347CHAPTER 10

Adult Health and Illness and Medical–Surgical Nursing

Tonya A. Schneidereith and Gwen Anderson

Two major categories of genetic disorders are particularly important in adult health:

In addition, other single gene mutation disorders can occur along a continuous spectrum of severity, including mild forms that become evident in adulthood. Increasingly, persons with genetic disorders that typically present in childhood, such as cystic fibrosis (CF) and congenital heart disease, are living into early and middle adulthood. This can present unique care challenges since many health care practitioners specializing in adult health may not have experience managing these disorders. Also, minimal knowledge may exist about the interaction of certain genetic conditions with the normal process of aging. The sex chromosome disorders such as Turner syndrome, Klinefelter syndrome, triple X syndrome, and XYY syndrome are often not diagnosed until adolescence or adulthood, but may be detected in childhood as outlined in Chapter 9.

In this chapter, some of the most commonly manifested genetically inherited disorders in adulthood are described: HD, autosomal dominant polycystic kidney disease, Marfan disease, Gaucher disease, and hemochromatosis, as well as adulthood effects of premutation carriers of fragile X syndrome. The common multifactorial conditions of cardiac disease, emphysema, diabetes mellitus (DM), and Alzheimer disease are also included.

348SINGLE GENE INHERITED BIOCHEMICAL DISORDERS TYPICALLY MANIFESTING IN ADULTHOOD

Examples of inherited biochemical disorders due to mutation in a single gene are included here. In each case, the mutant gene is present at birth and could be detected at any time (including prenatally), but the usual signs and symptoms are not usually manifested until adulthood.

Huntington Disease

HD is a progressive, degenerative, incurable disease of the nervous system. It is inherited in an autosomal dominant manner. Described by George Huntington in 1872, HD was earlier known as “chorea.” It is believed that some of the women burned as witches in Salem, Massachusetts, in the 1690s had HD. For many years, the famous folk singer Woody Guthrie was erroneously believed to be an alcoholic rather than a person with HD. Symptoms usually do not appear until age 35 years or older. Before DNA testing, one could not be said to be absolutely free of the disorder until the age of 70 years.

HD occurs in 3 to 7 per 100,000 people of European descent and is less common in those of Asian (Chinese and Japanese) and African heritage. HD is caused from a mutation in the HTT gene, located on chromosome 4p16.3. The gene, which encodes for the huntingtin protein, belongs to a family of genes known as endogenous ligands. Although the exact function of huntingtin is unknown, it is believed to play a role in normal prenatal development of neurons in the brain.

The DNA contains a triplicate repeat of three nucleotides, CAG, normally occurring 10 to 35 times within the gene. In HD, this triplicate repeat is expanded from 36 to more than 120 repeats.

Individuals with 36 to 39 repeats may or may not develop signs and symptoms of HD, while those with 40 or more will become symptomatic. The problem with the elongated versions of the protein comes from the resultant fragments that accumulate in the neurons and interrupt normal neuronal function. The cerebellum, striatum, and cerebral cortex are affected, leading to symptoms of emotional lability and uncoordinated movements. It may begin with subtle behavioral changes such as forgetting, inattention, irritability, impaired judgment, poor concentration, hypochondriasis, personality changes, and carelessness about hygiene. Symptoms such as slurred speech or unsteady gait can lead to arrest for alcoholism (known patients should wear medical identification). Promiscuity or an increased sexual drive may occur, resulting in increased numbers of descendants at risk. Over a period of as much as 10 to 20 years, the patient progressively deteriorates, showing increased tremor. Eventually he or she becomes bedridden and develops swallowing difficulties, choking, and the loss of bladder and bowel control. These families are under great stress not only because of the condition of the family member, but also because of the possible and uncertain onset.

Presymptomatic or predictive testing for HD is available for affected families. The trinucleotide expansion typically increases with each generation, so many families 349want this information early for planning and preparation. People with 27 to 35 repeats may be asymptomatic, but are at risk for having a child with the disease. Those with 40 to 50 CAG repeats have adult-onset disease, which appears in mid-adulthood while those with more than 60 repeats will develop a juvenile onset, presenting in childhood or adolescence. Family support can be found through the Huntington’s Disease Society of America website (http://hdsa.org/about-hdsa/support-groups/).

Polycystic Kidney Disease

Autosomal dominant (adult) polycystic kidney disease (ADPKD) is the fourth leading cause of renal failure in adults. It is a systemic disorder that usually manifests in adulthood, although renal cysts may begin in the fetus. Its frequency is 1 in 1,000 people in the United States. The renal cysts increase in both size and number, damaging the structure and function of the kidney, but loss of function usually is not seen until the 30s or 40s. By age 50 years, about half of all patients develop renal failure, and about half have end-stage renal disease by 60 years of age.

Other symptoms and complications include pain, infection, and hypertension. Extrarenal manifestations include polycystic liver disease, intracranial aneurysms, and cardiac defects, which may manifest and affect women more severely than men. Hormonal influences such as pregnancy, birth control pills, and postmenopausal estrogen use are associated with more severe polycystic liver disease.

Approximately 85% of patients with ADPKD have mutations in PKD1 (polycystic kidney disease-1 on chromosome 16p13.3) coding for polycystin-1, while mutation of PKD2 (on chromosome 4q21-23) coding for polycystin-2 is milder and accounts for 10% to 15%. Although the exact functions of the proteins encoded by PKD1 and PKD2 are not completely understood, it is believed that they work together to promote normal kidney development and function. PKD1 and PKD2 belong to a family of genes called transient receptor potential cation channels (TRP), while PKD2 also belongs to the EF-hand domain containing genes. There are over 1,200 known mutations of PKD1 and over 200 of PKD2 and those with truncating mutations appear to have more severe disease.

DNA testing for these mutations can be done presymptomatically or to confirm diagnosis in someone with symptoms. An advantage of presymptomatic testing in persons at risk for inheriting a mutated ADPKD gene is that they can practice good diet habits and keep their blood pressure under control. A positive genetic test for one or both of these mutations does not predict time of onset or severity of disease. A positive ultrasound in utero can be the first indicator of polycystic disease and subsequent genetic testing in other family members.

Recently, clinical trials are targeting medications that decrease levels of cyclic AMP as cAMP signaling is believed to have a role in the hyperproliferation of renal cells in ADPKD. Tolvaptan is a highly potent and selective receptor antagonist of arginine vasopressin V2 receptor that has shown tremendous success following a 3-year trial. However, it is not yet approved in the United States for treatment of ADPKD. Other therapies undergoing investigation include somatostatin (SST) analogs, bosutinib (an SRC/ABL inhibitor), and pravastatin.

350Resources for patients and families can be found on the Polycystic Kidney Disease Foundation website (www.pkdcure.org).

Hemochromatosis

Hemochromatosis is an inborn error of iron metabolism, which causes increased iron stores and subsequent organ damage. It is the most common autosomal recessive disorder in Caucasians, with a homozygote frequency of 1 in 200 (Caucasians) to 1 in 400 (Bretons) and a carrier frequency of 10% in White populations. It is most frequent in those of Scottish, Irish, Swedish, and English descent.

The most commonly mutated gene in classic hereditary hemochromatosis, also known as hemochromatosis type 1, is HFE, located on chromosome 6 (6p21.3); it has over 20 known disease-causing mutations. Most North Americans (85%) have a mutational change known as C282Y (accounts for over 90% of cases), which substitutes tyrosine for cysteine at position 282 of the HFE protein, in contrast to others who have H63D mutations in the same gene.

However, not all persons with the mutated gene show symptoms. This finding raises the possibility that modifier loci contribute to the disease phenotype. It has been suggested that the mutations in the HFE gene modulate the uptake of transferrin-bound iron by intestinal crypt cells that program absorptive capacity of enterocytes that are derived from these cells in the mucosa of the small intestine responsible for the final step in digestion and micronutrient absorption.

Laboratory tests include elevated iron saturation of serum transferrin (fasting) of 45% to 50% or higher in females and 60% or higher in males, as well as serum ferritin in which values over 200 ng/mL in premenopausal females and above 300 ng/mL in males and postmenopausal females are very suggestive. Confirmation of the genetic status is often by genotyping for the two major HFE gene mutations.

Most individuals are not symptomatic before the age of 40. Men may show more serious disease than women, probably because of the physiological loss of iron due to menstruation and pregnancy in women. Iron is deposited in the liver, joints, heart, 351pancreas, and endocrine glands. Initial symptoms are somewhat vague, including lethargy, weakness, and abdominal and/or joint pain. Later, loss of libido, dyspnea, cardiac complaints, liver disease, DM, arthritis, skin pigmentation, and hypogonadism and infertility may be seen.

The prevalence of DM in those with hemochromatosis is 13% to 23% and is related to the destruction of pancreatic islet cells. Another frequently occurring comorbidity is musculoskeletal involvement, including symptoms of osteoarthritis, gout, and rheumatoid arthritis.

Liver biopsy is no longer the gold standard for diagnosis. Molecular genetic testing has surpassed liver biopsy, except in cases where genetic testing cannot confirm diagnosis.

Hemochromatosis has been suggested for population screening because of the potential for prevention of damage. While there is a high population frequency, gene mutations do not always cause disease. Population screening raises questions about the best time for testing and other issues such as penetrance and actual disease development.

Lifelong therapeutic phlebotomy is an effective treatment for hemochromatosis. Approximately 500 mL of blood is removed, usually weekly initially and then every 3 to 4 months, depending on iron levels and tolerance. If early treatment is not initiated, cirrhosis, liver failure, liver cancer, portal hypertension, carbohydrate intolerance, and diabetes may occur, as may cardiomegaly, dysfunction, and arthropathy. It has been suggested that hemochromatosis is so common because it once conferred some type of selective advantage. For example, heterozygous women might have a reproductive advantage because of less likelihood of iron deficiency anemia, and for both men and women, survival in times of starvation might have been enhanced.

Vitamin C supplementation can increase iron overload, as can supplemental iron. In addition, persons with hemochromatosis are susceptible to infection with Vibrio vulnificus, a bacterium present in raw oysters that thrives in iron-rich blood and organs; deaths have occurred from ingestion. Some teaching pointers include those shown in Box 10.1.

Resources for patients and families can be found on the Iron Disorders Institute website (www.irondisorders.org/hemochromatosis).

Marfan Syndrome

Marfan syndrome is an autosomal dominant disorder that is extremely pleiotropic (multiple phenotypic effects from a single gene). It is a connective tissue disorder caused by mutations in the fibrillin gene, FBN1, on chromosome 15q21.1. FBN1 encodes fibrillin-1, a glycoprotein in the extracellular matrix, which combines with other molecules to form the microfibrils used for strength and flexibility of connective tissue. Additionally, microfibrils are used to store and release transforming growth factor-β (TGF-β), a critical growth factor.

Over 1,300 mutations of FBN1 have been identified with Marfan syndrome. Most of the mutations cause a change in a single amino acid of the protein, ultimately leading to decreased formation of microfibrils and activation of increased levels of TGF-β. This causes decreased stability of connective tissues and overgrowth. It has also been found that mutations in genes encoding TGF-β receptors can result in individuals with symptoms similar to Marfan syndrome.

Diagnosis is sometimes difficult due to the variable clinical expression. Some persons with Marfan syndrome are detected in childhood or adolescence, often because of height. Others remain undetected until adulthood. Marfan syndrome is believed present in about 1 in 5,000 persons but may be more frequent and underrecognized; 15% to 30% represent new mutations, meaning that others in the family do not have this mutant gene, and may be due to paternal age.

Among the characteristic features are skeletal findings including tall stature compared to normal family members, ectopia lentis (dislocated lens), strabismus, and other ocular findings; aortic dilatation, dissecting aneurysms of the aorta, mitral valve prolapse, and other cardiovascular manifestations; pectus excavatum (hollow chest) or pectus carinatum (pigeon chest), reduced upper- to lower-segment ratio, arm span that may be greater than the height, scoliosis, joint hypermobility, and arachnodactyly (long, spider-like hands and long thumbs). Other features are a narrow, highly arched palate with crowding of the teeth and extreme overbite. Marfan syndrome is the major reason for aortic dilatation and aortic aneurysms in persons under 40 years of age.

Because of their tall stature, it is not unusual for persons with Marfan syndrome to be athletes. Isaiah Austin, a Baylor University basketball star who at age 20 was 7 foot, 1 inch tall, was given a career-ending diagnosis of Marfan syndrome. Thus, it is important that school nurses and practitioners ensure adequate sports physicals and, if Marfan syndrome is suspected, make a referral for a full diagnostic examination including echocardiography, a slit lamp examination by an ophthalmologist, and others, depending on the symptoms.

353Most morbidity and mortality for individuals with Marfan syndrome is due to aortic dissections and rupture. Therefore, treatment is aimed at decreasing heart rate and blood pressure through the use of β-blockers, including propranolol or atenolol. Treatment with invasive surgery is most often indicated when the diameter of the aortic root is greater than 50 mm.

Activity needs modulation, and pregnancy poses increased risks needing close supervision depending on the person’s cardiac status. Population screening in this group for both carrier status and disease is possible, but accurate genetic counseling that includes prognosis can be difficult because of variability in expression. Information for individuals and families can be found on the Marfan Foundation website (www.marfan.org/about/marfan).

Gaucher Disease

Gaucher disease is a lysosomal storage disorder caused by deficiency of β-glucocerebrosidase, the enzyme required to reduce glucocerebroside (GLC) to glucose and ceramide (a fat molecule). The disease occurs in three forms: type 1, the visceral form that is usually chronic, often first appearing in adulthood; type 2, an acute neurologic form often appearing in infancy; and type 3, a subacute neurologic type often appearing first in childhood.

The disease is autosomal recessive and affects 1 in 50,000 to 100,000 people, with an increased frequency in those of Ashkenazi Jewish heritage of one in 500 to 1,000. The mutation of the GBA gene on chromosome 1q21 leads to an altered, nonfunctional form of β-glucocerebrosidase, with subsequent increases of GLC in macrophages and damage to organs and tissues. Detection of carriers and prenatal diagnosis is possible.

In contrast to many of the other disorders in this category, the adult form is the most prevalent, accounting for about 80% of cases. Multiple alleles may cause mutations in the GBA gene, with five mutations responsible for about 97% of the disease alleles among Ashkenazi Jews. A particular mutation, 1448C, occurs as a polymorphism in northern Sweden, leading to type 3 disease. Another specific mutation, 1226G, leads to mild type 1 disease in homozygotes; such individuals often are undetected unless revealed in the course of family or population studies. A rare perinatal-lethal type has been described, and is often associated with hydrops fetalis.

In adult type 1, which is non-neuronopathic, Gaucher cells with accumulated GLC infiltrate the spleen, liver, and bones. Patients may first experience nonspecific symptoms such as fatigue, easy bruising, and enlarged abdomen with hepatosplenomegaly. Hepatopulmonary syndrome is a known complication of this disease. Eventually bone fractures, infarctions and necrosis, pain, thrombocytopenia, anemia, and infection occur. The pain may be nonspecific and migratory, with episodes lasting 1 to 3 days. In addition, this disease is associated with peripheral insulin resistance with known effects on insulin receptor functioning. Ocular manifestations include “white spots” in the corneal epithelium, anterior chamber angle, ciliary body, and pupil margin.

The age of onset is variable, ranging from birth to 80 years but commonly first presents in adulthood. Some may be asymptomatic entirely, and others may not develop disease manifestations until in their 50s, in which case all of their children 354will already have inherited one mutant gene. This finding may be related to as yet unknown epigenetic moderators that affect post-translational processing of the GBA gene and have not been correlated to genotype. Consequently, the issue of population screening is unsupported due to the inability to predict disease onset or severity.

Historically, the diagnosis was made from chemical analysis of a 24-hour urine collection. “Magnetic resonance imaging (MRI) is a sensitive method for detecting bone involvement” (OMIM, 2013). Detection of low activity of β-glucocerebrosidase is the gold standard for diagnosis. Genetic testing for GBA mutations has limited utility because a positive test result can be expected to identify asymptomatic homozygotes as well as individuals along a continuum of phenotype characteristics that depend on the specific types of mutations on both alleles, as well as other factors.

Clinical trials for treatments of Gaucher disease include enzyme replacement therapy (ERT; enzymes to replace defective β-glucocerebrosidase) and substrate reduction therapy (SRT; reduces the amount of influx of GLC into the lysosome). Other treatment options include partial splenectomy to manage thrombocytopenia, control anemia, and reduce bone involvement postsurgery, as well as bone marrow transplantation with stem cells.

Support for individuals and families can be found on the website for the National Gaucher Foundation (www.gaucherdisease.org).

Fragile X Premutation Carriers

Fragile X syndrome is a disorder due to expansion of trinucleotide repeats in the FMR1 gene located on the Xq27.3 (Chapters 4 and 9). The FMR1 gene is responsible for making the fragile X mental retardation protein (FMRP), which facilitates communication between nerve cells in the brain. The DNA of this gene normally contains 5 to 40 repeats of three nucleotides, CGG. Mutations of the gene lead to an expansion in the number of the trinucleotide repeats that are greater than normal, but fewer than those with fragile X syndrome. These individuals are known as premutation carriers.

Males and females who are premutation carriers may exhibit 55 to 200 CGG repeats and can manifest with fragile X-associated tremor/ataxia syndrome (FXTAS) or fragile X-associated primary ovarian insufficiency (FXPOI). Symptoms of FXTAS consist of parkinsonism, intention tremors, cerebellar ataxia, autonomic dysfunction, peripheral neuropathy, and weakness in the legs and cognitive decline, plus short-term memory loss and executive function deficits. FXPOI is the leading heritable form of ovarian failure and infertility, with symptoms including irregular or absent menstrual periods and elevated levels of FSH before 40 years of age.

The premutation affects 1 in 250 females and 1 in 800 men. It is believed that about one third or more of all male carriers will develop FXTAS over time and approximately 20% of women will develop FXPOI. Progression of FXTAS is variable, so those who manifest ataxia and intention tremor should be screened for the FMR1 gene mutation, even in the absence of a positive family history. Additional environmental and intrinsic determinants for who will develop effects of premutation have yet to be determined.

355For men who carry the mutation, all their daughters will carry the premutation. Almost all the daughters of premutation mothers will be fragile X mutation carriers. These daughters have a 50% chance of having a child who carries a fragile X premutation. Whether a child will have a full mutation depends on the size of the repeat carried by the mother. Approximately 33% to 50% of females with a full mutation show clinical symptoms of fragile X syndrome.

Other Disorders Manifesting in Adulthood

Many of the single gene disorders have forms that first appear in adulthood. In these cases, with severe infantile forms and moderate juvenile forms, the adult forms tend to be milder. An example is the case of a 38-year-old man who was misdiagnosed with schizophrenia for 8 years but actually had Niemann–Pick disease type C, an autosomal recessive neurometabolic disorder associated with chorea, ataxia, seizures, and other signs most common in childhood.

Mitochondrial Disorders Manifesting in Adulthood

Mitochondrial DNA contains 37 genes, many of which are essential to the production of adenosine triphosphate (ATP), transfer RNA, and ribosomal RNA, and are similarly subject to mutation. Mitochondrial DNA deletions occur de novo, thus often affecting only one family member. The majority of mitochondrial conditions present at a rate of 1 in 10,000 births and most manifest in childhood. Some cases of early stroke (below 50 years of age) are mitochondrial disorders that have stroke as a feature, such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), which can present in childhood, adolescence, or adulthood. Persons with Leber hereditary optic neuropathy (LHON), another mitochondrial disorder, typically present in their 20s or 30s with sudden and painless central visual loss and central scotoma. Other symptoms may include headache at onset, cardiac conduction defects, and dystonia with lesions in the basal ganglia. A type of epilepsy called myoclonic epilepsy with ragged red fibers (MERRF) is associated with multiple mtDNA point mutations with the most frequent being 8344A>G change in the transfer RNA for the lysine protein. This condition has variable age of onset and clinical features.

COMMON/COMPLEX DISEASES OF ADULTHOOD

The common (complex) diseases have long been observed to “run in families.” The genetic contribution to the common or complex diseases is of particular interest to medical geneticists because of the potential for early identification of susceptible individuals followed by targeted interventions that might prevent the disease, prevent or ameliorate complications, or allow initiation of early treatment. In general, the common diseases refer to disorders that are frequent in the population and that are not, in large part, attributable to single gene mutations. A subset of most of the common diseases may be due to single gene mutations, especially cases with an early age of onset, but for most of them, causation appears due to multiple gene mutations 356and environmental influences (multifactorial inheritance is described in Chapter 4). These may include coronary artery disease, cerebrovascular disease, DM, cancer, and emphysema.

The genetic contribution of adult diseases could be one or two major genes in combination with minor ones; several minor ones with additive effects; several genes, some with protective effects; or other inherited or acquired epigenetic combinations. Environment could be internal or external and includes dietary components, exposure to infectious agents, biochemical toxins, level of exercise, temperature extremes, sunlight exposure, radiation, and the molecular milieu of cells. There may be many susceptibility factors for a given condition and these may vary in different populations. Susceptibility does not necessarily mean disease development, so some persons with multiple gene mutations or epigenetic biochemical alterations may develop the condition, while others may not.

In some instances, forms of a multifactorial common disorder may be inherited as a single gene mutation or Mendelian disorder. These tend to have an earlier age of onset with a decreased frequency in normal, young individuals. An example is a subtype of type 2 DM known as maturity-onset diabetes of the young (MODY).

A major problem that plagued early investigations of the genetic component in common disorders is variation in the disease phenotype. A variety of methods have been used to look for genetic components in common disorders, including complex trait genome-wide association studies (GWAS), used to sort out gene–gene and gene–environment interactions that could impact disease susceptibility. To understand disease-causing mechanisms, molecular pathway analysis regarding novel gene–gene interactions and certain environmental exposures are under investigation to uncover disease risk loci. Below, the known genetic components of common diseases are described, including heart disease, Alzheimer disease, emphysema, and DM.

Cardiac Disease

Cardiac disease is the leading cause of death in most industrialized countries. In some cases, a single gene mutation results in direct heart disease either alone (e.g., long QT syndrome, discussed in the section “Arrhythmias”), or as part of other genetic syndromes (e.g., Marfan syndrome, discussed previously). For these Mendelian mutations, genetic testing using a single chip for specific inherited mutations involved in heart disease is available. While some rare gene mutations result in heart disease, most cases involve minute effects of many gene-to-gene and gene-to-environment interactions; in other words, changes to the epigenome that are biochemical and acquired.

The use of GWAS has identified dozens of novel gene variants called single-nucleotide polymorphisms (SNPs). More than 50 gene variants for coronary artery disease (CAD) have been identified. However, combinations of gene variants still explain only a small fraction of heritable genetic factors with a typical odds ratio of 1.3% or lower. This limits the predictive value of genetic testing and adds a layer of complexity still quite foreign to most clinicians. Many of the identified loci are mapped to genes associated with lipid traits that affect lipid metabolism and inflammation. These gene variants provide new targets for potential new biotherapies for CAD prevention.

357It is possible for gene mutations to have indirect cardiac effects. For example, gene mutations may affect conditions that contribute to cardiac risk factors such as obesity, DM, and hypertension. Genes may also influence response to therapy for cardiovascular disease. Early heart disease is more likely to have a stronger genetic component than heart disease that develops in middle age or later and may be due to mutations in single genes. Besides congenital heart disease (discussed in Chapter 9), the major categories of heart disease that are caused by or are heavily influenced by genetics are the diseases due to:

Disorders of Lipid Metabolism

The risks of diseases associated with lipid metabolism involve both dietary intake and genetic influences. Genetically determined defects and deficiencies of lipoprotein components, alone or in combination, and their transport and metabolism are known to affect the risk of developing CAD. Both established and emerging cardiovascular risk factors are known, including small, dense low-density lipoprotein (LDL) levels, metabolic syndrome, and homocysteine levels.

Numerous conditions have been identified as risk factors for coronary artery disease. The major ones include elevated total or low-density lipoprotein cholesterol (LDL-C); decreased high-density lipoprotein cholesterol (HDL-C); family history of myocardial infarction (MI) or sudden death in male or female parents or siblings before 55 years and 65 years, respectively; male gender aged 45 or above; female gender aged 55 or above; DM; obesity; cigarette smoking; and hypertension. Other factors that affect lipoproteins include high-fat diets, stress, sedentary lifestyle, liver disease, renal disease, certain medications, and excessive alcohol intake. The association between hyperlipidemia, the process of atherosclerosis, and CAD is generally accepted. Some characteristics have been noted assessing genetic susceptibility to CAD that would then allow clinicians to stratify individuals and in some cases families into population or average-, familial or moderate-, and heritable or high-risk categories. Based on the risk category, early detection and prevention approaches could be designed. Genetic susceptibility characteristics are shown in Box 10.2.

Categories of single gene disorders causing hyperlipidemias and subsequent CAD include defects in the genes that produce apolipoproteins (APO). For example, APOB deficiency leads to an excessively short protein that impacts a variety of lipid events in the bloodstream, liver, and intestines with mutations such as: receptor defects (e.g., LDL receptor disorder leading to familial hypercholesterolemia), enzyme defects (e.g., lipoprotein lipase deficiency), and defects in transfer proteins (e.g., cholesteryl ester transfer protein deficiency).

Aside from those with single gene defects, hyperlipidemia is not a single disorder; it exists as various types, each with its own causes, manifestations, and profiles. In the general population, plasma lipid levels are modulated by the interaction of environmental factors within the boundaries set by genetic determinants. Environmental factors such as diet act on the person with a single gene disorder affecting lipoprotein, gene–gene interactions, and thus the degree of gene expression. Blood lipid levels are a continuous curve in the general population and are influenced by age and sex.

Because of their solubility properties, dietary lipids such as cholesterol and triglycerides are transported in the blood mainly in the form of complex macromolecules called lipoproteins. These molecules often consist of a core of nonpolar lipids, a surface layer of polar lipids, and apoproteins (APO-I). Each class of lipoprotein contains triglycerides (esters of glycerol and long chain fatty acids), cholesteryl esters (esters of cholesterol and long chain fatty acids), free cholesterol, apoproteins, and phospholipids combined in different proportions. Each component in the system has some control, as do other factors such as hormones, cholesterol intake, and metabolic alterations. The components, enzymes, and cell surface receptors are involved in the regulation of lipid levels. In another example, an inherited MTTP gene mutation affects absorption of dietary fats, cholesterol, and fat-soluble vitamins. The signs and symptoms of abetalipoprotein or malabsorption can appear in the first few months of life, later in childhood, or in adults in their 30s and 40s.

Familial Hypercholesterolemia (FH)

FH is an autosomal dominant (AD) disorder due to mutations in several genes including LDLR, APOB, and PCSK9. These mutations cause disposition of atherosclerotic plaque and early age onset coronary heart disease, most commonly manifested as angina or MI. Because it is an autosomal dominant disorder, both heterozygotes and 359homozygotes are affected. Penetrance for FH is nearly 90% with heterozygote LDLR pathogenic variants.

In the United States, the prevalence of heterozygotes and homozygotes is 1 in 500 and 1 in 1 million, respectively, making it a very common genetic disorder. Among survivors of MIs, the frequency of heterozygotes has been estimated at 1 in 20. The result of the gene mutation is reduced or defective LDL receptors, depending on which mutant allele is present. This results in the decreased ability or inability of LDL-C to bind to its cell surface receptors. LDL-C therefore cannot enter the cell for degradation, accumulates in the plasma, and is deposited in abnormal sites such as the arteries (causing atheromas and atherosclerosis), the soft tissue of the eyelids, the cornea (arcus corneae), the tendons, elbows, ankles, and knees. Tendon xanthomas (fatty deposits resembling bumps) of the dorsum of the hand and Achilles tendon may be very painful and are characteristic. They do not usually manifest in the heterozygote before 20 years of age. The finding of such xanthomas on physical examination should alert the practitioner to the need for increased testing. In heterozygotes, LDL-C levels are about 3 times normal; in the homozygote, they may be 6 to 10 times normal.

The heterozygote is exposed to the effects of premature and accelerated atherosclerosis even in early childhood. Whether to institute vigorous therapy at an early age is debatable because myelination of the central nervous system is not complete until about 6 years of age, and LDL-C is important in the delivery of lipids to the tissues. For male heterozygotes, the typical age of onset of coronary heart disease is 40 years of age; by 60 years, 85% will have had an MI as compared to 15% for males without the mutant gene. For females, the typical age of onset is 55 years of age, and by 60 years, 50% will have a MI as compared with a 10% risk in unaffected females. Both the heterozygote and homozygote may also have peripheral or cerebral vascular disease.

The homozygote is much more severely affected. By 4 years of age, most patients will have developed planar yellow-orange xanthomas at the knees, buttocks, elbows, and hands, especially between the thumb and the index finger, as well as tendon xanthomas and arcus corneae. MI, angina pectoris, and even sudden death usually occur in the homozygote between 5 and 20 years of age. MIs have been reported as early as 18 months. Few live past 30 years, and death may occur in childhood. The statins are a mainstay of therapy, but different LDL receptor mutation genotypes can result in varying responses to therapy. For both the heterozygote and homozygote, diet therapy alone will not lower lipid levels to the normal range, but may be used as adjunctive therapy. The most promising approach is gene therapy.

Genetic screening can be valuable for individuals at risk for the three known gene mutations described above, as 60% to 80% of the cases with this diagnosis are identified though molecular testing. Such screening is somewhat controversial, especially for infants and children. Targeted or cascade testing can be useful for at-risk families:

Nursing points related to genetic factors in hyperlipidemia and coronary disease are given in Box 10.3. Information for individuals and families can be found on the FH Foundation website (thefhfoundation.org).

Cardiomyopathies

Cardiomyopathies and channelopathies are diseases of the heart muscle that may be primary or secondary to other inherited disorders such as glycogen storage disease II. 361There are five major classifications of cardiomyopathy phenotype: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM), left ventricular noncompaction cardiomyopathy (LVNC), and arrhythmogenic right ventricular cardiomyopathy (ARVC). The channelopathies include long QT syndrome (LQTS), short QT syndrome (SQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome (BrS), and familial atrial fibrillation. The cardiomyopathies are believed to be responsible for about 2% of sudden deaths. These cardiac conditions are marked by heterogeneity of genotype variants and their phenotypic presentation. Clinical genetic testing for these conditions is available commercially and can be useful for diagnosis and treatment decisions. See Table 10.1 for a list of important genes involved in cardiomyopathy. Support for individuals and families can be found on the website for the Cardiomyopathy Association (www.cardiomyopathy.org).

Hypertrophic Cardiomyopathy. The prevalence of HCM in the general population is about 1 in 500, with an autosomal dominant mode of transmission. Genetic heterogeneity is prevalent. The pattern of phenotypic expression may be influenced by other modifying genes and environmental factors. HCM results from genes that encode cardiac sarcomere proteins that are essential for heart muscle contraction. Two myosin genes account for 40% of this condition (MYH7 and MYBPC3). However, there are 16 genes associated with HCM. For patients diagnosed with HCM, clinicians should consider genetic testing so that other family members can benefit from early diagnosis. In families with known HCM, clinical surveillance may need to be continued throughout adulthood.

HCM is characterized by left ventricular hypertrophy. It has been the most common cause of sudden death in children and adolescents, especially in athletes. Sometimes the initial presentation is sudden death without previously recognizable symptoms. For others, there can be varying degrees of clinical severity, including a slow, relatively benign course. The most common initial complaints in the 50% who present with symptoms are chest pain, dyspnea, mild exercise intolerance, and syncope. Atrial fibrillation may develop in about 10% to 25%. In those without symptoms, detection usually occurs during a routine physical exam such as for a school athletic physical or electrocardiogram (ECG). Further exploration such as a transthoracic echo Doppler examination and studies to detect ventricular function is necessary in those with a suggestive family history. Outcomes vary and include sudden death, heart failure with congestive features, and atrial fibrillation. Treatment depends on manifestations. Both surgical and nonsurgical approaches are used for septal reduction. An automatic implantable cardioverter defibrillator may be needed to prevent sudden death. Molecular techniques can be used for gene testing and will identify about 60% to 70% of those with HCM. Presymptomatic testing is possible. If a family member has been diagnosed with HCM as a result of sudden death, screening of children or adolescents may be warranted so that preventive measures may be taken. The nurse should be alert to this when taking family histories. In families with multiple affected members, adolescents, even if symptom-free, may be advised to avoid strenuous athletics.

ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVNC, left ventricular noncompaction cardiomyopathy; RCM, restrictive cardiomyopathy.

Source: Tariq and Ware (2014).

Dilated Cardiomyopathy. DCM, which occurs with a prevalence of 36.5 per 100,000, is a chronic heart muscle condition characterized by dilatation and impaired contractility of the left or both ventricles. It may result from genetic causes or from viral, toxic, or metabolic agents, alcohol use, immune dysfunction, or idiopathic causes. Men are more frequently affected. There is usually a long period in which the person has no symptoms and the disorder remains unrecognized. The typical age of onset is 20 to 50 years. The most frequent presentation is end-stage heart failure manifested by exercise intolerance, exertional dyspnea, and chest pain. Sometimes the enlarged heart or ECG abnormalities are detected during a routine examination. Conduction abnormalities may be frequent. Nearly 30% of relatives of persons with DCM have ECG abnormalities. Ventricular dilatation may lead to impaired systolic contraction, congestive heart failure, and sudden death. The heart is increased in weight. Mendelian inheritance is seen in about 25% of cases. Inheritance is most commonly autosomal dominant, but autosomal recessive, mitochondrial mutation, and X-linked recessive inheritance have been described.

More than 30 genes have been linked to familial DCM, most in those encoding proteins to make cardiomyocytes. One gene, TTN, is responsible for the production of titin, used to create structure in sarcomeres of muscle cells (including cardiomyocytes). The truncated version of this protein is responsible for 20% of DCM. Some other gene mutations have been identified, including those in cardiac actin (15q14), desmin (2q35), and 8-sarcoglycan genes (5q33-34), and loci have been linked to the AD form, including CMD1D (chromosome 1q32), CMD1G (2q31), and CMD1B (9q13-22), as well as locations on other chromosomes. In some cases, 364DCM is associated with other features such as sensorineural hearing loss (6q23-24). DCM frequently accompanies both Duchenne and Becker muscular dystrophy (see Chapter 9). The Heart Failure Society of America has published guidelines for genetic testing for patients with DCM (http://www.hfsa.org/hfsa-wp/content/uploads/2015/04/HFSA-2010-HF-Guidelines-Section-17.pdf).

Treatment includes weight control, restricted sodium intake, angiotensin-converting enzyme (ACE) inhibitors, digitalis, diuretics, anticoagulants, β-blockers, and other medications, depending on symptoms and need. Currently, DCM is the major indication for heart transplant.

Arrhythmias. Primary disorders of the cardiac electrical system resulting from genetic abnormalities include primary rhythm disturbances. Certain gene variations may also increase the risk of arrhythmias resulting from treatment with certain medications and are thus significant for treatment choices. The actual prevalence of dysrhythmias due to genetic causes is underestimated.

The best-described arrhythmia is LQTS, a cardiac arrhythmia showing a prolonged QT interval on ECG. LQTS consists of recurrent syncope with abnormal myocardial repolarization and sudden death, usually from ventricular arrhythmias. Occasionally, an affected person presents with seizures. It has both autosomal dominant (Romano–Ward syndrome) and autosomal recessive (Jervell and Lange-Nielsen syndrome) inheritance patterns.

The Romano–Ward syndrome occurs in approximately 1 in 7,000 individuals and is the most common form of inherited LQTS. Mutations in five genes (KCNE1, KCNE2, KCNH2, KCNQ1, and SCN5A) alter the structure or function of ion channels, leading to abnormal electrical conduction through the heart muscle.

The autosomal recessive form of LQTS is known as the Jervell and Lange-Nielsen syndrome. Worldwide, it is an uncommon disease, affecting 1.6 to 6 per million people; however there is a higher prevalence in Denmark of 1 in 200,000. The prognosis for Jervell and Lange-Nielsen syndrome is poor, with an estimated mortality rate of 93% by the age of 40 years. About 90% of this syndrome is caused by mutations in the KCNE1 gene, located on 21q22.12. The alterations of this protein inhibit movement of potassium through cardiac cells and cells of the inner ear. This leads to altered cardiac conduction and profound hearing loss. Additionally, mutations in the KCNQ1 genes (11p15.5) can also cause LQTS. These proteins interact with proteins from KCNE1 genes to form potassium channels and are associated with congenital sensory deafness as well. LQTS has been reported in up to 1% of children with congenital deafness, so children who have congenital deafness should be screened for LQTS.

Unexplained cases of near-drowning have revealed families with inherited LQTS, and women with hereditary LQTS are at risk for untoward cardiac events in the postpartum period, which may be prevented prophylactically by using β-adrenergic blockers.

Most individuals with LQTS can be treated with β-blockers, but they are not effective in those with Jervell and Lange-Nielsen syndrome. Implantable cardioverter defibrillators (ICDs) have been used in combination with β-blocker therapy or in those with a history of MI. Information for patients and families can be found on the website Sudden Arrhythmia Death Syndromes (www.sads.org).

365Other Conditions

Other conditions with a genetic component may also result in heart disease. For example, there is a cardiac form of hereditary transthyretin amyloidosis that causes a build-up of amyloid proteins in cardiac tissue. There are over 100 mutations in the TTR gene on chromosome 18q12.1, which affect production of transthyretin, altering its ability to transport vitamin A and thyroxine. This condition is particularly common among Black populations, affecting 3% to 3.9% of African Americans and 5% of people in West Africa. This same population possesses the TTR mutation that replaces the amino acid valine with isoleucine at position 122 in the transthyretin protein. Symptoms, including arrhythmias and cardiomegaly, vary widely and can present between 20 and 70 years of age.

Alterations in the renin–angiotensin system may be related to heart disease. A particular genotype of the angiotensin I converting enzyme gene (ACE; 17q23.3), DD, has been associated with a susceptibility to MI, CAD, and stroke, probably because of aberrant blood pressure regulation. The use of ACE inhibitors may be useful in prevention.

Aging and Alzheimer Disease

With the rapid increase of the elderly population, 85 years and older, the study of aging has intensified. The influence of genetics on biologic aging can affect length of life or longevity, patterns of aging, the aging process, and maximum life span. The search for specific aging genes has resulted in interest in disorders with a known genetic basis that have some of the characteristics of aging. These include conditions such as Down syndrome (discussed in Chapter 9) and rarer genetic syndromes such as progeria, Werner syndrome, and Cockayne syndrome.

Various dementias are not necessarily a consequence of aging. Dementias, however, may accompany aging. One of these, Alzheimer disease (AD), is the fourth leading cause of death in the United States and the most common form of dementia (50%–70%). It affects 2.4 to 4.5 million Americans.

The lifetime risk of developing AD ranges between 10% and 15% in the general population. AD is characterized by dementia involving personality changes; memory loss; deterioration of cognitive functions such as language, as well as poor judgment, motor skills, perception, and attention with neuronal cell loss; and deposition of increased amounts of amyloid plaques and neurofibrillary tangles in the cerebral cortex. There may also be associated symptoms such as depression, emotional outbursts, agitation, withdrawal, gait disorders, seizures, incontinence, and sexual disorders.

Cases of AD may be early-onset (before 65 years of age) or late. The early-onset form is least common, accounting for approximately 5% of cases, and is inherited in an autosomal dominant pattern. Most early-onset disease is caused by mutations in one of three genes: amyloid β precursor protein (APP; 21q21.3), presenilin 1 (PSEN1; 14q24.3), or presenilin 2 (PSEN2; 1q42.13). When any of these genes are mutated, increased build-up of amyloid β protein creates plaque in brain cells, characteristic of AD. Because of the mutations associated with chromosome 21, individuals with Down syndrome are at an increased risk of developing AD.

366Most cases of AD are of the late-onset form and do not involve the genes in early-onset disease. GWAS have identified a short list of genes associated with late stage AD: BIN1, CLU, PICALM, and CR1; however, the Alzheimer Disease & Frontotemporal Dementia Mutation Database maintains an up-to-date list of all reported mutations (www.molgen.ua.ac.be/ADMutations). An additional genetic mechanism for this form of the disease is associated with the apolipoprotein E (APOE) gene on chromosome 19q13.2; it has at least seven allelic forms, ε1 through ε7. To date, three allelic variants are known to be associated with AD. One specific form, the APOε4 gene variant, is the most important predictive risk factor for AD; however, 50% of individuals with AD do not have an ε4 allele. Presence of the ε2 allele may have a protective effect by lowering the risk and increasing the age of onset. These findings have implications for genetic testing, drug treatment, and preventive drug compounds that might mimic the action of APOE ε2.

Genetic testing for the APOE genotype can be used for confirmatory diagnosis of a person who shows symptoms of dementia or for those who are asymptomatic and at risk (predictive or presymptomatic testing). The issue of clinical testing for the APOE genotype has provoked various cautionary statements regarding genetic testing of APOE alleles for predictive screening in asymptomatic persons because the APOE ε4 allele is also found in persons without AD. A major issue with susceptibility testing for late-onset AD disease is the associated uncertainty of the meaning of the results. However, first-degree relatives have a lifetime risk of 20% to 25%, which is 2.5 times higher than background population risk.

Most drug treatment for AD is focused on decreasing the amyloid cascade, including amyloid β proteins. So far, these have yielded disappointing results, but identifying other molecular targets may provide additional avenues for drug development.

Resources for patients and families can be found on the Alzheimer’s Foundation of America website (www.alzfdn.org/?gclid=CPLA386mmcMCFZYjgQodRHkAlg).

Emphysema and Alpha-1-Antitrypsin Deficiency

 

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