Genetic Diseases Overview Medical Author: Melissa Conrad Stppler, MD Medical Editor: William C. Shiel Jr.

, MD, FACP, FACR What is a genetic disease? A genetic disease is any disease that is caused by an abnormality in an individual's genome. The abnormality can range from minuscule to major -- from a discrete mutation in a single base in the DNA of a single gene to a gross chromosome abnormality involving the addition or subtraction of an entire chromosome or set of chromosomes. Some genetic disorders are inherited from the parents, while other genetic diseases are caused by acquired changes or mutations in a preexisting gene or group of genes. Mutations occur either randomly or due to some environmental exposure. What are the different types of inheritance? There are a number of different types of genetic inheritance, including the following four modes: Single gene inheritance Single gene inheritance, also called Mendelian or monogenetic inheritance. This type of inheritance is caused by changes or mutations that occur in the DNA sequence of a single gene. There are more than 6,000 known single-gene disorders, which occur in about 1 out of every 200 births. These disorders are known as monogenetic disorders. Some examples of monogenetic disorders include: cystic fibrosis, sickle cell anemia, Marfan syndrome, Huntington's disease, and hemochromatosis. Single-gene disorders are inherited in recognizable patterns: autosomal dominant, autosomal recessive, and Xlinked. Multifactorial inheritance Multifactorial inheritance, also called complex or polygenic inheritance. Multifactorial inheritance disorders are caused by a combination of environmental factors and mutations in multiple genes. For example, different genes that influence breast cancer susceptibility have been found on chromosomes 6, 11, 13, 14, 15, 17, and 22. Some common chronic diseases are multifactorial disorders. Examples of multifactorial inheritance include: y heart disease, high blood pressure, Alzheimer's disease, arthritis, diabetes, cancer, and obesity. Multifactorial inheritance also is associated with heritable traits such as fingerprint patterns, height, eye color, and skin color. Chromosome abnormalities Chromosomes, distinct structures made up of DNA and protein, are located in the nucleus of each cell. Because chromosomes are the carriers of the genetic material, abnormalities in chromosome number or structure can result in disease. Abnormalities in chromosomes typically occur due to a problem with cell division. For example, Down syndrome or trisomy 21 is a common disorder that occurs when a person has three copies of chromosome 21. There are many other chromosome abnormalities including: y Turner syndrome (45,X), y Klinefelter syndrome (47, XXY), and y cri du chat syndrome, or the "cry of the cat" syndrome (46, XX or XY, 5p-).

Diseases may also occur because of chromosomal translocation in which portions of two chromosomes are exchanged. Mitochondrial inheritance This type of genetic disorder is caused by mutations in the nonchromosomal DNA of mitochondria. Mitochondria are small round or rod-like organelles that are involved in cellular respiration and found in the cytoplasm of plant and animal cells. Each mitochondrion may contain 5 to 10 circular pieces of DNA. Since egg cells, but not sperm cells keep their mitochondria during fertilization, mitochondrial DNA is always inherited from the female parent. Examples of mitochondrial disease include: y an eye disease called Leber's hereditary optic atrophy; y a type of epilepsy called MERRF which stands for myoclonus epilepsy with Ragged Red Fibers; and y a form of dementia called MELAS for mitochondrial encephalopathy, lactic acidosis and stroke-like episodes. Down Syndrome trisomy 21 life span of about 40 years Incidence 1 per 700-1,000 births Characteristicsa Children with Down syndrome have one extra chromosome. Physical characteristics include a protruding tongue, thick lips, flat nose, short neck, wide gaps between toes, short fingers, specific health problems, and risks for heart problems and hearing loss. Mental retardation can range from mild to severe. Children often have good visual discrimination skills and may be better at understanding verbal language than producing it. Implications for Care Provide explicit instruction in any delayed skills (e.g., in language). Address health issues such as heart problems and potential feeding difficulties. Sickle Cell Disease autosomal recessive inheritance chromosome 11 Incidence 1 per 500-600 children of African (Black) descent; rates are also elevated in people of Mediterranean descent Characteristicsa Children with this recessive-gene defect develop problems with blood circulation. The disease causes red blood cells to grow rigid, and passage of blood through small vessels causes pain. Children may experience many serious conditions, including stroke, infection, tissue damage, and fatigue. Symptoms become obvious during the first or second year of life. Implications for Care Be alert to medical crises, such as strokes. Offer comfort to children who are tired or in pain. Treatments include blood transfusions, medication for pain and infections, and other medicines to reduce frequency of medical crises. Cystic Fibrosis (CF) autosomal recessive inheritance caused by mutation in the cystic fibrosis conductance regulator gene (CFTR) on chromosome 7q Incidence

1 per 3,300 children from European American backgrounds and 1 per 9,500 children from Hispanic American backgrounds Characteristicsa Children with this recessive-gene defect have glands that produce large amounts of abnormally thick, sticky mucus, which creates serious problems for breathing and digestion. CF is usually noticed in infancy due to persistent coughing, wheezing, pneumonia, and big appetite with little weight gain. Many individuals with CF now live well into their 40s. Implications for Care Be aware of symptoms that require medical care. The condition is often treated with physical therapy, medication, and bronchial drainage. Alzheimers disease is a deterioration of the brain, or dementia, that usually affects people over 60. The disease is caused by a chemical deficiency in the brain cells, which prevents them from passing messages to one another. There is no known cure, but there are drugs that may slow the progress of the disease. Symptoms of Alzheimers disease The first signs of Alzheimers disease are forgetfulness and loss of memory for recent events. Victims may be able to remember quite clearly things that happened long ago but are unable to recall what they had for breakfast or where they left their purse only a few minutes before. As the disease progresses, the patient may have difficulty in speaking and in understanding things, be less able to reason, and lose interest in familiar pastimes and activities, sometimes even in news of relatives and friends. Victims can become emotionally unbalanced, tending to swing between apathy and aggressive behavior. They no longer keep themselves clean. Eventually, they may be so confused that they wander around in a daze and cannot safely be left alone. They may eventually need full-time care in a residential institution. The underlying cause of Alzheimers disease is still unknown, but genetic forms of the disease are known and other possible causes are being intensively investigated. Mitochondria/ maternal inheritance diseases= affected males never produce affected children, but affected females do produce affected children of both sexes when they mate with unaffected male (Kaplan Peds, p 249) = with mitochondrial inheritance, only an affected mother can transmit the disease phenotype, the offspring of affected males are always unaffected = mitochondrial disorders = a group of diverse hereditary disorders caused by genetic mutation of mitochondrial DNA; includes ragged red fiber myopathy; progressive external ophthalmoplegia; Leigh syndrome; myoclonic epilepsy with ragged red fiber myopathy (MERRF); mitochondrial myopathy, encephalopathy, lactic Acidosis (= lactacidosis), and stroke (MELAS); and Lieber optic neuropathy. 1. Leber hereditary optic neuropathy (LHON) = point mutation in subunit 4 of NADH dehydrogenase. (genetics pg 299). Leber hereditary optic atrophy= degeneration of the optic nerve and papillomacular bundle with resulting loss of central vision and blindness, progressive for several weeks, then usually becoming stationary with permanent central scotoma; the age of onset is variable, most often in the third decade; more males than females are affected. Mitochondrial or cytoplasmic inheritance via the maternal lineage, caused by mutation in the mitochondrial gene(s) acting autonomously or in association with each other.

MONOGENIC DISORDERS Monogenic or single gene disorders are caused by individual mutant genes, and frequently they show obvious and characteristic patterns of inheritance. There are approximately 6000 single gene disorders. Individually they are rare, usually affecting from 1 in 10 000, to 1 in 100 000. However, taken all together single-gene disorders are common, affecting 1% of the population. Certain single-gene disorders depend on an environmental trigger before the phenotype is expressed: y Lactose intolerance is not seen in the absence of lactose in the diet. y Severe emphysema in individuals homozygous for 1- antitrypsin deficiency mutations is largely confined to smokers. Single-gene disorders generally follow Mendelian patterns of inheritance, and relatives in families in which these disorders are present are at a much higher risk of developing the condition than the general population as a whole. GENE: A small segment of DNA that codes for the synthesis of a specific protein. Genes are located on the chromosomes. Examples: ABO blood group gene, Rh blood group gene. CHROMOSOMES: genes for the same traits, in the same order. LOCUS: Position or location of a gene on a chromosome. ALLELE: Refers to the different forms of a gene at one locus. GENOTYPE: The specific pair of alleles present at a single locus. This are features seen genetically but may or may not have phenotypic (observable) characteristics. PHENOTYPE: The clinical features or the observable characteristics of an individual determined by a pair of genes at a given locus (or genotype). The phenotype can vary following interaction with modifying genes or the environment. PENETRANCE: The frequency with which individuals carrying a given gene will show the clinical manifestations associated with the gene.

An introduction to pedigrees A pedigree is a record of ones ancestors, offspring, siblings and their offspring that can be used to determine the pattern of certain genes or disease inheritance within a family ( Fig. 8.4 ). Gregor Johann Mendel (July 20, 1822[1] January 6, 1884) was an Austrian[2] scientist and Augustinian friar who gained posthumous fame as the founder of the new science of genetics. Mendelian inheritance of single-gene disorders Mendelian traits generally occur in predictable proportions among the offspring of parents with that trait. The pattern of inheritance seen depends on the chromosomal location of the gene (sex-linked or autosomal) and whether the phenotype is dominant or recessive. Therefore, there are five patterns of Mendelian single-gene inheritance: 1 . Autosomal dominant 2 . Autosomal recessive 3 . X-linked dominant 4 . X-linked recessive 5 . Y-linked/holandric. A sixth pattern of single-gene inheritance, mitochondrial, is non-Mendelian. In medical genetics, a dominant phenotype is one that is expressed in heterozygotes, whereas a recessive trait is expressed only in homozygotes. If the expression of each allele can be detected in the presence of the other, the two alleles are termed codominant. Dominant and recessive inheritance is defined according to clinical phenotypes, which may not always reflect the behaviour of the allele at the molecular level. Mutations in the retinoblastoma protein are recessive at the cellular level because one allele expresses enough protein for biological function. However, at the phenotypic level the predisposition to cancer is inherited dominantly because random loss of the compensating allele always occurs in at least one cell. Autosomal dominant disorders Autosomal dominant inheritance A dominant gene is phenotypically expressed in homozygotes and heterozygotes for that gene. In this pattern of inheritance: y affected parents have affected children this is sometimes termed vertical inheritance, to reflect the pattern seen in genetic pedigrees y unaffected family members usually have unaffected partners and they produce normal children y affected family members usually have unaffected partners, and they produce a 1:1 ratio of normal and affected children y usually both sexes are equally affected, and they are equally likely to pass on the disease. Homozygotes for the trait are rare. Autosomal recessive disorders Autosomal recessive inheritance An autosomal recessive (AR) gene or trait is expressed only in homozygotes for the abnormal gene ( Fig. 8.8 ). In autosomal recessive inheritance: y affected individuals will usually have phenotypically normal parents this is sometimes termed horizontal inheritance, to reflect the pattern seen in genetic pedigrees y affected individuals usually have unaffected partners and all their children will be carriers y if a carrier has an unaffected partner, there is a 50% chance of the children being carriers y only matings between heterozygotes will produce affected individuals, with an expected frequency of 1 in 4

both sexes are equally affected there is an association with consanguinity due to sharing of genes in families (rare recessive genetic disorders are more likely to arise through consanguinity). Consanguinity occurs where there is a mating between two people who have a familial relationship closer than that of second cousins. y y X-linked disorders X-linked dominant inheritance The X-linked dominant (XD) inheritance pattern is rare and difficult to distinguish from AD except that affected males have normal sons, but all daughters are affected ( Fig. 8.10 ). Examples of X-linked dominant conditions include: Aicardi syndrome, vitamin D resistant rickets, Retts syndrome. X-linked recessive inheritance For X-linked recessive (XR) genes the inheritance pattern ( Fig. 8.11 ) is as follows: y many more males than females show the recessive phenotype y the disease is transmitted by a carrier female, who is usually asymptomatic y if a mother is a carrier, her sons have a 50% chance of being affected and her daughters a 50% chance of being carriers y an affected male will usually have no affected offspring, but all his daughters will be carriers y no sons of the affected male will inherit the gene (i.e. there is no male-to-male transmission) y affected males may have unaffected parents, but they will often have an affected maternal uncle or cousin. Y-linked inheritance Since only males have the Y chromosome, only males can pass on the Y to offspring and only male offspring can receive it. The Y chromosome is inherited with no interchromosomal genetic recombination, however, in order to allow it to pair with the X chromosome at cell division; the Y chromosome contains pseudoautosomal regions . Non-Mendelian inheritance of single-gene disorders A number of disorders have been identified that do not follow classic patterns of Mendelian inheritance. The molecular mechanisms underlying these observations are now beginning to be understood. Mitochondrial inheritance Mitochondrial DNA (MtDNA) is maternally inherited (the sperm contributes no mitochondria to the zygote); therefore, affected males can not transmit the disease to their offspring ( Fig. 8.14 ). Mitochondria are distributed randomly in daughter cells, so these may contain entirely normal mitochondrial DNA or entirely mutant DNA (homoplasmy), or else a mixture of both (heteroplasmy), leading to variable expression of disease depending upon the relative proportion of normal to mutant DNA. Examples of mitochondrial disease include: y Leber hereditary optic neuropathy y mitochondrial encephalomyopathy, lactic acidosis and stroke-like syndrome (MELAS) y myoclonus with epilepsy and with ragged red fibres (MERRF). POLYGENIC INHERITANCE AND MULTIFACTORIAL DISORDERS Introduction Multifactorial disorders result typically from mutations in several genes, in combination with environmental factors. Although multifactorial disorders tend to recur in families, they are much more prevalent than single-gene disorders and they do not show Mendelian patterns of inheritance. Multifactorial inheritance is implicated in the aetiology of many common conditions including:

y y y

congenital malformations e.g. neural tube defects, developmental dysplasia of the hip (DDH), pyloric stenosis, cleft lip and palate and congenital heart disease common disorders of adult life e.g. diabetes mellitus, obesity, epilepsy, hypertension and schizophrenia normal human characteristics e.g. blood pressure, height, dermatoglyphics (finger ridges) and intelligence.

Multifactorial disorders A continuous normal (Gaussian) distribution curve of the trait within the population as a whole is typical, but not diagnostic, of multifactorial disorders. Abnormalities do not usually have a distinct phenotype, but are extremes of the curve. The number of genes involved may be very few as, even when a single locus is implicated, variation in the environment can ensure normal distribution of the trait. Twin studies highlight the relative importance of genes and the environment. For example, cleft lip and palate has a population incidence of 1 in 1000, but: y concordance in monozygotic twins is 40% if due to genetics alone there would be 100% concordance, so genes are important, but other factors are also involved y concordance in dizygotic twins is 4% these twins are not genetically identical (having on average, like all siblings, 50% of their genes in common), but they generally share a similar environment, showing the importance of environmental factors where the concordance rate = [both affected / (one affected + both affected)] 100. DDH is an example of a condition with multifactorial inheritance. Implicated genetic factors include: acetabular dysplasia, familial general joint laxity and transient joint laxity at pregnancy term. Related environmental factors include: breech presentation and response to maternal hormones; oestrogen in particular, which increases ligamentous laxity, is thought to contribute. The higher incidence of DDH seen in females is attributed to additional oestrogen produced by the female foetus. CHROMOSOMAL DISORDERS Introduction Although chromosomal disorders occur in over 7.5% of conceptions, live-birth incidence is only 6 in 1000 since most end in spontaneous abortion. Such chromosomal disorders may be numerical or structural. Numerical disorders concern: y extra single chromosomes (e.g. trisomy) y missing single chromosomes (e.g. monosomy lethal except for X0) y extra haploid sets (e.g. tetraploids or triploids). These disorders result in gene-dosage effects. In the case of polyploidy and trisomy, disease results from over expression of the chromosomal genes (simple gain of function). In monosomies disease results from haploinsufficiency (loss of function) of the genes that are expressed from the missing chromosome. Structural disorders include conditions resulting from: y translocation y inversion y isochromosome y duplication and deletion of chromosomal segments involving many genes y ring chromosomes. Disease arising from these disorders may result from gene dosage effects or misexpression of critical genes due to disruption of the regulatory regions.