USMLE Step 1 Biochemistry: Genetics

multiple endocrine neoplasias

Multiple endocrine neoplasia syndromes are rare, inherited disorders in which several endocrine glands develop noncancerous (benign) or cancerous (malignant) tumors or grow excessively without forming tumors.

Genetic Terms: Locus Heterogeneity

Mutations at different loci can produce a similar phenotype. Albinism.

myotonic muscular dystrophy

Myotonic dystrophy is part of a group of inherited disorders called muscular dystrophies. It is the most common form of muscular dystrophy that begins in adulthood. Myotonic dystrophy is characterized by progressive muscle wasting and weakness. People with this disorder often have prolonged muscle contractions (myotonia) and are not able to relax certain muscles after use. For example, a person may have difficulty releasing their grip on a doorknob or handle. Also, affected people may have slurred speech or temporary locking of their jaw. Other signs and symptoms of myotonic dystrophy include clouding of the lens of the eye (cataracts) and abnormalities of the electrical signals that control the heartbeat (cardiac conduction defects). Some affected individuals develop a condition called diabetes mellitus, in which blood sugar levels can become dangerously high. The features of myotonic dystrophy often develop during a person's twenties or thirties, although they can occur at any age. The severity of the condition varies widely among affected people, even among members of the same family. There are two major types of myotonic dystrophy: type 1 and type 2. Their signs and symptoms overlap, although type 2 tends to be milder than type 1. The muscle weakness associated with type 1 particularly affects muscles farthest from the center of the body (distal muscles), such as those of the lower legs, hands, neck, and face. Muscle weakness in type 2 primarily involves muscles close to the center of the body (proximal muscles), such as the those of the neck, shoulders, elbows, and hips. The two types of myotonic dystrophy are caused by mutations in different genes.

Cystic Fibrosis: Complications

Recurrent pulmonary infections (eg, S areus [infancy and early childhood], P aeruginosa [adulthood]), chronic bronchitis and bronchiectasis >> reticulonodular pattern on CXR, opacification of sinuses (sinus inflammation). Pancreatic insufficiency, malabsorption with steatorrhea (the excretion of abnormal quantities of fat with the feces owing to reduced absorption of fat by the intestine), fat-soluble vitamin deficiencies (A,D,E,K), biliary cirrhosis (progressive disease of the liver caused by a buildup of bile within the liver (cholestasis) that results in damage to the small bile ducts that drain bile from the liver. Over time, this pressure build-up destroys the bile ducts leading to liver cell damage), liver disease. Meconium ileus (Meconium ileus is a bowel obstruction that occurs when the meconium in your child's intestine is even thicker and stickier than normal meconium) in newborns. Infertility in men (absence of vas deferens, spermatogenesis may be affected) and subfertility in women (amenorrhea [absence of menstruation], abnormally thick cervical mucus). Nasal polyps, clubbing of nails.

X-linked Recessive Disorders

*O*rnithine transcarbamylase deficiency *F*abry disease *W*iskott Aldrich syndrome *O*cular albinism *G*6PD deficiency *H*unter syndrome *B*ruton agammaglobulinemia *H*emophilia A and B *L*esch-Nyhan syndrome *D*uchenne (and Becker) muscular dystrophy X-inactivation (lyonization)- one copy of female X chromosome forms a transcriptionally inactive Barr body. Female carriers variably affected depending on the pattern of inactivation of the X chromosome carrying the mutant vs normal gene. "*O*blivious *F*emale *W*ill *O*ften *G*ive *H*er *B*oys *H*er x-*L*inked *D*isorders" Females with turner syndrome (45,XO) are more likely to have an X-linked recessive disorder

autosomal recessive polycystic kidney disease (ARKPD)

An inherited disorder in which clusters of cysts develop in the kidneys. The cysts in polycystic kidney disease are noncancerous sacs containing water-like fluid. They can grow very large. Many people with this condition have kidney failure by age 60. Symptoms include high blood pressure, back or side pain, and a swollen abdomen. Treatments include medication to control blood pressure, pain relievers, and cyst removal. A kidney transplant might be needed.

cystic fibrosis

An inherited life-threatening disorder that damages the lungs and digestive system. Cystic fibrosis affects the cells that produce mucus, sweat, and digestive juices. It causes these fluids to become thick and sticky. They then plug up tubes, ducts, and passageways. Symptoms vary and can include cough, repeated lung infections, inability to gain weight, and fatty stools. Treatments may ease symptoms and reduce complications. Newborn screening helps with early diagnosis.

thalassemias

A blood disorder involving less than normal amounts of an oxygen-carrying protein. Thalassemia is an inherited blood disorder characterized by less oxygen-carrying protein (hemoglobin) and fewer red blood cells in the body than normal. Symptoms include fatigue, weakness, paleness, and slow growth. Mild forms may not need treatment. Severe forms may require blood transfusions or a donor stem-cell transplant.

Genetic Terms: Codominance

Both alleles contribute to the phenotype of the heterozygote. Blood groups A,B, AB; alpha1-antitrypsin deficiency; HLA groups

Modes of Inheritance: Autosomal Dominant Diseases

Achondroplasia , autosomal dominant polycystic kidney disease, familial adenomatous polyposis, familial hypercholesterolemia, hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome), hereditary spherocytosis, Huntington disease, Li-Fraumeni syndrome, Marfan syndrome, multiple endocrine neoplasias, myotonic muscular dystrophy, neurofibromatosis type 1 (von Recklinghausen disease), neurofibromatosis type 2, tuberous sclerosis, von Hippel-Lindau disease.

Achondroplasia

Achondroplasia is a disorder of bone growth that prevents the changing of cartilage (particularly in the long bones of the arms and legs) to bone. It is characterized by dwarfism, limited range of motion at the elbows, large head size (macrocephaly), small fingers, and normal intelligence.

Modes of Inheritance: Autosomal Recessive Disease

Albinism, autosomal recessive polycystic kidney disease (ARKPD), cystic fibrosis, Friedreich ataxia, glycogen storage disease, hemochromatosis, Kartagener syndrome, mucopolysaccharidoses (except Hunter syndrome), phenylketonuria, sickle cell anemia, sphingolipadoses (except Fabry disease), halassemias, Wilson disease

alport syndrome

Alport syndrome is a genetic condition characterized by kidney disease, hearing loss, and eye abnormalities. People with Alport syndrome experience progressive loss of kidney function. Almost all affected individuals have blood in their urine (hematuria), which indicates abnormal functioning of the kidneys.

autosomal dominant polycystic kidney disease

An inherited disorder in which clusters of cysts develop in the kidneys. The cysts in polycystic kidney disease are noncancerous sacs containing water-like fluid. They can grow very large. Many people with this condition have kidney failure by age 60. Symptoms include high blood pressure, back or side pain, and a swollen abdomen. Treatments include medication to control blood pressure, pain relievers, and cyst removal. A kidney transplant might be needed

Cystic Fibrosis: Genetics

Autosomal recessive; defect in CFTR gene on chromosome 7; commonly a deletion of PHe508. Most common lethal genetic disease in Caucasian population.

Cystic Fibrosis: Pathophysiology

CFTR encodes an ATP-gated Cl- channel that secretes Cl- in lungs and GI tract, and reabsorbs Cl- in sweat glands. Most common mutation >> misfolded protein >> protein retained in RER and not transported to cell membrane, causing decreased Cl- (and H2O) secretion; increased intracellular Cl- results in compensatory increased Na+ reabsorption via epithelial Na+ channels (ENaC) >> increased H2O reabsorption >> abnormally thick mucus secreted into lungs and GI tract. Increased Na+ reabsorption also causes more negative transepithelial potential difference.

Genetic Terms: Allelic Heterogeneity

Different mutations in the same locus produce the same phenotype. Beta-thalassemia.

Duchenne and Becker Muscular Dystrophy

Duchenne and Becker muscular dystrophies have similar signs and symptoms and are caused by different mutations in the same gene. The two conditions differ in their severity, age of onset, and rate of progression. In boys with Duchenne muscular dystrophy, muscle weakness tends to appear in early childhood and worsen rapidly. Affected children may have delayed motor skills, such as sitting, standing, and walking. They are usually wheelchair-dependent by adolescence. The signs and symptoms of Becker muscular dystrophy are usually milder and more varied. In most cases, muscle weakness becomes apparent later in childhood or in adolescence and worsens at a much slower rate. Both the Duchenne and Becker forms of muscular dystrophy are associated with a heart condition called cardiomyopathy. This form of heart disease weakens the cardiac muscle, preventing the heart from pumping blood efficiently. In both Duchenne and Becker muscular dystrophy, cardiomyopathy typically begins in adolescence. Later, the heart muscle becomes enlarged, and the heart problems develop into a condition known as dilated cardiomyopathy. Signs and symptoms of dilated cardiomyopathy can include an irregular heartbeat (arrhythmia), shortness of breath, extreme tiredness (fatigue), and swelling of the legs and feet. These heart problems worsen rapidly and become life-threatening in most cases. Males with Duchenne muscular dystrophy typically live into their twenties, while males with Becker muscular dystrophy can survive into their forties or beyond.

Genetic Terms: Dominant Negative Mutation

Exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning. Mutations of a transcription factor in its allosteric site. Nonfuctioning mutant can still bind DNA, preventing wild-type transcription factor from binding. A mutation whose gene product adversely affects the normal, wild-type gene product within the same cell. This usually occurs if the product can still interact with the same elements as the wild-type product, but block some aspect of its function. Examples: 1. A mutation in a transcription factor that removes the activation domain, but still contains the DNA binding domain. This product can then block the wild-type transcription factor from binding the DNA site leading to reduced levels of gene activation. 2. A protein that is functional as a dimer. A mutation that removes the functional domain, but retains the dimerization domain would cause a dominate negative phenotype, because some fraction of protein dimers would be missing one of the functional domains.

Fabry disease

Fabry disease is a rare inherited disorder of glycosphingolipid (fat) metabolism resulting from the absent or markedly deficient activity of the lysosomal enzyme, α-galactosidase A (α-Gal A). This disorder belongs to a group of diseases known as lysosomal storage disorders. This enzymatic deficiency is caused by alterations (mutations) in the α-galactosidase A (GLA) gene that instructs cells to make the α-galactosidase A (α-Gal A) enzyme. Lysosomes function as the primary digestive tract of cells. Enzymes within lysosomes break down or digest particular compounds and intracellular structures. α-Gal A functions to break down complex sugar-lipid molecules called glycolipids, specifically, globotriaosylceramide (GL-3 or Gb3), its deacylated form Lyso-GL-3/Gb3 and related glycolipids, by removing the terminal galactose sugar from the end of these glycolipid molecules. The enzyme deficiency causes a continuous build-up of GL-3/Gb3 and related glycolipids in the body's cells, resulting in the cell abnormalities and organ dysfunction that particularly affect small blood vessels, the heart and kidneys

Familial Adenomatous Polyposis (FAP)

Familial adenomatous polyposis (FAP) is an inherited disorder characterized by cancer of the large intestine (colon) and rectum. People with the classic type of familial adenomatous polyposis may begin to develop multiple noncancerous (benign) growths (polyps) in the colon as early as their teenage years. Unless the colon is removed, these polyps will become malignant (cancerous). The average age at which an individual develops colon cancer in classic familial adenomatous polyposis is 39 years. Some people have a variant of the disorder, called attenuated familial adenomatous polyposis, in which polyp growth is delayed. The average age of colorectal cancer onset for attenuated familial adenomatous polyposis is 55 years. In people with classic familial adenomatous polyposis, the number of polyps increases with age, and hundreds to thousands of polyps can develop in the colon. Also of particular significance are noncancerous growths called desmoid tumors. These fibrous tumors usually occur in the tissue covering the intestines and may be provoked by surgery to remove the colon. Desmoid tumors tend to recur after they are surgically removed. In both classic familial adenomatous polyposis and its attenuated variant, benign and malignant tumors are sometimes found in other places in the body, including the duodenum (a section of the small intestine), stomach, bones, skin, and other tissues. People who have colon polyps as well as growths outside the colon are sometimes described as having Gardner syndrome.

Fragile X Syndrome

Fragile X syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. Usually, males are more severely affected by this disorder than females. Affected individuals usually have delayed development of speech and language by age 2. Most males with fragile X syndrome have mild to moderate intellectual disability, while about one-third of affected females are intellectually disabled. Children with fragile X syndrome may also have anxiety and hyperactive behavior such as fidgeting or impulsive actions. They may have attention deficit disorder (ADD), which includes an impaired ability to maintain attention and difficulty focusing on specific tasks. About one-third of individuals with fragile X syndrome have features of autism spectrum disorder that affect communication and social interaction. Seizures occur in about 15 percent of males and about 5 percent of females with fragile X syndrome.

Friedreich ataxia

Friedreich ataxia is a genetic condition that affects the nervous system and causes movement problems. People with this condition develop impaired muscle coordination (ataxia) that worsens over time. Other features of this condition include the gradual loss of strength and sensation in the arms and legs; muscle stiffness (spasticity); and impaired speech, hearing, and vision. Individuals with Friedreich ataxia often have a form of heart disease called hypertrophic cardiomyopathy, which enlarges and weakens the heart muscle and can be life-threatening. Some affected individuals develop diabetes or an abnormal curvature of the spine (scoliosis). Most people with Friedreich ataxia begin to experience the signs and symptoms of the disorder between ages 5 and 15. Poor coordination and balance are often the first noticeable features. Affected individuals typically require the use of a wheelchair about 10 years after signs and symptoms appear.

G6PD deficiency

Glucose-6-phosphate dehydrogenase deficiency is a genetic disorder that occurs almost exclusively in males. This condition mainly affects red blood cells, which carry oxygen from the lungs to tissues throughout the body. In affected individuals, a defect in an enzyme called glucose-6-phosphate dehydrogenase causes red blood cells to break down prematurely. This destruction of red blood cells is called hemolysis.

glycogen storage disease

Glycogen storage disease (GSD) is a rare condition that changes the way the body uses and stores glycogen, a form of sugar or glucose. Glycogen is a main source of energy for the body. Glycogen is stored in the liver. When the body needs more energy, certain proteins called enzymes break down glycogen into glucose. They send the glucose out into the body. When someone has GSD, they are missing one of the enzymes that breaks down glycogen. When an enzyme is missing, glycogen can build up in the liver. Or glycogen may not form properly. This can cause problems in the liver or muscles, or other parts of the body. GSD is passed down from parents to children (is hereditary). It is most often seen in babies or young children. But some forms of GSD may appear in adults.

hemochromatosis

Hemochromatosis is a disorder where too much iron builds up in your body. Sometimes it's called "iron overload." Normally, your intestines absorb just the right amount of iron from the foods you eat. But in hemochromatosis, your body absorbs too much, and it has no way to get rid of it. So, your body stores the excess iron in your joints and in organs like your liver, heart, and pancreas. This damages them. If it's not treated, hemochromatosis can make your organs stop working.

Disorders of Imprinting

Imprinting-one gene copy is silenced by methylation, and only the other copy is expressed >> parent-of-orgin effects.

Hemophilia A and B

Hemophilia is a rare, inherited bleeding disorder in which blood cannot clot normally at the site of a wound or injury. The disorder occurs because certain blood clotting factors are missing or do not work properly. Because a clot does not form, extensive bleeding can be caused from a cut or wound. This is called external bleeding. Bleeding inside the body, called internal bleeding, can occur as well, especially in muscles and in joints like the hips and knees. Hemophilia affects males almost exclusively, but there are rare circumstances when a female can be affected with the disorder. There are two main types of inherited hemophilia: -Type A, the most common type, is caused by a deficiency of factor VIII, one of the proteins that helps blood to form clots. This type is known as classic hemophilia. -Type B hemophilia is caused by a deficiency of factor IX. This type is also called Christmas disease.

hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)

Hereditary hemorrhagic telangiectasia (tuh-lan-jee-uk-TAY-zhuh) is an inherited disorder that causes abnormal connections, called arteriovenous malformations (AVMs), to develop between arteries and veins. The most common locations affected are the nose, lungs, brain and liver. These AVMs may enlarge over time and can bleed or rupture, sometimes causing catastrophic complications. Spontaneous and unprovoked nosebleeds, sometimes on a daily basis, are the most common feature. Persistent bleeding from the nose and the intestinal tract can result in severe iron deficiency anemia and poor quality of life. Also known as Osler-Weber-Rendu disease, hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder that you inherit from your parents. Its severity can vary greatly from person to person, even within the same family.

hereditary spherocytosis

Hereditary spherocytosis is an abnormality of red blood cells, or erythrocytes. The disorder is caused by mutations in genes relating to membrane proteins that allow for the erythrocytes to change shape. The abnormal erythrocytes are sphere-shaped (spherocytosis) rather than the normal biconcave disk shaped. Dysfunctional membrane proteins interfere with the cell's ability to be flexible to travel from the arteries to the smaller capillaries. This difference in shape also makes the red blood cells more prone to rupture.[1] Cells with these dysfunctional proteins are degraded in the spleen. This shortage of erythrocytes results in hemolytic anemia.

Hunter syndrome

Hunter syndrome is a very rare, inherited genetic disorder caused by a missing or malfunctioning enzyme. In Hunter syndrome, the body doesn't have enough of the enzyme iduronate 2-sulfatase. This enzyme's job is to break down certain complex molecules, and without enough of this enzyme, the molecules build up in harmful amounts. The buildup of massive amounts of these harmful substances eventually causes permanent, progressive damage affecting appearance, mental development, organ function and physical abilities. Hunter syndrome is far more common in boys. The condition is one type of a group of inherited metabolic disorders called mucopolysaccharidoses (MPSs). Hunter syndrome is also known as MPS II.

Huntington disease

Huntington disease is a progressive brain disorder that causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition). Adult-onset Huntington disease, the most common form of this disorder, usually appears in a person's thirties or forties.

Genetic Terms: Loss of Heterozygosity

If a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. This is not true of oncogenes. Retinoblastoma and the "two-hit hypothesis," Lynch syndrome (HNPCC), Li-Fraumeni syndrome.

Genetic Terms: Hardy-Weinberg Population Genetics

If a population is i Hardy-Weinberg equilibrium and if p and q are the frequencies of separate alleles, then: p^2 + 2pq + q^2 = 1 and p + q = 1, which implies that: The values of p and q remain constant from generation to generation. p^2 =frequency of homozygosity for allele A q^2 = frequency for homozygosity for allele a 2pq = frequency of heterozygosity (carrier frequency, if an autosomal recessive disease). Hardy-Weinberg law assumptions include: -no mutation ocurring https://www.khanacademy.org/science/ap-biology/natural-selection/hardy-weinberg-equilibrium/v/applying-hardy-weinberg

myopathy

In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness.

Cystic Fibrosis: Diagnosis

Increased Cl- concentration in pilocarpine-induced sweat test is diagnostic. Can present with contraction alkalosis (excessive blood alkalinity) and hypokalemia (blood's potassium levels are too low) (ECF effects analogous to a patient taking a loop diuretic) because of ECF H2O/Na+ losses via sweating and concomitant renal K+/H+ wasting. Increased immunoreactive trypsinogen (newborn screening).

Genetic Terms: Anticipation

Increased severity or earlier onset of disease in succeeding generations Trinucleotide repeat disease (eg, Huntington Disease)

Disorders of Imprinting: Prader-Willi Syndrome

Maternally derived genes are silenced (imprinted). Disease occurs when the *Paternal allele is deleted or mutated, although 25% of cases are due to maternal uniparental disomy. Results in hyperphagia, obesity, intellectual disability, hypogonadism, and hypotonia. Associated with a mutation or deletion of chromosome 15 of paternal origin. *Prader has no *Papa (*paternal deletion)

Kartagener syndrome

Kartagener's syndrome is a rare, autosomal recessive genetic ciliary disorder comprising the triad of situs inversus, chronic sinusitis, and bronchiectasis. The basic problem lies in the defective movement of cilia, leading to recurrent chest infections, ear/nose/throat symptoms, and infertility.

Lactic acidosis

Lactic acidosis is a medical condition characterized by the buildup of lactate (especially L-lactate) in the body, with formation of an excessively low pH in the bloodstream. It is a form of metabolic acidosis, in which excessive acid accumulates due to a problem with the body's oxidative metabolism.

Lesch-Nyhan syndrome

Lesch Nyhan syndrome is a condition characterized by neurological and behavioral abnormalities and the overproduction of uric acid in the body. It occurs almost exclusively in males. Signs and symptoms may include inflammatory arthritis (gout), kidney stones, bladder stones, and moderate cognitive disability. Nervous system and behavioral disturbances also occur, such as involuntary muscle movements and self injury (including biting and head banging). People with Lesch Nyhan syndrome usually cannot walk, require assistance sitting, and generally use a wheelchair. Lesch Nyhan syndrome is caused by changes (mutations) in the HPRT1 gene and is inherited in an X-linked recessive manner. Treatment is symptomatic and supportive. Affected people often do not survive past the first or second decade of life due to renal failure.

Li-Fraumeni Syndrome (LFS)

Li-Fraumeni syndrome (LFS) is an inherited familial predisposition to a wide range of certain, often rare, cancers. This is due to a change (mutation) in a tumor suppressor gene known as TP53.

Marfan syndrome

Marfan syndrome (MFS) is a genetic disorder that affects the connective tissue. Those with the condition tend to be tall and thin, with long arms, legs, fingers, and toes. They also typically have overly-flexible joints and scoliosis. The most serious complications involve the heart and aorta, with an increased risk of mitral valve prolapse and aortic aneurysm. The lungs, eyes, bones, and the covering of the spinal cord are also commonly affected. The severity of the symptoms of MFS is variable. MFS is caused by a mutation in FBN1, one of the genes that makes fibrillin, which results in abnormal connective tissue. It is an autosomal dominant disorder.

mucopolysaccharidoses

Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans (GAGs). These long chains of sugar carbohydrates occur within the cells that help build bone, cartilage, tendons, corneas, skin and connective tissue. GAGs (formerly called mucopolysaccharides) are also found in the fluids that lubricate joints. Individuals with mucopolysaccharidosis either do not produce enough of one of the eleven enzymes required to break down these sugar chains into simpler molecules, or they produce enzymes that do not work properly. Over time, these GAGs collect in the cells, blood and connective tissues. The result is permanent, progressive cellula

Cystic Fibrosis: Treatment

Multifactorial: chest physiotherapy, albuterol, aerosolized dornase alfa (DNase), and hypertonic saline facilitate mucus clearance. Azithromycin used as anti-inflammatory agent. Ibuprofen slows disease progression. In patients with Phe508 deletion: combination of lumacaftor (corrects misfolded proteins and improves their transport to cell surface) and ivacafter (opens Cl- channels >> improved chloride transport).

neurofibromatosis type 1 (von Recklinghausen disease)

Neurofibromatosis 1 (NF1), also called von Recklinghausen's disease, is a genetic disorder characterized by the development of multiple noncancerous (benign) tumors of nerves and skin (neurofibromas) and areas of abnormal skin color (pigmentation). Areas of abnormal skin pigmentation typically include pale tan or light brown discolorations (cafe-au-lait spots), freckling in atypical locations such as under the arms (axillary region) or in the groin (inguinal region). Such abnormalities of skin pigmentation are often evident by one year of age and tend to increase in size and number over time. At birth or early childhood, affected individuals may have relatively large, benign tumors that consist of bundles of nerves and other tissue (plexiform neurofibromas). Individuals with NF1 may also develop benign nodules on the colored regions of the eyes (Lisch nodules), or tumors in the nerves of the visual pathway (optic pathway gliomas). More rarely, affected individuals may develop certain malignant (cancerous) tumors. NF1 may also be characterized by an unusually large head size (macrocephaly) and relatively short stature. Additional abnormalities may also be present, such as episodes of uncontrolled electrical activity in the brain (seizures); learning disabilities, and attention deficits; speech difficulties; abnormally increased activity (hyperactivity); and skeletal malformations, including progressive curvature of the spine (scoliosis), bowing of the lower legs (pseudoarthrosis), and improper development of certain bones. Associated symptoms and findings may vary greatly in range and severity from person to person, even within the same family. Most people with NF1 have normal intelligence but learning disabilities appear in about 50% of children with NF1.

neurofibromatosis type 2

Neurofibromatosis type 2 is a disorder characterized by the growth of noncancerous tumors in the nervous system. The most common tumors associated with neurofibromatosis type 2 are called vestibular schwannomas or acoustic neuromas. These growths develop along the nerve that carries information from the inner ear to the brain (the auditory nerve). Tumors that occur on other nerves are also commonly found with this condition. The signs and symptoms of neurofibromatosis type 2 usually appear during adolescence or in a person's early twenties, although they can begin at any age. The most frequent early symptoms of vestibular schwannomas are hearing loss, ringing in the ears (tinnitus), and problems with balance. In most cases, these tumors occur in both ears by age 30. If tumors develop elsewhere in the nervous system, signs and symptoms vary according to their location. Complications of tumor growth can include changes in vision, numbness or weakness in the arms or legs, and fluid buildup in the brain. Some people with neurofibromatosis type 2 also develop clouding of the lens (cataracts) in one or both eyes, often beginning in childhood.

Genetic Terms: Incomplete Penetrance

Not all individuals with a mutant genotype show the mutant phenotype. % penetrance x probability of inheriting genotype = risk of expressing phenotype. BRCA1 gene mutations do not always result in breast or ovarian cancer

Ocular albinism

Ocular albinism primarily affects pigment production in the eyes. Several vision problems can occur with ocular albinism including an involuntary movement of eyes back and forth (nystagmus), reduced iris pigment in some individuals, reduced retinal pigment, lack of development of the fovea (foveal hypoplasia) leading to blurred vision, and abnormal connections in the nerves from the retina to the brain that prevents the eyes from tracking together and reduces depth perception. Crossed eyes (strabismus) and sensitivity to light (photophobia) are also common. Typically individuals have normal hair and skin pigmentation.

Genetic Terms: Uniparental Disomy

Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent. Heterod*Isomy (heterozygous) indicates a meiosis *I error. *Isod*Isomy (homozygous) indicates a meiosis II error or postzygotic chromosomal duplication of one of a pair of chromosomes, and loss of the other of the original pair. Uniparental is euploid (correct number of chromosomes). Most occurrences of uniparental disomy (UPD) in an individual manifesting a recessive disorder when only one parent is a carrier. Emaples: Prader-Willi and Angelman syndromes. https://www.youtube.com/watch?v=NL6UAUbUKY0

Modes of Inheritance: Autosomal Dominant

Often due to defects in structural genes. Many generations, both males and females are affected. Often pleiotropic (multiple apparently unrelated effects) and variable expressive (different between individuals). Family history crucial to diagnosis. With one affected (heterozygous) parent, on average, 1/2 of children affected.

Genetic Terms: Pleiotropy

One gene contributes to multiple phenotypic effects. Untreated phenylketonuria (PKU) manifests with light skin, intellectual disability, and musty body odor.

Ornithine transcarbamylase deficiency (OTC)

Ornithine transcarbamylase (OTC) deficiency is a rare X-linked genetic disorder characterized by complete or partial lack of the enzyme ornithine transcarbamylase (OTC). OTC is one of six enzymes that play a role in the break down and removal of nitrogen the body, a process known as the urea cycle. The lack of the OTC enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood. Excess ammonia, which is a neurotoxin, travels to the central nervous system through the blood, resulting in the symptoms and physical findings associated with OTC deficiency. Symptoms include vomiting, refusal to eat, progressive lethargy, and coma.

Angel*Man Syndrome

Paternally derived UBE3A gene is silenced (imprinted). Disease occurs when the *Maternal allele is deleted or mutated. Results in inappropriate laughter ("happy puppet"), seizures, ataxia, and severe intellectual disability. Associated with mutation or deletion of the UBE3A gene on the maternal copy of chromosome 15. 5% of cases due to paternal unipaternal disomy.

Genetic Terms: Variable expressivity

Patients with the same genotype have varying phenotypes. 2 patients with neurofibromatosis type 1 (NF1) may have varying disease severity.

phenylketonuria

Phenylketonuria (PKU) is an inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine. Untreated, PKU can lead to intellectual disability, seizures, behavioral problems, and mental disorders. It may also result in a musty smell and lighter skin. A baby born to a mother who has poorly treated PKU may have heart problems, a small head, and low birth weight. Phenylketonuria is a genetic disorder inherited from a person's parents. It is due to mutations in the PAH gene, which results in low levels of the enzyme phenylalanine hydroxylase. This results in the buildup of dietary phenylalanine to potentially toxic levels. It is autosomal recessive, meaning that both copies of the gene must be mutated for the condition to develop.

Genetic Terms: Heteroplasmy

Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrially inherited disease. Beta-thalassemia.

Genetic Terms: Mosaicism

Presence of genetically distinct cell lines in the same individual. Somatic mosaicism- mutation arises from mitotic errors after fertilization and propagates through multiple tissues or organs. Gonadal mosaicism- mutation only in egg or sperm cells. If parents and relatives do not have the disease, suspect gonadal (or germline) mosacism. McCune-Albright syndrome- due to G(S)-protein activating mutation. Presents with unilateral cafe-au-lait spots with ragged edges, polyostitic fibrous dysplasia (bone is replaced by collagen and fibroblasts), and at least one endocrinopathy (eg, precocious puberty). Lethal if mutation occurs before fertilization (affecting all cells), but survivable in patients with mosaicism.

Modes of Inheritance: X-linked Recessive

Sons of heterozygous mothers have 50% chance of being affected. No male-to-male transmission. Skips generations. Commonly more severe in male. Females usually must be homozygous to be affected.

sphingolipadoses

Sphingolipidoses are a class of lipid storage disorders relating to sphingolipid metabolism. The main members of this group are Niemann-Pick disease, Fabry disease, Krabbe disease, Gaucher disease, Tay-Sachs disease and metachromatic leukodystrophy. They are generally inherited in an autosomal recessive fashion, but notably Fabry disease is X-linked recessive.

Genetic Terms: Linkage Disequilibrium

Tendency for certain alleles at 2 linked loci to occur together more often than expected by chance. Measured in a population, not in a family, and often varies in different populations. https://www.youtube.com/watch?v=DvrAuMyu4wU

Modes of Inheritance: Mitochondrial Inheritance

Transmitted only through the mother. All offspring of affected females may show signs of disease. Variable expression is in a population or even within a family due to heteroplasmy. Mitochondrial myopathies- rare disorders; often present with myopathy, lactic acidosis, and CNS disease, eg, MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Secondary to failure in oxidative phosphorylation. Muscle biopsy often shows "ragged red fibers" (due to accumulation of disease mitochondria in the subsarcolemma of the muscle fiber). Leber hereditary optic neuropathy- cell death in optic nerve neurons >> subacute bilateral vision loss in teens/young adults, 90% males. Usually permanent.

Modes of Inheritance: X-linked Dominant

Transmitted through both parents. Mothers transmit to 50% of daughters and sons; fathers transmit to all daughters but no sons. Hypophosphatemic Rickets- formerly known as vitamin D-resistant rickets. Inherited disorder resulting in increased phosphate wasting at proximal tubule. Results in rickets-like presentation. Other examples: fragile X syndrome, alport syndrome

tuberous sclerosis

Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung disease, and kidney disease. TSC is caused by a mutation of either of two genes, TSC1 and TSC2, which code for the proteins hamartin and tuberin, respectively, with TSC2 mutations accounting for the majority and tending to cause more severe symptoms. These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation.

von Hippel-Lindau disease

Von Hippel-Lindau syndrome is an inherited disorder characterized by the formation of tumors and fluid-filled sacs (cysts) in many different parts of the body. Tumors may be either noncancerous or cancerous and most frequently appear during young adulthood; however, the signs and symptoms of von Hippel-Lindau syndrome can occur throughout life. Tumors called hemangioblastomas are characteristic of von Hippel-Lindau syndrome. These growths are made of newly formed blood vessels. Although they are typically noncancerous, they can cause serious or life-threatening complications. Hemangioblastomas that develop in the brain and spinal cord can cause headaches, vomiting, weakness, and a loss of muscle coordination (ataxia). Hemangioblastomas can also occur in the light-sensitive tissue that lines the back of the eye (the retina). These tumors, which are also called retinal angiomas, may cause vision loss. People with von Hippel-Lindau syndrome commonly develop cysts in the kidneys, pancreas, and genital tract. They are also at an increased risk of developing a type of kidney cancer called clear cell renal cell carcinoma and a type of pancreatic cancer called a pancreatic neuroendocrine tumor. Von Hippel-Lindau syndrome is associated with a type of tumor called a pheochromocytoma, which most commonly occurs in the adrenal glands (small hormone-producing glands located on top of each kidney). Pheochromocytomas are usually noncancerous. They may cause no symptoms, but in some cases they are associated with headaches, panic attacks, excess sweating, or dangerously high blood pressure that may not respond to medication. Pheochromocytomas are particularly dangerous in times of stress or trauma, such as when undergoing surgery or in an accident, or during pregnancy. About 10 percent of people with von Hippel-Lindau syndrome develop endolymphatic sac tumors, which are noncancerous tumors in the inner ear. These growths can cause hearing loss in one or both ears, as well as ringing in the ears (tinnitus) and problems with balance. Without treatment, these tumors can cause sudden profound deafness. Noncancerous tumors may also develop in the liver and lungs in people with von Hippel-Lindau syndrome. These tumors do not appear to cause any signs or symptoms.

Bruton agammaglobulinemia

X-linked agammaglobulinemia (XLA) is a condition that affects the immune system and occurs almost exclusively in males. People with XLA have very few B cells, which are specialized white blood cells that help protect the body against infection. B cells can mature into the cells that produce special proteins called antibodies or immunoglobulins. Antibodies attach to specific foreign particles and germs, marking them for destruction. Individuals with XLA are more susceptible to infections because their body makes very few antibodies.

Wilson disease

Wilson disease is a rare genetic disorder characterized by excess copper stored in various body tissues, particularly the liver, brain, and corneas of the eyes. The disease is progressive and, if left untreated, it may cause liver (hepatic) disease, central nervous system dysfunction, and death. Early diagnosis and treatment may prevent serious long-term disability and life threatening complications. Treatment is aimed at reducing the amount of copper that has accumulated in the body and maintaining normal copper levels thereafter. Wilson disease is a rare genetic disorder beginning with liver dysfunction where damage begins by six years of age, but usually presents clinically in teenage years or early twenties. Common signs of associated liver disease include a yellow discoloration (jaundice) of the skin, mucous membranes and the membranes (sclera) that line the eye, swelling (edema) of the legs and abdomen (ascites) due to abnormal retention of fluid, presence of abnormal blood vessels in the esophagus that may bleed (esophageal varices), a tendency for bruising and prolonged bleeding, and excessive tiredness (fatigue). Some individuals with Wilson disease may have only abnormalities of liver function test and may show no other symptoms until many years later.

Wiskott-Aldrich Syndrome (WAS)

Wiskott-Aldrich syndrome is characterized by abnormal immune system function (immune deficiency), eczema (an inflammatory skin disorder characterized by abnormal patches of red, irritated skin), and a reduced ability to form blood clots. This condition primarily affects males. Individuals with Wiskott-Aldrich syndrome have microthrombocytopenia, which is a decrease in the number and size of blood cells involved in clotting (platelets). This platelet abnormality, which is typically present from birth, can lead to easy bruising, bloody diarrhea, or episodes of prolonged bleeding following nose bleeds or minor trauma. Microthrombocytopenia can also lead to small areas of bleeding just under the surface of the skin, resulting in purplish spots called purpura, or variably sized rashes made up of tiny red spots called petechiae. In some cases, particularly if a bleeding episode occurs within the brain, prolonged bleeding can be life-threatening.

Modes of Inheritance: Autosomal Recessive

With 2 carrier (heterozygous) parents, on average: 1/4 of children will be affected (homozygous), 1/2 of children will be carriers, and 1/4 of children will be neither affected nor carriers. Often due to enzyme deficiencies. Usually seen in only 1 generation. Commonly more severe then dominant disorders; patients often present in childhood. Increased risk in consanguineous families. Unaffected individual with affected sibling has 2/3 probability of being a carrier.

Muscular Dystrophies: Duchenne

X-linked disorder typically due to frameshift deletions or nonsense mutations >> truncated or absent dystrophin protein >> progressive myofiber damage. Weakness begin in pelvic girdle muscles and progresses superiorly. Pseudohypertrophy of calf muscle due to fibrofatty replacement of muscle. Waddling gait. Onset before 5 years of age. Dilated cardiomyopathy is common cause of death. Gowers sign- patient uses upper extremities to help stand. Classically seen in duchenne muscular dystrophy, but also seen in other muscular dystrophies and inflammatory myopathies (eg, polymyostasis) *Duchenne= *deleted *dystrophin. Dystrophin gene (DMD) is the largest protein-coding human gene >> increased chance of spontaneous mutation. Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle. It connects the intracellular cytoskeleton (actin) to the transmembrane protein alpha- and beta-dystroglycan, which are connected to the extracellular matrix (ECM). Loss of dystrophin >> myonecrosis. Increased CK and aldolase; genetic testing confirms diagnosis.

Muscular Dystrophies: Becker

X-linked disorder typically due to non-frameshift deletions in dystrophin gene (partially functional instead of truncated). Less severe than Duchenne. Onset in adolescence or early adulthood. Deletions can cause both Duchenne and Becker muscular dystrophies. 2/3 of cases have large deletions spanning one or more exons.