Classifying causes

The causes of mental retardation may be classified according to the particular clinical entity, the causative agent or presumed cause, or the timing of the causative factor.(5,l3,!4) The newer and more successful classification systems are based on timing.(!, ,!6) 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

Table 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 mental retardation

1. genetic causes;

2. central nervous system malformations of unknown origin;

3. external paranatal factors;

4. disorders acquired in the paranatal period;

5. disorders acquired postnatally;

6. untraceable or unclassified causes.

The paranatal period is defined as the period from 1 week before to 4 weeks after birth. Genetic causes

The term genetic refers to disorders that can be recognized by aberrations in the genetic material. The genetic aberration may be hereditary or non-hereditary. l920

and 21)

Chromosomal disorders include all mental retardation 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 retardation account for up to 40 per cent of severe cases, and 10 to 20 per cent of mild cases. (!,5,,8.,9and 19

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, Williams, and Wolf-Hirschorn syndromes. Parental imprinting modifies the expression of the genes involved in the Prader-Willi and Angelman syndromes. (!,,i0,)

Subtelomeric deletions or chromosomal rearrangements have been found in some persons with mental retardation of hitherto unknown aetiology. Subtelomeric aberrations may explain up to 6 per cent of previously unknown causes. (i9

Single-gene disorders include states with mental retardation 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 35 disorders, of which nine manifest with central nervous symptoms and some others may have them.(22) The single mutant gene codes for an abnormal protein which influences development adversely and produces a specific disorder. Most of these conditions have characteristic clinical phenotypic features, but there are a considerable number of non-syndromic individuals, especially in early infancy.(23)

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 mental retardation. 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, a-thalassaemia-mental retardation syndrome, and possibly Rett syndrome. The most common mental retardation syndrome caused by mutation of a single gene is fragile X syndrome. The pattern of its inheritance is X-linked dominant with decreased penetrance.(!8,23)

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. (20)

Multifactorial mental retardation may be a state of pure familial mental retardation 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 mental retardation. (!,19)

Mitochondrial disorders are inherited only maternally. Examples with central nervous symptoms are the Kearns-Sayren, MELAS (mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes), MERRF (myoclonus epilepsy with ragged red fibres), and NARP (neuropathy, ataxia, retinitis pigmentosa) syndromes/23

Central nervous system malformations of unknown origin

Approximately 30 per cent of the 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, genetic malformations, intrauterine infections, and other teratogenic agents. (.1.,5,.2 25) The development of the central nervous system may be disturbed at the following stages:(2,2,2 27 and 28)

1. dorsal induction at the third to seventh weeks of gestation, leading to anencephaly, encephalocele, meningomyelocele, or other neural-tube-closure defects;

2. ventral induction at the fifth to sixth weeks of gestation, causing prosencephalies and other faciotelencephalic malformations;

3. proliferation of the neurones at the second to fourth month of gestation, leading to microcephaly or macrocephaly;

4. migration of the neurones at the third to fifth month of gestation, causing gyrus anomalies and heterotopias;

5. organization of neurones from the sixth month of gestation to a year postpartum, leading to disturbances in the formation of dendrites and synapses;

6. myelination from sixth month of gestation to a year postpartum, disturbing the proliferation of oligodendrocytes and the formation of the myelin sheets.

The malformation sequence is a type of multiple malformation which includes secondary anomalies caused by an earlier anomaly, for example equinovarus with meningomyelocele. Multiple malformation syndromes are caused by the disturbances in blastogenesis or organogenesis. Multiple malformation syndromes of unknown origin include some whose causes are unknown such as the Goldenhaar and Sotos syndromes, and research may show that some of these aetiologically unknown syndromes have a genetic cause/1,2.9

External prenatal factors

The nature of the impairments or malformations, and the severity of resulting mental retardation appear to relate, at least partially, to the timing of the causative factor as discussed earlier. Also dosage may be important. Effects are most serious when the cause acts early in embryonic development; during blastogenesis or organogenesis, when it may result in multiple malformations. Effects on the central nervous system of causes acting later may be severe even though outward signs may be lacking. These causes include congenital infections such as rubella, cytomegalovirus, herpes simplex type 2, HIV infection, as well as toxoplasmosis and syphilis. Exposure to medication and other substances such as hydantoin, lipid solvents, alcohol, cocaine, and other drugs can affect the developing fetus. (25,8,29

Maternal disorders that may contribute to the causes of mental retardation include maternal diabetes, arterial hypertension, placental insufficiency, pre-eclampsia, pre- and postmaturity, multiple pregnancy, and fetal growth retardation. In other causes no specific causes can be identified with certainty but available data strongly suggest a prenatal external cause of central nervous system impairment such as exposure to ionizing radiation or trauma. (2,39

Disorders acquired in the paranatal period

The effects of the last week of pregnancy extend to the neonatal period and are very important for the outcome of the newborn, (i7) and combinations of the prenatal and postnatal factors are not rare. Infections are transmitted via placenta or the birth canal. They include neonatal septicaemia, pneumonia, meningitis, and encephalitis, which may lead by several mechanisms to neurological deficits, mental retardation, and sometimes microcephaly, or in bacterial meningitides also to hydrocephalus. Congenital infections of herpes simplex and HIV as well as tertiary syphilis may manifest later. Problems during delivery may lead to asphyxia, intracranial haemorrhage, or other birth injuries and cause various symptoms of cerebral palsy and epilepsy. Other newborn complications include hypoglycaemia, hyperbilirubinemia, and respiratory distress. Paranatal aetiologies may cause disorders of cognitive functions, as well as motor and sensory impairments. (2324)

Disorders acquired postnatally

Improved postnatal care has reduced the frequency of these causes, which include infections such as meningitides and encephalitides. (31,32,) Other causes of postnatal damage to the central nervous system include toxic agents, vascular accidents, brain tumours, hypoxia, and traumas. Traffic accidents, other traumas, submersions, and cerebral tumours are common causes of disability in childhood. Lead poisoning continues to be a problem in the United States, iodine deficiency in some regions of the world, and malnutrition almost world-wide/5,8,2.^ Psychosocial problems causing mental retardation are not as common as was thought in the past, partly because of better identification of medical factors.(33) Severe maternal mental or chronic physical illness, parental alcohol or drug abuse, and some consequences of poverty may be contributory causes leading to inadequate care and stimulation. Deprived environments are linked to other risks such as malnutrition, poor medical care, child abuse, usage of alcohol and other substances, and teenage pregnancies. (34,35)

Untraceable or unclassified causes

The aetiology of mental retardation can be classified as unknown if the causative factor or timing of the brain damage cannot be established. Pure non-familial mental retardation is the term used when there is no family history of mental retardation and no signs and symptoms suggesting brain damage. It represents the extreme of normal variation. In the untraceable group, the second category is mental retardation of unknown aetiology with other symptoms and signs of the central nervous system suggesting brain damage, but with no family history of mental retardation and no identified malformations or dysmorphic features (see Table 1).

Common examples are mental retardation associated with cerebral palsy, epilepsy, or autism. Patients should not be assigned to this group if the diagnostic work-up is incomplete.'51/.' If so, the aetiology is still unclassified.

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