Aetiology of intellectual disability: general issues and prevention
Markus Kaski
Causation
The complexity of causes
Intellectual disability can follow any of the biological, environmental, and psychological events that are capable of producing a decline of cognitive functions. Some factors do not directly or inevitably cause intellectual disability but add to the effects of a previous primary cause. Genetic causes may be hereditary or non-hereditary, and may or may not produce specific syndromes. Some lead to inborn errors of metabolism.(1)
Neurological symptoms during the neonatal period are strongly associated with prenatal developmental disturbances. For example in maternal pre-eclampsia, placental insufficiency may lead to malnutrition, foetal asphyxia, intrauterine growth retardation and prematurity, and subsequently to perinatal problems including asphyxia, intracranial haemorrhage, hyperbilirubinaemia, and hypoglycaemia. It is important to detect these coexisting conditions, because their effects may add to or interact with those of the primary cause.(2)
The biomedical cause of intellectual disability may lead to additional disorders or disabilities, or may itself be progressive.(1,2,3) In fact, intellectual disability exists commonly with many other symptoms in a patient, for example with sensory problems, dysphasia, cerebral palsy, epilepsy, or autism. These additional factors affect opportunities for gaining experiences necessary for development. Activity may be restricted by sickness, or the effects of medication. Motor disability may reduce mobility, or cause dysphasia. Sensory impairment may restrict vision or hearing. These restrictions add to the effects of the primary cause and interact with environmental and emotional factors to retard the development of the individual.(1,2,3,4)
How often do we know the cause(s)?
The various concepts of intellectual disability and its causes have led to different epidemiological estimates. The population at risk consists of survivors, but some figures include also all live born. Differences in the definition and detection of cases, the classification system used, the population studied, the timing of the study in relation to measures of the general population, the resources available for the study, and sources of the data make it difficult to compare both the frequency of persons with intellectual disability and the frequency of various causes obtained in different studies. However, a specific cause for intellectual disability can be identified for approximately 80 per cent for persons with severe intellectual disability (IQ <50, includes the groups of moderate, severe, and profound intellectual disability in ICD-10) and 50 per cent of persons with mild intellectual disability. The principal cause of intellectual disability is estimated to be prenatal in 50 to 70 per cent, perinatal in 10 to 20 per cent, and postnatal in 5 to 10 per cent of persons.(3,4,5,6,7) In general, knowledge of aetiologies is more accurate for people with severe intellectual disability than for those with mild intellectual disability.(8, 9)
Classifying causes
The causes of intellectual disability may be classified according to the particular clinical entity, the causative agent or presumed cause, or the timing of the causative factor. The newer and more successful classification systems are based on timing.(10) The principle is biomedical in nature and it is intended to elucidate the earliest factor that has affected the development of the central nervous system. The discovery of the primary cause (or sequential causes) aids family counselling and may lead to identification of a preventable general risk.
Viewed in this way, diagnoses can be divided into six main groups according to the probable cause and the timing of damage to the central nervous system (Table 10.3.1) (11):
genetic causes;
central nervous system malformations of unknown origin;
external prenatal factors;
disorders acquired in the paranatal* period;
disorders acquired postnatally; and
untraceable or unclassified causes.
Table 10.3.1 Aetiology based on the time and mechanism of the injury to the central nervous system and the history helping identification, timing, and diagnosis of intellectual disability | ||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ||||||||||||||||||||||||||||||||||||||||||||
(a) Genetic causes
Chromosomal disorders include all intellectual disability caused by a proven chromosomal aberration or a clinically obvious chromosomal syndrome such as Down syndrome. However, chromosome analysis should be performed in Down syndrome because translocation, mosaicism, or other abnormalities are found in 5 per cent of cases. Chromosomal anomalies associated with intellectual disability account for up to 40 per cent of severe cases, and 10 to 20 per cent of mild cases.(3,6,12,13) However, the detection rates for chromosome abnormalities with the novel molecular karyotyping methods, such as microarray-based comparative genomic hybridization (array CGH), range from 5 to 17 per cent in individuals with normal results from prior routine cytogenetic testing.(14) Array CGH has the ability to detect any genomic imbalance including deletions, duplications, aneuploidies, and amplifications.
Malformations due to microdeletion include many malformation syndromes whose causative agent is obscure. A new method of using DNA probes and fluorescence in situ hybridization has increased understanding of the causes of syndromes such as the Angelman, Cornelia de Lange, CATCH 22 (cardiac defects, abnormal face, thymic hypoplasia, cleft palate, and hypocalcaemia) (velocardiofacial syndrome), Miller-Dieker, Prader-Willi, Rubinstein-Taybi, Smith-Magenis, Sotos, Williams, and Wolf-Hirschhorn syndromes. Parental imprinting modifies the expression of the genes involved in the Prader-Willi and Angelman syndromes.(12, 14,15,16)
Subtelomeric deletions or chromosomal rearrangements have been found in some persons with intellectual disability of hitherto unknown aetiology. Subtelomeric aberrations may explain up to 5 to 10 per cent of previously unknown causes.(13,15)
Single-gene disorders include states with intellectual disability in which the pedigree is highly suggestive of a single-gene origin. Some are caused by a mutant gene with simple Mendelian inheritance. Single-gene mutations may increase or diminish in frequency in areas with long-standing populations of the same origin, or in populations isolated by language or culture. For example, the so-called Finnish disease heritage includes 36 disorders, from which 10 manifest with central nervous symptoms and some others may have them.(17) Most of the specific disorders due to mutant gene have characteristic clinical phenotypic features, but there are a considerable number of non-syndromic individuals, especially in early infancy.(12,18,19)
Autosomal dominant inheritance causes tuberous sclerosis, myotonic dystrophy, Gorlin syndrome, neurofibromatosis I, Apert syndrome, Menkes syndrome, and Huntington’s disease.
Autosomal recessive inheritance is the cause of most metabolic diseases with intellectual disability. These diseases include phenylketonuria, homocystinuria, maple syrup urine disease, aspartylglucosaminuria, mannosidosis, Salla disease, I-cell disease, mucopolysaccharidoses (except type II), neuronal ceroid lipofuscinoses, Tay-Sachs disease, metachromatic leucodystrophy, Smith-Lemli-Opitz syndrome, and Joubert syndrome.
X-linked inherited disorders include the fragile X, Aicardi, Lesch-Nyhan, Lowe, Norrie, and Coffin-Lowry syndromes, mucopolysaccharidosis II, Duchenne muscular dystrophy, α-thalassaemia intellectual disability syndrome, and Rett syndrome. The most
common intellectual disability syndrome caused by mutation of a single gene is fragile X syndrome. The pattern of its inheritance is X-linked dominant with decreased penetrance.(17,19,20) The prevalence of the 24 other genes identified to date in the X chromosome is low.(20) Dystrophic myotony, fragile X syndrome, and Huntington’s disease are caused by so-called dynamic mutation in which the length of the repeated sequence of three DNA bases can vary from generation to generation increasing the variability in the phenotype.(21) In Rett syndrome female inactivation of X chromosome may be skewed. It explains the existing of the syndrome in a male or the very mild phenotype in a female.(22) Epigenetic regulatory factors are also involved in the aetiology of Rett syndrome.(23)
common intellectual disability syndrome caused by mutation of a single gene is fragile X syndrome. The pattern of its inheritance is X-linked dominant with decreased penetrance.(17,19,20) The prevalence of the 24 other genes identified to date in the X chromosome is low.(20) Dystrophic myotony, fragile X syndrome, and Huntington’s disease are caused by so-called dynamic mutation in which the length of the repeated sequence of three DNA bases can vary from generation to generation increasing the variability in the phenotype.(21) In Rett syndrome female inactivation of X chromosome may be skewed. It explains the existing of the syndrome in a male or the very mild phenotype in a female.(22) Epigenetic regulatory factors are also involved in the aetiology of Rett syndrome.(23)
Mitochondrial disorders are inherited in most cases due to mutations in the nuclear genes encoding proteins targeted to this organelle. Autosomal dominant, recessive, or X-linked inheritances are possible. In addition, mitochondrial dysfunction is shown among others in patients with fragile-X, Rett, and Wolf-Hirschhorn syndromes or autism. (24,25,26,27) Mitochondrial DNA (mtDNA) is inherited maternally. Sporadic deletions and duplications are also found (Kearns-Sayre syndrome, sporadic deletion or partial duplication in mtDNA). Examples of the maternally inherited (mtDNA) syndromes with central nervous symptoms are the MELAS (mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes), MERRF (myoclonus epilepsy with ragged red fibres), and NARP (neurogenic muscle weakness, ataxia, retinitis pigmentosa), FSFD (facio-scapulo-femoral muscular dystrophy, familial cerebellar ataxia, recurrent Reye syndrome, cerebral palsy with intellectual disability), and cytochrome c oxidase (COX) deficiency (deafness, myoclonic epilepsy, ataxia, and intellectual disability) syndromes. Nuclear genes are often involved in mitochondrial DNA depletion and Leigh syndromes, which are severe progressive diseases in early childhood.(11, 18, 21)
Multifactorial intellectual disability may be a state of pure familial intellectual disability or associated to some multifactorially inherited conditions, for example neural-tube defects. One or more first-degree relatives are also affected. Similar pervasive developmental disorders or childhood or other psychoses in one or more of first-degree relatives or otherwise strong family background suggest a polygenic component of intellectual disability.(12, 21)
(b) Central nervous system malformations of unknown origin
Approximately 30 to 40 per cent of all malformations are genetic and 10 per cent have exogenous causes. The aetiology of the rest is unknown. The number included in this aetiological group decreases with more accurate diagnosis of genetic malformations, intrauterine infections, other teratogenic agents, or deficiencies of essential ingredients needed for the normal development.(28,29) The development of the central nervous system may be disturbed at the following stages(2,12,21,28,29):
1 dorsal induction at the 3rd to 7th weeks of gestation, leading to anencephaly, encephalocele, meningomyelocele, or other neuraltube-closure defects;
2 ventral induction at the 5th to 6th weeks of gestation, causing prosencephalies and other faciotelencephalic malformations;Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
