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CHAPTER 2:

CAUSES AND PREVENTION

ASHOK ROY, MEERA ROY

A confusing range of terms has been used to describe people with what is now called learning disability. Terms such as idiocy and cretinism were replaced by subnormality and handicap. More recently mental handicap has been superseded by terms like learning disability and learning difficulty.  Some of these terms (impairment, disability and handicap) have been defined by the World Health Organisation (see Chapter 1),  although they are also used in a less accurate way in some pieces of legislation such as the Mental Health Act.

 Intelligence is normally distributed in the population as shown in the bell shaped curve (see Fig 2.1)This means that the majority of people in the general population have an IQ of around 100 (the arithmetic mean, or average, IQ). Smaller numbers of people have lower or higher IQs, and very small numbers have very high or very low IQs. This creates the bell shaped curve with the highest numbers clustering around the IQ 100 mark, and smaller numbers at either extreme.

         35             70              100             130              160  

Figure 2.1

Many people with mild learning disability do not have an identifiable cause for their disability. Such people are also much more likely to have parents belonging to socio-economic groups 4 and 5. People with severe learning disability are evenly distributed among socio-economic groups at birth, and are very likely to have an identifiable cause for their disability. However, where a person with mild learning disability is born into a family where their siblings and parents are in socio-economic groups 1 or 2, they are likely to have an identifiable cause for their disability. This illustrates the interaction between genetic influences which could be regarded as setting a ceiling on possible attainment and environmental factors which determine to what extent one's genetic potential is fulfilled. In practice, the effects of genetic and environmental factors are difficult to separate because they influence and modify each other. Parents from higher socio-economic groups are likely to have more disposable income to devote to books and other educational resources, may have higher expectations of academic success and different attitudes to schooling and service provision to parents from lower socio-economic groups.

 However, mild and severe learning disability are not aetiologically separate entities. Some studies on people with mild learning disabilities have found that chromosomal aberrations were relatively common, affecting around 19% ( Gostason et al, 1991 ). Similarly, not all people with severe learning disabilities have an identifiable cause for their disability ( McGuffin et al ,1994 ).  

 The causes of learning disability are numerous and complex, and many factors interact to influence the extent of learning disability in adult life. These include factors operating at specific stages of development, including:

1) Prenatal factors, which affect the development of the foetus before birth and may involve factors operating before conception, such as exposure of reproductive organs to radiation.

 2) Perinatal factors , which affect the new-born baby at the time of birth, such as lack of oxygen leading to brain damage and thus learning disability

 3) Postnatal factors, which affect the child after birth, such as brain damage following measles infection, or lack of stimulation due to the baby's mother being depressed.

 Many factors can act at these different stages of development. The nature of the agent, and the time at which it exerts its effect on development, will influence the degree and pattern of learning disability which results. Interactions occur so that, for example, infants with causes of learning disability that result in poor muscle tone at the time of birth (e.g. those with Prader-Willi syndrome) are more likely to have complicated births - the baby may not play a normal role in the birth process and may be vulnerable to additional disabilities resulting from lack of oxygen during birth. Agents  may act before, at, or after birth to produce learning disability in this way.In about one third of cases it is not possible to identify the cause of  learning disability. It is useful to divide causes of learning disability into those that primarily affect the child, and those which are secondary to maternal factors.

 Prenatal and Perinatal Factors

1)Infective or inflammatory agents

 The developing foetus can be damaged by a variety of maternal infections. The most common examples are the ToRCH infections (toxoplasma, rubella, cytomegalovirus and herpes simplex). Other  infections include those caused by the human immunodeficiency virus and bacterial agents which cause meningitis, such as meningicoccal meningitis. Congenital syphilis used to be an important cause of learning disabilities.

2)Toxic and metabolic factors

 Alcohol consumption during pregnancy can lead to intellectual impairment. Environmental toxins such as lead and the mother smoking during pregnancy have been implicated. Other agents are drugs prescribed to the mother (such as lithium and phenytoin) and metabolic diseases which she may suffer from such as phenylketonuria resulting in the production of substances which are detrimental to development . Research has established dietary folic acid deficiency as a major cause of neural  tube defects such as spina bifida (DoH Expert Advisory Group,1992).

 3)Neoplastic processes

 Neoplastic processes involve the abnormal growth of tissue, as in the production of cancers or benign tumours. If these processes affect the brain, mental development may be slowed or become abnormal in some other way. An example of this is the learning disability, epilepsy and autistic features which may occur in tuberous sclerosis.

 4)Traumatic factors

 These include events in the perinatal period or around birth. Mechanical factors such as the use of forceps, and hypoxia (lack of oxygen) can result in brain damage. Prematurity, especially associated with low birth weight, can lead to delayed development.

 5)Chromosomal and genetic disorders

 These are of particular importance because they account for a proportion of the causation of severe learning disability which is increasing as new genetic techniques, able to detect more subtle abnormalities, become available. The proportion of people with disabilities of 'unknown' origin is slowly declining. The investigation of adults with learning disability has to be clinically justifiable (e.g. because appropriate treatment could depend on a diagnosis being confirmed or refuted, or because siblings may need genetic counselling if the learning disability can be shown to be due to a particular condition). 

 6)Endocrine disorders

 Of all endocrine glands, thyroid dysfunction is most commonly associated with Learning Disabilities. If the underfunctioning is picked up early, thyroxine replacement can usually prevent cognitive impairment

Post natal factors

Meningitis and encephalitis can produce brain damage, as can infections which lead to dehydration and electrolyte imbalance. Injuries can be accidental (e.g. road traffic accidents) or non-accidental (e.g. violent shaking). Inadequately treated diseases such as epilepsy, diabetes and hypothyroidism can result in significant brain damage and disability.

Psychological traumas such as neglect and sexual abuse can lead to failure to thrive in infants, or slowed or abnormal development in older children. Other environmental factors such as social deprivation and lack of stimulation are important influences on development and intelligence.

 Maternal Causes

These include conditions such as anaemia , hypertension, diabetes and bleeding during  pregnancy. They either reduce nutrition to the foetus or lead to prematurity. An unstimulating and deprived environment associated with neglect or abuse has been implicated with developmental delay.

 Genetics and Learning Disability

As discussed earlier, genetic disorders are often responsible for learning disability syndromes. Genetics is the study of heredity and variation in the inherited characteristics of an organism. Genetic material is contained in chromosomes within the nuclei of the cells which make up an organism. They can be seen as thread like structures within the dividing nucleus, and consist of deoxyribonucleic acid (DNA) complexed with proteins. DNA is made up of 2 chains of nucleotide bases wrapped around each other in a double helix held together by hydrogen bonds between the bases.  A nucleotide is made up of three components : a nitrogenous purine base, a pentose sugar and a protein.The four bases in the DNA are adenine (A), guanine (G), cytosine (C)  and thymine (T).These can lie in any order along the sugar phosphate back bone. A always pairs with T, and C with G. One strand thus contains a sequence of bases complimentary to the other so that each can be used as a template to copy the other.

A gene is a length of DNA that codes for the production of a particular protein. Genes are arranged on the chromosomes linearly, each occupying a particular position or locus. Other forms of the gene occupying the same position are called alleles. Each chromosome carries only one allele at a particular locus though there may be many alleles in the population. In many genes in man the coding regions (called exons) are interrupted by stretches of non coding sequences (called introns).Every species has a characteristic number of chromosomes called the karyotype. Human beings have 46 chromosomes consisting of 23 pairs which have the same genetic loci in the same order, though at any locus they may have the same or different alleles. If the same allele is present , the individual is homozygous for the trait and heterozygous if they are different. One member of each pair of chromosomes is inherited from the father and one from the mother. The twenty two pairs which are present in both men and women are called autosomes. Normally the members of a pair of autosomes are indistinguishable microscopically.

 The last pair of chromosomes are the sex chromosomes and differ in men and women. Women have 2 X chromosomes while men have one X chromosome and a smaller Y chromosome. Thus the human male karyotype is described as 46,XY and the female, 46XX. In women each cell contains only one active X chromosome . The other is usually inactivated and can be seen as a densely staining area called the Barr body in cell smears taken from the inside of the cheek.Chromosome analysis is usually carried out on white blood cells which are cultured, spread on slides  and stained with different techniques. Banded staining uses dyes that differentially stain parts of the chromosome producing a characteristic pattern for each pair. Each chromosome has a long (q) arm and a short (p) arm separated by a centromere. Particular chromosomes can be identified by their size and banding patterns.

Mitosis is the process by which the cells divide for the body to grow and replace dead or injured cells. Meiosis, or reduction division results in the production of sperm cells and ova. The result of a mitotic division is 2 cells which are identical to the parent cell with the full complement of chromosomes and are said to be diploid. The meiotic division produces gametes (sperms and ova) which contain only one representative of each pair of chromosomes and are said to be haploid. The union of the sperm and ovum brings the number of chromosomes back to the diploid state.

Mitosis is a single stage division while meiosis is in 2 stages. There is the initial division of each chromosome into 2 chromatids and the homologous chromosomes form a quadruple structure. Later both sister chromatids and homologous pairs are separated and passed into 4 different daughter cells. The disjunction of paired homologous chromosomes is essential for the number of chromosomes to remain constant. Nondisjuction results in abnormalities in the number of chromosomes. Nondisjunction of chromosome 21 leads to trisomy 21 and is responsible for the majority of people who have Down Syndrome. Trisomy 18 results in Edward’s syndrome and trisomy 13 in Patau’s syndrome.

Aneuploidy is a term used to describe alterations in the number of chromosomes. In Turner’s syndrome affected women have a 45,XO karyotype. The karyotype in Triple X syndrome may be 47XXX, in Klinefelter’s syndrome 47XXY and 47XYY in the XYY syndrome.

During the meiotic divisions the homologous chromosomes may exchange genetic material by breakage and recombination. A whole series of abnormalities can occur during this process. There may be deletions where a segment of chromosome is lost. Examples of deletions are the Cri du Chat syndrome where there is a deletion of the short arm of chromosome 5 and the Prader- Willi with deletion in the long arm of chromosome 15. Inversion is where a piece of chromosome breaks and is then reattached in the opposite orientation, and duplication where two copies of a segment of a chromosome occur. Reciprocal translocation occurs when chromosomes of two different pairs exchange segments. In a small number of people with Down syndrome, the trisomy is due to translocation between chromosome 21 and 14 or between the two chromosome 21s.

  Genomic imprinting refers to the phenomenon by which the expression of a gene or a set of genes differs according to whether the relevant chromosomes are of maternal or paternal origin. The best known examples of this are Prader- Willi syndrome and Angelman syndrome both of which show a deletion of chromosome 15. In the former, two thirds of cases have a deletion on chromosome 15 of paternal origin while a large majority of those with Angelman syndrome show the deletion on chromosome 15 of maternal origin. In both syndromes uniparental disomy also occurs, where both the chromosome 15s are from one parent, so that there is no genetic contribution from the other parent’s chromosome 15.

The next important group of genetic disorders associated with learning disability are the single gene disorders. The affected genes may be on the autosomes or the sex chromosomes. Several genes may be associated one disorder, or a single genetic disorder may be associated with several clinical variants. Advances in molecular genetics have helped localise many of the genes responsible for these conditions.

 The inheritance of autosomal disease is dominant when one affected parent passes the condition to the child. Examples of autosomal dominant disorders associated with learning disability are tuberous sclerosis, Apert’s syndrome and mandibulofacial dysostosis.  The manifestation of autosomal dominant disease may be of different severity in successive generations.

 In autosomal recessive disease parents are not affected, but both carry the gene and may pass the condition to their children if they inherit an abnormal copy from each parent. Important examples associated with learning disabilities are phenylketonuria, disorders of lipid mechanism such as Tay Sachs disease and mucoploysaccharidoses. In practice, these conditions are comparatively uncommon. The frequency of autosomal recessive disease is more common in populations with high rates of consanguinity such as that resulting from cousin to cousin marriages.

 If the genetic abnormality is on the X chromosome, a characteristic pattern of inheritance is seen with no male to male transmission  (men always pass on a Y chromosome to their sons). Women may be carriers if they inherit the abnormal X chromosome. They then pass the condition to their sons. It has long been recognised that men with learning disabilities outnumber women. Fragile X syndrome is an example of an x- linked condition though its genetics and clinical features are atypical ( see chapter 3). Some other X linked conditions associated with learning disabilities are Lesch-Nyhan syndrome, Duchenne muscular dystrophy, and Hunter’s syndrome.

 A mutation is a change in the base sequence of a gene. It can be either neutral, having little or no effect, or pathological, being associated with significant effects on cellular structure and metabolism. Those occurring during the production of sperm and ova cause some of the single gene disorders such as tuberous sclerosis, where 80% of cases arise as a result of such mutations, rather than through inheritance. A number of pathological mutations have been shown to involve variations in the number of trinucleotide repeat sequences such as cytosine-guanine-guanine (CGG) leading to disruption of gene function. Such unstable DNA trinucleotides have been observed in Fragile X syndrome (see Chapter 3).

A more comprehensive account of genetic factors and lists of psychiatric disorders may be obtained from text books of genetics such as Seminars in Psychiatric Genetics by Peter McGuffin  et al published by the Royal College of Psychiatrists.

PREVENTION

Prevention may be primary, secondary or tertiary. Primary prevention depends on knowledge of the causes of learning disability, and implementing preventive strategies, as detailed in Figure 2.2.

Genetic and chromosomal disorders

The first step in prevention is the accurate and specific diagnosis of the suspected condition. Once an accurate diagnosis is made, the parents of the affected child should be given counselling, giving them information on the risk of the next child having the condition. If the index person is an adult, similar counselling would need to be given to siblings. If conception has not taken place, the family needs to have an understanding of the condition causing concern, the risk and extent of learning disability associated, the mode of inheritance, carrier status of the parents and the risk of  the planned pregnancy leading to the birth of  a child with learning disability. If conception has taken place the an assessment needs to be made of risk factors such as maternal age, family history, and exposure to deleterious environmental factors such as infections in early pregnancy. This may need to be followed by investigations such as the measurement of alpha fetoprotein or amniocentesis (study of cells taken from the fluid surrounding the foetus) to detect abnormal chromosomes. After a diagnosis is made, the parents must be helped sensitively to make a decision as to whether they want to continue with the pregnancy or terminate it. Some investigations, such as amniocentesis, which are associated with a risk to the baby will only be undertaken if parents are considering termination of a pregnancy in the event of an abnormality being found.

Universal screening of new born infants for phenylketonuria has been effective in reducing intellectual impairment due to this cause. In the USA, by screening healthy adults for Tay Sach’s disease among Jewish people of Ashkenazi descent, followed by genetic counselling, the condition has almost been eliminated amongst them. It has been suggested that populations at risk of Fragile X syndrome would benefit from DNA based screening (Sabaratnam et al,1994; Slaney et al,1995 ).

In the U.K, women are offered a  triple assay of maternal serum alpha foetoprotein, unconjugated oestriol and human chorionic gonadotrophin at 16 to 18 weeks of pregnancy.  Based on the results, a calculation can be made about the risk of the foetus having Down syndrome and a decision can be made about whether to proceed with amniocentesis. 

Infections 

Widespread immunisation programmes for diseases such as rubella and measles have dramatically reduced the incidence of babies born with handicapping diseases.                                                

Endocrine and metabolic diseases

The prevention of these disorders can be effective if they are detected early and remedial measures instituted early. Screening at birth for hypothyroidism and phenylketonuria can lead to replacement therapy or a special diet being commenced at once thereby reducing the level of learning disability. 

 Toxic and nutritional factors

The most effective strategy in the amelioration of these factors is health education and health promotion with a consequent adoption of healthy lifestyles. Benefits would include reduction of alcohol intake, cigarette smoking, improvement of maternal diet and improved antenatal care leading to early detection and treatment of conditions such as diabetes, hypertension and anaemia. Specific advice on high folate diet to prevent neural tube defects is important.   

Perinatal factors

Improved obstetric care can prevent or reduce brain damage at birth caused by obstruction and hypoxia. An important contribution is made by early detection and treatment of  babies who need additional support for hypoxia.

Postnatal factors and risks in early life

Preventative measures are directed to the various risk factors that may occur during development. Early detection and vigorous treatment of  infections, and optimal  management of chronic conditions such as epilepsy, hypothyroidism and phenylketonuria can significantly reduce the incidence and severity of disability. Accident prevention measures in and out of the home, early detection and management of non accidental injury and other forms of abuse and neglect and stimulating environments have all been used with success.

Secondary and tertiary prevention

Secondary prevention aims to treat or ameliorate the underlying condition in order to prevent or reduce disability. Examples are dietary regimes low in phenylalanine for people with phenylketonuria, and thyroxine replacement in neonates with congenital hypothyroidism.

Tertiary prevention is aimed at minimising the sequelae of an existing disability. Examples include regular hearing, visual and thyroid checks for people with Down syndrome and physiotherapy for children with cerebral palsy. Vigorous management of delays in motor skills and communication can help ameliorate physical and psychological effects of understimulating home environments. Early diagnosis and appropriate treatment of coexisting epilepsy and psychiatric disorders will also reduce associated disabilities. 

In a substantial majority of people with learning disabilities, it is difficult to establish a cause. A genetics laboratory will require information about which conditions are being considered, in order to run appropriate tests. It is not currently possible to run broad genetic screens for any type of deletion, for example; the laboratory will need to know which chromosome or chromosomes are likely to be affected. Clinical features of some of the commoner syndromes associated with learning disabilities are described in chapter 3.

FIGURE  2.2: PRIMARY PREVENTION

 REFERENCES

 Gostason,R., Wahlsrom,J., et al(1991) Chromosomal aberrations in the mildly mentally retarded. Journal of Mental Deficiency Research, 35, 240 - 246.

 Department of Health Expert Advisory Group (1992) Folic Acid and the prevention of neural tube defects. London :DoH

 McGuffin,P. (1994) Seminars in Psychiatric Genetics. Gaskell. London.

 Sabaratnam,M. , Laver,S., Butler,L., et al (1994) Fragile X syndrome in North East Essex: towards systematic screening : clinical selection. Journal of Intellectual Disability Research, 38,27 - 35

 Slaney, S.F., Wilkie,A.O.M., Hirst,M.C., et al (1995) DNA testing for Fragile X syndrome in schools for learning difficulties. Archives of Disease in Childhood,72, 33 - 37.

 FURTHER READING

 McGuffin ,P. ( 1994 ) Seminars in Psychiatric Genetics, Gaskell, London.

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