8.3.1 Biological Causes of Intellectual Disability

Biological Causes of Intellectual Disability, Including Genetic and Environmental Effects, and the Clinical Characteristics of Reasonably Common Biological Conditions Associated with Intellectual Disability Such as Down Syndrome, Fragile-X Syndrome and Foetal Alcohol Syndrome

Intellectual disability (ID) is a neurodevelopmental disorder characterized by significant limitations in intellectual functioning and adaptive behaviour. Intellectual disability can arise from a range of genetic and environmental causes, including chromosomal abnormalities, single-gene mutations, and prenatal exposure to teratogens.

In most cases of intellectual disability (ID), a specific cause can be determined, with 80% in severe cases and 50% in mild cases. The categorization of causative factors relies on the timing of the event, with 50-70% due to prenatal factors, 10-20% to perinatal factors, and 5-10% to postnatal factors.

Types of malformation and the timing of the causative event:

Timing (in gestation)	CNS event	Malformation
3–7weeks	Dorsal induction	Anencephaly, encephalocele, meningomyelocele, and other neural tube closure defects
5–6weeks	Ventral induction	Prosencephalies and other facio-telencephalic defects
2–4months	Neuronal proliferation	Microcephaly or macrocephaly
3–5months	Neuronal migration	Gyrus anomalies and heterotopias
6-12 months	Neuronal organization	Myelination. Disturbed connectivity (dendrite/synapse formation). The disturbed proliferation of oligodendrocytes and myelin sheets

Genetic causes:

Several genetic conditions can cause intellectual disability, ranging from chromosomal abnormalities to single-gene mutations. Chromosomal abnormalities occur when there is an abnormal number or structure of chromosomes, leading to impaired development of the brain and other organs. Down Syndrome is a common chromosomal abnormality that arises from the presence of an extra copy of chromosome 21. Individuals with Down Syndrome typically have a cognitive impairment, language delay, and a characteristic facial appearance, among other clinical features (Roizen & Patterson, 2003). Fragile X Syndrome is another genetic disorder that causes intellectual disability. It is caused by a mutation in the FMR1 gene, leading to reduced expression of the Fragile X Mental Retardation Protein (FMRP). This protein is critical for normal brain development, and its absence leads to cognitive impairment, social deficits, and behavioural problems (Hagerman, 2002). Other genetic conditions associated with intellectual disability include Rett Syndrome, Angelman Syndrome, and Prader-Willi Syndrome (Van Buggenhout et al., 2010).

Examples of genetic causes:

• Autosomal chromosome disorders e.g. Down’s syndrome
• Sex chromosome disorders
• Deletions and duplications
• Autosomal dominant and recessive conditions
• X-linked recessive and dominant conditions.
• Presumed polygenic conditions e.g. neural tube defects, pervasive developmental disorders
• Mitochondrial disorders, maternally inherited e.g. myoclonic epilepsy with ragged red fibres (MERRF)

Environmental causes:

Prenatal exposure to teratogens can also cause intellectual disability. Teratogens are substances that can interfere with fetal development, leading to structural and functional abnormalities of the brain and other organs. Fetal Alcohol Syndrome (FAS) is a well-known example of a teratogenic condition that causes intellectual disability. FAS is caused by prenatal exposure to alcohol, which can disrupt the normal development of the brain, leading to cognitive impairment, behavioural problems, and physical abnormalities (Chudley et al., 2005). Other teratogenic substances that can cause intellectual disability include lead, mercury, and certain medications (e.g., valproic acid).

Clinical characteristics of common genetic conditions associated with intellectual disability

Down Syndrome is one of the most common genetic causes of intellectual disability, affecting approximately 1 in 700 live births (Roizen & Patterson, 2003). Individuals with Down Syndrome typically have a cognitive impairment, language delay, and a characteristic facial appearance, among other clinical features. They may also have a range of medical problems, including congenital heart defects, hearing loss, and thyroid dysfunction (Roizen & Patterson, 2003).

Fragile X Syndrome is another genetic disorder associated with intellectual disability, affecting approximately 1 in 4,000 males and 1 in 8,000 females (Hagerman, 2002). Individuals with Fragile X Syndrome typically have a cognitive impairment, social deficits, and behavioural problems, including anxiety and hyperactivity (Hagerman, 2002). They may also have physical features such as long and narrow faces, large ears, and a high-arched palate.

Fetal Alcohol Syndrome is a common teratogenic condition that can cause intellectual disability. The prevalence of FAS is estimated to be between 0.2 and 1.5 cases per 1,000 live births (Chudley et al., 2005). Children with FAS may have cognitive impairment, behavioural problems, and physical abnormalities such as small head size, a smooth philtrum, and a thin upper lip (Chudley et al., 2005).

Condition	Genetic Effects	Environmental Effects	Clinical Characteristics
Down Syndrome	Presence of an extra copy of chromosome 21	None	Cognitive impairment, language delay, characteristic facial appearance (e.g., upward slanting eyes, small ears), congenital heart defects, hearing loss, thyroid dysfunction
Fragile X Syndrome	Mutation in the FMR1 gene, leading to reduced expression of the Fragile X Mental Retardation Protein (FMRP)	None	Cognitive impairment, social deficits, behavioural problems (e.g., anxiety, hyperactivity), physical features (e.g., long and narrow face, large ears, high-arched palate)
Fetal Alcohol Syndrome	N/A	Prenatal exposure to alcohol	Cognitive impairment, behavioural problems (e.g., hyperactivity, impulsivity), physical abnormalities (e.g., small head size, smooth philtrum, thin upper lip), growth deficits, hearing and vision problems, heart defects, kidney and bone problems (depending on the severity of exposure)

Please note that this is a simplified summary table and does not include all possible clinical characteristics or variations within each condition.

Intellectual disability is a complex disorder that can arise from a range of genetic and environmental causes. Down Syndrome, Fragile X Syndrome, and Fetal Alcohol Syndrome are three common conditions associated with intellectual disability that have distinct genetic and environmental etiologies. These conditions are characterized by a range of clinical features, including cognitive impairment, language delay, social deficits, and physical abnormalities. A comprehensive understanding of the biological causes and clinical characteristics of these conditions is critical for the accurate diagnosis, treatment, and management of individuals with intellectual disabilities.

References:

1. Chudley, A. E., Conry, J., Cook, J. L., Loock, C., Rosales, T., & LeBlanc, N. (2005). Fetal alcohol spectrum disorder: Canadian guidelines for diagnosis. Canadian Medical Association Journal, 172(5_suppl), S1-S21.
2. Hagerman, R. J. (2002). The physical and behavioral phenotype. In Fragile X Syndrome: Diagnosis, Treatment, and Research (pp. 3-109). Johns Hopkins University Press.
3. Roizen, N. J., & Patterson, D. (2003). Down’s syndrome. The Lancet, 361(9365), 1281-1289.
4. Van Buggenhout, G. J., Trommelen, J. C., & Van Ravenswaaij-Arts, C. M. (2010). Cognitive and behavioural genetics in intellectual disability. European Journal of Human Genetics, 18(3), 292-298.