hand movements.
Lesch-Nyhan disease:
Lesch-Nyhan disease is a sex-linked recessive condition caused by an inborn error of (purine nucleotide) metabolism, with a prevalence rate of 1:380,000. (With each pregnancy the mother will have a 25% chance of having an affected male, a 25% chance of having a carrier female, and a 50% chance of having an unaffected child.) Occurrence in women is extremely rare. Prenatal testing is available.
Clinical Features: Overproduction of uric acid may vary from mild to severe; movement disorder; anemia and growth retardation; cognitive disability; behavioral disorder including self-injury. Self-biting may progress to deliberate self-harm, such as head banging, eye poking, pulling fingernails, persistent psychogenic vomiting.
The severity of cognitive impairment reflects the severity of L-N variant. Severity of symptoms are correlated with uric acid levels and deficiencies in dopamine transport in basal ganglia structures, but at present are not fully explained at a biochemical level.
Prader-Willi syndrome:
PWS is the most common dysmorphic form of obesity because of the compulsive hyperphagia. It was identified as a syndrome of obesity, short stature, cryptorchidism, and intellectual disability. Hypotonia, hypogonadism, small hands and feet, and dysmorphic facies are also reported. It occurs in 1:10,000 to 1:22,000 live births; lifespan is dependent upon control of obesity and its secondary medical complications, especially diabetes, and heart failure. Over 90% of cases occur sporadically; paternal deletion of 15q11-q13, or maternal uniparental disomy of chromosome 15, or imprinting center mutation.
Behavioral Features: Compulsive food-hoarding, gorging, and seeking food; skin picking; irritability, anger, and low frustration tolerance; stubbornness. Depressive and anxiety symptoms are very common; 50% of children and adults with PWS have behavioral symptoms requiring specialized attention. Some test in the normal IQ range, while most are in the mild to moderate IQ range. Learning disabilities may be more severe than the individual IQ would suggest.
Angelman syndrome:
AS involves a defect on chromosome 15 in the same region as PWS of the chromosome inherited from the mother; the prevalence rate is 1:12,000 to 1:20,000 persons. Most cases are spontaneous sporadic mutations, though familial inheritance is reported. Typical physical features include a wide mouth, smiling, with a thin upper lip, pointed chin, prominent tongue, and wide-spaced teeth; head circumference is usually below 50%; approximately half have fair hair and skin; two third have strabismus. Motor milestones are delayed and truncal hypotonia is seen; many walk only between 3 and 4 y of age. Eighty percent have seizure disorders, with onset between 1.5 to 2 y of age; myclonic seizures and drop attacks are most common. Speech is much delayed.
Behavioral Features: AS often laugh inappropriately and frequently; hand flapping occurs with arousal; sleep is characteristically interrupted by frequent awakenings; hyperactivity interferes with concentration and socialization. Difficulties in speech and coordination contribute to underestimation of intellectual abilities, which are described as severely impaired. Comprehension is much better than expressive language.
Williams syndrome:
Williams, Barratt-Boyes and Lowe identified a syndrome that includes supravalvular aortic stenosis, peripheral pulmonary stenosis, intellectual disability, and characteristic facial appearance. It is a contiguous gene deletion disorder resulting from a hemizygous deletion of 1.5 Mb on one copy of chromosome 7 at 7q11.23. The facial features include broad forehead, medial eyebrow flare, depressed nasal bridge, stellate patterned iris, widely spaced teeth, and full lips (often described as “elfin-like”). Cognitive pattern is one of visuospatial difficulties, with strengths in auditory processing and in language. These school-based tasks remain seriously limited throughout the lifespan, though the capacity to understand what others are feeling and thinking has been demonstrated to approach normal function.
Behavioral Features: Often recognized by an overfriendly manner, excess sociability with strangers, high degree of empathy, attentional difficulties, and expressive language ability (better than IQ would lead one to expect). In some cases, perseverative behaviors, excessive anxiety, attention deficit disorder and sleep disorders are cause of dysfunction. Adaptive living skills are often impaired so that independent living in the community is feasible in <25%.

DS, down syndrome; PWS, prader-willi syndrome; AS, angelman syndrome; IQ, intelligence quotient.

E. Nonverbal learning disorders

There are a group of children that may present with some degree of intellectual impairment, social awkwardness, and a variety of behavioral disturbances such as extremes of rage, poor attention, and poor organization. Formal neuropsychological assessment typically shows problems in several domains including graphomotor skills, reading comprehension, mechanical arithmetic, and mathematical reasoning/abstraction, and science. Interpersonal and behavioral problems may be evident in difficulties adapting to novel situations, awkward social interactions, and mood disturbances. This profile can make the individual appear intellectually more impaired than they are. A variety of terms have been used to describe these children including right hemisphere syndrome and the more common term nonverbal learning disorders (NVLD). The underlying pathophysiology of this disorder is not clear but is speculated to involve a developmental white matter disconnection syndrome, which affects the right hemisphere disproportionately.

F. Exposure to medications/drugs/toxins

Many prescribed drugs (e.g., antiepilepsy, antidepressants, antipsychotics, and antibiotics) can result in developmental abnormalities from facial midline variants to cardiac defects and even lack of cognitive and emotional control. Prevention is achieved by frank discussions with patients before pregnancy, planning to reduce medications to the lowest levels possible or discontinuation of medications, and supporting informed choices made by the patient. Drugs of abuse may cause direct harm, or may be associated with infectious diseases such as human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) or sexually transmitted diseases that cause ID. Among the most common and best recognized of this category are fetal alcohol syndrome (FAS) disorder and fetal alcohol effects (FAE) or alcohol, related neurodevelopmental disorders (ARND), and lead exposure.

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