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  • DNA Banking for Medical Information

    Edwin M. Knights Jr., M.D.

    Although we are grouping mental and neurological diseases together, the fact that there’s overlapping symptomatology is deceptive because we’re dealing with a diversity of diseases, many of which are very common. Just how common mental illness is depends upon who did the survey, when it was done and what criteria are used. Some of the results tax credibility. In 1962 it was reported that 81.5 percent of Manhattan’s residents showed signs of mental illness. Were the epidemiologists from New Jersey or Connecticut? The figures seem somewhat skewed!

    Some studies have suggested that one person out of four has significant mental disease. A suggested test: Think of your three best friends. If all of them are perfectly normal -- well, how about you? !

    Tracing mental disease in your family can be difficult, unless your relatives were institutionalized. Brief episodes of balmy behavior are so common that investigators tend to confirm the diagnosis by looking for clustered signs and symptoms accompanied by inability to function. Ignore data collected from all teenagers and avid sports fans, especially basketball fans in March. Symptomatology varies with the sport. Baseball fans can undergo wide mood swings on a daily basis. With football fans it’s a seasonal weekly phenomenon, and whether it is bipolar or unipolar has a positive geographic correlation. Devotees of curling exhibit remarkable mental stability, rarely demonstrating any emotion except for repetitive sweeping with brooms.!

    Temporary aberrations in mental stability overshadow the reality that around 15 to 20 percent of the overall population suffers from a recognized mental illness at any given time, but these figures do include a significant number of addictive problems. These mental illnesses are not only common but are serious enough to impair thinking, cause emotional instability, stiffle motivation, posing major obstacles to normal social interation for many children and adults. We will later look at mental retardation, the product of over 350 inborn errors of metabolism which lead to conditions such as Down syndrome and Fragile X. !

    Molecular Genetics of Mental Disorders!

    The U.S. Public Health Service set a high priority on studying the molecular genetics of mental disorders and the National Institutes of Mental Health (NIMH) are sponsoring research projects employing the latest available diagnostic and analytic procedures to study large enough samples to prove statistically significant data to identify genomic regions which might harbor loci increasing susceptibility to schizophrenia, bipolar disorder, or early-onset recurrent unipolar depression. They also are conducting research to find the chromosomal locations of these loci. Their goal is to use this genetic information to improve diagnosis, treatment and prevention of diseases. It’s not easy, because of the complex interrelationship between genetic and non-genetic contributions to these illnesses. Although familial occurence of some of the diseases has been recognized for some time, the transmission is usually not of simple Mendelian type and identification of loci conferring susceptibility or otherwise influencing the clinical course hasn’t advanced rapidly. After identifying the appropriate genetic loci, it will still be necessary to devise means of modifying or neutralizing them to achieve the desired effects. We will review some of common entities and see what progress is being made. Studies involve finding out how many loci are involved in heritability, how dissimilar they are, and how they all interact. Already, some promising sites have turned out to have little influence, inconsistent effects, and even false positive results. !

    ANXIETY DISORDERS!

    There are about seven types of anxiety disorders and many varieties of mood disorders, including manic-depressive (now called unipolar and bipolar), schizophrenia, anoroxia and others. In children and adolescents 9 to 17, the distribution is: 13 percent with anxiety, 6.2 percent with mood disorders, 10.3 percent with disruptive disorders and perhaps 2 percent where there is associated substance abuse. The estimated direct costs in the U.S. in 1990 were estimated at $78.6 billion. The NIMH are focusing DNA research on these mental diseases. Diagnostic information and blood samples are sought from affected persons and their relatives. Where possible, cell lines are established with transformed cells so that unlimited quanitites of DNA can be made available for research. The research protocols are of three types:!

    Linkage studies are designed to find genes which control susceptibility to mental disorders!

    Linkage-disequilibrium studies are done on isolated populations with genealogical evidence that one or more founding members transmitted the gene. Concentrating efforts on a limited group makes success in locating susceptibility genes much more likely. Association studies are done, in which the investigator seeks a version of a gene which varies between affected and non-affected individuals. After locating the genetic anomalies, they can be further tested and identified with the eventual hope of using them for early diagnosis and perhaps “tailored” treatment of a disorder.!

    ATTENTION-DEFICIT HYPERACTIVITY!

    Because of its strong hereditary influence, one of the conditions already studied extensively is attention-deficit hyperactivity disorder (ADHD). Appearing early in childhood, symptoms include inattention, impulsive behavior and hyperactivity. Because other conditions can mimic this disorder, it can be difficult to diagnose. There is an increased rate of occurence in first degree relatives. The genetic pattern in ADHD suggests the dominant single major locus type of transmission of classical Mendelian inheritance. Confusion results because the symptoms are not always full-blown. Geneticists explain this as representing “an incompletely penetrant dominant or additive autosomal single major locus.” As a result, only 46 percent of boys and 31 percent of girls with ADHD gene will appear to have this disorder.!

    AUTISM!

    Autism is a childhood disease presenting with mild to severe symptoms which include impaired ability to communicate, either verbally or nonverbally, and impaired social interaction, in which the child seems unaware of feelings of others and has no appropriate social responses. Body movements may be repetitive and there is inappropriate preoccupation with objects or routines. Males seem more involved than females. Inheritance of autism is not sharply defined because it’s hard to separate genetic from environmental causes. The complex transmission probably includes many genes, each having a relatively weak effect.!

    Asperger sydrome is considered a form of childhood autism, with many similar features. The patients are of normal or above normal intelligence but exhibit impaired social interaction, repetitive behavior patterns, inflexible adherence to routines and preoccupation with certain activities. Links have been found to specific chromosomes and X-linked varieties have been described. A study of 38 Finnish families found 1/3 of probands had related conditions in first degree relatives. !

    BIPOLAR DISORDER!

    Long known as “manic-depressive” disorder, it is now divided into two varieties: Bipolar, with mood swings between manic and depressive states, and unipolar when the sole symptom is depression. The first case I ever saw, as a medical student, was a highly successful stock broker, which horrified me at the time and I wondered how this behavior went undetected on Wall Street. Years later I realized he blended right in with many of his cohorts.!

    The risk of having bipolar disorder in the U.S. is about 0.8 percent, according to the NIMH. International studies report lifetime risks of 0.3 to 1.5 percent and are equal in men and women. Bipolar disorder usually starts in adolescence or early adult life. Overuse of drugs or alcohol occurs in over 50 percent of affected individuals.!

    About half of the patients with bipolar illness have a family history of the disorder, and there are “multiplex families” in which it occurs in many members involving several generations. There is no Mendelian pattern of inheritance; if you have bipolar disorder but your spouse does not, nor do other family members, there is about a 10 percent chance that your child will develop it. Familial risk is said to be higher with bipolar than unipolar disorders. Complex inheritance patterms point to multiple interacting genes. While markers have been found on chromosomes 18 and 22, no single one has been replicated. All of the susceptibility loci, the recurrence risks or interactions are not yet known. An excellent review of the subject is on the NIMH web site. Konradi et al. have found molecular evidence for mtDNA dysfunction in bipolar disorder.!

    DEPRESSION!

    The many reported epidemiological studies show considerable ethnic variability, with higher risks in males in England, Sweden and Iceland. In the United States, women have a 21 percent chance for a major depressive episode vs. a 13 percent rate in men. There was a progressive increase in the rates of depression for all ages between 1960 and 1975, with the risk of depression consistently 2 to 3 times higher among women than men, and this trend has continued. Family studies have found the age-adjusted risk for unipolar depression in a first degree relative in the range of 5 to 25 percent. The risks seem to be higher when the early-onset cases are involved. Depression is a major cause of suicide in teen-aged children and not easily diagnosed. Symptoms include a depressed mood, little interest in sports or other social activities, insomnia, fatigue and feels of guilt with low self-esteem.!

    As in many other mental states, depression has a complex genetic pattern and a significant environmental impact. Multilocus genetic effects, rather than shared environmental ones, seem to be more important risk factors.!

    So far, the pattern seems to be of multiple genes have individually weak effects. !

    DOWN SYNDROME!

    Down syndrome is the most common cause of mild to moderate mental retardation, occurring in 1/ 800 live births. From 3,000 to 5,000 babies are born each year with this disorder, involving about 250,000 families in the United States. It has benefitted from intensive medical research.!

    For some time it has been recognized that Down syndrome is the results of abnormalities affecting chromosome 21. There are three variations that are responsible. In 92 percent of the cases there is an extra chromosome 21 in all cells of the individual, having originated during the development of either the sperm or the egg. This condition is called trisomy 21. In about 2 to 4 percent of cases, the extra chromosome 21 is present in some, but not all cells, because of an early error during chromosome division has resulted in some of the cells acquiring this extra chromosome. The result is known as mosaic trisomy 21. In each of these situations, then, some or all of the body’s cells have 47 instead of the usual 46 chromosomes. There is a third type of Down syndrome, in 3 to 4 percent of cases, in which the body has the usual 46 chromosomes in each cell. Material from a chromosome 21 becomes adherent or translocated to another chromosome, resulting in an excess of chromsome 21 material. This type of Down syndrome is translocation trisomy 21.!

    Environmental factors or behavioral activity of the parents haven’t been implicated, maternal age is important -- so much so, that many physicians recommend that women becoming pregnant at age 35 or old undergo prenatal testing for Down syndrome. Although at the present time, only 9 percent of pregnancies occur in women aged 35 or older, about 1 /4 of the babies with Down syndrome come from in this age group. The table created by E. G. Hook and A. Lindsjo gives a dramatic view of the increased chance of Down syndrome in progressively older mothers. (Ref.: Table 1) !

    Table l.
    RELATIONSHIP OF DOWN SYNDROME TO MOTHER’S AGE

    Mother’s Age Incidence of Down Syndrome
    Under 30 Less than 1 in 1,000
    30 1 in 900
    35 1 in 400
    36 1 in 300
    37 1 in 230
    38 1 in 180
    39 1 in 135
    40 1 in 105
    42 1 in 60
    44 1 in 35
    46 1 in 20
    48 1 in 16
    49 1 in 12
    Children with Down syndrome tend to be small, with slower physical and mental development. Mild to moderate mental retardation occurs in most, but some have no mental retardation and others are are severely retarded. Physical abnormalities can include flattening of the back of the head, slanted eyelids with skin folds at the inner corners of the eyes, nasal bridge depression, decreased muscle tone, and small ears, mouth, hands and feet. Other features which may or may not be present are hearing deficits in one or both ears (in 66 to 89 percent of children with Down syndrome), congenital heart disease, visual disorders and hypothyroidism.

    Prenatal Screening

    Prenatal screening can help identify pregnant women whose babies might be at risk for heritary birth defects, including Down syndrome. They are not diagnostic but positive results can be confirmed with other studies.

    They are also advocated by many obstetricians even if there is no apparent risk. If any hidden abnormalities are found, genetic counseling and discussion of the family medical history may be indicated. Often three of these procedures are done at once, as a “triple test,” on a small sample of the mother’s blood. The three tests are maternal serum alpha fetoprotein, chorionic gonadotropin and unconjugated estriol. Results may suggest Down’s syndrome of the fetus. Additional types of diagnostic testing may be indicated, such as alpha fetoprotein, HCG and estriol to rule out other congential defects. A recent study in the U.S. shows that improved medical care has doubled the life span of people with Down syndrome since 1983.

    Specific Prenatal Testing

    Prenatal tests that can be performed to find evidence of Down syndrome include amniocentesis, chorionic villus sampling (CVS) and percutaneous umbilical blood sampling (PUBS). As none of these are without risk, as well as benefits, genetic counseling may be of value. The umbilical blood sampling is most accurate of the three and is sometimes used to confirm the results of the other two follow-up procedures. It can’t be done until late in pregnancy (18th to 22nd weeks) and has the greatest risk of miscarriage.

    Newer testing methods under study include analyzing fetal cells which are normally circulating in the mother’s blood. Another type of diagnosic approach in preimplantation diagnosis, or blastomere analysis before implantation (BABI), permitting detection of chromosome imbalances before an embryo is implanted during in vitro fertilization. The method enables a genetic diagnosis to be made prior to implantation and has been used successfully in cases of cystic fibrosis and Tay Sachs disease, offering a possible alternative to prenatal testing.

    A Strategy for X-Linked Disorders

    Costa, Benachi and Gautier recommend a much safer strategy for the prenatal diagnosis of X-linked disorders. Cell-free DNA circulating in maternal plasma offers the possibility of a noninvasive approach, enabling the determination of the sex of the fetus with 100 percent accuracy when maternal serum is analyzed during the first trimester of pregnancy. They determined the sex of the fetus in 131 pregnant women by analysis of maternal serum between 10 and 13 weeks of gestation, followed by chorionic-villus sampling only if the fetus was identified as a male. Chorionic-villus sampling was not performed if the fetus was a female. Fetal sex was confirmed later in the pregnancy by ultrasonography. All women received genetic counseling and gave written informed consent.

    In two cases, the sex of the fetus couldn’t be determined because of spontaneous miscarriage, but in all other cases, the laboratory diagnosis was confirmed by the actual fetal sex. Identification of all 70 male fetuses was confirmed by karyotyping of chorionic villi, while the sex of the female fetuses was confirmed by ultrasonography, averting the potental hazard of loss of female fetuses. If ultrasonography happens to reveal a misdiagnosis of sex, prenatal diagnosis is still possible by means of amniocentesis.

    The proposed strategy results in a substantial decrease in the use of risky, unnecessary and costly diagnostic tests such as karyotyping and molecular analysis of chorionic villi in the case of female fetuses. The authors listed the X-linked genetic diseases that were included in their series. (Ref. Table 2)

    Table 2. X-Linked Genetic Diseases Studied with New, Safer Strategy
    (Costa J-M, Benachi A, Gautier E: N Engl J Med 2002; 346:1502)
    Disease No. of Cases
    Hemophilia 39
    Muscular dystrophy 31
    X-linked mental retardation 8
    Adrenoleukodystrophy 7
    Alport’s syndrome 7
    X-linked severe immunodeficiency 6
    Retinitis pigmentosa 6
    X-linked hydrocephalus 5
    Anhidrotic ectodermal dysplasia 4
    Hunter’s syndrome 3
    Menkes’ symdrome 3
    Lesch-Nyhan syndrome 2
    Other 10

    Studies of the Parents

    It is important to study the chromosomes of parents of a child who has the translocation type of Down syndrome. Usually this extra chromosome 21 is attached to chromosome 14, 21 or 22. At least 1/3 of the parents of such children will be a balanced carriers of the translocation. If neither of the parents is a balanced carrier, there is no increased risk of having a Down syndrome baby in future pregnancies. Chromosome 21 research has found that it is derived from the mother in 88 percent of the cases, from the father in 8 percent, and there are mitotic mutations in cell division in the other cases. Down syndrome research continues, including a mouse model for studying the developmental aspects. These mice have genes similar to those on human chromosome 21 on their number 16 chromosomes. It is hoped that it will be possible to find means of intervention and specific treatments.

    EATING DISORDERS

    Eating disorders usually begin in adolescence or early adulthood and may present as anorexia nervosa or bulimia nervosa. Anorexia nervosa patients refuse to maintain the minimum recommended body weight for the age and height, with an intense fear of gaining weight, a distorted body image and amenorrhea in women. In bulimia nervosa there is persistent overconcern with body shape and weight, frequent binge eating during whith uncontrolled consumption of food and self-induced vomiting. The individual may use fasting or strict dieting, laxatives, diuretics or repeated vigorous exercise to prevent weight gain.

    Both types of eating disorders are more prevalent in females. Some family studies showed a slightly icnreased rate of mood disorders among relatives. High heritability rates have been reported for both conditions, with those for anorexia nervosa being slightly higher. A multi-centered international team identified a genetic link to anorexia nervosa on chromosome 1 in 2002. The disease is almost certain to have multiple genetic influences.

    FRAGILE X SYNDROME

    Fragile X is the most common form of intellectual disability, more commonly known as mental retardation. It is found throughout the world, affecting one in 1,500 males, one in 2,500 females; one in 260 females are carriers. Carrier females have a 30 to 40 percent chance of giving birth to a retarded male and a 15 to 20 percent chance of bearing a retarded female. There will be a maternal family history for a relative with mental retardation or developmental and learing disabilities.

    This is a genetic syndrome carried by the X chromosome. Females have two X chromosomes, one from each parent. Males have one, inherited from the mother. If the single X chromosome in a male is affected, the male will have the fragile X syndrome. Females having one of the two X chromosomes involved are somewhat less affected. The discovery of the fragile X gene (FRAXA) occurred in 1991.

    Most males having a full mutation are mentally retarded, with typical features of fragile X. Of females with full mutations, 1/3 have normal intelligence, 1/3 are borderline, and 1/3 are mentally retarded. There is associated gene inactivation in severe cases, which causes an important part of the syndrome. In a few fragile X patients there is a different genetic mechanism responsible. The American College of Medical Genetics makes the following recommendations for diagnostic testing:

    * Individuals of either sex with mental retardation, developmental delay or autism, especially if they have (a) any physical or behavioral characteristeics of fragile X syndrome, (b) a family history of fragile X syndrome, or (c) male or female relatives with undiagnosed mental retardation. *Individuals seeking reproductive counselling who have (a) a family history of fragile X syndrome or (b) a family history of undiagnosed mental retardation. *fetuses of known carrier mothers. *patients who have a cytogenetic fragile X test that is discordant with their phenotype. These include patients who have a strong clinical indication (including risk of being a carrier) and who have had a negative or ambiguous test result, and patients with an atypical phenotype who have had a positive test result.

    PANIC DISORDER, ANXIETY DISORDERS, AGORAPHOBIA, OBSESSIVE-COMPULSIVE DISORDERS

    The onset of panic disorder is most often between ages 15-37, marked by recurrent unanticipated panic attacks during a sharply defined interval of minutes to hours. These uncomfortable episodes of intense fear or discomfort are accompanied by trembling, accelerated heartbeat, sweating, chest pain, dizziness, shortness of breath and other related symptoms, including fear of dying. The affected individual becomes persistently apprehensive about recurrence of similar experiences. There are some substances, such as caffeine, carbon dioxide, sodium lactate and cholecystokinin which can bring on an attack.

    Panic attacks are about twice as common in females. Studies have found a risk for panic disorder of about 14 percent in first-degree relatives and over 95 percent in second degree relatives. A review with meta-analysis of panic disorder, generalized anxiety disorder, phobias and obsessive-compulsive disorders in 2001 found all had significant familial aggregations. The role of non-shared environment was significent; the role of family environment uncertain. There are multiple recent reports of various genetic loci being linked to panic disorder and related conditions.

    SCHIZOPHRENIA

    Schizophrenic patients have abnormal thoughts, perception of self and of others, along with strained social relationships. Psychotic symptoms are variable, but can include persistent paranoid obsessions, delusional disorders and inappropriate moods or behavior. Worldwide the incidence is about 1 percent. There is considerable heritability, especially in an early-onset variant. One study found heritability of 89 percent with no environmental contributions. Another showed 74 percent, also with no environmental relationship. But the NIH states, “The modes of ineritance of schizophrenia and mood disorders are complex and likely involve environmental factors and multiple genes in interaction.”

    The mode of inheritance is complex and appears to involve numerous interacting genes, and scientists are still debating whether the condition is dominant or recessive. Although genetic evidence itself so far in schizophrenia seems to be rather schizophrenic, the NIH has confidence that fast new genotyping and mapping of polymorphisms will soon bear fruit. Prior research depended largely upon three types of procedures:
    • localizing key zones on chromosomes by linkage analysis with family data
    • study of haplotypes for linkage disequilibrium mapping
    • direct detection of functional variants in affected individuals by means of association analysis.
    New methods of large-scale data collection and analysis will enable whole-genome studies and offer opportunities for major progress in understanding the genetic role in mental disorders. Improved, more stringent diagnostic criteria are urgently needed in order to provide precise linkage evidence for the molecular genetic research. Statistics are no better than the data provided -- as the old saying goes, “garbage in, garbage out.” World-wide uniformity for diganosis, perhaps based upon newly created molecular pathology tests, would enhance the value of all research and place scientists on the fast track to understanding and dealing successfully with mental diseases.

    Molecular Genetics and Neurodegenerative Disorders

    Some neurodegenerative diseases are commanding increasing attention by afflicting our burgeoning burden of aging humans. Chronic and progressive, they place ever-increasing psychological and financial loads on society as they relentlessly expand the numbers of individuals who are no longer self-sufficient. The pathologic features of these diseases have long been recognized, as they selectively and symmetrically disrupt and destroy motor, sensory and cognitive functions.

    In contrast to the mental disorders, the inheritance patterns are clearly apparent in many of these diseases. (Table 3) Family history is present in nearly every case of Huntington’s disease, and autosomal dominant traits are demonstrable in up to 10 percent of amyotrophic lateral scerosis (AMS), Alzheimer disease and Parkinson’s disease cases. Mutant genes have been demonstrated in over 50 nervous system diseases. These few include some you might encounter in your medical pedigree.

    ALZHEIMER DISEASE

    Alzheimer Disease (AD), affecting over 4 million people in the United States, is the leading cause of cognitive impairment and the fourth leading cause of death in adults, killing over 100,000 annually and costing more than $60 billion. There is an early-onset familial form of Alzheimer disease (AD), but risk of AD rises sharply with age most cases appearing in the 7th to 9th decades of life, where it causes senile dementia of the Alzheimer type.

    The two main types of AD are familial and sporadic. It is now recognized that at least four genes can cause Alzheimer disease. Offspring in the same generation have a strong chance of developing AD if one parent had the disease. The sporadic, or late-onset type (although it occurs as young as age 35) is much more common and is related to the APOE gene on chromosome 19. This gene is in several forms, or alleles, and one of these alleles greatly increases the risk for AD. That APOE is present does increase the risk but doesn’t define the degree of risk, so testing for the allele is currently more valuable for predictive screening.

    Because of the physical, psychological and social impacts, adults having one parent afflicted with AD are becoming very concerned about their own risk for the disease, and some seek information from clinicians about their own APOE. Meanwhile, some groups have recommended against disclosing this information to unaffected individuals. As a result, a multi-institutional study, Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) was established in 1999 by the National Human Genome Research Institute to establish the risk of providing this information to offspring of an AD patient. Resultant research has provided predictive risk curve graphs for first degree relatives of various ages, but there are many aspects of this problem, such as appropriate education and genetic counseling, which remain to be resolved.

    Warning: Before having this test performed, a subject should be aware of its possible implications if it becomes a part of the individual’s medical records. One can only speculate on how employers, insurance companies and health care providers would react to this information. We hope that this dilema will be resolved by the discovery of efficent means of slowing the progression or curing AD. Table 5 shows some genetic factors which link other neurodegenerative disorders to Alzheimer disease.

    Table 4. Genetic Factors Linking Other Diseases to Alzheimer Disease
    (Modified from Martin JB: Mechanisms of Disease: Molecular basis of the neurodegenerative disorders. N Engl J Med 1999; 340: 1970-1980)

    Genetic Factor Chromosome Involved
    Down syndrome 21
    Amyloid precursor protein mutation 21
    Presenilin 1 mutation 14
    Presenilin 2 mutation 1
    Alpha2-macroglobulin mutation 12
    Apolipoprotein E (APOE) e-4 allele 19

    HUNTINGTON’S DISEASE

    Huntington’s disease (HD) was first reported by George Huntington in 1872 and for many years the disease was known as “Huntington’s Chorea” because of the involuntary, irregular movements he described in his cases. It has long been recognized as being familial, an autosomal dominant state with high penetrance passed from parent to children and equally affecting either sex. The disorder does not skip generations and often it appears earlier in succeeding generations. The defective gene was identified on chromosome 4 back in 1983, which is almost a prehistoric era in the world of molecular genetics! Further studies found the source of mutation in the gene and determined it to consist of a series of repeated units of information, known as cAG repeats. Only about 10 percent of HD cases appear before age 20, with the peak occurrence during the 4th and 5th decades. The younger-aged patients usually inherited HD from their father, and old-aged from the mother. Cases becoming symptomatic under age 20 are known as juvenile HD and are usually also accompanied by progressive Parkinsonism, dementia, ataxia and seizures. Adult cases more often present with clumsiness, slowed movement and rigidity. In juvenile HD, death is usually in 8 to 10 years; the illness lasts about 15 years in adult HD. The clinical course is complicated by progressive motor dysfunction, dementia, dysphagia and incontinence.

    The HD gene is called the huntingtin gene and can be used to confirm a diagnosis where HD is suspected in adults or juvenile HD in minors, plus it is a predictive test for asymptomatic relatives at 50 percent risk. It is also used for prenatal diagnosis in high risk families.

    Because of the complexity of the DNA testing for Huntington disease, the American College of Medical Genetics prepared updated technical standards and guidelines for testing laboratories in 2004. These are not intended to establish fixed diagnostic criteria but to act as a helpful guide for using those procedures which are currently available and providing some uniformity in the methodolgy.

    Several drugs have been used to treat HD, but these help control emotional and movement problems. In February, 2002, a drug called cystamine was reported by L.Steinman, M. Karpuji and associates to aleviate tumors and prolong life in mice with the gene mutation for HD. It seems to stop the formation of huntingtin clumps in the brain and scientists are hopeful it might prevent them in humans. Research efforts are being expanded to evaluate this new treatment.

    MULTIPLE SCLEROSIS

    Multiple sclerosis (MS) is one of the most common neurological diseases of young adults, with between 250,000 to 300,000 patients in the United States and 200 new cases occurring each week. The highest prevalence rates are in Iceland, Scandinavia, British Isles and the countries settled by their emigrants. An underlying genetic susceptibility is clearly apparent in its etiology, with familial clustering, and a strong case was by Dr. Charles M. Poser in 1994 that Vikings were instrumental in spreading this susceptibility in those areas and other parts of the world. He felt that the custom of capturing and keeping or selling women and children, plus the flourishing slave trade in men, were important factors in this genetic dissemination.

    As MS strikes seemingly healthy young adults with normal life expectancies and has a median duration of over 30 years, it creates an enormous economic impact, with medical and supportive care costs of $2.5 billion each year.

    Candidate Genes

    MS is an autoimmune neurological disorder, and its etiology is complex. Numerous studies have shown that genes play a significant role in MS susceptibility, and the major histocompatibility complex (MHC) is an important linkage component, but as many as 50 other loci need further identification.

    Genetic analysis has largely focused on candidate genes, comparing the frequencies of marker alleles in groups of patients vs. healthy controls and stastistically analyzing the results. The figure gives the relative risk of an individual developing the disease if her or she carries the particular allele. More productive research has utilized family-based studies, permitting identification of specific haplotypes and better statistical analyses. Modern genetic techniques should make it possible to support or disprove Dr.Poser’s Viking theories.

    Family-Based Studies for Genealogists?

    Family-based studies would appear to be of particular value to the genealogist because they are more adaptable to combining more specific genetic analyses with multiple statistical approaches. All we have to do is become experts in both genetics and statistics! Using this approach it could be possible to create family collections consisting of extended multigenerational pedigrees, affected sib pairs, alone or with parents and other affected sibs. Family-based studies, properly analyzed and interpreted, appear to offer the best opportunities to evaluate linkage and association to a particular marker.

    Environmental Considerations

    There is some evidence for an environmental role in MS. The disease is much more common in northern Europe than southern Europe. An epidemic of MS in the Faeroe Islands was suggestive of a viral agent, but toxins are also under suspicion. The highest reported incidence of cases, at 250/100,000, is in the Orkney Islands off of the coast of Scotland. MS is uncommon in Japan (2/100,000), Asia, Africa and native populations of Oceania and the Americas. Gypsies in Hungary, a high risk area, seem resistant to the disease. If a person’s mother, father, brother or sister has MS, the person’s risk of developing MS is 20-50 times higher; if an identical twin has MS, the risk is 300 times higher. In spite of these statistics, anyone can develop MS, and over 80 percent of the patients have no immediate family history of the disease.

    Genetic Goulash

    The genetic findings represent a real stew, and it seems that there are multiple genetic influences but none are particularly strong. Area 6p21 on chromosome 6 is definitely linked to MS, as combinations of alles from this area render persons susceptible to the disease. Another region that appears in several studies is within chromosome 19q13. A unique Finnish familial connection exists with a gene encoded for myelin basic protein on chromosome 18. DNA studies may open up the possibilities of new treatments or more effective uses of ones already available.

    PARKINSON DISEASE

    Parkinson disease (PD) is the second most common neurodegenerative disorder, second only to Alzheimer disease, affecting 2 percent of people over age 65. About 50,000 cases are reported each year. It is the result of degeneration of motor neurons in the brain, nerve cells which control muscle movements. The loss of these cells causes a shortage of dopamine, a neurotransmitting chemical, so that body movements are impaired. Symptoms start with a tremor of a limb when the body is at rest, then movements become slow and difficult, with rigidity, a stooped posture and a shuffling gait. Facial expressions are reduced and the disease can also be associated with personality changes, dementia, sleep disturbances, and a soft voice with slurred speach.

    There is increasing evidence of a genetic role in PD, especially in the early-onset variety where there is continual reporting of new linkage data and most cases occur in specific family groups. Defective genes that regulate the molecules alpha synuclein and parkin occur in many cases, with alpha synuclein involved in both genetic and sporadic types. Genetic mutations of the gene encoding parkin cause autosomal recessive PD. To date, 8 defective genetic markers are known to be associated with dominant or recessive forms of PD. There is also evidence that mitochondrial abnormalities, which affect cellular energy, can contribute to PD pathogenesis.

    There are other genetic factors which point to an increased risk for PD, such as mutations found in some patients with Gaucher’s disease, a recessively inherited disorder affected the storage of glyolipids. Influenza and other viruses have long been implicated with development of Parkinsonism; environmental toxins and infections are also being investigated. But the most promising research appears to be genetically-related.

    TOURETTE’S SYNDROME

    Tourette’s syndrome is a neurological disorder that usually appears before the age of 18, occurs in all ethnic groups and affects males three to four times more often than females. It is characterized by repeated, involuntary body movements (tics) and uncontrollable vocal sounds (vocal tics), not necessary presenting concurrently. Tics can occur frequently during the day and over a period of a year. Once thought to be rare, the American Academy of Physicians states that up to 20 percent of children have at least a transient tic disorder at some point, but the diagnosis of Tourette’s syndrome is usually reserved for the more complex and severe cases. The tics can be accompanied by attention deficit/hyperactivity disorder, obsessive-compulsive behavior and learning disabilities.

    The syndrome is genetically inherited in an autosomal dominant pattern of genetic vulnerability for variable types, from mothers or fathers to sons or daughters. Ninety-nine percent of males with Tourette’s syndrome are symptomatic, but only 70 percent of females. The genetic degree of expression of symptoms is referred to by molecular geneticists as penetrance. Although researchers have been seeking the Tourette genetic locus for over 20 years, they are still “on the threshold” of finding it. Diagnosis at this time is the old-fashioned way, by history and physical examination, as there are no prenatal, biochemical or genetic tests specific for the syndrome. There is one potential genetic tool, but it is to protect the patient, rather than for diagnosis. Rare children are genetically incapable of metabolizing fluoxetine, one of the drugs that is effective in controlling tics. A nine year-old boy died from very high blood levels of this drug. It is now possible to identify this type of genetic polymorphism in patients, but unfortunately it is not yet practical because of the time and difficulties involved trying to get such a procedure performed. Withholding medication is not always an option because many of the affected children vocalize socially inappropriate insulting words and phrases, known as coprolalia, which can be quite upsetting to their peers. This could result in the Timex syndrome for the unfortunate child, who takes a licking but keeps on ticking.

    SELECTED REFERENCES
    Genetics and Mental Disorders: Report of NIMH Genetics Workshop
    http://www.nimg.nih.gov/research/genetics

    Molecular Genetics of Mental Disorders, Nat. Inst. of Mental Health 1998
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    Table 3
    EXAMPLES OF INHERITED NEURODEGENERATIVE DISORDERS

      Disease and Site
    Usually Affected
    Mode of Transmission
    Cerebral Cortex
      Alzheimer’ disease Autosomal dominant (3-5%)
      Pick’s disease Autosomal dominant (rarely)
      Lewy body dementia Sporadic
    Basal Ganglia
      Huntington’s disease Autosomal dominant
      Parkinson’s disease Autosomal dominant
      Parkinson’s disease Autosomal recessive
    Brain Stem and Cerebellum
      Friedreich’s ataxia Autosomal recessive
      Multiple system atrophy Sporadic
    Motor System
      Amyotrophic lateral sclerosis Sporadic or autosomal dominant
    (1-10% of cases)
      Spinal and bulbar muscular atrophy X-linked
      Spinal muscular atrophy Autosomal recessive
      Familial spinal paraparesis Autosomal dominant or recessive

    Adapted from Martin, Joseph B: MECHANISMS OF DISEASE: Molecular Basis of the Neurodegenerative Disorders. N Engl J Med 1999; 340:(25), p. 1971
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