Pathophysiology: Medical School Crash Course

Pathophysiology

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TABLE OF CONTENTS Preface........................................................................................................ 1 Chapter 1: Genes and Genetic Diseases ....................................................... 5 Chromosomal Disorders .................................................................................................. 5 Autosomal Dominant Disorders ...................................................................................... 7 Autosomal Recessive Disorders ..................................................................................... 10 X-Linked Disorders........................................................................................................ 14 Key Takeaways ............................................................................................................... 16 Quiz .................................................................................................................................17 Chapter 2: The Immune System and Immune Disorders ........................... 21 Inflammation ................................................................................................................. 21 Infection ......................................................................................................................... 28 Immunodeficiency ......................................................................................................... 35 Transplant Immunology ................................................................................................ 36 Autoimmune Disease ..................................................................................................... 38 Key Takeaways ............................................................................................................... 42 Quiz ................................................................................................................................ 43 Chapter 3: Neurological Disorders ............................................................ 47 Delirium ......................................................................................................................... 47 Dementia ........................................................................................................................ 49 Hydrocephalus ............................................................................................................... 52 Traumatic Brain Injury .................................................................................................. 54

Seizures .......................................................................................................................... 57 Intracranial Infections ................................................................................................... 59 Parkinson’s Disease ....................................................................................................... 63 Multiple Sclerosis ........................................................................................................... 65 Peripheral Neuropathy .................................................................................................. 66 Guillain-Barre Disease ................................................................................................... 68 Myasthenia Gravis ......................................................................................................... 68 Key Takeaways ............................................................................................................... 70 Quiz .................................................................................................................................71 Chapter 4: Endocrine Disorders................................................................ 75 Overview......................................................................................................................... 75 Pituitary Disease ............................................................................................................80 Thyroid Disease.............................................................................................................. 82 Adrenal Disease ............................................................................................................. 85 Multiple Endocrine Neoplasia .......................................................................................88 Diabetes Mellitus ........................................................................................................... 89 Parathyroid Disease ....................................................................................................... 91 Key Takeaways ............................................................................................................... 93 Quiz ................................................................................................................................ 94 Chapter 5: Hematological Disorders ......................................................... 98 Nutritional Anemias ...................................................................................................... 98 Hemolytic Anemia and Hemolysis ...............................................................................101 Aplastic Anemia ........................................................................................................... 104 Lymphoma ................................................................................................................... 106

Leukemia ...................................................................................................................... 109 Hemoglobinopathies .....................................................................................................110 Polycythemia vera ......................................................................................................... 113 Neutropenia .................................................................................................................. 114 Platelet Disorders.......................................................................................................... 116 Key Takeaways .............................................................................................................. 118 Quiz ............................................................................................................................... 119 Chapter 6: Cardiovascular Disease .......................................................... 123 Atherosclerosis ............................................................................................................. 123 Heart Failure .................................................................................................................127 Heart Muscle Diseases ................................................................................................. 130 Infective Endocarditis .................................................................................................. 133 Deep Vein Thrombosis................................................................................................. 135 Lipid Disorders ............................................................................................................ 136 Pericarditis ....................................................................................................................137 Key Takeaways ............................................................................................................. 138 Quiz .............................................................................................................................. 139 Chapter 7: Pulmonary Disorders ............................................................. 143 Obstructive Lung Diseases........................................................................................... 143 Asthma ......................................................................................................................... 145 Interstitial Lung Diseases ............................................................................................ 147 Upper Respiratory Infections ...................................................................................... 148 Community-acquired Pneumonia ............................................................................... 149 Tuberculosis .................................................................................................................. 151

Pleural Effusion ........................................................................................................... 154 Key Takeaways ............................................................................................................. 156 Quiz ...............................................................................................................................157 Chapter 8: Digestive System Diseases ...................................................... 161 Esophageal Disease ....................................................................................................... 161 Peptic Ulcer Disease..................................................................................................... 163 Malabsorption .............................................................................................................. 164 Crohn’s Disease ............................................................................................................ 167 Ulcerative Colitis .......................................................................................................... 168 Pancreatitis .................................................................................................................. 169 NASH and Cirrhosis...................................................................................................... 171 Cholecystitis ..................................................................................................................172 Key Takeaways ............................................................................................................. 174 Quiz ...............................................................................................................................175 Chapter 9: Renal and Urological Diseases ................................................ 179 Acute Kidney Injury ..................................................................................................... 179 Chronic Kidney Disease ............................................................................................... 182 Nephrotic Syndrome .................................................................................................... 184 Nephritic Syndrome ..................................................................................................... 185 Urinary Tract Infections .............................................................................................. 186 Bacterial UTIs .............................................................................................................. 186 Key Takeaways ............................................................................................................. 190 Quiz ............................................................................................................................... 191 Chapter 10: Electrolyte Disorders ........................................................... 195

Hypernatremia ............................................................................................................. 197 Hypokalemia ................................................................................................................ 198 Hyperkalemia ............................................................................................................... 199 Acid-Base Disorders.................................................................................................... 200 Hypocalcemia ............................................................................................................... 201 Hypercalcemia ............................................................................................................. 203 Key Takeaways .............................................................................................................204 Quiz .............................................................................................................................. 205 Chapter 11: Reproductive System Diseases .............................................. 209 Prostatitis .....................................................................................................................209 Orchitis ......................................................................................................................... 210 Epididymitis .................................................................................................................. 211 Testicular Torsion ........................................................................................................ 212 Erectile Dysfunction .................................................................................................... 213 Amenorrhea ................................................................................................................. 214 Abnormal Uterine Bleeding ......................................................................................... 216 Pelvic Inflammatory Disease ........................................................................................217 Endometriosis .............................................................................................................. 218 Polycystic Ovary Syndrome ......................................................................................... 219 Infertility ......................................................................................................................220 Key Takeaways ............................................................................................................. 222 Quiz .............................................................................................................................. 223 Chapter 12: Musculoskeletal System Disorders ....................................... 227 Osteoporosis................................................................................................................. 227

Paget Disease ............................................................................................................... 228 Osteomyelitis ............................................................................................................... 229 Autoimmune Myositis ................................................................................................. 230 Rheumatoid Arthritis ................................................................................................... 232 Osteoarthritis ............................................................................................................... 233 Spondyloarthropathies ................................................................................................ 235 Gout and Pseudogout ................................................................................................... 237 Key Takeaways ............................................................................................................. 239 Quiz ..............................................................................................................................240 Chapter 13: Integumentary System Disorders ......................................... 244 Skin Infections ............................................................................................................. 244 Psoriasis ....................................................................................................................... 247 Atopic Dermatitis ......................................................................................................... 248 Acne .............................................................................................................................. 250 Rosacea ........................................................................................................................ 251 Erythema Multiforme .................................................................................................. 252 Bullous Pemphigoid ..................................................................................................... 252 Key Takeaways ............................................................................................................. 254 Quiz .............................................................................................................................. 255 Chapter 14: Cancer .................................................................................. 258 Lung Cancer ................................................................................................................. 258 Breast Cancer ............................................................................................................... 259 Stomach Cancer ........................................................................................................... 261 Colon Cancer ................................................................................................................ 261

Brain Tumors ............................................................................................................... 262 Prostate Cancer ............................................................................................................ 262 Uterine Cancer ............................................................................................................. 263 Renal Cell Cancer ......................................................................................................... 263 Thyroid Cancer............................................................................................................. 264 Testicular Cancer ......................................................................................................... 265 Ovarian Cancer ............................................................................................................ 265 Skin Cancer .................................................................................................................. 266 Key Takeaways ............................................................................................................. 267 Quiz .............................................................................................................................. 268 Summary ................................................................................................ 272 Course Questions .................................................................................... 276

PREFACE This course is based on the premise that you are a healthcare professional and that you already understand physiology but want a crash course in pathophysiology or the study of disease states. The study of pathophysiology recognizes that there are normal homeostatic mechanisms in place in the healthy person that drive health and defend against disease. For a variety of reasons—from genetic disorders, to stress or wear-andtear on the system, to patient behaviors—there are things that throw off these homeostatic mechanisms, creating an environment where the normal compensatory activities in place that defend against aberrations in the human body are driven off course. The end result is the creation of diseases you will learn about as part of this course.

The first chapter in the course introduces pathophysiology by identifying some of the many genetic diseases involving humans. As you know, there are 23 pairs of human chromosomes with an estimated 19,000-20,000 human protein-coding genes. The estimate of the number of human genes has been repeatedly revised down from initial predictions of 100,000 or more. Genetic disease can be chromosomal, autosomal dominant, autosomal recessive, or x-linked recessive. The basis of these and the types of genetic disorders seen in the different categories is covered in this chapter.

The focus of chapter two in the course is the immune system and the pathophysiology of immune disorders. This chapter talks about inflammation and infection, which are two different but interrelated dysfunctions of the immune system. In addition, there are individuals who have immunodeficiency states, which can be primary or acquired, as is the case with human immunodeficiency virus or HIV disease and when individuals receive immunosuppressants after a transplant. Finally, there can be overactivity of the immune system with autoimmune disorders that involve action of the immune system against the individual’s own cells or cell components.

Chapter three in the course focuses on the pathophysiology of the diseases of the nervous system. This includes diseases of the brain, including delirium, dementia,

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seizures, brain infections, and traumatic brain injury. Other degenerative diseases, such as Parkinson disease, are covered as part of the discussion as well. Diseases of the peripheral nerves, including peripheral neuropathy and Guillain-Barre disease, are important to the discussion of the nervous system and are covered as part of this chapter.

Chapter four discusses the different endocrine disorders in the body. The discussion starts with an overview of the coordination between the hypothalamus and the pituitary gland—both of which can be called a “master gland” because of the far-reaching implications of their activities. The other glands have more specific functions and include the thyroid gland, the adrenal gland, the parathyroid gland, and endocrine pancreatic gland. Each of these glands produces hormones and will have various dysfunctions based on overactivity or underactivity of the gland.

The topic of chapter five in the course is hematological disorders. There are three main cellular components in human blood: the red blood cells or erythrocytes, the white blood cells or leukocytes, and the platelets. These cells are all made in the bone marrow and many of them will mature there. Each type of cell serves a different function within the body. Red blood cells carry oxygen, white blood cells fight infection, and platelets aid in blood clotting. Disorders of these cells and cell fragments are covered as part of this chapter.

The focus of chapter six in the course is heart disease. This involves a wide-reaching discussion of true heart diseases, such as heart muscle disorders, heart failure, endocarditis, and pericarditis, as well as blood vessel-related diseases. It talks about atherosclerosis, which is a disease that can involve the heart, the brain, and the peripheral vascular system. Other disorders involving clotting, including deep venous thromboses and dyslipidemia (which leads to heart disease), are covered as part of this chapter.

Chapter seven involves a discussion of the pulmonary system and lung disorders.

Chronic diseases of the lungs involve chronic obstructive pulmonary disease, which encompasses chronic bronchitis and emphysema, and asthma. Interstitial lung diseases are usually relatively chronic as well. Acute pulmonary diseases can be as simple as an

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acute respiratory infection or as severe as pneumonia. Tuberculosis can be acute or chronic and may not always involve the lungs. The discussion concludes with coverage of the causes and pathophysiology of pleural effusion, which also may or may not always involve the lungs.

Chapter eight in the course talks about the various digestive system diseases—from the esophagus to the large bowel. Esophageal diseases involve the various motility disorders of the esophagus. Stomach disease usually means some type of peptic ulcer disease. Malabsorption syndromes are many and include celiac disease and other disorders of the small bowel. The GI tract as a whole can be affected by Crohn disease, while the large bowel is affected by ulcerative colitis. Other disorders of the digestive system include acute and chronic pancreatitis, non-alcoholic steatohepatitis, cirrhosis, and acute and chronic cholecystitis.

The topic of chapter nine is kidney disease and other urologic diseases. There are many possible insults that can involve the kidneys, including acute processes leading to acute kidney injury and chronic processes leading to chronic kidney disease. These can lead to nephrotic syndrome as well as what can be described as nephritic syndromes.

There are also several different types of urinary tract infections—the vast majority of which are bacterial and involve the bladder and/or kidneys.

Chapter ten in the course encompasses the various electrolyte and acid-base disorders. These represent the various causes of hyponatremia, hypernatremia, hypokalemia, hyperkalemia, hypocalcemia, and hypercalcemia. There are many checks and balances which yield a normal electrolyte level; several disorders can lead to an imbalance of one or more organ functions, with the patient developing an electrolyte abnormality. Acid-base disorders can be secondary to a problem with the kidneys, a problem with the lungs, or a dysfunction of both of these organs.

The focus of chapter eleven is reproductive system disease. It involves the various disorders that can affect the male reproductive system, such as prostatitis, orchitis, epididymitis, testicular torsion, and erectile dysfunction. Females also have a wide range of reproductive system diseases, including those affecting the menstrual cycle, endometriosis, pelvic inflammatory disease, and polycystic ovary syndrome. The

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problem of infertility affects both males and females; it can also be a combined problem, with problems involving both the male and female fertility leading to the couple’s infertility.

Chapter twelve in the course focuses on the various musculoskeletal system disorders, including bone diseases, muscle diseases, and disorders of the joints. These can include osteoporosis and osteomyelitis, as well as Paget disease of the bone.

Autoimmune myositis, which includes dermatomyositis, is also covered in this chapter.

There are many different joint diseases, some of which are immune-related.

Osteoarthritis, gout, and pseudogout are not immune-related, although rheumatoid arthritis and the different types of spondyloarthropathies have more of an immune etiology.

The purpose of chapter thirteen is to cover some of the more common and important skin diseases. There are several types of skin infections that vary in the common pathogens and in presentation. Acne is another skin disease affecting young people, while rosacea has the appearance of acne, seen in older individuals. Psoriasis is an immune disease of the skin, as is bullous pemphigoid. Another common skin disease is atopic dermatitis, which can affect individuals as early as in infancy.

Chapter fourteen in the course is a brief look at the pathophysiology of different types of cancer. Cancer can affect any part of the body with varying degrees of virulence.

Some cancers, such as lung cancer, certain brain cancers, and ovarian cancer have a high mortality rate, while others are not particularly lethal. In all cases, there is the uncontrolled growth of cells in the body that is accompanied by a relative lack of apoptosis or programmed cell death.

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CHAPTER 1: GENES AND GENETIC DISEASES This first chapter introduces pathophysiology by identifying some of the many genetic diseases involving humans. As you know, there are 23 pairs of human chromosomes with an estimated 19,000-20,000 human protein-coding genes. The estimate of the number of human genes has been repeatedly revised down from initial predictions of 100,000 or more. Genetic disease can be chromosomal, autosomal dominant, autosomal recessive, or x-linked recessive. The basis of these and the types of genetic disorders seen in the different categories is covered in this chapter.

CHROMOSOMAL DISORDERS Chromosomal disorders can involve the lack of an entire chromosome, the duplication of a chromosome (which becomes a trisomy), or a deletion of part of a chromosome.

Many of these are spontaneous genetic diseases that are not necessarily inherited directly from a parent. Some chromosomal diseases include the following: •

Angelman syndrome—this is not autosomal dominant or autosomal recessive but stems from errors in meiosis. It involves a deletion on the short arm of the maternal chromosome 15, and represents an example of genomic imprinting, which means that the expression of the disease depends on the parent who gave the disease. When the deletion involves the chromosome 15 that came from the father, the child has Prader-Willi syndrome, but when the deletion involves the chromosome 15 that came from the mother, the child has Angelman syndrome.

Typical symptoms include ataxic gait, mental retardation, inappropriate laughter, and seizures.

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Cri du Chat syndrome—this is a 5p- deletion of the long arm of chromosome 5.

There is severe mental retardation, a characteristic cat-like cry, low birth weight, facial features, and microcephaly. Some die within a year but many live into their 50s.

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Down syndrome—this stems from trisomy 21, seen in increasing maternal age.

There is a familial form involving a translocation of chromosome 21 onto another chromosome but this is rare. This is the most common cause of mental retardation; there will also be characteristic facial features with classical epicanthic folds. The hands will have a simian crease. There is a risk of congenital heart disease, increased risk of Alzheimer’s disease, and an increased risk of leukemia.

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Edward syndrome—this is trisomy 18. There is mental retardation, rockerbottom feet, micrognathia, congenital heart disease, and death by the age of one year.

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Patau syndrome—this is trisomy 13. There is mental retardation, microphthalmia, cleft lip and palate, rocker-bottom feet, polydactyly, congenital heart disease, and death within a year. This is more severe than Edward syndrome.

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Prader-Willi Syndrome—this is deletion of part of the short arm of chromosome 15 on the paternal side, another example of genomic imprinting. There is mental retardation, obesity, short stature, hypotonia, increased appetite, hypogonadism, and small hands and feet.

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Fragile-X syndrome—this involves progressively longer tandem repeats on the long arm of chromosome X. The more repeats, the worse the symptomatology is.

The number of tandem repeats increases through the generations. It is rare but twice as common in males. It causes mental retardation (the second most common cause next to Down syndrome). There are enlarged testes in boys.

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Klinefelter’s syndrome—this is an XXY disease from nondisjunction of the Xchromosome in meiosis. It is only seen in males after puberty and reveals hypogonadism, tall stature, gynecomastia, with mild mental retardation.

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Turner’s syndrome—this is from non-disjunction of the X-chromosome during anaphase I of meiosis. It is an XO syndrome seen only in girls who do not go through puberty, have short stature, webbed neck, but no mental retardation.

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XXX syndrome—this is trisomy XXX and other multiple X-chromosomal abnormalities. Many of these girls are phenotypically normal but may have mild mental retardation and menstrual abnormalities.

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DiGeorge syndrome—this is also known as 22q11.2 deletion syndrome and is a syndrome caused by the deletion of a small segment of chromosome 22. There is failure of the development of the third and fourth pharyngeal pouches so there is agenesis of the parathyroid glands and thymus. There is T-cell deficiency, hypocalcemia, congenital heart problems, certain facial features, frequent infections, developmental delay, learning problems and cleft palate.

AUTOSOMAL DOMINANT DISORDERS Autosomal dominant disorders have the characteristic of being associated with an autosomal gene and not a sex gene. It is dominant, meaning there is no carrier state as the individual who has the disorder will likely have the disease unless there is incomplete penetrance. The likelihood of passing on this type of gene disorder is 50 percent to both male and female offspring. These are the major autosomal dominant disorders: •

Autosomal dominant polycystic kidney disease—this has an onset in adult life and can lead to chronic renal failure and death. There are multiple cysts in the kidneys, leading to enlarged kidneys. There may also be liver cysts. People with this condition are born with one mutated copy of the PKD1 or PKD2 gene in each cell. About 90 percent of these cases are inherited with the rest being sporadic mutations.

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Ehlers-Danlos syndrome—this represents a wide-ranging group of inherited, usually autosomal dominant disorders, involving different defects in collagen synthesis. This connective tissue disease involves joint laxity, extreme elasticity of the skin, and poor wound healing. The most common cause of death is a dissecting aortic aneurysm.

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Familial hypercholesterolemia—this is an autosomal dominant defect in the LDLreceptor. It leads to accelerated atherosclerosis in the person who is heterozygous 7

and, in the person who is homozygous, it leads to a high possibility of an MI by thirty-five years of age. Patients will have obvious xanthomas in the skin.

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Osler-Weber-Rendu Syndrome—this is also referred to as hereditary hemorrhagic telangiectasia syndrome. This is an autosomal dominant syndrome in which the person has multiple telangiectasias of the mucus membranes and skin. These patients will have nose bleeds but will have a normal life expectancy.

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Hereditary spherocytosis—this is an autosomal dominant disorder involving a defect in the RBC membrane, leading to a spherical shape to the red blood cells.

Patients will have hemolytic anemia from sequestration of spherocytes in the spleen and will have splenomegaly.

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Huntington disease—this is an autosomal dominant disease with 100 percent penetrance. There is a genetic defect of chromosome 4, leading to atrophy of the putamen, caudate nuclei, and frontal cortex. Progressive dementia results with athetosis, choreiform movements, and early onset dementia.

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Marfan syndrome—this is an autosomal dominant connective tissue disease.

There is a deficiency of the fibrillin protein so that the elastin protein has no anchor. These patients tend to be tall and thin. Patients can die from a dissecting aortic aneurysm and will have subluxation of the lens and mitral valve prolapse.

There will also be a risk of arachnodactyly (in which the fingers and toes are abnormally long and slender).

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Neurofibromatosis—this is also referred to as von Recklinghausen disease. It is an autosomal dominant disorder from a defect in the NF1 gene. This leads to multiple neurofibromas of the nerve tissue, with the possibility that these can become malignant, Lisch nodules (pigmented hamartomas of the iris), and caféau-Lait spots in the skin. There is an increased risk for other cancers or tumors, such as Wilms tumor, leukemias, and pheochromocytoma.

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Tuberous sclerosis—this is an autosomal dominant disorder caused by changes (mutations) in either the TSC1 or TSC2 gene. These genes are involved in regulating cell growth, leading to multiple glial nodules called tubers. Patients

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will have mental retardation, facial lesions, angiomyolipomas, and myocardial rhabdomyomas.

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Von Hippel-Lindau syndrome—this is an autosomal dominant disorder that involves the short arm of chromosome 3, which is the same gene region associated with renal cancer. Besides a high risk for renal cancer, patient will have visceral cysts, adenomas, and hemangioblastomas of the brain or retina.

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Selective IgA deficiency—this can be either autosomal dominant or autosomal recessive. It involves deficiency of IgA from a failure of heavy-chain gene switching. It is the most common hereditary immune deficiency disease. There are diseases related to IgM and IgG deficiency but these are not as common.

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Job’s syndrome—this is an autosomal dominant hyper IgE syndrome that is secondary to the failure to make gamma-interferon by the helper T cells. This leads to an increase in TH2 cells and high IgE levels. The histamine levels will be high and there will be eosinophilia. Recurrent staphylococcus infections and eczema are seen in people who have this. There is a related disorder that is autosomal recessive.

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Chronic mucocutaneous candidiasis—this is autosomal dominant or autosomal recessive and leads to T-Cell deficiency specific to Candida. The individual with this disorder will have recurrent candida infections that require ongoing treatment with anti-fungal medications.

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Osteogenesis imperfecta—this is an autosomal dominant connective tissue disease that leads to defects in type 1 collagen formation. There will be a history of frequent fractures starting in infancy, thin skin, and progressive deafness in some patients. There are mild and severe cases.

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AUTOSOMAL RECESSIVE DISORDERS Autosomal recessive disorders are those that are inherited by means of the autosomal genes. Being recessive, they are not necessarily clinically apparent when the gene is inherited because there will be another gene that will “cover” for the abnormal gene so that the individual won’t get the disorder until the person has two copies of the abnormal gene. This leads to the possibility of a carrier status, in which the person has the ability to pass on the gene but does not have the disease themselves. Two carriers will have a 25 percent chance of having a child with the disease.

These are the common autosomal recessive diseases: •

Cystic fibrosis—this is an autosomal recessive disease that involves a defect in the CFTR gene on chromosome 7. Chloride ion transport fails to happen so there are excessively viscous mucous secretions. Children will have meconium ileus from thick meconium, respiratory bronchiectasis, pancreatic insufficiency, high sweat chloride concentration, and a high risk of Pseudomonas pneumonia infections.

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Fanconi anemia—this is an autosomal recessive pancytopenia, leading to both anemia and neutropenia. Children will have mental retardation, short stature, microcephaly, hypogenitalism, microphthalmia, and bony abnormalities.

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Hartnup’s disease—this is a defect in the gastrointestinal uptake of certain amino acids and niacin. It is autosomal dominant and leads to a syndrome typical of pellagra, with diarrhea, dermatitis, and dementia. They will have brain dysfunction with transient cerebellar ataxia.

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Kartagener’s syndrome—this is an autosomal recessive disorder that leads to a lack of motility of the cilia. It leads to recurrent sinus and lung infections and situs inversus due to impaired ciliary motion during embryogenesis. The thoracic organs will also be on the opposite side of the body with possible dextrocardia.

Males will be sterile because of a lack of ciliary motion.

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Pyruvate dehydrogenase deficiency—this is an autosomal recessive disorder and a deficiency of the enzyme pyruvate dehydrogenase. This causes lactic acidosis from a buildup of lactate and pyruvate in the bloodstream. The treatment is to 10

increase the amount of ketogenic nutrients in the diet (such as leucine and lysine) so that acetyl CoA can be increased in the cells.

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Xeroderma pigmentosum—this is an autosomal defect involving inability to adequately repair DNA. It leads to a high degree of excessive damage to skin as well as skin cancer. The skin will be dry with a high risk of pre-malignant and malignant skin cancers. There can be eye and nerve-related abnormalities as well.

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Congenital fructose intolerance—this is an autosomal recessive disease in which there is an aldolase B deficiency. This leads to a buildup of fructose-1-phosphate in the tissues so that both glycogenolysis and gluconeogenesis are impaired. This leads to severe hypoglycemia when fructose is in the diet. The treatment is to remove fructose from the diet.

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Galactosemia—this is an autosomal recessive defect in carbohydrate metabolism.

It results in an inability to convert galactose to glucose so that galactose accumulates in the tissues. More than one galactose enzyme may be defective.

Infants will have cataracts, failure to thrive, hepatic failure from cirrhosis that often leads to death. The treatment is to remove galactose from the diet.

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Cori’s disease—this is a glycogen storage disease and is autosomal recessive.

Glycogen cannot be broken down at its branch points so it builds up. This leads to hepatomegaly, stunted growth, and low blood sugar levels.

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McArdle’s disease—this is an autosomal recessive muscle phosphorylase deficiency so that skeletal muscle cannot be utilized. It is another glycogen storage disease. It leads to muscle cramps, weakness, easy fatigability, and myoglobinuria with exercise.

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Pompe’s disease—this is another glycogen storage disease involving alpha 1,4glucosidase deficiency states. Glycogen cannot be broken down, leading to hepatomegaly, cardiomegaly, and early death.

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Von Gierke’s Disease—this is an autosomal recessive glycogen storage disease, involving the inability to breakdown glycogen. There is severe fasting hypoglycemia and hepatomegaly from excessive amounts of glycogen in the liver.

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Von Willebrand disease—this is a type of hemophilia that has both autosomal dominant and autosomal recessive types. It leads to a defect in the initial formation of platelet plugs in the formation of blood clots and a shorter half-life of factor VIII in the bloodstream. This leads to an increase in bleeding. There are mild, intermediate, and severe types of the disorder.

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Ataxia-telangiectasia—this is an autosomal recessive immune deficiency state. It leads to telangiectasias of the face (enlarged facial capillaries), B cell deficiency and T cell deficiencies along with an IgA deficiency. Patients will have cerebellar ataxia.

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SCID (Severe combined immunodeficiency disease)—this is autosomal recessive and results from an adenosine deaminase deficiency and a decrease in DNA precursors. There are severe deficiencies of both cellular and humoral immunity secondary to impaired DNA synthesis. It can sometimes be treated with a bone marrow transplant.

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Gaucher’s disease—this is a lysosomal storage disease that is autosomal recessive.

The defect is in the level of glucocerebrosidase in the system so the glucocerebrosides will be increased in the lysosomes. There are three types, which can be extremely severe and seen in infancy or less severe and seen in adults.

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Niemann-Pick lipidosis—this is an autosomal recessive lysosomal storage disease. It is a defect in the sphingomyelinase enzyme so that sphingomyelin builds up in the phagocytes (in the lysosomes). These patients will die prior to the age of three from multiple organ problems.

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Hurler’s syndrome—this is an autosomal recessive lysosomal storage disease involving alpha-L-iduronidase deficiency so that mucopolysaccharides build up throughout the body. It leads to Gargoyle facies, mental deterioration, and death

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by the age of 10. It is otherwise similar to Hunter’s syndrome but is different with respect to the way it is inherited.

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Tay-Sachs disease—this is a lysosomal storage disease that is autosomal recessive. It is secondary to a hexosaminidase A deficiency with accumulation of GM2 ganglioside in the neurons. There is blindness, mental retardation, and CNS degeneration with death before four years of age.

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Albinism—this is an autosomal recessive defect of nitrogen metabolism. It involves a tyrosinase deficiency and an inability to make melanin from tyrosine.

It leads to lack of pigmentation, pink eyes in some cases, and an increased risk of skin cancer.

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Alkaptonuria—this is an autosomal recessive homogentisic oxidase deficiency so that phenylalanine and tyrosine do not get made. The urine turns dark with standing and there is pigmentation of fibrous and cartilaginous tissues. The cardiac valve can be involved but the disease otherwise isn’t severe.

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Homocystinuria—this is an autosomal recessive defect in cystathionine synthase so that homocysteine builds up in the body with a relative lack of cysteine. There is mental retardation, failure to thrive, and thromboembolic disease. It can be treated by giving cysteine and pyridoxine.

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Maple syrup urine disease—this is an autosomal recessive deficiency of branched chain keto-acid decarboxylase so that branched chain amino acids build up.

There can be CNS deterioration, mental retardation, and early death unless these amino acids are removed from the diet.

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Phenylketonuria—this is an autosomal recessive defect in phenylalanine hydroxylase. Phenylalanine can build up if not removed from the diet. The symptoms are CNS deterioration, hypopigmentation of the skin and eyes, with death if not treated.

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Glycolytic enzyme deficiencies—these are red blood cell diseases that involve a defect in any enzyme responsible for glycolysis in the red blood cells. RBCs rely

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completely on glycolysis for energy so they get hemolyzed more easily. It is autosomal recessive.

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Autosomal recessive polycystic kidney disease—this is less likely to be the case compared to autosomal dominant disease. There are numerous bilateral cysts in the collecting ducts of the kidneys.

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Fanconi’s syndrome type I—this is child-onset cystinosis and is an autosomal recessive kidney disease. It involves cystine deposition in the entire body and cystinuria with defective tubular resorption leading to amino aciduria and chronic acidosis. The patient will have vitamin D-resistant rickets.

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Fanconi’s syndrome type II—this is adult-onset, autosomal recessive renal disease. It is similar to type I disease but does not involve cystinosis. Adults with disease will have osteomalacia, amino aciduria, polyuria, and glycosuria.

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Bartter’s syndrome—this is an autosomal recessive renal disease that results in juxtaglomerular cell hyperplasia and primary hyperreninemia. There is hypokalemic alkalosis, increased renin and aldosterone levels but no hypertension.

X-LINKED DISORDERS X-linked disorders involve a defect carried on the X chromosome. These are almost exclusively recessive traits. Males have the disease to a much higher degree when compared to women. Female carriers will pass the disease onto half of all boys and will lead to a carrier status in half of all girls. A male with the disease will not pass the disease onto their sons but will lead to a carrier status in all female children.

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Wiskott-Aldrich syndrome—this is an x-linked immune deficiency disease in which there is an inability to mount an IgM response to the capsules of pyogenic bacteria. It leads to increased infections in infancy, thrombocytopenia, excessive bleeding, and eczema.

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Glucose-6-phosphate dehydrogenase deficiency—this is an x-linked recessive disease affecting the enzyme G6PD. It leads to oxidative damage in the RBCs and hemolytic anemia.

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Hunter’s syndrome—this is a lysosomal storage disease that is x-linked and related to L-iduronosulfate sulfatase deficiency, leading to a buildup of mucopolysaccharides. It is less severe than Hurler syndrome but will cause mild mental retardation, micrognathia, and joint stiffness.

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X-linked agammaglobulinemia—this is also called Bruton’s disease and is an immune deficiency disease that affects gene coding for tyrosine kinase so that pre-B cells do not differentiate into B-cells. There will be recurrent pyogenic infections after six months of age when the maternal antibodies are no longer present. It can be treated with gamma globulin preparations.

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Fabry’s disease—this is a lysosomal storage disease that is x-linked and secondary to alpha-galactosidase A deficiency. There are skin lesions, severe burning pain in the extremities, heart problems, and cerebrovascular involvement.

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Chronic granulomatous disease—this is usually x-linked and involves an NADPH oxidase deficiency so that there are no peroxides and super-oxides, leading to a lack of an oxidative burst in the phagocytes. This leads to an increased risk of Staph infections and other infections even though the T cells and B cells are normal.

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Hemophilia A—this is an x-linked factor VIII deficiency, leading to an increase in hemorrhage, hematuria, and bleeding into the joints. The PTT will be prolonged.

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Hemophilia B—this is an x-linked factor IX deficiency, leading to a milder disease than is seen in hemophilia A but there will still be prolongation of the PTT.

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KEY TAKEAWAYS •

There are 22 pairs of autosomal genes and two sex-linked genes in the human chromosome.

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Chromosomal abnormalities lead to missing chromosomes, extra chromosomes, deletions or additions to chromosomes.

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Many chromosome abnormalities are not directly inherited but are caused by defects in meiosis.

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Many chromosomal abnormalities lead to mental retardation; however, Turner syndrome is not one of them.

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Autosomal dominant disorders are passed on in each generation to half of the affected person’s children.

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Autosomal recessive disorders involve a carrier state that is an unaffected person who passes the disease on only if the other parent is also a carrier or has the disease.

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X-linked recessive traits involve a variety of diseases that do not affect girls nearly as much as boys. Girls are often carriers of the disease.

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