12 Intellectual disability12.3 Aetiology
12.3 Aetiology of intellectual disability
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Written by Resident Doctor Committee · Published
Grouping causes by timing
Causes are grouped by when the causative event acts.
Timing | Share of cases | Examples |
|---|---|---|
Prenatal | 50 to 70% | Chromosomal and single-gene disorders, congenital rubella or cytomegalovirus, alcohol or some antiseizure medicines |
Perinatal | 10 to 20% | Severe hypoxic-ischaemic injury |
Postnatal | 5 to 10% | Childhood central nervous system infection, head injury including inflicted injury, hypoxic injury, tumour, toxin, deprivation |
A cause counts as postnatal only if it acts after the neonatal period.
Grouping causes by aetiology
Aetiological group | Share of cases |
|---|---|
Heredity | About 5% |
Early embryonic alterations: sporadic chromosomal errors, prenatal toxins and infections | About 30% |
Pregnancy and perinatal problems | About 10% |
Acquired medical conditions | About 5% |
Environmental influences and other mental disorders | 15 to 20% |
No clear cause | 30 to 40% |
Subcultural and biological intellectual disability
In subcultural (familial) intellectual disability, first-degree relatives tend to have intelligence in the borderline range.
In biological (organic) intellectual disability, first-degree relatives usually have average intelligence.
Genetic mechanisms
Mechanism | What happens | Examples |
|---|---|---|
Deletion or microdeletion | A segment of a chromosome is lost | Williams, Wolf-Hirschhorn, cri du chat, 22q11.2 deletion, most Angelman |
Aneuploidy | Nondisjunction adds or removes a whole chromosome, a numerical change | Free trisomy 21, Klinefelter, Turner |
Repeat expansion | A repeated sequence of bases lengthens | Fragile X |
De novo point mutation | A new single-gene mutation arises in the child | Sporadic single-gene disorders |
Chromosomal syndromes
Sex chromosome aneuploidy
Turner syndrome (45,X) is the sex chromosome monosomy; the other sex chromosome aneuploidies are polysomies.
Klinefelter syndrome (47,XXY) arises sporadically from nondisjunction of the sex chromosomes in one gamete, a chance error, not Mendelian inheritance.
Deletion syndromes
Syndrome | Deletion | Features |
|---|---|---|
Williams | Microdeletion at 7q11.23 removing the elastin gene | Supravalvular aortic stenosis, infantile hypercalcaemia, overfriendly manner, visuospatial skills lagging behind language |
Wolf-Hirschhorn | 4p16.3, the tip of the short arm of chromosome 4 | Helmet-like facial profile, seizures, growth failure, severe intellectual disability |
Cri du chat | Short arm of chromosome 5, critical region 5p15 | Cry striking in the newborn that fades with age, microcephaly, often severe intellectual disability |
22q11.2 deletion | 22q11.2 | Cardiac, palatal, immune and developmental difficulties; psychosis in about a quarter of adults studied |
Imprinting: Prader-Willi and Angelman
Genomic imprinting means a gene's expression depends on which parent it came from.
Prader-Willi syndrome follows loss of the 15q11-q13 genes expressed only from the paternal chromosome, through paternal deletion, maternal uniparental disomy or an imprinting defect.
Angelman syndrome most often follows deletion of the maternally derived 15q11-q13, because neurons express only the maternal UBE3A copy.
Down syndrome
Down syndrome results from extra chromosome 21 material, and free trisomy 21 is the most common chromosomal cause of intellectual disability.
Form | Share | Mechanism | Recurrence | Cognition |
|---|---|---|---|---|
Free trisomy 21 | About 95% | Meiotic nondisjunction, usually maternal | Sporadic | Full chromosome 21 dose in every cell |
Robertsonian translocation | About 4% | Most often 14;21; inherited or new | Highest; the only heritable form | Unbalanced translocation gives the full dose in every cell |
Mosaicism | About 2% | Mixed normal and trisomic cell lines | Sporadic | Mildest when trisomic cells are few, as dosage is diluted |
Translocation is inherited through a clinically normal balanced Robertsonian carrier parent of either sex.
With a 14;21 carrier, recurrence is about 10 to 15% if the mother carries it and 2 to 5% if the father does.
Maternal age raises the risk of a Down syndrome birth steeply: about 1 in 350 at 35, 1 in 100 at 40 and 1 in 30 at 45.
Fragile X syndrome
Fragile X syndrome is the commonest inherited cause of intellectual disability; Down syndrome is the commonest genetic cause overall but is mostly sporadic.
The CGG repeat expansion lies in FMR1 at a fragile site on the X chromosome (Xq27.3), not on the Y.
Category | CGG repeats | Significance |
|---|---|---|
Normal | Up to 44 | Usually stable |
Intermediate (grey zone) | 45 to 54 | Some instability, not a full mutation |
Premutation | 55 to 200 | Can expand to a full mutation when passed on by the mother |
Full mutation | Over 200 | Methylation silences FMR1, causing fragile X syndrome |
Larger, methylated expansions cut production of the FMR1 protein (FMRP) and lower intelligence quotient, so cognitive outcome follows the amount of FMRP made.
Affected females are usually milder and more variable than males, because random X-inactivation leaves some cells making FMRP from the normal X.
Fragile X syndrome is classically described as X-linked dominant with reduced penetrance, so an affected man has only affected daughters and unaffected sons.
A man with a premutation passes it to all his daughters and none of his sons, because daughters receive his X and sons his Y.
Premutation carriers risk fragile X-associated tremor/ataxia syndrome later in life, mainly men, and about one fifth of female carriers develop primary ovarian insufficiency.
Other single-gene disorders
Disorder | Inheritance |
|---|---|
Phenylketonuria | Autosomal recessive |
Tuberous sclerosis | Autosomal dominant |
Hurler and Sanfilippo syndromes | Autosomal recessive |
Hunter syndrome (mucopolysaccharidosis type II) | X-linked recessive |
In untreated phenylketonuria, phenylalanine accumulates and causes severe impairment; newborn screening and early sustained treatment greatly improve outcome.
Lesch-Nyhan syndrome is X-linked deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase, caused by mutation of its gene, HPRT1.
It presents in a boy with severe self-injury by lip and finger biting, intellectual disability, microcephaly, dystonia and urate overproduction.
Prenatal alcohol exposure
Prenatal alcohol exposure is the most common acquired, preventable cause of intellectual disability in the UK; no safe threshold is known, and UK advice is to avoid alcohol in pregnancy.
Fetal alcohol syndrome combines characteristic facial features, growth restriction and central nervous system impairment, but many people on the wider spectrum lack the full facial pattern.
Its core neurodevelopmental feature is lasting, non-progressive intellectual impairment; seizures occur in a minority.
Early deprivation
The English and Romanian Adoptees study linked longer severe early deprivation with persistent developmental and social difficulties, and earlier adoption with better recovery, but set no fixed six-month cut-off.