Prenatal conditions (genetic)
Trisomy 21 or Down syndrome
-
This disorder accounts for 25–50% of persons with severe intellectual disability (ID); Down syndrome occurs in approximately 1 per 600–800 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 approximately 40%. 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 25 to 50. Generally, verbal-linguistic skills lag behind visual-spatial skills and social performance is usually above the mental age.
-
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 ID.
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 intellectual disability.
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 ID.
Fragile X syndrome
The population prevalence of this disorder is approximately 1 in 3500 males, giving a prevalence within the ID population of about 1 in 76. For males with severe ID, the prevalence rises to about 1 in 13. Other studies have found in populations of those with ID-positive fragile X studies in 5.9% of males and 0.3% of females. [13] About 1 in 2000 females carries the fragile X (FraX) gene. Current studies suggest that FraX is the most prevalent form of inherited ID.
Males with the full FMR1 trinucleotide repeat expansion (ie, the full mutation) usually function in the moderate to severe range of ID. [14] 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 ID.
Mitral valve prolapse and seizures may occur.
Up to 20% of FraX males meet criteria for autism; autistic-like 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 by methylation studies.
Angelman syndrome
-
The Angelman syndrome (AS) also involves deletion at 15q11-q13 (deletion of the maternal copy of the gene region).
-
ID, 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 methylation 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.
-
ID, short stature, brachydactyly, minor skeletal and facial anomalies, sleep disturbance, self-injurious behaviors, and other organ system malformations characterize this contiguous gene deletion syndrome. [15]
-
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 ID and comorbid psychiatric disorders including schizophrenia and mood disorders with psychosis.
Williams syndrome
-
The Williams syndrome involves deletion at 7q11. [16]
-
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 ID, 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 ID 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 ID. 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.
-
ID 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 ID.
-
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.
-
Behavioral aspects include variable degrees of impulsivity, distractibility, instability of mood, and stereotypies. [17]
-
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. The syndrome results from mutations in the RSK2 gene, which encodes a CREB kinase (Xp22.2-p22.1). [18]
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). [19]
Smith-Lemli-Opitz syndrome
-
Malformations consistent with holoprosencephaly sequence, syndactyly of toes 2 and 3, micrognathia, cleft palate, and moderate to severe ID 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 "co*cktail" has shown some promise in this syndrome.
Costello syndrome
-
Characteristic clinical features include polyhydramnios, failure to thrive, cardiac anomalies, and tumor predisposition.
-
Mean IQ is in the mild ID range, but the spectrum extends from severe ID to average intelligence. Affected males are lower functioning than females and have significantly more behavioral problems. [20]
-
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. [21]
Many other single-gene disorders are associated with ID with additional phenotypic and behavioral features including such problems as microcephaly, seizures, or short stature, with or without dysmorphic facies.
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. [22] 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 ID 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 ID. 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 ID, 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 ID 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 populations
Trichom*oniasis during pregnancy [23]
Neurodegenerative disorders
