dr. TRIWANI, M.KesBLOK 20FK UNSRIGENETIC ASPECT IN MENTAL HEALTH AND BEHAVIOUR

Possible routes or mechanisms by which parental mental health might have an impact on their children Genetic factorsSocial impactDirect effects of parental symptoms on childrenImpacts on children mediated less directly, by disruptions in parenting

Genetic Factors:There is a significant variation in the estimates of heritability between the different parental mental illnesses. Nevertheless, it is documented the existence of a genetic component in the transmission from parent to child in depression and schizophrenia

Social impact:It is mainly related to the stigmatising effects of parental illness on children.Children are often the recipients of thoughtless or pitying remarks from peers, teachers, strangers, or neighbours; these remarks may initially mobilise a great deal of distress in the children of a newly handicapped parent (Romano, 1976)

Direct effects of parental symptoms on children:Children may be neglected because of the parental mental illnessChildren may be victimised by experiencing aggressiveness and violenceChildren may become a target of parents delusional behaviourChildren may be exposed to the parents unpredictable or irrational behaviour

Impact on children mediated indirectly, by disruptions in parenting:Parents may be uncommunicative with and unavailable to their children because of their mental illness.

E.g. a depressed mother may be preoccupied and withdrawn due to her mental illness

Marital disharmony and domestic violence due to parental mental illness may impact on parenting in a number of way

Genetic causality in mental disordersAs of 2002, genes appear to influence the development of mental disorders in three major ways:

they may govern the organic causes of such disorders as Alzheimer's disease and schizophrenia; they may be responsible for abnormalities in a person's development before or after birth; and they may influence a person's susceptibility to anxiety, depression, personality disorders

Genetic causality in mental disordersAs recently as the 1960s and 1970s, for example, schizophrenia was generally attributed to "refrigerator mothers" and a chilly emotional climate in the patients' extended families. As of 2002, however, the application of computer models to schizophrenia indicates that the heritability of the disorder may be as high as 80%. Another instance is autism , which was also blamed at one time on faulty parenting but is now known to be 90+% heritable.

Mental disorders with organic causes The two most important examples of mental disorders caused by organic changes or abnormalities in the brain are late-onset Alzheimer's disease and schizophrenia.

Other caseFragile X syndromeHuntington diseaseDown syndrome

SCHIZOPHRENIASchizophrenia is a syndrome of unknown pathophysiology characterized by psychotic symptomssuch as hallucinations, delusional ideas, disordered speech and thinking, as well as deficits in emotional and social behavior.

SCHIZOPHRENIA Researchers have known for many years that first-degree biological relatives of patients with schizophrenia have a 10% risk of developing the disorder, as compared with 1% in the general population.

The identical twin of a person with schizophrenia has a 40%-50% risk

SCHIZOPHRENIAA case study that involved a Chinese immigrant and his 20-year-old nephew, both diagnosed with schizophrenia, led the researchers to a locus on the short arm of chromosome 5. In 1988, a study of schizophrenia in several Icelandic and British families also pointed to chromosome 5.

SCHIZOPHRENIAIn late 2001, a multidisciplinary team of researchers reported positive associations for schizophrenia on chromosomes 15 and 13

Chromosome 15 is linked to schizophrenia in European American families as well as some Taiwanese and Portuguese families

SCHIZOPHRENIA

A recent study of the biological pedigrees found among the inhabitants of Palau (an isolated territory in Micronesia) points to chromosomes 2 and 13

Still another team of researchers has suggested that a disorder known as 22q deletion syndrome may actually represent a subtype of schizophrenia, insofar as people with this syndrome have a 25% risk of developing schizophrenia.

ALZHEIMER'S DISEASE. Late-onset Alzheimer's disease (AD) is unquestionably a polygenic disorder. It has been known since 1993 that a specific form of a gene for apolipoprotein E (apoE4) on human chromosome 19 is a genetic risk factor for late-onset Alzheimer's.

ALZHEIMER'S DISEASE. People who have the apoE4 gene from one parent have a 50% chance of developing AD; a 90% chance if they inherited the gene from both parents. They are also likely to develop AD earlier in life.

ALZHEIMER'S DISEASE. In other words, some people who have the apoE4 gene do not develop Alzheimer's, and some who do not have the gene do develop the disorder. In 1998, another gene on chromosome 12 that controls the production of bleomycin hydrolase (BH) was identified as a second genetic risk factor that acts independently of the apoE gene. In December 2000, three separate research studies reported that a gene on chromosome 10 that may affect the processing of amyloid-beta protein is also involved in the development of late-onset AD.

ALZHEIMER'S DISEASE. There are two other forms of AD, early-onset AD and familial Alzheimer's disease (FAD), which have different patterns of genetic transmission. Early-onset AD is caused by a defect in one of three genes known as APP, presenilin-1, and presenilin-2, found on human chromosomes 21, 14, and 1, respectively.

ALZHEIMER'S DISEASE.Early-onset AD is also associated with Down syndrome, in that persons with trisomy 21 often develop this form of Alzheimer's. The brains of people with Down syndrome age prematurely, so that those who develop early-onset AD are often only in their late 40s or early 50s when the symptoms of the disease first appear. Familial Alzheimer's disease appears to be related to abnormal genes on human chromosomes 21 and 14.

TRIPLET REPEAT DISORDERS Since 1991, expansion mutations have been identified as the cause of thirteen different diseases. Some, like Huntington's disease, are characterized by long expansion mutations of the trinucleotide sequence CAG, which in effect adds so much glutamine to the protein being synthesized that it becomes toxic to the nervous system. A second category of triplet repeat disorders contains extra triplets that add an amino acid called alanine to the protein.

TRIPLET REPEAT DISORDERSThe best-known expansion mutation in this group causes the disorder known as fragile X syndrome. Fragile X syndrome is the most common inherited form of mental retardation and should be considered in the differential diagnosis of any child with developmental delays, mental retardation, or learning difficulties.

HUNTINGTON'S DISEASE Huntingtons disease, or Huntington's chorea, is a neurological disorder that kills the cells in the caudate nucleus, the part of the brain that coordinates movement. It also destroys the brain cells that control cognitive functions. In 1983, the gene that causes Huntington's disease was discovered on the short arm of human chromosome 4.

HUNTINGTON'S DISEASETen years later, the gene was identified as an instance of a triplet or trinucleotide repeat. Nucleotides are the molecular "building blocks" of DNA and RNA. Three consecutive nucleotides form a codon, or triplet, in messenger RNA that codes for a specific amino acid.

HUNTINGTON'S DISEASEIn 1991, researchers discovered not only that nucleotide triplets repeat themselves, but that these repetitions sometimes expand in number during the process of genetic transmission. This newly discovered type of mutation is known as a dynamic or expansion mutation

HUNTINGTON'S DISEASEThe reported prevalence rates for this disease from the UK and USA have been 59/100 000. Although the disease most often appears in subjects in their late 30s and early 40s, onset in adolescence and over the age of 50 years is well recognized. A preponderance of juvenile-onset cases show male transmission. The Huntington gene has been localized to the short arm of chromosome 4.The gene displays an expanded and unstable trinucleotide repetition (3786 repeat units in one series) compared with 1134 copies in the normal chromosome. The age of onset of the disease is inversely correlated with the repeat length

CTs atrophy nucleus caudatusUpper: pedigreeLower:DNA gel trinucleotide repeat 40-52

HUNTINGTON'S DISEASEJuvenile cases (onset before the age of 20 years) approximately 5% of cases and usually inherit the disease from affected fathers. In these cases, an akineticrigid syndrome is more likely than the classical presentation. At the other end of the age spectrum, Huntington's disease may also present atypically. Families are described in whom the disease usually presents after the age of 50 years and then in the form of chorea, with little or no evidence of dementia.Typically, these patients survive for much longer than classical cases.

FRAGILE X SYNDROME

Fragile X syndrome

FRAGILE X SYNDROMEFragile X syndrome is a frequent form of mental retardation Prevalence of about 1:3000-6000 males. Cause by expanded CGG trinucleotide repeats in the 5 untranslated region of the FMR1 gene on the distal long arm of the X chromosome at Xq27.3 the increase number of CGG repeats result in transcriptional silencing, loss of the FMR1 protein, and defective translational control of neuronal synaptic protein. Identified in 1991 as the fist human disease to be cause by unstable trinucleotide repeat sequence. (Oberle et al., 1991; Verkerk et al., 1991

GENOMIC IMPRINTING Another recent discovery in the field of biological psychiatry is the phenomenon of genomic imprinting, which distinguishes between chromosomes derived from a person's father and those derived from the mother. Genomic imprinting was discovered in the late 1980s as an exception to Gregor Mendel's laws of biological inheritance

GENOMIC IMPRINTING A small subset of human genes are expressed differently depending on the parent who contributes them to a child's genetic makeup.

This phenomenon has helped researchers understand the causation of three well-known genetic disorders Prader-Willi, Angelman, and Beckwith-Wiedemann syndromes.

PRADER WILLI

GENOMIC IMPRINTINGIn the 1980s, researchers studying Prader-Willi syndrome and Angelman syndrome noticed that both disorders were caused by a deletion on the long arm of chromosome 15 in the very same region, extending from 15q11 to 15q13. This finding was surprising, because the two syndromes have markedly different phenotypes.

GENOMIC IMPRINTING Children with Prader-Willi syndrome have severe mental retardation, poor muscle tone, small hands and feet, and a voracious appetite (hyperphagia) that begins in childhood.

As a result, they are often obese by adolescence.

Children with Angelman syndrome, on the other hand, do not speak, are often hyperactive, and suffer from seizures and sleep disturbances.

GENOMIC IMPRINTING In the late 1980s, advances in molecular genetics revealed that the different expressions of the same deletion on the same chromosome were determined by the sex of the parent who contributed that chromosome.

Children with Prader-Willi syndrome had inherited their father's copy of chromosome 15 while the children with Angelman syndrome had inherited their mother's.

Highly specific diagnostic tests for these two disorders have been developed within the past decade.

BEHAVIORAL PHENOTYPES Examples of behavioral phenotypes are those associated with Down, Prader-Willi, and Williams syndromes. Children with Down syndrome have an increased risk of developing early-onset Alzheimer's disease. They are usually quiet and good-tempered, but may also be hyperactive and impulsive. Their behavioral phenotype includes delayed language development and moderate to severe mental retardation.

BEHAVIORAL PHENOTYPES A behavioral phenotype is the characteristic set of behaviors found in patients with a genetic disorder. Behavioral phenotypes include patterns of language usage, cognitive development, and social adjustment as well as behavioral problems in the narrow sense. It is important for psychiatrists who treat children and adolescents to understand behavioral phenotypes, because they are better able to identify problem behaviors as part of a genetic syndrome and refer children to a geneticist for an accurate genetic diagnosis.

DOWN SYNDROMEDown syndrome is the name for the pattern of physical features and disorders that usually occur from an extra 21st chromosome. Chromosomes are the materials that store people's genetic information. 47,XY,+21 OR 47,XX,+21

DOWN SYNDROMEDown syndrome have an extra chromosome, the body's natural balance is upset. This upset in balance leads to various birth defects and problems of growth and development. Many of the birth defects in people who have Down syndrome are like those seen in other children. People with Down syndrome simply are likely to have birth defects more often than others.

DOWN SYNDROMEDown syndrome is usually caused by an extra 21st chromosome. Most people have 46 chromosomes in each cell of their bodies, exist in pairs, for a total of 23 pairs. The pair associated with Down syndrome is called pair 21. Why an extra copy of this chromosome causes the features of the Down syndrome is not known

DOWN SYNDROMEGenetic material on the 21st chromosome pair directs the formation of compounds that the body needs to perform various functions and for normal development. The overload of information caused by the extra copy leads to the Down syndrome. Scientists have recently identified 99.7% of the genes on this chromosome. This knowledge may lead to a better understanding of the syndrome and, perhaps, even treatments for some of the effects.

DOWN SYNDROMEDown syndrome occurs in roughly 1 of every 750 births. There is a strong link between the risk of Down syndrome and the age of the mother. The risk of having a child with Down syndrome is less than 1 in 2,500 among young women. This risk increases to roughly 1 in 350 when women reach 35 years of age. After age 45, the risk is roughly 1 in 25.

Symptoms & Signssmaller-than-average physical size poor muscle tone, which tends to improve somewhat over time a small head, the back of which is flatter than average flat facial profile upward slant of the eye slits an extra fold of skin at the inner corners of the eyes small mouth with a tendency to protrude the tongue small hands with short fingers and a single crease across the palms congenital heart disease, or heart defects that are present at birth learning disabilities an IQ that is rarely higher than 50 (with normal IQ being around 100) faster aging process, with a tendency to develop diseases of aging, such as Alzheimer's disease, at a relatively early age

DOWN SYNDROMEPeople with Down syndrome are more at risk for some diseases and conditions, including: leukemia gastroesophageal reflux disease (GERD) and other digestive disorders frequent ear infections, including acute otitis media diabetes hypothyroidism, or a low level of thyroid hormone lung infections, such as pneumonia Alzheimer''s disease, which causes memory loss and impaired thinking

DOWN SYNDROMEThe life span for people with Down syndrome is shorter than average. Congenital heart disease is the leading cause of death in infants with Down syndrome. Otherwise, 3 of 4 people with Down syndrome reach 30 to 35 years of age. Common causes of death in older individuals include lung disease, infections, hepatitis, and leukemia, a cancer of the blood. Chronic infections of the eyes and nose, tooth disease, and thyroid gland problems are common at all ages.

DOWN SYNDROMEDown syndrome is not contagious. Males with Down syndrome have not been known to have children and females rarely do. Therefore, the disorder usually is not passed from one affected person to another. Possibly because of genetic reasons, parents who have had one affected child are at slightly higher risk than others to have another affected child. In some cases, the risk may be much higher if the parents have certain genetic problems. For this reason, genetic counseling for families of people with Down syndrome may be helpful.

DOWN SYNDROME

DOWN SYNDROME

Robertsonian Translocation

Mental retardationMental retardation is defined by three things. First, the person must have had the condition since childhood, or age 18 years or younger. Second, the person has a score of 70 or less on intelligence tests, or IQ tests. Third, the person has limitations in at least two aspects of living skills, such as:

communication education, including reading, writing, and basic math motor function personal care, such as bathing, dressing, eating, and toileting social skills thinking skills, such as decision making, problem solving, and self-direction working

Mental retardationPeople with mental retardation have reduced intellectual function. Sometimes it is because the brain has not formed properly. Or the brain is damaged after the child is born.

Mental retardationMore than 500 genetic disorders can cause mental retardation. Three are listed here: Down syndrome fragile X syndrome phenylketonuria, or PKU