AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Mental retardation (MR) and other neurodevelopmental disabilities are seen often in a general pediatric practice. Approximately 10% of children are learning impaired, while as many as 3% manifest some degree of MR. The population prevalence of these combined disorders of learning rivals that of the common childhood disorder asthma.

MR originates during the developmental period (ie, conception through age 18 years) and results in significantly subaverage general intellectual function with concurrent deficits in functional life skills. The diagnosis of MR requires an intelligence quotient (IQ) score of at least 2 standard deviations (SD) below the mean IQ of 100 (ie, IQ <70). Equivalent deficits in at least 2 areas of functional life skills or adaptive skills also must be present to meet the diagnostic criteria for MR. Adaptive skills encompass functional life skills within the domains of communication, self-care, home living, social and interpersonal skills, use of community resources, self-direction, functional academic skills, work, leisure, health, and safety.

MR can be categorized broadly as follows:

MR also can be categorized as syndromic, if associated with dysmorphic features, or nonsyndromic, if not associated with dysmorphisms or malformations. Although the understanding of specific MR syndromes is expanding with recent molecular genetic advances, for the vast majority of individuals with MR no etiology is identifiable. In contrast, over 800 recognized syndromes listed in the Online Mendelian Inheritance in Man (OMIM) database are associated with MR, reflecting clinical diagnostic advances in the field.

Some forms of MR are due to nongenetic factors and are identifiable by their associated dysmorphisms and clinical presentation. Examples include prenatal exposure to teratogens (eg, anticonvulsants, warfarin, alcohol) or prenatal thyroid dysfunction. Prenatal and postnatal exposure to lead and the associated decrement in IQ may increase an individual's chance of functioning in the MR range.

Pathophysiology

MR is the manifestation of a group of disorders of CNS function; dysfunction is localized primarily to the cortical structures, including the hippocampus and the medial temporal cortex. Most individuals with significant cognitive impairment have no discernible structural abnormalities of the brain. CNS malformations, a visual correlate of the disorders, are diagnosed in only 10-15% of cases; the most common malformations consist of neural tube defects, hydranencephaly, and microcephaly. Less commonly, CNS malformations include disorders of migration (the lissencephalies) and agenesis of the corpus callosum.

Multiple congenital anomaly syndromes with malformations confined to nonneurologic organ systems may be present in 5% of all patients with MR. Between 3% and 7% of cases may be associated with a wide array of inborn errors of metabolism complicated by multi-organ system disease. Alcohol exposure in utero may account for as many as 8% of those with mild MR.

Most individuals with mild MR and other learning disorders are free of neurologic complications, CNS malformations, and dysmorphisms. They are more likely, however, to be born into families of low socioeconomic status, low IQ, and little education. The etiologic contribution of poverty to their poor cognitive function remains unclear. Clearly, however, poor cognitive functioning and MR are correlated positively with a life of poverty.

Frequency

United States

The frequency of MR of all degrees ranges from 1.6-3% of the population.

International

A study with excellent ascertainment conducted in Aberdeen, Scotland, yielded a prevalence of 1 in 300 for severe MR and 1 in 77 for mild MR. Among those with severe MR were more boys than girls (male-to-female ratio 1.2:1), and among those with IQ >70, in the mild range of deficiency, boys exceeded girls by a ratio of 2.2:1.

Although prevalence rates vary from country to country, the variance in prevalence may be attributed to ascertainment bias, the standardization methods employed from study to study, and a generalized upward drift in IQ scores over time. Even so, the greatest variance in statistics of prevalence is most likely to fall within the category of mild MR, a group for which the ascertainment bias is large.

Mortality/Morbidity

• MR itself is not necessarily associated with an increased premature death rate. However, individuals with severe to profound cognitive impairment experience a decreased life expectancy related to the underlying etiology or additional complicating neurologic disorders such as epilepsy. Neurologic dysfunction resulting in immobility, significant oral motor incoordination, dysphagia, and aspiration confers a greater risk of premature death than MR itself. When significant neurologic dysfunction is associated with other organ system anomalies, an individual's life expectancy is shortened further.
• Respiratory disease is the most prevalent cause of death among individuals with profound MR. In particular, respiratory infections were the leading cause of death among a Finnish cohort of mentally retarded children. For those affected by mild cognitive impairment, life expectancy is not known to differ from that of the general population.
• Comorbid psychiatric conditions are diagnosed more frequently in the cognitively impaired than in the general population. Even so, psychiatric disorders probably are underappreciated in this population.
  • Schizophrenia may have a prevalence of 3% in individuals with MR, compared to 0.8% in the general population.
  • Bipolar illness has a 2- to 3-fold greater prevalence in the cognitively impaired than in the general population.
  • Attention deficit/hyperactivity disorder (ADHD) is diagnosed in 8-15% of children and 17-52% of adults with MR.
  • Self-injurious behaviors require treatment in 3-15%, particularly in the severe range of MR.
  • Major depression, autistic spectrum disorders, obsessive-compulsive disorder, anxiety disorders, conduct disorder, tic disorders, and other stereotypic behaviors are diagnosed more commonly in the cognitively impaired.
• In the 1970 Isle of Wight study, as many as 30% of children with MR exhibited an emotional or behavioral disorder, compared to 6% of children in the general population. MR compounded by epilepsy conferred a 56% risk of comorbid psychiatric disease in this study.
• Occult visual and auditory deficits occur in 50% of those with MR, particularly when refractive errors are considered.
• The rates of transmittable diseases, including sexually transmitted diseases (STDs), hepatitis B, and Helicobacter pylori infection, are increased significantly among individuals with MR.
• One in 5 individuals with MR also has cerebral palsy (CP).
• As many as 20% of individuals with MR have seizures.
• GI complications with MR include feeding dysfunction, excess drooling, reflux esophagitis, and constipation.
• GU complications with MR include urinary incontinence and poor menstrual hygiene.
• A profound social morbidity affects individuals with MR and their families. This morbidity can be measured in lost wages, dependence on social services, impaired long-term relationships, and emotional suffering.

Race

Consistent racial differences in prevalence of MR and associated mortality rates are not known to exist.

Sex

The gender ratios for mortality and morbidity do not differ from the gender ratio noted in the severe/profound ranges of cognitive impairment (ie, male-to-female ratio, 1.2:1).

Age

In a comparison of groups with and without Down syndrome from the California Department of Developmental Services cohort, excess mortality in the Down syndrome group tended to decrease with advancing age up to 35-39 years but increased thereafter. The increase in death rate from age 40 years was steeper in patients with Down syndrome than in those without Down syndrome.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The presenting symptoms and signs of MR typically include behavioral and emotional disturbances, language delay, and delays in adaptive and problem-solving skills.

• Behavioral disturbances
• • The rate of psychopathology in the MR population is 3 times greater than that in the cognitively normal population. Frequently associated behaviors include aggression, self-injury, defiance, inattention, hyperactivity, anxiety, depression, sleep disturbances, and stereotypic behaviors.
  • Even before an age at which psychopathology can be identified, infants and toddlers with MR are more likely to have difficult temperaments, noncompliance, hyperactivity, disordered sleep, colic, poor social skills, and delays in play skills.
• Language delay
• • Many children with delayed expressive language development (per parental report) eventually are diagnosed with MR.
  • Many infants are thought to be deaf at presentation owing to lack of expressive language and environmental inattention.
• Fine motor/adaptive delay
• • Significant delays in self-feeding, toileting, and play skills typically are reported in children with MR.
  • Prolonged and messy finger feeding often is accompanied by oral-motor incoordination.
  • Children with MR often display lack of interest in age-appropriate toys and delays in imaginative play and reciprocal play with age-matched peers. Odd, repetitive behaviors often replace imaginative play with symbolic toys.
• Gross motor delay
• • Delays in gross motor development infrequently accompany the language and fine motor/adaptive delays associated with MR, unless the underlying condition results in both MR and CP.
  • Subtle delays in gross motor acquisition, or clumsiness, can be identified in the developmental assessment.
• Neurologic and physical abnormalities
• • Prevalence of MR is increased among children with seizure disorders, microcephaly, macrocephaly, history of intrauterine or postnatal growth retardation, prematurity, and congenital anomalies.
  • In the process of addressing somatic problems, assessment of a child's cognitive abilities often is overlooked.

Physical

• Neurologic examination: This examination should include assessments of head growth, muscle tone, strength and coordination, deep tendon reflexes, primitive reflexes, ataxia, and other abnormal movements such as dystonia or athetosis.
• Sensory examination
• • Children with disabilities and MR are more likely than healthy children to have visual impairment (refractive errors, strabismus, amblyopia, cataracts, abnormal retinal pigmentation, and cortical blindness).
  • The prevalence of hearing deficits in the MR population is greatest among the severely impaired.
• Developmental assessment
• • For the diagnoses of developmental delay and MR, an expanded neurologic examination (including cognitive assessment and psychological tests) is required.
  • For the purpose of screening, the physician can administer various tests, including the Denver Developmental Screening Test-II, the Capute Scales, the Slosson Intelligence Test, and the Vineland Adaptive Behavior Scales.
  • Key behavioral observations should focus on the child's communicative intent, social skills, eye contact, compliance, attention span, impulsivity, and style of play.
  • A licensed psychologist can administer various psychological tests to assess language comprehension, language expression, nonverbal problem-solving abilities, fine motor and adaptive abilities, attention span, memory, gross motor skills, and behaviors. The most common psychological tests include the Bayley Scales of Infant Development, the Stanford-Binet Intelligence Scale, the Wechsler Intelligence Scale for Children-III, and the Wechsler Preschool and Primary Scale of Intelligence-Revised.
• Physical examination
• • Measurement of all growth parameters must include head circumference. Microcephaly correlates highly with cognitive deficits. Macrocephaly may indicate hydrocephalus and is associated with some inborn errors of metabolism.
  • Short stature may suggest a genetic disorder, fetal alcohol syndrome, or hypothyroidism. Tall stature may suggest fragile X syndrome (FraX), Soto syndrome, or other overgrowth syndrome associated with MR.
  • Major organ system abnormalities may direct the etiologic investigation.
  • Cutaneous findings of etiologic interest include hyperpigmented and hypopigmented macules (café-au-lait macules, hypomelanosis of Ito, ash-leaf spots), fibromas, and irregular pigmentation patterns.
  • Examine for subtle dysmorphic features.
  • Although MR with multiple congenital anomalies and major malformations (MR/MCA) accounts for only 5% of all cases of MR, the majority of these affected individuals have 3 to 4 minor anomalies, especially involving the face and digits.

Causes

• Prenatal conditions (genetic)
• • Trisomy 21 or Down syndrome
    • This disorder accounts for 25-50% of persons with severe MR; Down syndrome occurs in approximately 1 per 800 live births.
    • In infancy, this disorder is recognized by specific facial features, including flat facial profile, brachycephaly, up-slanted and narrow palpebral fissures, and anomalous auricles.
    • Hypotonia, joint hyperextensibility, neonatal jaundice, simian crease, shortened digits, and excess skin on the back of the neck contribute to the clinical features.
    • Congenital heart disease is present in 40-60%. GI malformations are present in 5%. Congenital cataracts are found in 3%, and as many as 35% require treatment for strabismus or refractive error. Infantile spasms may develop in 5%.
    • The IQ score ranges from 40-55. Generally, verbal-linguistic skills lag behind visual-spatial skills.
    • In trisomy 21, gene expression of chromosome 21 is increased in a dosage-dependent fashion that varies by tissue type. While some trisomic 21 genes are not expressed at elevated levels, many are. Of those significantly increased, several encode proteins critical for mitochondrial function and for neurogenesis.
  • Other chromosomal abnormalities (eg, deletions, duplications, translocations) may be present in as many as 25% of individuals with severe MR.
    • The most commonly occurring abnormalities of this class, detectable at the 500 band level of chromosomal analysis, are 5p- (ie, Cri du chat syndrome) and 4p- (ie, Wolf-Hirschhorn syndrome).
    • Cryptic subtelomeric deletions are diagnosed with increasing frequency as fluorescently tagged molecular DNA probes allow detection of deletions below the microscopic resolution of a standard karyotype.
    • Cryptic subtelometric rearrangements now account for 5-6% of cases of idiopathic mental retardation.
    • Chromosomal analysis is undergoing further refinement with the application of gene array hybridization techniques that may detect abnormalities in up to 20% of cases of idiopathic mental retardation.
  • Fragile X syndrome
    • The population prevalence of this disorder is approximately 1 in 3500 males, giving a prevalence within the MR population of about 1 in 76. For males with severe MR, the prevalence rises to about 1 in 13. About 1 in 2000 females carries the fragile X (FraX) gene. Current studies suggest that FraX is the most prevalent form of inherited MR.
    • Males with the full FMR1 trinucleotide repeat expansion (ie, the full mutation) usually function in the moderate to severe range of MR. Other features include testicular enlargement in the postpubertal period and minor facial anomalies (eg, large forehead, elongated face, protuberant auricles, prominent chin).
    • Females with the full FMR1 trinucleotide repeat expansion may have no symptoms, although some have mild learning disabilities or even mild to moderate MR.
    • Mitral valve prolapse and seizures may occur.
    • Up to 20% of FraX males meet criteria for autism; autisticlike behaviors can be present in affected females as well.
    • Direct DNA analysis of the FMR-1 gene is the method of choice for diagnosing both affected individuals with the full trinucleotide repeat expansion (>200 repeats) and unaffected carriers with the premutation (60-200 repeats).
• Contiguous gene deletion syndromes
• • Although less common, some of these syndromes can be readily identified clinically. The following syndromes often can be confirmed by utilizing a fluorescence in situ hybridization (FISH) probe to the deleted region in question.
  • Prader-Willi syndrome
    • The Prader-Willi syndrome (PWS) involves deletion at 15q11-q13 (deletion of the paternally derived region).
    • Classic clinical features include neonatal and infantile hypotonia, feeding problems or failure to thrive in infancy, excessive weight gain with hyperphagia beginning between ages 12 months and 6 years, food compulsions, hypogonadism, global developmental delay, almond-shaped eyes, thin upper lip, and down-turned corners of the mouth.
    • The candidate gene within the Prader-Willi gene region is SNRPN, which encodes a ribonucleoprotein involved in mRNA splicing. How SNRPN contributes to the hypothalamic dysfunction that defines many clinical features of PWS is unclear.
    • It is the first known human disorder of genomic imprinting, leading to revolutionary changes in the field of molecular genetics and the understanding of uniparental disomy.
    • Negative FISH results in PWS may be due to maternal uniparental disomy (UPD) of chromosome 15 (2 number 15 chromosomes from the mother) and can be confirmed with molecular studies.
  • Angelman syndrome
    • The Angelman syndrome (AS) also involves deletion at 15q11-q13 (deletion of the maternal copy of the gene region).
    • MR, absent speech, microcephaly, seizures, puppetlike ataxic movements, inappropriate laughter, and facial dysmorphisms characterize AS.
    • The candidate genes within the AS critical region include UBE3A, whose protein product is important in the posttranslational modification of proteins by ubiquitination, and GABRA3, a subunit of the GABAa receptor.
    • Negative FISH results in AS may be due to paternal UPD of chromosome 15 (2 number 15 chromosomes from the father) and can be confirmed with molecular studies.
    • Point mutations occasionally are found in AS with negative results on FISH and UPD studies.
  • Smith-Magenis syndrome
    • Smith-Magenis syndrome (SMS) involves deletion at 17p11.2.
    • MR, short stature, brachydactyly, minor skeletal and facial anomalies, sleep disturbance, self-injurious behaviors, and other organ system malformations characterize this contiguous gene deletion syndrome.
    • Although as many as 100 genes may be deleted in SMS, the physical characteristics are subtle.
  • CATCH 22 syndrome
    • The CATCH 22 syndrome, which comprises DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCF), involves deletion at 22q11.
    • Infants with classic DGS are identified readily by aplasia or hypoplasia of the thymus, T cell lymphopenia, conotruncal cardiac defects, oral-motor dysfunction, and facial dysmorphisms (eg, low-set malformed ears, small jaw, palatal defects, hypertelorism, antimongoloid palpebral slant).
    • Minor variants may meet clinical criteria for the VCF syndrome. With a prevalence of 1 in 4,000 people, it is the most common known microdeletion disorder.
    • The majority of individuals with CATCH 22 have learning disabilities or mild MR and comorbid psychiatric disorders including schizophrenia and mood disorders with psychosis.
  • Williams syndrome
    • The Williams syndrome involves deletion at 7q11.
    • Characteristic facial features are described as "elfin." In the majority, valvular stenosis, poor growth, hypotonia, late-onset contractures, dental anomalies, infantile colic, oral-motor discoordination, and hyperacusis (ie, hypersensitivity to sound) are reported. Infantile hypercalcemia may be transient and is often subclinical.
    • Mild to moderate MR, relative preservation of language, and associated weakness in visual-spatial development are typical.
    • Elastin is the candidate gene presumed responsible for some of Williams syndrome features, including supravalvular aortic stenosis.
  • Wolf-Hirschhorn syndrome
    • The Wolf-Hirschhorn syndrome, also known as 4p- syndrome, involves deletion at 4p16.3.
    • Severe growth retardation, microcephaly, "Greek helmet" facies and orofacial clefts, and other midline fusion defects characterize this syndrome.
    • The region of deletion is gene dense, and an undefined number of genes may contribute to this phenotype.
  • Langer-Giedion syndrome
    • This syndrome, also known as trichorhinophalangeal syndrome type II, involves deletion at 8q24.1.
    • Learning disabilities and the presence of MR vary.
    • Facial dysmorphisms include microcephaly, large ears, bulbous nose, broad nasal bridge, elongated philtrum, and sparse scalp hair. Multiple nevi and skeletal anomalies may be present.
  • Miller-Dieker syndrome
    • The Miller-Dieker syndrome (MDS) involves deletion at 17p13.3.
    • Infants present with severe neurologic impairment, seizures, and hypotonia secondary to lissencephaly. The smooth cerebral cortex with absent or decreased gyral formation results from abnormal neuronal migration.
    • The identified gene LIS1 may function as a G protein subunit in cellular signal transduction that is important in telencephalon development.
  • Many contiguous gene deletion syndromes for which a FISH probe is not available have been recognized in association with MR. A comprehensive survey is beyond the scope of this article.
• Single gene mutation syndromes
• • Tuberous sclerosis
    • Hypopigmented cutaneous macules (ie, ash-leaf spots), calcified intracranial cortical tubers with or without heterotopias, seizures, retinal hamartomas, and renal angiomyolipomas characterize this hamartomatous condition.
    • MR may or may not be seen in affected individuals; the presence of seizures is the factor most associated with poor cognitive outcome. Autism is a rather common finding in children with tuberous sclerosis associated with MR.
    • This is an autosomal-dominant inherited condition with about half of affected individuals resulting from a new mutation. Two genes have been identified, one at 9q34 (TSC1) and the other at 16p13 (TSC2). A variety of deletions, rearrangements, and point mutations have been implicated in tuberous sclerosis.
  • Rubinstein-Taybi syndrome
    • Broad terminal phalanges, beaked nose, down-slanting palpebral fissures, epicanthal folds, and microcephaly characterize this syndrome.
    • This is an autosomal-dominant inherited condition, with the majority of cases representing new deletions or point mutations of the CREB-binding protein gene (16p13.3).
  • Coffin-Lowry syndrome
    • This syndrome is characterized by hypertelorism, down-slanting palpebral fissures, frontal prominence, thickened lips and nasal septum, as well as dental and skeletal anomalies.
    • It is an X-linked condition with females having mild manifestations resulting from mutations in the RSK2 gene, which encodes a CREB kinase (Xp22.2-p22.1).
  • Rett syndrome
    • Developmental stagnation then regression, progressive microcephaly, seizures, ataxia, and autisticlike behaviors are seen in affected females.
    • This X-linked dominant condition with presumed lethality for affected males is caused by mutations in MeCP2, a transcriptional repressor (Xq28).
  • Smith-Lemli-Opitz syndrome
    • Malformations consistent with holoprosencephaly sequence, syndactyly of toes 2 and 3, micrognathia, cleft palate, and moderate to severe MR are seen.
    • This autosomal-recessive inherited condition results from increases in 7-dehydrocholesterol (7-DHC) due to mutations in the 7-DHC reductase gene (11q12-q13).
    • Treatment with an oral cholesterol "cocktail" has shown some promise in this syndrome.
  • Costello syndrome
    • Characteristic clinical features include polyhydramnios, failure to thrive, cardiac anomalies, and tumor predisposition.
    • Mutation in HRAS is identified, resulting in a gain of function of the encoded protein and increased activation of the cellular signaling pathway Ras-MAPK.
  • Many other single-gene disorders are associated with MR with additional phenotypic and behavioral features including such problems as microcephaly, seizures, or short stature, with or without dysmorphic facies.
• Fewer than 13% of those with mild MR have an identifiable biomedical cause. Recent advances in genetic linkage analysis techniques in families with multiple affected members have revealed more than 50 candidate genes along the X chromosome. In some kindreds with a pattern of X-linked nonsyndromic mild MR (XLMR), linkage analysis has identified candidate genes that code for interleukin receptors, G protein signaling factors, transcription factors, and transcriptional repressors.
• Environmental causes
• • Fetal alcohol syndrome and fetal alcohol effect
    • Alcohol results in a wide range of teratogenic effects. The most severely affected individuals meet criteria for fetal alcohol syndrome (FAS) by demonstrating short palpebral fissures, dental crowding, camptodactyly flattened philtrum, thin vermillion border, flattening of the maxillary area, microphthalmia, prenatal and postnatal growth deficiency, microcephaly, and developmental delay.
    • Fetal alcohol effect (FAE) can be diagnosed only in the context of (1) maternal history of alcohol use and (2) a child with developmental and behavioral abnormalities that also manifests growth deficiency or the characteristic facial dysmorphisms.
    • The prevalence of FAS may be as high as 1.9 in 1000 live births and is the leading cause of MR in the western world. The impact of the milder FAE remains unknown. The teratogenic effects of alcohol may be responsible for as many as 8% of cases of mild MR. Alcohol's deleterious effects on cortical plasticity contribute to cognitive impairment.
  • Congenital hypothyroidism
    • Congenital hypothyroidism (known as cretinism in the past) is a neurologic syndrome that results from severe thyroid hormone deficiency during the fetal period. In the infant, the syndrome comprises deaf mutism, moderate to severe MR, spasticity, and strabismus.
    • Normal fetal brain development requires sufficient production of both maternal and fetal thyroid hormones. Normal glandular production of T4 and T3 requires sufficient dietary intake of iodine.
    • Iodine deficiency may affect an estimated 800 million people worldwide. It can result in endemic goiter, fetal wastage, milder degrees of developmental delay, and endemic congenital hypothyroidism.
• Perinatal/postnatal conditions: These conditions are responsible for fewer than 10% of all MR cases.
  • Congenital cytomegalovirus (CMV)
  • Congenital rubella - No longer an important etiology in countries with high vaccination rates
  • Intraventricular hemorrhage related to extreme prematurity - An important cause only in societies with advanced neonatal care and survival of the premature
  • Hypoxic-ischemic encephalopathy - Always results in combined CP/MR
  • Traumatic brain injury - Shaken baby syndrome, closed head injury sustained in motor vehicle accidents
  • Meningitis - Decreasing in importance as the incidence of Haemophilus influenzae type B decreases in vaccinated countries
  • Neurodegenerative disorders

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Autism/pervasive developmental disorder
CNS trauma
Environmental deprivation
Major sensory deficits (eg, deafness, blindness)
Malnutrition
Mitochondrial cytopathies

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• No laboratory and/or radiologic investigation is routine in MR. The examiner must determine the nature and extent of the laboratory investigation following a history and physical examination.
• DNA analysis of the FraX promoter region should be ordered on all prepubertal males with MR, particularly if autistic features are noted. In the postpubertal period, the clinical manifestations of FraX are likely to be readily apparent, such that DNA analysis can be ordered with more selectivity in this population.
• Karyotype at the 500 band level of resolution (at least) should be considered in all children with MR.
• • Chromosomal abnormalities (Tri 21 and others) may account for as many as 50% of those affected by severe to profound MR.
  • Sex chromosome aneuploidy is seen in as many as 5% of children with mild MR or learning disabilities.
• FISH probes are ordered as clinically indicated, as follows:
• • Prader-Willi/Angelman syndrome
  • Smith-Magenis syndrome
  • CATCH 22
  • Williams syndrome
  • Wolf-Hirschhorn syndrome
  • Cri du chat syndrome
  • Langer-Giedion (trichorhinophalangeal) syndrome
  • Miller-Dieker syndrome
• Metabolic labs are ordered only as clinically indicated.
• • Plasma amino acids (aminoacidopathies)
  • Urinary organic acids (organic acidopathies)
  • Urinary mucopolysaccharides and oligosaccharides (mucopolysaccharidoses)
  • Plasma 7-DHC (Smith-Lemli-Opitz syndrome)
  • Thyroid function tests
  • Very-long-chain fatty acids (peroxisomal disorders)
  • Creatine kinase (in the assessment of profound central hypotonia versus myopathy)

Imaging Studies

• Brain MRI
• • Brain imaging should be conducted in any child with developmental delay and abnormal findings on neurologic examination, including abnormalities of head size and/or facial dysmorphisms.
  • Brain MRI generally is preferred over CT scan, because the former has greater resolution and enhanced detection of abnormalities in the progression and timing of myelination, demyelination, and heterotopic gray matter.
• Head CT scan: This is the preferred imaging study for calcifications that may be identified with TORCH infections (ie, toxoplasmosis, other infections, rubella, CMV, herpes simplex), when tuberous sclerosis is suspected, or if craniosynostosis is a concern.
• Skeletal films: These assist with the phenotypic description, syndrome characterization, and assessment of growth.

Other Tests

• Detailed psychological assessment by a licensed psychologist is necessary to confirm the diagnosis of MR. Some of the most commonly used psychological tests in children include the following:
• • Bayley Scales of Infant Development
    • Normalized for ages 2-30 months
    • Subtest scores for receptive and expressive language, nonverbal problem-solving ability, and sustained attention
  • Stanford-Binet Intelligence Scale
    • Normalized for ages 2 years to 23 years
    • Fifteen subtests for assessment of 4 key areas of cognitive proficiency: verbal reasoning, abstract/visual reasoning, quantitative memory, and short-term memory
  • Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R)
    • Normalized for ages 3 years to 7.25 years
    • Twelve subtests for assessment of verbal and nonverbal intelligence
  • Wechsler Intelligence Scale for Children–IV (WISC-IV)
    • For ages 6 years to 16 years, 11 months
    • Verbal and nonverbal intelligence scores derived from 12 subtests
  • Vineland Adaptive Behavior Scales
    • For neonates to adults
    • Measures ability to perform daily activities required for personal and social sufficiency; adaptive or functional behaviors rated by interviewing the child's guardian
    • Deficiencies in at least 2 areas of adaptive skills required to meet the MR diagnostic criteria
• Electrophysiologic studies
• • EEG, if clinically warranted
  • Auditory evoked potentials in the context of audiologic assessment
  • Visual evoked potentials in cases of profound delay and suspected cortical blindness

Histologic Findings

Pathologic analysis of cortical tissue by the Golgi method in the 1970s suggested that in cases of profound, unclassified MR, dendritic spines were decreased and/or had immature morphology. These findings have been confirmed in cortical autopsy material from individuals with Down syndrome and FraX. Dendritic spine morphology is related directly to the intradendritic microtubular components and their organization.

Microtubules in dendrites of cortical neurons often are fragmented or in disarray in cases of developmental failure. In contrast, in some neuronal storage diseases associated with impaired cognition, dendritic spines are sprouted exuberantly beyond the developmental period and in ectopic locations. A relationship is implied, then, between dendritic spine morphology and number and cognitive development in the human.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• The mainstay of treatment of MR is developing a comprehensive management plan for the condition. The complex habilitation plan for the individual requires input from care providers from multiple disciplines, including special educators, language therapists, behavioral therapists, occupational therapists, and community services that provide social support and respite care for families affected by MR.
• No treatments are available specifically for cognitive deficiency. Although the pharmacologic enhancement of cognition is an area of interest, research on such nootropic (ie, knowledge-enhancing) compounds is limited. Such drugs have not become part of the routine or even experimental clinical management of this population.

Consultations

• Ophthalmology
• Genetic evaluation, testing, and counseling

Diet

Nutritional supplements are of no proven benefit.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No specific pharmacologic treatment is available for cognitive impairment in the developing child or adult with MR. Medications, when prescribed, are targeted to specific comorbid psychiatric disease or behavioral disturbances.

Development of nootropic drugs that may alter cognitive processes positively has been of interest to researchers. Medications currently prescribed for dementia, such as acetylcholinesterase inhibitors, are not accepted treatments for MR, although clinical trials have not been conducted in children. Phosphodiesterase inhibitors enhance cortical plasticity in an animal model of fetal alcohol syndrome.

Although vitamin and mineral therapies have gained popularity, their efficacy has not been established in clinical trials. The use of antioxidant supplements in patients with Down syndrome is of theoretical benefit but has not yet been tested vigorously.

Drug Category: CNS stimulants

The most common class of drugs prescribed in this population is the psychostimulants because of the coexistence of attention deficit with or without hyperactivity disorder (ADHD/ADD) in as many as 50%. The most widely used psychostimulants are methylphenidate and dextroamphetamine, which appear to enhance dopamine and norepinephrine activity in the CNS.

Drug Category: Antidepressants

These agents may be used when ADHD is comorbid with depression.

Drug Category: Alpha-adrenergic agonists

These agents are used commonly to modulate hyperactivity, aggression, tics, and dyssomnias.

Drug Category: Neuroleptic drugs (antipsychotics)

The neuroleptic drugs are the most frequently prescribed agents for aggression, self-injury, and hyperactivity in people with MR. Increasingly, they are more likely to be reserved for the older child or adult in whom intensive behavioral intervention has failed. Likewise, the prevalence of comorbid psychiatric disorders in MR increases with age. Neuroleptics interact with receptors for a variety of brain neurotransmitters, including dopamine, serotonin, acetylcholine, histamine, and norepinephrine. Their ability to antagonize dopamine receptors appears to correlate well with the efficacy of these drugs and imparts their antipsychotic properties. Likewise, antidopaminergic activity evokes extrapyramidal symptoms. Rarely, neuroleptic malignant syndrome may occur.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Individuals with MR should be evaluated at least annually by a neurologist or neurodevelopmental pediatrician with a special interest in the etiology and management of cognitive disorders. The physician should have adequate knowledge of the educational, social, and support services available in the community; assessing the appropriateness of the patient's individualized habilitation is important.
• To maximize the individual's functional independence, the following areas should be addressed by the physician at least annually:
• • Treatment of associated impairments
  • Pharmacotherapy
  • Behavior management
  • Educational services
  • Recreational needs
  • Family counseling
• The annual visit requires routine preventive medicine and coordination of specialized services such as dental and gynecologic care under sedation. Supplemental vaccines, including the influenza and hepatitis B vaccines, are particularly prudent for those in residential placements. A careful behavioral history is important to identify newly emerging maladaptive behaviors that may be treated effectively with behavior management.
• If patients have co-existing motor impairments, the physician should monitor for secondary orthopedic disease. Arthroplasty for progressive hip dislocation and/or tendon releases for progressive contractures due to spasticity may be required. Advanced knowledge in the pharmacologic management of spasticity and rigidity allows the clinician to refer the patient for botulinum toxin injections or baclofen pump insertion when appropriate.
• The health maintenance schedule for individuals with Down syndrome is well recognized. Ongoing audiologic monitoring, thyroid function tests, and screening for atlantoaxial instability are important components.

Prognosis

• Individuals with MR fare better today than at any other recorded time in world history.

Patient Education

• Family support and education around the issues of MR can be obtained from the following:
• • The Arc (formerly known as the Association for Retarded Citizens)
    Membership Department
    1010 Wayne Ave., Suite 650
    Silver Spring, MD 20910
  • American Association on Mental Retardation (AAMR)
    444 North Capital Street, NW
    Suite 846
    Washington, DC 20001-1512
    800-424-3688
  • Exceptional Parent Magazine
    P.O. Box 2078
    Department EP
    Marion, OH 43305-2178
• National Organization for Rare Disorders (NORD)
  National Organization for Rare Disorders
  55 Kenosia Avenue
  PO Box 1968
  Danbury, CT 06813-1968
• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Down Syndrome.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Individuals in the United States older than 18 years are no longer under the guardianship of their biological parents. No exceptions are made for children with MR. The majority of these individuals, particularly those in the range of mild MR, are capable of making appropriate legal decisions when adequately and appropriately informed of the decision outcomes.
• Some individuals may not be capable of comprehending the long-term implications of the medical or legal matter at hand. In such cases, the decision is best made by a member of the biological family; the family member must obtain guardianship status for power of attorney over these matters. If a family member is unavailable to serve as guardian, then a guardian ad litum can be assigned by the court for assistance in such legal and medical matters.
• Complex decisions, particularly those involving issues of sterilization, are perhaps best handled by committee with the assistance of the ethics committee of the involved medical institution.
• Failure to identify a genetic cause of MR with risks to other family members or risks to the patient for future medical complications are potential medical/legal pitfalls.
• Perhaps 1 in 8 convicts on death row in the United States has mental retardation. Many persons cannot fully comprehend the Miranda Rights and other critical concepts necessary to maneuver through the criminal justice system.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Apr 17, 2006