Definitions and Testing

Accurate diagnosis of global developmental delay or intellectual disability is an essential precondition to proper management and service provision. Accurate diagnosis serves many functions, including understanding the specific associated medical and psychiatric complications, eligibility for service and support provision and its specific attributes, family counseling, and legal recognition of disability [Shevell, 2009b].

The diagnosis of intellectual disability, as presently defined, requires demonstration of significant limitations in intellectual functioning and adaptive behavior [AAMR, 2002]. Intelligence, conceptualized as general mental capabilities, is represented “objectively” by an IQ score obtained through proper application of an appropriate assessment measure [Hernstein and Murray, 1994]. Adaptive behavior refers to skills (i.e., conceptual, social, and practical) that a person learns in order to function within the context of the expectations and challenges of everyday life. Limitations in these skills affect the ability to respond to changes and demands encountered, affecting performance in daily life and participation in available opportunities. Multiple standardized, age-appropriate measures have been normed and validated on normal populations to assess adaptive behavior skills [Spreat, 1999]. For intellectual function and adaptive behavior, a significant limitation thought sufficient to trigger possible inclusion under the rubric of intellectual disability is performance at least 2 standard deviations below the mean for an appropriate test [AAMR, 2002]. Some of the standardized measures for the evaluation of intellectual, neurodevelopmental, and behavioral testing are summarized in Table 43-1, and a qualitative description of IQ and index scores on Wechsler tests that categorize intelligence levels is provided in Table 43-2.

Table 43-1 Measures for Evaluation of Intellectual, Neurodevelopmental, and Behavioral Progress

David Wechsler, The Psychological Corporation, 2002, www.psychcorp.com Test of young children’s intellectual ability

Genomic Microarray

Genomic microarray technology is an evolving platform that arrays a representation of the human chromosome on a glass slide and hybridizes fluorescently labeled control and patient DNA to detect copy number changes in the genome [Bejjani et al., 2005]. The first-generation chips had approximately 3000 elements spaced approximately every 1.0 Mb [Pinkel et al., 1998]. Newer-generation chips have been developed that completely cover the genome (i.e., tiling arrays) using more than 100,000-oligonucleotide spots [Ishkanian et al., 2004]. All of these platforms aim to identify interstitial copy number changes or copy number variants. Initially, this approach has been used very successfully to identify chromosomal regions (and genes) involved in cancer progression. Studies done thus far suggest that this approach will likely find many additional regions that are implicated in neurodevelopmental disabilities, even in the setting of prior normal high-resolution karyotyping [Harada et al., 2004; Shaw-Smith et al., 2004; Engels et al., 2007; Shevell et al., 2008]. Many studies in autism, mental retardation, and cohorts with multiple congenital anomalies (who also have neurodevelopmental disabilities) show that a few loci occur repetitively and at a much higher frequency in affected individuals than in controls [Berkel et al., 2010; Koolen et al., 2006; Sharp et al., 2008]. This type of large-scale analysis can provide clinicians with the necessary information to advise families about the significance of these genetic findings.

However, one challenge that arises from this whole-genome analysis is distinguishing normal variation from disease-causing changes, particularly in cases in which the genetic variation has never been reported previously in the literature, or has been reported but its incidence in cases and controls is not well documented. The first step is to establish whether a documented copy number change is de novo or familial; this is essential with respect to determining the possible pathogenicity of such changes [Speicher and Carter, 2005], although there is an increasing number of reported cases now in which inherited loci have been shown to correlate with disease presentation [Girirajan et al., 2010; Kumar et al., 2008; Shinawi et al., 2009; Weiss et al., 2008]. As we continue to make strides in genetics that move away from simple mendelian disorders, this concept of “partial penetrance” will grow in clinical relevance. The establishment of comprehensive, computerized, publicly available genotype–phenotype databases will aid in the process of establishing pathogenicity of these less common copy number changes in the future [Speicher and Higgins, 2007].

Advances in Imaging

High-quality MRI has significantly advanced the ability to detect many brain malformations. Certain studies suggest that MRI is useful for detecting abnormalities in up to 50 percent of children with developmental delay. In some cases, such as bifrontal polymicrogyria, lissencephaly, and bilateral periventricular nodular heterotopia, certain genes are known to cause these inherited syndromes [Gaitanis and Walsh, 2004]. For most cases, the genetic or other cause of the malformation has yet to be determined. Proton MR spectroscopy measures the resonance of molecules in the brain. Given the unique resonance frequencies of many molecules, their abundance can be noninvasively measured. This approach has been useful for detecting changes in cerebral lactate in mitochondrial disorders, and for observing the absence of creatine in the three disorders of creatine deficiency [Stromberger et al., 2003], another cause of potentially treatable nonsyndromic mental retardation [Schulze, 2003]. This technique also has been useful for the detection of abnormalities in succinic semialdehyde dehydrogenase deficiency [Ethofer et al., 2004], and for those changes that precede the changes on conventional T2-weighted MRI for X-linked adrenoleukodystrophy patients [Eichler et al., 2002].

Another mode of MRI that holds promise for refinement of diagnostics is diffusion tensor imaging (DTI). Predicated on the assumption that water molecules most likely diffuse along the trajectory of axons within the white matter, DTI can measure this water diffusion and, by employing certain algorithms, can approximate the position and direction of the major white matter tracts in the cerebrum. This approach should refine the imaging results for mental retardation or autism in which no changes can be identified by conventional MRI [Barnea-Goraly et al., 2004].

Proteomics in Disease Analysis

Practical and theoretical concerns limit exclusive reliance on genetic information to understand the causes of mental retardation (even including only those that are genetically based). Proteomics potentially offers a rapid means to screen individuals for many specific diseases within a general category, particularly when the proteins are expressed in the blood or other tissue that is readily available for analysis. For example, the true prevalence of mitochondrial dysfunction as a cause of mental retardation is unknown, but some studies suggest that mitochondrial abnormalities can be detected in a high percentage of patients with developmental delay, seizures, and hypotonia [Fillano et al., 2002; Marin-Garcia et al., 1999]. Mitochondrial genetics are too complex to be approached directly, because most patients are thought to have autosomal-recessive mitochondrial disease, and hundreds of genes are necessary for proper mitochondrial function. In cases of maternal inheritance, this problem can be addressed by full sequencing of the mitochondrial genome in muscle samples of affected individuals. Given that the mitochondrial genome contains only 16,500 base pairs (bp), this is a feasible goal in the short term. Investigators have begun to undertake whole mitochondrial proteomics approaches (i.e., combining immunocapture with mass spectrometry peptide fingerprinting) to determine the quantitative values for the specific polypeptides in these multiprotein complexes [Lib et al., 2003]. Missing subunits can be readily identified, and the post-translational modifications (e.g., phosphorylation) can be monitored [Schulenberg et al., 2004].

General Considerations

The known specific causes of mental retardation are too numerous to be listed here. The term mental retardation returns more than 1200 entries in the Online Mendelian Inheritance in Man site alone, and this catalogs only identifiable genetic causes. Mental retardation usually is classified by prenatal, perinatal, postnatal, and undetermined causes (Table 43-3). In most studies, the largest category of known primary causes is genetic or chromosomal [Leonard and Wen, 2002]. Many of the environmental causes, such as low birth weight and prematurity, are measured as risk factors and do not rise to the level of actual biomedical causes. Just as the prevalence varies, the percentage of mental retardation resulting from each group of causes varies by location and by definitions. In a California epidemiologic study of mental retardation, 75 percent of the known cases of mental retardation were due to chromosomal aberrations, whereas fewer than 3 percent were caused by any endocrine or metabolic abnormality [Croen et al., 2001]. In a Taiwanese study, 82 percent of all the chromosomal causes of mental retardation were a result of Down syndrome, but these data were collected before the clinical use of subtelomeric fluorescent in situ hybridization (FISH) probes [Hou et al., 1998]. In some regions of the world, cretinism from severe iodine deficiency occurs in up to 2–10 percent of the population of isolated communities [Delange et al., 2001]. Mild mental impairment from iodine deficiency occurs five times more frequently than cretinism, making iodine deficiency the most common preventable cause of mental retardation. Treatment during the first trimester has a significant effect on the frequency of cretinism [Cao et al., 1994]. In regions of mainland China with iodine deficiency, children score on average 10 IQ points less than cohorts in iodine-rich regions. This link between iodine deficiency and mental retardation also has a strong genetic component, because specific alleles for the deiodinase type II gene and the ApoE4 allele confer a significantly greater risk of mental retardation when the pregnant mother is iodine-deficient [Guo et al., 2004; Wang et al., 2000]. Despite the tremendous wealth of information about the causes of mental retardation, the cause remains unknown in most individuals. Genetic and epidemiologic approaches likely will continue to make progress toward unraveling and treating these currently unelucidated causes.

Table 43-3 Categories and Causes of Mental Retardation

Fragile X Syndrome

The fragile X syndrome, caused by inactivation of the FMR1 gene, has an estimated prevalence of 1 in 3000 males and is one of the most common causes of mental retardation [Crawford et al., 2001]. Expansion of the trinucleotide sequence CGG to more than 200 copies results in CpG methylation and inactivation of the FMR1 gene. Patients have narrow and elongated faces, large protruding ears, macro-orchidism, and joint hyperlaxity. Up to 20 percent have epilepsy, and most have complex partial seizures [Willemsen et al., 2004]. Carrier females and males with somatic mutations have various levels of intellectual impairment; studies demonstrate that the amount of the residual FMR protein detected in hair roots correlates well with IQ [Willemsen et al., 2003]. Research on the FMR protein has shown that it participates in the transport of mRNA and the regulation of protein translation in neuronal dendrites [Zalfa et al., 2003]. This function perhaps explains the paucity of dendrites seen in autopsy series of these patients [Greenough et al., 2001]. Although previous studies suggested that premutation male carriers (55–200 repeats) were asymptomatic, later work from Hagerman and colleagues [1988] documented a progressive neurologic disorder, the fragile X-associated tremor/ataxia syndrome (FXTAS). After the age of 50, male patients present with intention tremor and cerebellar ataxia, and they may have cognitive decline [Jacquemont et al., 2004]. This syndrome, which is unique to these premutation males, may result from an increase in expanded repeat FMR1 mRNA that is consistent with a toxic “gain of function” mechanism [Hagerman and Hagerman, 2004]. Because the level of FMR protein correlates with disease severity, a number of investigators have tried to identify demethylating or hyperacetylating drugs as a means to activate FMR1 transcription [Chiurazzi et al., 1998, 1999]. Although these methods do not offer treatment for patients, this approach is generating new agents that can be tested for their ability to activate FMR1 without associated toxicity.

Other X-Linked Mental Retardation Conditions

The increased prevalence of mental retardation in males and the relative ease of detecting the familial transmission of X-chromosome mutations have facilitated the effort to uncover the genes on the X chromosome that cause mental retardation. Many excellent reviews have detailed the syndromic and nonsyndromic forms of X-linked mental retardation [Chelly and Mandel, 2001; Gecz, 2004]. Since 1996, more than 15 genes have been identified as causes of nonsyndromic mental retardation without other associated organ involvement or significant dysmorphology (Table 43-4).

An initial assumption had been that these genes would work directly at the level of the synapse. In certain cases, in vitro and animal model data confirm this idea. For example, the protein neuroligin on the postsynaptic membrane, and its binding partner neurexin on the presynaptic side, have been shown to promote synapse formation in vitro [Dean et al., 2003; Scheiffele et al., 2000]. Some reports have shown that two X-linked neuroligin genes (NLGN3 and NLGN4) are implicated in mental retardation and autism [Jamain et al., 2003; Laumonnier et al., 2004]. Similarly, multiple genes that participate in signaling through the small G protein RHO are mutated in many cases of X-linked mental retardation: GDI1, PAK3, OPHN1, and ARHGEF6 [Ramakers, 2002]. In a mouse gene deletion of oligophrenin (OPHN1), there were clear deficits in the formation of spines along dendrites, the critical subcellular structure on which central nervous system excitatory synapses form [Govek et al., 2004]. However, involvement in synapse formation does not preclude possibly important roles more generally in organ and body development. For example, further analysis showed that mutations in oligophrenin are also found in patients with epilepsy, profound cerebellar hypoplasia, and cerebral cortical atrophy [Bergmann et al., 2003; Philip et al., 2003]. The genes ARX and MECP2 can cause syndromic mental retardation (as in patients with X-linked lissencephaly with ambiguous genitalia [XLAG] and Rett’s syndrome) and nonsyndromic mental retardation, depending on the severity of the mutation [Gomot et al., 2003; Sherr, 2003]. These observations demonstrate the complexity of understanding how genetic alteration causes mental retardation, what form it takes, and how genotype may correlate with phenotype.

Nonsyndromic Autosomal Mental Retardation

The inheritance pattern of X-linked diseases accelerates the discovery of genes. However, because nonsyndromic mental retardation is not clinically unique, it is difficult to link families together by common features to find causative genes. In the only autosomal-recessive mental retardation gene identified, a single 4-bp deletion was found in the synapse-localized serine protease neurotrypsin [Molinari et al., 2002]. Although this same 4-bp deletion was identified in another proband with mental retardation, no confirmatory mutations were identified. Investigators have used an inclusive approach, sequencing candidate genes in many dozens of mental retardation families that link to the X chromosome. Looking for additional autosomal-recessive mental retardation genes by this approach will increase the complexity more than 20-fold.

History

The assessment of a child with suspected global developmental delay or intellectual disability begins with a detailed history, and much time and effort should be directed to this evaluation [Shevell, 1998, 2002, 2006, 2009c]. Fundamental to this process is obtaining a careful family history, searching for other affected family members with similar or other potentially relevant neurologic impairments. The possible presence of early postnatal deaths should be questioned. Parental or intrafamilial consanguinity needs to be ascertained, along with the ethnic heritage of the parents. Clues to consanguinity (which may not be willingly acknowledged by parents) include origin from the same village or sharing of the same last name within the family tree. The mother’s prior gestational history and her pregnancy with the affected child must be carefully probed, seeking evidence for adverse events or toxin exposures and clues to intrauterine difficulties. Timing and mode of delivery should be determined, and the reason for any forceps application or cesarean section must be identified. Birth weight, Apgar scores, head circumference measurement at birth, and duration of postnatal hospital stay are important objective markers of newborn health status. Difficulties in the newborn nursery, especially pertaining to possible clues for a neonatal encephalopathy (e.g., seizures, feeding difficulties prompting gavage), must be searched for and carefully documented. Box 43-1 lists commonly accepted risk factors for later developmental disability that can be apparent on maternal, gestational, or neonatal history-taking.

Box 43-1 Factors that Increase the Risk of Neonatal Mortality and Mental Retardation

Maternal Factors

Complications of pregnancy

Perinatal factors

Neonatal factors

Age younger than 16 or older than 40 years (over 35 years for a primigravida)

Cervical abnormalities (e.g., incompetence, tumor)

Consanguinity

Contracted pelvis

Women statistically at higher risk: unmarried, short, thin, malnourished, uneducated, nonwhite, low-income

Other diseases and disorders

Bacteriuria

Diabetes mellitus

Drug addiction

Malnutrition

Nephritis

Phlebitis

Proteinuria

Renal hypertension

Thyroid disease

History of abortion, stillbirth, neonatal death, live or stillborn infants weighing less than 1500 g, abruptio placentae, circumvallate placenta

Hemorrhagic shock

Polyhydramnios

Vaginal bleeding in the second or third trimester

Cesarean section after trial of labor

Conditions at Birth

Cyanosis

Need for resuscitation

Poor Apgar score

Presence of respiratory distress

Gestational age of less than 30 weeks

Hypoxic-ischemic encephalopathy

Intrauterine hypoxia associated with prolapsed umbilical cord, abruptio placentae, or toxemia of pregnancy

Midforceps delivery or breech presentation

Abnormal sucking, feeding, or crying

Anomalies

Asymmetry of face and extremities

Hyperbilirubinemia

Hypotonia

Injuries

Need for an incubator or oxygen

Poor weight gain or malnutrition

Seizures

Vomiting and fever

(Data from Denhoff E. Cerebral palsy, the preschool years. Springfield, IL: Charles C Thomas, 1967; from Pearson PH. The physician’s role in diagnosis and management of the mentally retarded. Pediatr Clin North Am 1968;15:835.)

The domain of first concern is the age at which this concern became manifested to the parents; it should be documented. The timing of developmental milestones across developmental domains should be determined for the affected child. Observant parents can usually and reliably recall motor skills in the first year of life, such as when their child rolled over, sat, crawled, cruised, and took the first steps. Parental recall of meaningful speech and language milestones is often not as certain [Majnemer and Rosenblatt, 1994]. The possibility of any loss or regression of previously acquired developmental skills should be specifically questioned, as this would mandate a different and more urgent approach to etiologic evaluation and follow-up. Current skill level in the various developmental domains and the degree of independence in activities of daily living must be ascertained. For the school-age child, important points include scholastic history, with special reference to actual school and classroom placement, and identification of the provision of any supplemental educational resources.

Coexisting medical problems, with particular reference to possible seizure disorders or feeding difficulties, should be questioned. Sleeping and problematic behaviors (e.g., aggressive, inappropriate, or self-injurious) may be particular concerns of the parents and are often under-appreciated by health professionals. The past medical history, including possible chronic medical conditions, prior hospital admissions, or surgical procedures, should be documented. Past and current medications prescribed, their indications, and their effects (beneficial or deleterious) must be assessed. The current social situation of the child and family must be carefully probed with reference to items such as socioeconomic status, parental educational attainment, marital status and home living arrangements, child custody, and existing support services. The examiner must determine whether the patient has access to appropriate rehabilitation services (e.g., occupational therapy, physiotherapy, speech therapy, special education, psychology), and whether previous relevant evaluations or laboratory investigations have been conducted.

By the end of the history-taking, the clinician should have clear ideas regarding evidence of a static or progressive encephalopathy; an approximate idea of the developmental and functional level of the affected child; the possible timing of an underlying cause; the possibility of an underlying etiologic cause; the social or rehabilitation status of the affected child; and the possibility of associated and relevant medical or behavioral conditions.

Physical Examination

Ideally, the physical examination begins with careful observation of the child as the history is being taken. The delayed child often presents a challenge to the clinician with respect to the formal examination because of inherent features, such as short attention span and limitations in understanding and cooperation. The availability of a play area with appropriate toys, including paper, crayons, dolls, and representational toys, that is amenable to observation by the examiner may allow for a nonintrusive and noninvasive assessment of developmental skills, dexterity, inquisitiveness, behavior, and interaction with the surroundings and others. Much of the neurodevelopmental examination can take place during extended history-taking by observation alone. In the older child, language skills, both spontaneous and responsive, expressive and receptive, should be established, together with an understanding of simple cognitive concepts (i.e., size, shape, analogies, action, commonalities, numbers).

The general physical examination should specifically ascertain possible dysmorphology, hepatosplenomegaly, and cutaneous markers of the phakomatoses. The spine should be carefully inspected, including the sacral region, to look for dermal sinuses, hair tufts, or other subtle signs of spinal dysraphism. Height and weight should be plotted. Genetic catalogs are indispensable for an accurate recognition of specific syndromes.

Current and previous occipitofrontal circumference should be obtained and plotted, with particular attention directed at microcephalic or macrocephalic measurements or changing percentile values over time. In cases of microcephaly or macrocephaly, the parental occipitofrontal circumferences also should be obtained and plotted. The head shape and status of the anterior and posterior fontanels in the infant, together with the sutures, should be observed. Determination of the presence of any focal or asymmetric neurologic findings is the primary objective of the formal neurologic examination. Careful evaluation of vision, in addition to aiding in a definitive diagnostic process, is indicated to minimize the contribution of potentially correctable visual impairment to the burden of disability. Similarly, this approach applies to evaluating for possible gross auditory impairments in the office setting.

Within the clinical office setting, several test instruments exist for use as objective screening assessments of development during the first years of life (i.e., Denver Developmental Screening Test [Frankenburg and Dodds, 1967], the Denver II [Frankenburg et al., 1992], and the CAT/CLAMS [Capute and Accardo, 1991], which focuses on language- and non-language-based reasoning abilities). These may be supplemented or complemented by the use of parent-based questionnaires (e.g., Child Developmental Inventory [Ireton, 1992], and Ages and Stages Questionnaire [Bricker, 1999]) that provide an aspect of objective developmental screening. Observed signs and symptoms and their association with various diagnostic entities that can result in global developmental delay or intellectual disability are summarized in Boxes 43-2 to 43-10. Definitive diagnosis of these associated entities often requires specific laboratory testing.

Box 43-2 Eye Abnormalities

Cataracts

Cerebrotendinous xanthomatosis

Cockayne’s syndrome

Cretinism

Down syndrome

Galactosemia

Lowe’s syndrome

Marinesco–Sjögren syndrome

Myotonic dystrophy

Pseudohypoparathyroidism

Rubella (gestational)

Trichothiodystrophy

Cherry-red spot in macular area

GM₁ gangliosidosis (generalized)

Neuraminidase deficiency

Niemann–Pick disease type A

Tay–Sachs disease

Chorioretinitis

Clouding of cornea

Congenital lues

Cytomegalic inclusion body disease

Hunter’s syndrome

Hurler’s syndrome

Lowe’s syndrome

Prenatal rubella (gestational)

Corneal ulcers

Familial dysautonomia

Dislocated lenses

Homocystinuria

Sulfite oxidase deficiency

Glaucoma

Lowe’s syndrome

Rubinstein–Taybi syndrome

Sturge–Weber syndrome

Nystagmus

Hyperpipecolatemia

Hypervalinemia

Joubert’s syndrome

Photophobia

Cockayne’s syndrome

Hartnup’s disease

Homocystinuria

Retinitis pigmentosa

Ataxia-telangiectasia

Cockayne’s syndrome

Hallervorden–Spatz syndrome

Hyperpipecolatemia

Kearns–Sayre syndrome

Laurence–Moon–Biedl syndrome

Mitochondrial encephalomyopathies

Neuronal ceroid-lipofuscinosis

Scleral telangiectasia

Vertical supranuclear gaze palsy

Niemann–Pick disease type C

Tauopathy dementia (progressive supranuclear palsy)

Box 43-3 Seizures

Generalized tonic-clonic seizures

Argininosuccinic aciduria

Neuronal ceroid-lipofuscinosis

Citrullinemia

Glycogen synthetase deficiency

Hyper-beta-alaninemia

Hyperammonemia

Hyperlysinemia

Hyperornithinemia-hyperammonemia and homocitrullinuria hyperprolinemia I

Hypoglycemia, particularly associated with glycogen storage diseases I, III, IV, and VII, and idiopathic hypoglycemia of infancy

Joseph’s disease

Ketotic hypoglycemia

Kinky hair disease (Menkes’ disease)

Lactic acidosis

Lysine intolerance with periodic ammonia intoxication

Maple syrup urine disease

Methionine malabsorption syndrome

Mitochondrial encephalomyopathies (e.g., MERRF [now MT-TK], MELAS defects)

Nonketotic hyperglycinemia

Phenylketonuria

Severe myoclonic epilepsy of infancy (SCN1A defect)

Tay–Sachs disease

X-linked infantile spasm syndrome (ARX [also called ISSX] mutation)

Seizures in the neonatal period

Argininosuccinic aciduria

Hyperammonemia I and II

Hyperprolinemia I

Hypoglycorrhachia (GLUT1 [now designated SCL2A1] deficiency syndrome)

Hypoxic-ischemic encephalopathy

Isovaleric acidemia

Joseph’s disease

Lactic acidosis

Maple syrup urine disease

Mitochondrial encephalomyopathy

Methylmalonic acidemia

Propionic acidemia

Box 43-4 Skin Abnormalities

Café au lait spots

Ataxia-telangiectasia

Bloom’s syndrome

Neurofibromatosis

Tuberous sclerosis

Depigmented nevi

Tuberous sclerosis

Eczema

Phenylketonuria

Linear nevus

Linear sebaceous nevus of Jadassohn

Malar flush

Homocystinuria

Photosensitivity

Hartnup’s disease

Tryptophanuria

Rash

Biotinidase deficiency

Holocarboxylase synthetase deficiency

Synophrys

Cornelia de Lange syndrome

Cretinism

Box 43-5 Hearing Abnormalities

Conduction deafness

Hunter’s syndrome

Hurler’s syndrome

Hyperacusis

GM₁ gangliosidosis (generalized)

Krabbe’s disease

Subacute sclerosing panencephalitis

Sulfite oxidase deficiency

Tay–Sachs disease

Sensorineural deafness

CHARGE syndrome (i.e., coloboma, heart defects, atresia choanae, retardation of growth and development, genitourinary problems, and ear anomalies) [Menenzes and Coker, 1990]

Kearns–Sayre syndrome

MELAS syndrome (i.e., mitochondrial myopathy, encephalopathy, lactacidosis, and stroke)

MERRF syndrome (i.e., myoclonus epilepsy associated with ragged red fibers)

Refsum’s disease

Box 43-6 Vomiting

Hyperammonemia (all types)

Hyperglycinemia

Hyperlysinemia

Hypervalinemia

Increased intracranial pressure

Lactic acidosis

Maple syrup urine disease

MELAS syndrome (i.e., mitochondrial myopathy, encephalopathy, lactacidosis, and stroke)

Box 43-7 Hair Abnormalities

Fine hair

Homocystinuria

Hypothyroidism

Friable and tufted hair (trichorrhexis nodosa)

Argininosuccinic aciduria

Kinky hair disease (Menkes’ disease)

Loss of scalp hair

Familial lactic acidosis with necrotizing encephalopathy

Premature gray hair

Ataxia-telangiectasia

Progressive cerebral hemisphere atrophy

White hair (patches)

Methionine malabsorption syndrome

Tuberous sclerosis

Box 43-8 Hepatosplenomegaly

Argininosuccinic aciduria

Gaucher’s disease

Glycogen storage disease types I and III

GM1 gangliosidosis (generalized)

Hydroxykynureninuria

Hyperpipecolatemia

Mucopolysaccharidoses

Neuronal ceroid-lipofuscinosis

Niemann–Pick disease

Box 43-9 Metabolic Acidosis

Ketotic hypoglycemia

Lactic acidosis

Maple syrup urine disease

Methionine malabsorption syndrome

Methylmalonic acidemia

Mitochondrial encephalomyopathy

5-Oxoprolinuria (pyroglutamic aciduria)

Propionic acidemia

Box 43-10 Other Abnormalities

Anterior horn cell disease (includes electrodiagnostic evidence of normal nerve conduction time in the presence of muscular denervation potentials)

Neuroaxonal dystrophy

Beta-methyl-crotonyl CoA decarboxylase deficiency

Ataxia (partial representative list)

Argininosuccinic aciduria

Ataxia-telangiectasia

Cockayne’s syndrome

Guanosine triphosphate (GTP) cyclohydrolase deficiency (dopa-responsive dystonia)

Hartnup’s disease

Hyperammonemia from any cause

Joubert’s syndrome

Kearns–Sayre syndrome

l-2-α-hydroxyglutaric aciduria

Marinesco–Sjögren syndrome

Metachromatic leukodystrophy

Mitochondrial disorders

Neuronal ceroid-lipofuscinosis

5-Oxoprolinuria (pyroglutamic aciduria)

Partington’s syndrome (ARX defect)

Pyruvate decarboxylase deficiency

Tryptophanuria

Broad thumbs and toes

Rubinstein–Taybi syndrome [Rubinstein and Taybi, 1963]

Choreoathetosis

Dentatorubral pallidoluysian atrophy

Glutaricaciduria type I

Huntington’s chorea

Joseph’s disease

Lesch–Nyhan disease

Pantothenate kinase-associated neurodegeneration (PKAN)

Phenylketonuria

Dystonia

Alexander’s disease

Canavan’s disease

Enlarged head

GM2 gangliosidosis (generalized)

GTP cyclohydrolase deficiency (dopa-responsive dystonia)

Histiocytosis X

Hydrocephalus

Mitochondrial disorders

Mucopolysaccharidoses

Pelizaeus–Merzbacher disease

PKAN

Sandhoff’s disease

Spongy degeneration

Subdural effusion

Subdural hematoma

Tay–Sachs disease

Wilson’s disease

Fat pad distribution, abnormal

Congenital disorders of glycosylation

Cornelia de Lange syndrome

Micromelia

Odors

Isovaleric acidemia

Maple syrup urine disease

Methionine malabsorption syndrome

Phenylketonuria

Peripheral neuropathy (includes electrodiagnostic evidence of decreased conduction time)

Cockayne’s syndrome

Krabbe’s syndrome

Metachromatic leukodystrophy

Niemann–Pick disease

Short stature

Bird-headed dwarf (Seckel type)

Cockayne’s syndrome

Cornelia de Lange syndrome

Cretinism

Leprechaunism [Dekaban, 1965]

Mucolipidoses

Mucopolysaccharidoses

Prader–Willi syndrome

Rubinstein–Taybi syndrome

Tremor

Citrullinemia

Hartnup’s disease

Hyperpipecolatemia

Hypersarcosinemia

Laboratory Testing

Laboratory testing is directed at establishing the possible cause of the individual’s delay or intellectual disability [Schaefer and Bodensteiner, 1992]. This testing may be confirmatory, directed at a suggested cause from the history and/or physical examination, or it may be undertaken on a screening basis, directed at finding a previously unsuspected cause. Some data exist on the diagnostic yield of various laboratory investigations of community-derived samples of children with global developmental delay or mental retardation, with older series restricted to more severe variants of institutionalized individuals [Hagberg and Kyllerman, 1983; Hunter et al., 1980; McLaren and Bryson, 1987], and more recent series derived from ambulatory community settings [Srour et al., 2006]. Controversy exists regarding the extent to which diagnostic investigations should be undertaken for a developmentally delayed or cognitively disabled child. However, consensus does exist that an all-inclusive “shotgun” approach is not warranted or feasible from medical, personal, or economic viewpoints [Shevell et al., 2003]. Laboratory testing is undertaken in the spirit that, although yield may be lower than in other clinical situations, the potential value of a definitive etiologic diagnosis from individual and familial perspectives may be substantial. Technologic advances, especially in the domains of genetic testing and neuroimaging, have resulted in improved diagnostic yield and precision. This is reflected in improved etiologic yield in community samples studied retrospectively and prospectively [Majnemer and Shevell, 1995; Shevell et al., 2000; Srour et al., 2006]. Aiding the formulation of a rational approach to laboratory investigations in this clinical population is the AAN practice parameter evidence report (see Figure 43-1) [Shevell et al., 2003; Michelson et al., 2011], the American College of Medical Genetics consensus [Curry et al., 1997], and the AAP technical document [Moeschler and Shevell, 2006] on this topic.

Routine metabolic testing for an extensive list of potential inborn errors of metabolism cannot presently be justified [Carson and Neill, 1962; Henderson et al., 1981; Reinecke et al., 1983]. However, diagnostic vigilance needs to be maintained for these disorders, given the implication for treatment, prognosis, and recurrent risk [Papavasiliou et al., 2000]. Clinical situations suggesting a possible inborn error of metabolism that should prompt careful and detailed metabolic testing include family history, parental consanguinity, documented developmental regression, suggestive dysmorphology, involvement of nonectodermal organ systems, and possible white matter involvement observed on imaging or peripheral electrophysiologic studies.

For the globally or intellectually delayed child without an apparent cause after history and physical examination, current recommendations would include beginning with microarray testing, followed, if clinically indicated, by a karyotype and high-resolution MRI [Miller et al., 2010; Michelson et al., 2011]. As mentioned above, if specific causes are considered, they should be tested for early on in the diagnostic evaluation. For instance, if the affected child is a male and his maternal uncles are similarly affected, there is good evidence to suggest that sequencing X chromosome mental retardation genes would be a high-yield diagnostic approach [Michelson et al., 2011].

Neuroimaging has greatly enhanced the clinical practice of neurology and improved etiologic yields. Although largely of little additional value in early reported studies [Lingham et al., 1982; Moeschler et al., 1981], later studies have indeed emphasized the added value of neuroimaging in detecting cerebral dysgenesis, acquired injury of various causes, or disturbances in white matter maturation [Bouhadiba et al., 2000; VanBogaert et al., 1992]. The superiority of MRI over computed tomography (CT) has made it the imaging modality of choice contingent on local availability and individual sedation restrictions.

Similar to metabolic studies, electrophysiologic studies, such as electroencephalography, should be undertaken only in the situation of a suspected coexisting paroxysmal disorder or evidence of language regression or behavioral abnormalities suggestive of an epilepsy syndrome, such as Landau–Kleffner or electrical status epilepticus during slow-wave sleep [Sheth, 1998]. Visual- and auditory-evoked potentials are of use in assessing the integrity of the visual and auditory systems in the young, uncooperative child.

The presence of certain clinical features predicts the success or failure of the etiologic search. Documented neonatal difficulties, microcephaly, focal neurologic findings, and positive family history all suggest an enhanced possibility of success. Coexisting autistic features have been found to be a negative predictor of detecting an underlying cause [Shevell et al., 2000; Srour et al., 2006].

Consultation and Follow-up

Concerns about the developmental and functional patterns highlighted at the time of specialty evaluation should prompt referrals to other health professionals with different but complementary expertise, permitting a multidisciplinary, comprehensive evaluation of the affected child [Shevell, 2002, 2006, 2009c]. These professionals, in addition to documenting various deficits objectively in a standardized way, usually assume responsibility for implementing goal-directed therapeutic interventions, and serve as conduits to appropriate community-based, long-term rehabilitation and educational resources. These health professionals represent occupational therapy (e.g., fine motor, activities of daily living, feeding), physical therapy (i.e., gross motor), speech and language pathology (i.e., language), and psychology (e.g., cognition, social, behavioral). Specific care needs, such as tube feeding, respite care, or financial difficulties, may prompt nursing or social service intervention. Vision and hearing screening is important because of the high frequency of potentially correctable primary sensory impairments in this population, and results should prompt ophthalmologic and audiologic evaluations [Kwok et al., 1996; Menacker, 1993; Warburg, 1994]. Concerns regarding a possible genetic cause or specific behavioral issues may require the expertise and intervention of genetic or psychiatric services.

A key part of the evaluation of the delayed or intellectually disabled individual is a second visit. This second visit is needed to review the results of laboratory investigations, integrate the reports of the various health professionals consulted, characterize the type and level of developmental disability, ascertain the provision of rehabilitation or relevant educational services, counsel the family appropriately, and by ascertaining developmental progress, exclude the possibility of a progressive encephalopathy or neurodegenerative process. Frequently, the opportunity exists to reconsider and refine the diagnostic evaluation over a longer interval because the child neurologist frequently participates directly in the on-going care of the child with developmental delay or intellectual disability who has coexisting and often challenging conditions requiring continuing medical management.

Psychiatric Disorders in the Mentally Retarded

The prevalence of coexistent Axis I psychiatric conditions and challenging, disruptive, or injurious (towards self or others) behaviors is higher among patients with intellectual disability than among people in the general population [Marco, 2009]. These conditions are generally under-recognized and undertreated. Under-recognition is the byproduct of several factors:

Diagnosis of challenging behavior and mental illness in those with developmental delays or intellectual disabilities requires modification in recognition that both takes into account developmental and cognitive abilities, and focuses on behavioral domains and standards for inferential diagnosis in the absence of objective markers. Multiple screening tools have been developed to assist in recognition. These include the Developmental Behavioral Checklist for Pediatrics (DBC-P) [Clarke et al., 2003], the Children’s Depression Inventory [Meins, 1993], and the Psychiatric Assessment Schedule for Adults with Developmental Disability Checklist (PAS-ADD checklist) [Mohr et al., 2005], amongst other instruments.

In one population-based study, 40 percent of mental retardation patients had a Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) diagnosis, one-fourth of this group had more than one diagnosis, and these disorders caused severe impairment in everyday functioning for more than one-half of patients. Of these mental retardation patients, 22 percent had anxiety disorders, 5 percent had mood disorders, and 25 percent had disruptive disorders. The most common diagnoses were specific phobias (17.5 percent), attention-deficit hyperactivity disorder (14.8 percent), and oppositional defiant disorder (13.9 percent). However, of all the children with a DSM-IV diagnosis, only 27 percent were receiving specific help for any of these problems [Dekker and Koot, 2003]. For those whose diagnoses caused severe impairment, only 41 percent received professional help. As is the case for the diagnosis of mental illness in children generally, eliciting a careful history from the parents or caretakers is essential to the accurate diagnosis and to the evaluation of treatment efficacy. Based on reasonable clinical inference, some modifications in specific diagnostic criteria are occasionally necessary.

Treatment of Psychiatric Disorders

Several studies support medical therapies for the treatment of psychiatric conditions in the intellectually disabled population. The newer neuroleptics (especially risperidone) have been effective for behavioral disorders, particularly aggression and impulsivity, in patients with mental retardation or autism, or both [Snyder et al., 2002]. However, side effects can include intolerable weight gain, particularly at higher doses [Cohen et al., 2001]. Other atypical antipsychotic agents, such as quetiapine and aripiprazole, have less effect on weight and may be effective for aggressive and aberrant behavior [Sajatovic, 2003; Stigler et al., 2004]. Clonidine has been effective for hyperactivity, hypersensitivity, and the less aggressive impulsive behaviors [Agarwal et al., 2001]. Methylphenidate is now available in varied long-acting formulations and has been effective for many patients with mental retardation [Aman et al., 2003; Pearson et al., 2004a, 2004b]; it is the most common class of medications used for fragile X syndrome males, in whom up to 67 percent showed a positive response in a controlled study [Hagerman et al., 1988]. Anxiety and compulsive and perseverative behaviors and mood symptoms can be managed with selective serotonin reuptake inhibitors (SSRIs). In particular, SSRIs have been shown to be helpful for the treatment of social anxiety and withdrawal [Santosh and Baird, 1999]. Chapter 49 reviews the psychopharmacologic agents that can be used for the treatment of some of these disorders.

Treatment of Epilepsy

Approximately 15–20 percent of intellectually disabled individuals also have epilepsy, a rate 10 times higher than the general population [Kelly et al., 2004; Mayville and Matson, 2004]. Many of these patients have intractable epilepsy. When treating seizures in these individuals, the same guidelines apply as for patients without intellectual disability: minimize side effects (i.e., sedation, altered mentation, behavioral changes) while eliminating or substantially reducing the number of seizures. Since many individuals with intellectual limitations will be unable to express their response to the medication verbally, the physician must be alert to other means of assessing side effects and seizure reduction. In the case of young children living at home, their parents or other primary caretakers can provide reasonable estimates of these parameters. In the case of multiple caretakers or of patients residing in assisted living environments, special care must be taken to ensure the accuracy and reliability of reporting between different observers. Clarification of which seizure types to record and maintaining a seizure diary before alteration of the medication regimen can help achieve this goal. In some instances, use of standardized instruments, such as the Glasgow epilepsy outcome measure, may be helpful [Espie et al., 2001]. Drug treatment should be guided primarily by the type of epilepsy. Patients with Lennox–Gastaut syndrome have responded well to lamotrigine, infantile spasms to vigabatrin, and nonsyndromic generalized seizures to valproic acid. In general, avoidance of barbiturates and benzodiazepines is preferable because of the propensity for sedation and impairment of cognition [Coulter, 1997]. Polypharmacy, with its cumulative and synergistic potential for side effects, should also be avoided whenever possible [Marco, 2009]. Intractable epilepsies may respond to the ketogenic diet, placement of a vagal nerve stimulator, or, especially if lesional in origin, surgical resection. Callosotomy is still rarely utilized for intractable atonic seizures.

Sleep Disorders

The most common sleep problem in the general population and among the developmentally impaired is insufficient sleep [Didde and Sigafoos, 2001]. Preadolescents sleep 9–10 hours per night, with sleep latencies of 20 minutes or more. Seizures during sleep are a frequent cause of sleep disruption. For generalized seizure disorders, one study determined that 34 percent of seizures occurred upon arousal to the waking state, 45 percent occurred only in sleep, and 21 percent occurred both diurnally and nocturnally [Marco, 2009]. Specific sleep epilepsy disorders, such as electrical status epilepticus of sleep, Landau–Kleffner syndrome, and nocturnal frontal lobe epilepsy, should be considered [Lancioni et al., 1999]. Many patients with intellectual disability also have hypotonia or extensive central nervous system abnormalities, or both, and central and obstructive sleep apnea is a common complication. Obstruction can occur at the pharyngeal level because of corticobulbar and bulbar weakness, or because of the inability of the muscles of respiration to overcome the normal change in airway resistance produced by progression from waking to non-rapid eye movement sleep to rapid eye movement sleep. This problem is exacerbated by the loss of muscle tone seen in rapid eye movement sleep. Since the circadian clock within the suprachiasmatic nucleus is chronobiologic and requires light input from the retina to entrain a rhythm, patients who are blind or who have had profound brain injury may suffer from disorganized sleep architecture.

In patients with a sleep problem, obtaining an accurate sleep history that includes sleep hygiene, nighttime awakenings, and daytime behavior is essential. If this approach is not informative, a formal sleep study with polysomnography may be indicated [Harvey and Kennedy, 2002]. Melatonin has been particularly useful for this population and has been effective for patients with global developmental delay and sleep disturbance in general [Coppola et al., 2004].

Vision and Hearing Impairment

Individuals with global developmental delay and intellectual disability are at an elevated risk for sensory impairment involving either hearing, vision, or both [MMWR, 1997]. These impairments may be congenital or acquired in origin, but often remains undiagnosed and untreated. This is indeed unfortunate, as early identification and treatment of these sensory impairments can improve overall outcome for these individuals [Yoshinaga-Itano, 2003]. Vigilant and early hearing and vision screening in this population should be a standard of clinical practice.

Feeding and Nutritional Disorders

Difficulties with nutritional intake, gut motility, and growth (i.e., failure to thrive) are common in individuals with global developmental delay and intellectual disability [Canadian Pediatric Society, 1994]. Oral motor incoordination and apraxia are frequent consequences of the underlying primary neurologic dysfunction. Altered esophageal sphincter tone, combined with oral motor incoordination, predisposes to gastro-esophageal reflux and frequent aspirations. Furthermore, the gastro-esophageal reflux may lead to pain and irritability that provoke additional management challenges. Swallowing studies employing video fluoroscopy are an indispensable tool for assessing upper gastrointestinal function. Both medical and behavioral interventions are available to improve feeding competency and comfort, but at times, the placement of a percutaneous feeding tube may be necessary if recurrent pain, aspiration, and malnutrition that limits functional status persists [Marco, 2009]. Enteric feeding may substantially improve quality of life for the affected individual and appreciably diminish the burdens of care upon the family [Sanders et al., 1990].

Pharmacologic Treatment of Cognitive Impairment

Pharmacologic treatment of cognitive impairment is a prominent goal of clinicians and researchers. There are tantalizing studies in animal models and some preliminary data from studies of patients. Unfortunately, there is not yet solid evidence supporting a role for pharmacologic enhancement of cognition in the mental retardation population as a whole. The animal model for the Rubinstein–Taybi syndrome exemplifies the potential of this approach [Bourtchouladze et al., 2003]. Rubinstein–Taybi syndrome, which manifests with mental retardation and characteristic physical findings (i.e., broad thumbs and toes, short stature, and craniofacial anomalies), occurs in approximately 1 in 125,000 births and is caused by mutations in the cAMP-responsive element binding protein (CREB)-binding protein (CBP). Many patients with Rubinstein–Taybi syndrome are heterozygous for de novo CBP truncation mutations or deletions involving the gene, implying that the phenotype is expressed in an autosomal-dominant fashion. Analogously, CBP heterozygous knockout (+/−) mice share features with Rubinstein–Taybi syndrome patients, whereas the CBP homozygous knockout (−/−) pattern in mice is embryonically lethal. In one study, treatment with inhibitors of phosphodiesterase-4 resulted in an improvement in cognitive performance for the CBP +/− mice [Bourtchouladze et al., 2003]. A similar improvement in cognition was demonstrated in the mouse model of neurofibromatosis type 1. Neurofibromatosis type 1 results from an autosomal-dominant heterozygous mutation in neurofibromin [Costa and Silva, 2002]. Additional experimental data suggest that overactivation of the small GTP protein RAS by the mutant neurofibromin is the cause of cognitive dysfunction. Inhibition of RAS through pharmacologic manipulation (i.e., farnesyl transferase inhibitors) or by genetic modification increases cognitive performance in neurofibromatosis type 1 mice and improves physiologic correlates for learning [Costa et al., 2002], such as long-term potentiation.

Successful changes in cognitive function in patients have been much more limited, and most reports are uncontrolled and anecdotal. One open-label study with these methodologic limitations suggested that donepezil (a cholinesterase inhibitor) improved language performance in patients with Down syndrome [Heller et al., 2003].