Diseases and Drugs 2nd M2M Flashcards

Question

Denys-Drash & Frasier Syndrome

Answer 1

``` o Sex reversal with 46, XY o Due to mutations in the WT1 gene o Both cause different types of chronic kidney disease ♣ Diffuse mesangial sclerosis ♣ Focal segmental glomerulosclerosis ``` o Increased risk for Wilms Tumor o WT1 – transcription factor for SRY gene ♣ SRY gene is not functioning properly (the Y gene Thee cause of DDS is most commonly (96% of patients) an abnormality in the WT1 gene (Wilms tumor suppressor gene). These abnormalities include changes in certain exons (9 and 8) and mutations in some alleles of the WT1 gene. Genetically, the syndrome is due to mutations in the Wilms tumor suppressor gene, WT1, which is on chromosome 11 (11p13). These mutations are usually found in exons 8 or 9, but at least one has been reported in exon 4

Answer 2

Phenylketonuria High phenylalanine in blood due to lacking a critical enzyme, phenylalanine hydroxylase. Will lead to mental retardation, hyperactivity and epilepsy. Caused by mutations for phenylalanine hydroxylase at chromosome 12. Treated by a low phenylalanine diet and possible neutral amino acid supplementation Cause of Phenylketonuria ♣ High amount of Phenylalanine levels in the blood, due to the defective nature or lack of enzyme phenylalanine hydroxylase • Phenylalanine Hydroxylase (PAH): Normally found in the liver, is used to turn phenylalanine Tyrosine • Defects cause 98% of the diseases Defect in Cofactor BH4 ( a cofactor for PAH) Need the cofactor B4 to bind to the phenylalanine hydroxylase enzyme (and for dopamine/serotonin) • This causes 1-2% of the cases of Phenylketonuria • Lacking BH4 Also leads to a loss of neurotransmitters such as dopamine and serotonin Possible phenotypes from Phenylketonuria High phenylalanine metabolites in urine, hyperactivity, mental retardation, epilepsy, microcephaly Molecular defects in PAH The PAH gene is at chromosome 12q22-24. Most mutations in PAH are partial or complete loss-of-function alleles. PAH gene exhibits high allelic heterogeneity; over 400 alleles have been identified. Most PKU patients are compound heterozygotes (i.e. having two different mutant alleles of the PAH gene). Severity of phenotype varies and probably reflects compound heterozygosity Treatment Low-Phenylalanine Diet: • From birth through childhood, and beyond • For women, throughout child-bearing years BH4 supplementation • Kuvan® : long-term safety and effectiveness? Other treatments: • Neutral amino acid supplementation o Dietary supplementation with large neutral amino acids(LNAAs), with or without the traditional PKU diet is another treatment strategy. The LNAAs (e.g. leu, tyr, trp, met,his, ile, val, thr) compete with phe for specific carrier proteins that transpor

Answer 3

1-antitrypsin deficiency (ATD) A disease where a protease inhibitor (Serpina1 gene) is inhibited, allowing the protease elastase run rampant, destroying connective tissue elastin in lungs, leading to lung emphysema and liver disease Phenotype ATD patients have a 20-fold increased risk of developing emphysema, with more severe symptoms among smokers. This disorder is late-onset, especially in non-smokers, but 80- 90% of deficient individuals will eventually develop disease symptoms. Many patients also develop liver cirrhosis and have increased risk of liver carcinoma due to the accumulation of a misfolded α1-AT mutant protein in the liver Different conditions it leads to : • Emphysema of lungs and lung disease • Liver Cancer and Liver Cirhosis Earlier and more severe symptoms in smoker (ecogenetics). Mechanism of 1-antitrypsin deficiency (ATD) α1-antitrypsin (ATT or SERPINA1) is made in the liver and secreted into plasma. SERPINA1 is a member of serpins (serine protease inhibitor), which are suicide substrates that bind and inhibit specific serine proteases. The main target of SERPINA1 is elastase, which is released by neutrophils in the lung. When left unchecked, elastase can destroy the connective tissue proteins (particularly elastin) of the lung, causing alveolar wall damage and emphysema. ♣ Deficiency in a1-antitrypsin protein (SERPINA1, AAT), a protease inhibitor ♣ SERPINA1 is a suicide substrate of the serine protease elastase. • Elastase is released by activated neutrophils at the airway, destroying elastin in the connective tissues. • It’s macrophages that release signals to summon neutrophils the neutrophils will release the Elastase ♣ ATD patients have an imbalance of elastase and SERPINA1 levels ATD: Molecular Basis The SERPINA1 gene is on chromosome 14 (14q32.13). There are ~20 different mutant alleles, although the Z & S alleles account for most of the disease cases. The Z allele (Glu342Lys) encodes a misfolded protein that aggregates in the endoplasmic reticulum (ER) of liver cells, causing damage to the liver in addition to the lung. The S allele (Glu264Val) expresses an unstable protein that is less effective. ♣ ATD is caused by mutations in a1-AT (SERPINA1) gene. ♣ a1-antitrypsin (elastin inhibitor) is produced in the liver and transported to the lungs via the blood. Three common M alleles encodes functional proteins. • Z allele (Glu342Lys) is the most common mutant allele. (Glu at 342 is replaced by Lysine) o Individuals with Z/Z genotype have ~15% of normal SERPINA1 level. o The Z allele makes a protein that is not folded properly and tends to accumulate in the endoplasmic reticulum of liver cells, leading to liver damage. ``` S allele (Glu264Val) makes unstable SERPINA1 protein. o Individuals with S/S genotype has 50-60% of normal SERPINA1 level. ```

Answer 4

antitrypsin deficiency (ATD) treatment: Two approaches of delivering human SERPINA1 to the pulmonary epithelium are being studied: intravenous infusion and aerosol inhalation. ♣ Inhaled bronchodilators and inhaled steroids ♣ O2 therapy and possibly lung replacement ♣ In the future: Enzyme Replacement Therapy and Gene therapy are possibilities 1-antitrypsin deficiency (ATD) and Smoking: Ecogenetics (Ecogenetics) Smoking accelerates the onset of emphysema in ATD patients. Tobacco smoke damages the lung, prompting the body to send more neutrophils to the lung for protection. More neutrophils release more elastase, causing more severe lung damage. (Dont have α1-antitrypsin to inhibit elastase)

Answer 5

Tay-Sachs is an inherited disorder that progressively destroys neurons in the brain and spinal cord. The most common form of T-S is an early-onset, fatal disorder apparent in infancy. T-S infants appear normal until the age of 3-6 months, when early symptoms such as muscle weakness, decreased attentiveness, and increased startle response appear. Biochemical defects of Tay-Sachs disease T-S is a lysosomal storage disease. Inability to degrade GM2 ganglioside results in up to 300-fold accumulation of this sphingolipid inside swollen lysosomes in neurons of the central nervous system. A defective hexosaminidase A (HexA) needed for in metabolizing GM2 is responsible for T-S. HexA is a heterodimer of αβ, which are encoded by the HEXA and HEXB genes, respectively. Although HexA is a ubiquitous enzyme, the impact of T-S is primarily in the brain where most of GM2 ganglioside is synthesized.

Answer 6

``` Sandhoff disease (GM2 gangliosidosis type II) presents the same neurological symptoms as T-S. Sandhoff disease patients have defects in both genes Hexosaminidase A and Hexosaminidase B (HexB) Inability to degrade GM2 ganglioside results in up to 300-fold accumulation of this sphingolipid inside swollen lysosomes in neurons of the central nervous system. ``` * T-S is caused by a defective α subunit; only HexA activity is affected. Sandhoff disease is caused by a defective Hex A and defective Hex B, leading to defective Alpha and Beta units in Hexosaminidase A * The α subunit gene HEXA and the β subunit gene HEXB reside on chromosomes #15 and #5, respectively

Answer 7

Tay-Sachs is caused by a defective α subunit; only HexA gene activity is affected. Sandhoff disease is caused by a defective Hex A and defective Hex B, leading to defective Alpha and Beta units in Hexosaminidase A If the GM2AP activator is defective, then you cant bring Ganglioside to the hexosaminidase

Answer 8

Karotype of a patient with Turner’s Syndrome o 45X, a female is only born with one X chromosome o The Banding Pattern on the X Chromosome, the Location of Pseudoautosomal Regions (PAR1 and PAR2), and the Putative Locations of Regions and Genes Responsible, in Part, for the Phenotypic Features of Turner Syndrome. ♣ POF2 denotes the premature ovarian failure gene, an unidentified gene hypothesized to be responsible for ovarian failure on the basis of the study of translocations. The POF1 gene is homologous to the diaphanous gene (DIAPH2) in the fruit fly. SHOX is located within PAR1. Inheritance ♣ In the majority of cases where monosomy occurs, the X chromosome comes from the mother.[37] This may be due to a nondisjunction in the father. Meiotic errors that lead to the production of X with p arm deletions or abnormal Y chromosomes are also mostly found in the father.[38] Isochromosome X or ring chromosome X on the other hand are formed equally often by both parents.[38] Overall, the functional X chromosome mostly comes from the mother. ♣ In most cases, Turner syndrome is a sporadic event, and for the parents of an individual with Turner syndrome the risk of recurrence is not increased for subsequent pregnancies. Rare exceptions may include the presence of a balanced translocation of the X chromosome in a parent, or where the mother has 45,X mosaicism restricted to her germ cells. Summary of physical Ailments o Eye: Inner canthal folds, blue sclerae, ptosis o Ear: nose Prominent Auricles, low-set, high narrow mouth palate; small mandible o Neck : Low posterior hairline, webbing o Chest: Broad widely spaced Nipples; pectus excavatum o Skeleton: Cubitus valgus, short fourth metacarpal and/or metatarsal, madelung deformity, scoliosis Autoimmunity Thyroid Dysfunction and Celiac Disease, with hypothyroidism being most common o Both thyroid dysfunction and celiac disease occur in a significant proportion of individuals who have TS. Hypothyroidism is most common; hyperthyroidism occurs far less often. Approximately 4% to 6% of girls who have TS develop celiac disease. Importantly, all of these conditions can affect growth and development. Lymphatics o Some of the most evident features associated with TS in the neonate are peripheral lymphedema and webbed neck, which are sequelae of the prenatally present cystic hygroma and lymphedema. • Sexual characteristics Turner syndrome is a cause of primary amenorrhea, premature ovarian failure (hypergonadotropic hypogonadism), streak gonads and infertility. Failure to develop secondary sex characteristics (sexual infantilism) is typical. o Amenorrhea is the absence of a menstrual period in a woman of reproductive age. Treatment for Turner’s Syndrome: As a chromosomal condition, there is no cure for Turner syndrome. However, much can be done to minimize the symptoms. For example:[42] o Doctors might use a shot of a growth hormone known as Genotropin (Pfizer) o Estrogen replacement therapy such as the birth control pill, has been used since the condition was described in 1938 to promote development of secondary sexual characteristics. Estrogens are crucial for maintaining good bone integrity, cardiovascular health and tissue health.[42]

Answer 9

Turner syndrome is due to a chromosomal abnormality in which all or part of one of the X chromosomes is missing or altered. While most people have 46 chromosomes, people with TS usually have 45.[6] The chromosomal abnormality may be present in just some cells in which case it is known as TS with mosaicism The different types of abnormalities in Turner’s Syndrome, Cardiovascular In general, many different possible defects with the aorta: ♣ Bicuspid Aortic Valve (only two valves instead of three leading to heart) ♣ Coarctation of the aorta (narrowing of the descending aorta) ♣ Systemic Hypertension, Prolonged QTc Syndrome, ♣ Partial anomalous pulmonary venous connection ♣ Persistent left SVC ♣ Congenital Heart Disease o Eye deformities Some common aspects of the appearance of the eyes are epicanthal folds, upslanting palpebral fissures, ptosis, and hypertelorism. Recognizing these features in a girl presenting with short stature can assist in diagnosing TS clinically. Hyperopia and strabismus each occur in approximately 25% to 35% of patients. Summary: Normal skeletal development is inhibited due to a large variety of factors, mostly hormonal. The average height of a woman with Turner syndrome, in the absence of growth hormone treatment, is 4 ft 7 in (140 cm). Patients with Turner's mosaicism can reach normal average height. The fourth metacarpal bone (fourth toe and ring finger) may be unusually short, as may the fifth. Due to inadequate production of estrogen, many of those with Turner syndrome develop osteoporosis. This can decrease height further, as well as exacerbate the curvature of the spine, possibly leading to scoliosis. It is also associated with an increased risk of bone fractures. Diagnosis o Prenatal Turner syndrome may be diagnosed by amniocentesis or chorionic villus sampling during pregnancy. o Postnasal Turner syndrome can be diagnosed postnatally at any age. Often, it is diagnosed at birth due to heart problems, an unusually wide neck or swelling of the hands and feet. However, it is also common for it to go undiagnosed for several years, typically until the girl reaches the age of puberty/adolescence and she fails to develop properly (the changes associated with puberty do not occur). In childhood, a short stature can be indicative of Turner syndrome Treatment for Turner’s Syndrome: As a chromosomal condition, there is no cure for Turner syndrome. However, much can be done to minimize the symptoms. For example:[42] o Doctors might use a shot of a growth hormone known as Genotropin (Pfizer) o Growth hormone, either alone or with a low dose of androgen, will increase growth and probably final adult height. Growth hormone is approved by the U.S. Food and Drug Administration for treatment of Turner syndrome and is covered by many insurance plans.[42][43] There is evidence that this is effective, even in toddlers.[44] Estrogen replacement therapy such as the birth control pill, has been used since the condition was described in 1938 to promote development of secondary sexual characteristics.

Answer 10

o Mutations that occur in the egg or sperm or immediately after fertilization o These explain an autosomal dominant disorder seen in a child without affected parents

Answer 11

Is a common cause of dwarfism. It occurs as a sporadic mutation in approximately 80% of cases (associated with advanced paternal age) or it may be inherited as an autosomal dominant genetic disorder. People with achondroplasia have short stature, with an average adult height of 131 centimeters (52 inches) for males and 123 centimeters (48 inches) for females. o Autosomal dominant o Most common skeletal dysplasia o 1 in 15,000-40,000 newborns o 80% new mutation rate o 100% penetrance They will show the disease for sure o Clinical Meifestation ♣ Small stature Males 4’ 3” Females 4’ ♣ Rhizomelic limb shortening ♣ Short fingers ♣ Genu varum ♣ Trident hands ♣ Large head/frontal bossing ♣ Midfacial retrusion Their nose and cheeks look bound ♣ Small Foramen Magnum/Craniocervical instability • Small hole in the head Gene of Achondroplasia Mutation of the FGFR3 gene leads to an amino acid substitution (missense mutation) ultimately affecting bone growth by limiting bone formation from cartilage FGFR3-Fibroblast Growth Factor Receptor 3 Regulates bone growth by limiting the formation of bone from cartilage ♣ Chromosome 4p16.3 nucleotide 1138 Amino acid substitution – missense mutation ♣ Mutation increases the activity of the protein interfering with skeletal development o Nucleotide 1138 of the FGFR3 gene has the highest new mutation rate known in man ♣ Like Down’s Syndrome with women ♣ As men grow older, the paternal passing down of FGFR3 will mutate • Aging= greater risk of mutated FGFR3 • Pure dominant versus Incomplete Dominance o Pure dominant Homozygotes and Heterozygotes are both equally affected o Incomplete Dominant Homozygotes are affected more severely

Answer 12

Gene of Achondroplasia Mutation of the FGFR3 gene leads to an amino acid substitution (missense mutation) ultimately affecting bone growth by limiting bone formation from cartilage FGFR3--->Fibroblast Growth Factor Receptor 3 Regulates bone growth by limiting the formation of bone from cartilage Chromosome 4p16.3 nucleotide 1138 Amino acid substitution – missense mutation c.1138G>A;p.Gly380Arg Mutation increases the activity of the protein interfering with skeletal development Nucleotide 1138 of the FGFR3 gene has the highest new mutation rate known in man ♣ Like Down’s Syndrome with women ♣ As men grow older, the paternal passing down of FGFR3 will mutate • Aging= greater risk of mutated FGFR3

Answer 13

o Pure dominant Homozygotes and Heterozygotes are both equally affected o Incomplete Dominant Homozygotes are affected more severely

Answer 14

Malignant tumor of the retina o 1 in 15,000 live births o RB1 gene on chromosome 13 RB protein is part of the cell cycle o Retinoblastoma Associated protein regulates the cell cycle o 90% penetrance ♣ Will have a 90% chance of showing the disease Sometimes will not see it in the parents, still are carrying the gene and they will likely pass it down oThis happen when you see the white reflection (bad) in youths -Want a healthy red reflection for normal retina health

Answer 15

``` Neurofibromatosis Type 1: Is a tumor disorder that is caused by the mutation of a gene on chromosome 17 that is responsible for control of cell division. NF-1 causes tumors along the nervous system and can grow anywhere on the body. NF-1 is one of the most common genetic disorders and is not limited to any persons race or sex there are at least 100,000 people currently in the U.S. who have been diagnosed with NF. Common symptoms of NF-1 include brownish-red spots in the colored part of the eye called Lisch nodules, benign skin tumors called neurofibromas, and larger benign tumors of nerves called plexiform neurofibromas. o Autosomal dominant o 1 in 3000 births o 50% new mutation rate o Exhibits Variable Expressivity ``` NIH Diagnostic Criteria 2 or more of the following 6 or more café-au-lait spots •Little blotches on the skin, will develop over time 2 or more neurofibromas • Light brown raised skin (larger than moles) • Will cluster 1 plexiform neurofibroma ♣ Freckling in the axillary or inguinal area Optic glioma ♣ 2 or more Lisch Nodules • These are freckling in the eyes ♣ Distinctive osseous lesions ♣ Affected first degree relative o Mutation for Neurofibromatosis Type 1 NF-1 is a microdeletion syndrome caused by a mutation of a gene located on chromosomal segment 17q11.2 on the long arm of chromosome 17 which encodes a protein known as neurofibromin ♣ NF1 • Neurofibromin- tumor suppressor gene ♣ Chromosome 17q11.2 • Loss of function mutation • Over 1000 mutations have been described on this c ♣ Although considered dominant must have a mutation in both genes to show the phenotype of NH1 • If you carry this mutation you are still at major risk • If you have inherited one mutation, you are more likely to develop the second mutation De novo o Possibly will develop the second mutation and have Neurofibromatosis Type 1

Answer 16

Mutation for Neurofibromatosis Type 1 NF-1 is a microdeletion syndrome caused by a mutation of a gene located on chromosomal segment 17q11.2 on the long arm of chromosome 17 which encodes a protein known as neurofibromin NF1 • Neurofibromin- tumor suppressor gene Chromosome 17q11.2 • Loss of function mutation • Over 1000 mutations have been described on this c Although considered dominant must have a mutation in both genes to show the phenotype of NH1 • If you carry this mutation you are still at major risk • If you have inherited one mutation, you are more likely to develop the second mutation De novo o Possibly will develop the second mutation and have Neurofibromatosis Type 1

Answer 17

``` Tuberous Sclerosis Autosomal dominant 1 in 6,000 Exhibits Variable Expressivity o 1/3 inherited; 2/3 de novo o Fully penetrant-->Will see in 100% ``` ``` o Skin Findings on tuberous sclerosis Hypopigmented Patches -Blotches of white Angiofibroma • Around the nose bumps/red pigments ♣ Shagreen Patch ♣ Ungual fibroma • Growth around nose ``` ``` o Other organs affected Kidneys • Renal Cysts • Renal angiomyolipomas Lungs • Lymphangioleiomyomatosis Heart • Cardiac rhabdomyoma (in infants) o Central nervous System Subependymal nodules Subependymal giant cell astrocytomas (SEGAs) Other cortical dysplasias ``` ``` o Seizures Neuropsychiatric Disorders ♣ Cognitive impairment ♣ Autism ♣ ADHD ♣ Other behavioral and emotional problems ``` ``` o Clinical criteria – Two major features or One major feature with 2 minor features Major features: • Angiofibromas • Cardiac rhabodmyoma • Cortical dysplasias • Hypomelanotic macules • Lymphangioleiomyomatosis • Multiple retinal nodular hamartomas • Renal angiomyolipoma • Shagreen Patch • Subependymal nodule • SEGA • Ungual Fibroma Minor Features: • Confetti skin lesions • Dental Enamel pits (>3) • Intraoral fibromas • Multiple renal cysts • Nonrenal hamartomas • Retinal achromic patch ``` ``` Mutation in Tuberous Sclerosis TSC1 encodes for the protein hamartin, is located on chromosome 9 q34. TSC2 encodes for the protein Tuberin, is located on chromosome 16 p13.3 The Hamartin and the Tuberin protein both regulate cell growth and proliferation TSC1, TSC2 -Encode hamartin and tuberin proteins • Regulate cell growth and proliferation ♣ Chromosome 9 and 16 ♣ Loss of function mutations ```

Answer 18

TS is a rare multi-system genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung 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. These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation.[1] ``` Mutation in Tuberous Sclerosis TSC1 encodes for the protein hamartin, is located on chromosome 9 q34. TSC2 encodes for the protein Tuberin, is located on chromosome 16 p13.3 The Hamartin and the Tuberin protein both regulate cell growth and proliferation TSC1, TSC2 -Encode hamartin and tuberin proteins • Regulate cell growth and proliferation ♣ Chromosome 9 and 16 ♣ Loss of function mutations ```

Answer 19

Osteogenesis Imperfecta Type 1 also known as brittle bone disease or Lobstein syndrome,[1] is a congenital bone disorder characterized by brittle bones that are prone to fracture. People with OI are born with defective connective tissue, or without the ability to make it, usually because of a deficiency of type I collagen.[2] Eight types of OI can be distinguished. Most cases are caused by mutations in the COL1A1 and COL1A2 genes. ♣ Autosomal dominant ♣ 1 in 30,000-50,000 ♣ Exhibits Variable Expressivity ``` o Clinical Manifestations of Osteogenisis Imperfecta Type 1 ♣ Multiple fractures ♣ Mild short stature ♣ Adult onset hearing loss ♣ Blue sclera not always the case o Mutation of Osteogenisis Imperfecta 1 ♣ COL1A1 ``` • Collagen type 1 alpha 1 ♣ Chromosome 7q21.3 ♣ Reduced production of pro-alpha 1 chains that reduces the type 1 collagen production by half ♣ Molecular and biochemical testing available

Answer 20

Marfan Syndrome Is a genetic disorder of connective tissue. It has a variable clinical presentation, ranging from mild to severe systemic disease. The most serious manifestations involve defects of the heart valves and aorta, which may lead to early death if not properly managed. The syndrome also may affect the lungs, eyes, dural sac surrounding the spinal cord, the skeleton, and the hard palate. People with Marfan syndrome tend to be unusually tall, with long limbs and long, thin fingers and toes. ♣ Autosomal dominant ♣ 1 in 5000 births ♣ 25% new mutation rate ♣ Variable Expressivity o Clinical Manifestation of Marfan Syndrome ♣ Systemic disorder of connective tissue ``` Connective Tissues are the tissues in our body including muscle, ligaments and tendons. Connective tissues are also part of our vascular system, most importantly in the large arteries in our bodies ♣ Ocular ♣ Skeletal ♣ Cardiovascular o Diagnosis: o Scoliosis, Thumb and wrist sign, Pectus Excavatum ♣ Signs for the disease o Ectopia Lentis ♣ Displaced lens o Cardiovasuclar System ♣ Looking at the Aorta, seeing if it has a larger Diameter • Aortic root enlargement ``` ``` Plus one of the following: Ectopia Lentis -Displaced lens o FBN1 mutation o Systemic score >7 Positive Family History • Ectopia Lentis • Systemic score of >7 • Aortic root enlargement ``` Mutation in the Mafran syndrome rfan syndrome is caused by mutations in the FBN1 gene on chromosome 15,[14] which encodes fibrillin-1, a glycoprotein component of the extracellular matrix. Fibrillin-1 is essential for the proper formation of the extracellular matrix, including the biogenesis and maintenance of elastic fibers. The extracellular matrix is critical for both the structural integrity of connective tissue FBN1 • Fibrillin- extracellular matrix protein Chromosome 15q21.1 • Dominant negative activity mutation • A mutation whose gene product adversely affects the normal, wild-type gene product within the same cell ♣ Severe reduction in the number of microfibrils •

Answer 21

Mutation in the Mafran syndrome rfan syndrome is caused by mutations in the FBN1 gene on chromosome 15,[14] which encodes fibrillin-1, a glycoprotein component of the extracellular matrix. Fibrillin-1 is essential for the proper formation of the extracellular matrix, including the biogenesis and maintenance of elastic fibers. The extracellular matrix is critical for both the structural integrity of connective tissue FBN1 Fibrillin- extracellular matrix protein Chromosome 15q21.1 • Dominant negative activity mutation • A mutation whose gene product adversely affects the normal, wild-type gene product within the same cell Severe reduction in the number of microfibrils • Slipped Mispairing o Mispairing of bases in regions of repetitive DNA replication coupled with inadequate DNA repair systems o As the repeat grows longer the probability of subsequent mispairing increases

Answer 22

Trinucleotide Repeat Disorders are a set of genetic disorders caused by trinucleotide repeat expansion, a kind of mutation where trinucleotide repeats in certain genes exceed the normal, stable threshold, which differs per gene. The mutation is a subset of unstable microsatellite repeats that occur throughout all genomic sequences. o Expansion of a segment of DNA consisting of three or more nucleotides Just adding a bunch of repeating trio’s of nucleotides ♣ CAGCAGCAGCAGCAGCAG o Slipped Mispairing ♣ Mispairing of bases in regions of repetitive DNA replication coupled with inadequate DNA repair systems ♣ As the repeat grows longer the probability of subsequent mispairing increases o Anticipation In genetics, anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase of severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders Severity and/or onset of disease increases in next generation Parental Transmission Bias ♣ Trinucleotide expansion more prone to occur in gametogenesis of the male or the female o AD, AR and X-linked transmission

Answer 23

``` Huntington Disease is a neurodegenerative genetic disorder that affects muscle coordination and leads to mental decline and behavioral symptoms ♣ Autosomal Dominant ♣ Trinucleotide repeat disorder (CAG) ♣ 1 in 10,000 ♣ Anticipation ♣ Parent of origin • Early onset – paternal • Later onset - maternal ♣ Clinical Manifestations: ``` Progressive neuronal degeneration causing motor, cognitive and psychiatric disturbances • Age of onset 35-44 • Death approximately 15 years after onset ♣ Mutation: HD is one of several trinucleotide repeat disorders which are caused by the length of a repeated section of a gene exceeding a normal range. The HTT gene is located on the short arm of chromosome 4at 4p16.3. HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat. CAG is the 3-letter genetic code (codon) for the amino acid glutamine •HTT---> Huntingtin o Chromosome 4p16.3 • The expansion of glutamine may cause an altered structure or biochemical property of the protein

Answer 24

Progressive neuronal degeneration causing motor, cognitive and psychiatric disturbances • Age of onset 35-44 • Death approximately 15 years after onset Mutation: HD is one of several trinucleotide repeat disorders which are caused by the length of a repeated section of a gene exceeding a normal range. The HTT gene is located on the short arm of chromosome 4at 4p16.3. HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat. CAG is the 3-letter genetic code (codon) for the amino acid glutamine •HTT gene---> Huntingtin o Chromosome 4p16.3 The expansion of glutamine may cause an altered structure or biochemical property of the protein

Answer 25

``` Myotonic Dystrophy Type 1 ♣ Autosomal Dominant ♣ Trinucleotide repeat disorder (CTG) ♣ 1 in 20,000 ♣ Anticipation ♣ Maternal transmission ``` ``` o Clinical Manifestations ♣ Adult onset muscular dystrophy ♣ Progressive muscle wasting and weakness ♣ Myotonia ♣ Cataracts ♣ Cardiac conduction defects ``` o Mutation In DM1, the affected gene is called DMPK, which codes for myotonic dystrophy protein kinase,[2] a protein expressed predominantly in skeletal muscle.[3] The gene is located on the long arm of chromosome 19. DMPK--->Myotonic dystrophy protein kinase ♣ Chromosome 19q13.3 ♣ Plays important role in muscle, heart and brain cells o CTG Repeat for Mystonic Dystrophy In DM1, there is an expansion of the cytosine-thymine-guanine (CTG) triplet repeat in the DMPK gene. Between 5 and 37 repeats is considered normal, while individuals with between 38 and 49 repeats are considered to have a pre-mutation and are at risk of having children with further expanded repeats and, therefore, symptomatic disease.[5] Individuals with greater than 50 repeats are almost invariably symptomatic, with some noted exceptions.[ref] Longer repeats are usually associated with earlier onset and more severe disease. ♣ 5-34 normal ♣ 34-49 premutation range • Risk at having children with more repeats and the disease ♣ >50 full mutation with 100% penetrance

Answer 26

Mutation In DM1, the affected gene is called DMPK, which codes for myotonic dystrophy protein kinase,[2] a protein expressed predominantly in skeletal muscle.[3] The gene is located on the long arm of chromosome 19. DMPK--->Myotonic dystrophy protein kinase ♣ Chromosome 19q13.3 ♣ Plays important role in muscle, heart and brain cells o CTG Repeat for Mystonic Dystrophy In DM1, there is an expansion of the cytosine-thymine-guanine (CTG) triplet repeat in the DMPK gene. Between 5 and 37 repeats is considered normal, while individuals with between 38 and 49 repeats are considered to have a pre-mutation and are at risk of having children with further expanded repeats and, therefore, symptomatic disease.[5] Individuals with greater than 50 repeats are almost invariably symptomatic, with some noted exceptions.[ref] Longer repeats are usually associated with earlier onset and more severe disease. ♣ 5-34 normal ♣ 34-49 premutation range • Risk at having children with more repeats and the disease ♣ >50 full mutation with 100% penetrance

Answer 27

Sickle Cell Anemia Single base mutation at codon #6 in the β-globin gene changes glutamate to valine. HbS is 80% less soluble than HbA when not bound to O2, and polymerizes into long fibers that distort the RBC into a characteristic sickle shape. o These sickled cells become lodged in the micro-capillaries and further exacerbate the sickling crisis. -Due to HbS being 80% less sobule than HbA o The loss of red blood cell elasticity is central to the pathophysiology of sickle-cell disease. Normal red blood cells are quite elastic, which allows the cells to deform to pass through capillaries. In sickle-cell disease, low-oxygen tension promotes red blood cell sickling and repeated episodes of sickling damage the cell membrane and decrease the cell's elasticity. These cells fail to return to normal shape when normal oxygen tension is restored o Is typically considered an autosomal recessive disease

Answer 28

HbCC Caused by a single base mutation at codon#6 of the β-globin gene, changing glutamate to lysine. o A milder form of hemolytic anemia than sickle cell anemia. Hemoglobin C disease (HbCC) A milder form of hemolytic anemia than sickle cell anemia. Caused by a single base mutation at codon#6 of the β-globin gene, changing glutamate to lysine. ♣ HbC is less soluble than HbA and tends to form crystals, reducing the deformability of RBC. (glutamate to lysine at codon six) ♣ Is also an autosomal recessive disease

Answer 29

Thalassemias are caused by an imbalance in the relative levels of the α and β globin chains, which leads to the precipitation of the globin in excess and decreases the life span of the RBC. Alpha Thalassemia • low or zero alpha-globin o beta- & gamma-globin in excess & precipitates. • both fetal and postnatal defects. • usually caused by deletion of the a-globin gene(s). Beta Thalassemia • low or zero beta-globin, alpha-globin in excess & precipitates. • postnatal defects only. • usually caused by point mutations in the b-globin gene. • occasionally caused by deletions in the LCR or the b-gene cluster. o Low or zero synthesis of one globin chain ♣ Due to the gene being altered

Answer 30

Mostly caused by deletions of one or both copies of the α-globin gene in the α-cluster. Thus, γ- and β-globin are in excess. Affects the formation of both fetal and adult hemoglobins. α-thal-1 allele (- -) Common in Southeast Asia. Caused by deletion of both copies of α-globin genes in the α- cluster. Homozygous state (- -/- -) results in "hydrops fetalis" (stillborn). Most fetal hemoglobin is γ4 (Hb Bart’s) although there is enough ζ2γ2 (Hb Portland) to sustain fetal development. Heterozygotes (αα/--) have mild anemia, a.k.a. α-thalassemia-1 trait. α-thal-2 allele (α -) Common in Africa, Mediterranean, and Asia. Deletion of one of the two α-globin genes in the α-cluster. 50% decrease in α-globin synthesis. No disease phenotype in heterozygote (αα/α-, silent carrier). Mild anemia in homozygotes (α-/α-), a.k.a. α-thalassemia-2 trait. α-thal-1/α-thal-2 (α -/- -) Compound heterozygous individuals with only 25% of normal α-globin level. Severe anemia. a.k.a. HbH disease. About 5-30% of their hemoglobin is β4 (HbH), which precipitates.

Answer 31

β-Thalassemias o Show a wide range of severity and can be cause by virtually every possible type of mutation in the β-globin gene. High allelic heterogeneity means most patients with β-thalassemia are compound heterozygotes carrying two different mutant alleles of the β-globin gene. Categorization of β-thalassemias Thalassemia major: Characterized by severe anemia, in which most RBCs are destroyed before being released into the circulation. Thinning bone cortex, enlarged liver and spleen resulted from massive effort of blood production at these sites. Treat temporarily with blood transfusions; however, iron accumulation from repeated transfusion leads to organ failure. Iron chelation therapy (e.g. desferrioxamine) is used to reduce the complications of iron overload. Thalassemia minor: Clinically normal, carriers of one β-thalassemia allele. o Simple and Complex Thalassemia Simple β-thalassemia: Caused by mutations or deletions that impair the production of the β-globin chain alone. Other genes in the β-globin cluster unaffected. Complex thalassemia: Caused by large deletions that remove the β-globin gene plus other genes in the β-cluster, or the LCR. Note that some deletions within β-cluster cause HPFH instead of thalassemia (see below). β+ -thalassemia: Most common form of β-thalassemia (90% of the cases). Some β-globin is made so that some HbA is present. Decrease in β-globin synthesis can be caused by mutations affecting transcription, RNA processing, or protein stability. β0 -thalassemia: Zero β-globin synthesis so that no HbA (adult hemoglobin) is present. Caused by deletion of the β-globin gene, nonsense or frameshift mutations at the 5’ of the coding region that lead to an early stop codon, or mutations that result in no RNA synthesis. [Hb] is ~5% of normal level (of which 95% is α2γ2 with 5% α2δ2), which is not enough for good survival.

Answer 32

HPFH (hereditary persistent fetal hemoglobin) is a benign condition in which significant fetal hemoglobin (hemoglobin F) production continues well into adulthood, disregarding the normal shutoff point after which only adult-type hemoglobin should be produced. o No δ or β synthesis because of deletions of both genes. Increased γ-globin expression caused by either of the two following mechanisms: (1) extended deletion of additional downstream sequences, which likely brings a cis-acting enhancer element closer to the γ-globin gene, or (2) mutations in the promoter region of one of the two γ-globin genes that destroy the binding site of a repressor, thereby relieving postnatal repression of γ. HPFH individuals are disease free, since adequate levels of γ chains are still made due to the disruption of the perinatal globin switch from γ to β. 100% of hemoglobin is HbF (α2γ2), which is about 17-35% of normal level of total hemoglobin production. HPFH individuals have higher HbF (17-35%) level than δβ0 -thalassemia individuals (5-18%). Significance of HPFH Understanding the mechanism of HPFH may make it possible to express HbF at high levels postnatally to treat patients of β-thalassemia and sickle cell anemia.

Answer 33

Duchenne muscular dystrophy (example of loss of function mutation o DMD Xp21.2 the largest gene in the genome (DMD) can have a variety of mutations, such as deletions, nonsense or frameshift mutations. Can make a non-functional protein. Is a an x-linked gene • Large deletions (multiple exons) • Nonsense (stop) mutations / frameshift mutations premature termination • (in-frame deletions milder Becker muscular dystrophy)

Answer 34

Becker Muscular Dystrophy (less severe, later onset) In-frame deletions (and also missense mutations) of DMD gene = major loss-of (i.e. reduction)-function in Becker Muscular dystrophy Protein that is reduced in function (still exists to some extent) There can be in-frame deletions, a shorted protein that is a little more functional o Small amount of functional protein better than none • X-linked inheritance • Clinically • Boys with abnormal gait at 3-5 years • Calf pseudohypertrophy • Gower maneuver (YouTube) • Progressive involvement of respiratory muscles • Median age of death 18 years • Women may cardiomyopathy o Duchenne muscular Dystrophy (more severe, earlier onset) ♣ Frameshift deletions of DMD gene = major loss-of-function mechanism in Duchenne Muscular Dystrophy ♣ Make a truncated protein that does not work at all!

Answer 35

o Duchenne muscular Dystrophy (more severe, earlier onset) ♣ Frameshift deletions of DMD gene = major loss-of-function mechanism in Duchenne Muscular Dystrophy ♣ Make a truncated protein that does not work at all! o Becker Muscular Dystrophy (less severe, later onset) ♣ In-frame deletions (and also missense mutations) of DMD gene = major loss-of (i.e. reduction)-function in Becker Muscular dystrophy ♣ Protein that is reduced in function (still exists to some extent)

Answer 36

HNPP Disease Deletion of PMP22 gene = Loss-of-function Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) ♣ PMP22 protein is an integral membrane glycoprotein in nerves ♣ Notice that deletions often leave to the most dysfunctional or non-existent proteins Lacking the PMP22 protein for glycoprotein membrane o Clinically: ♣ repeated focal pressure neuropathies (e.g. carpal tunnel syndrome and peroneal palsy with foot drop) ♣ First attack usually in 2nd-3rd decade • Recovery from acute neuropathy is often complete • Incomplete recovery mild disability ♣ Autosomal Dominant PMP22 Gene Unequal crossing over between two highly homologous repeats on chromosome 17p12 can result in: • 3 copies of the PMP22 gene with the CMT1A phenotype or • the reciprocal with 1 copy of the PMP22 gene with the HNPP phenotype. o (HNPP) Disease will develop

Answer 37

Unequal crossing over between two highly homologous repeats on chromosome 17p12 can result in: • 3 copies of the PMP22 gene with the CMT1A phenotype or • the reciprocal with 1 copy of the PMP22 gene with the HNPP phenotype. o (HNPP) Disease will develop HNPP Disease Deletion of PMP22 gene = Loss-of-function Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)

Answer 38

Osteogeneis Imperfecta Type I Clinically: ♣ Brittle bones, increased fractures (non-deforming) ♣ blue sclerae ♣ normal stature. ♣ First fracture may occur with diapering, but more typically once infant begins to walk (and fall) • Easy to assume baby abuse, usually because of weak bones Autosomal Dominant Due to dffect of the type 1 procollagen protein ♣ Affected individuals may have anywhere from a few fractures to more than 100M ♣ Progressive hearing loss in adults Genetic Cause ♣ The structure of type I procollagen. Note that type I procollagen is composed of two proα1(I) chains and one proα2(I) chain = 3 chains total (2 pro alpha1 and 1 pro alpha2) • Normally the alleles COLA1 and COL1A1 (2 of them) pump out 2 pro-alpha1 chains • COL1A2 and COL1A2 (2 of them) make only 1 pro-alpha 2 chain • These four genes will make the three necessary genes Very important structure in bones ♣ OI Type I: Premature termination codons (nonsense and frameshift) in COL1A1 mRNA unstable mRNA degraded reduction of normal COL1A1 protein • One of the COL1A1 genes is knocked out (frameshift or nonsense), making only 1 pro-alpha1 chains when you need 2 chains o Makes very brittle bones from missing the pro-alpha1 chain (you need two of them)

Answer 39

Hemoglobin Kempsey example of a “gain of function” mutation, will have a higher oxygen affinity. Problem is that the hemoglobin will bind to oxygen too well, won’t release it in cells. Body may produce too much RBC and cause polycythemia (too much red blood cells) o Beta hemoglobin gene ♣ Asp99Asn missense mutation ♣ Higher oxygen affinity • In normal hemoglobin binding of oxygen allowing for shift from tense (deoxygenated) to relaxed (oxygenated) form ♣ 99Asn mutation prevents this shift ♣ Hemoglobin remains ‘locked’ in the relaxed state (which has higher oxygen affinity) = Gain Of Function (kinda) o Consequences: ♣ Hb Kempsey unloads less oxygen in tissues ♣ Body ‘thinks’ it needs more oxygen makes more red blood cells polycythemia

Answer 40

Charcot Marie Tooth Syndrome Type IA A large amount of muscle waste due to nerve atrophy, the CMT1A protein “gains a new function” mutation by destroying nerve o Duplication of PMP22 gene = Gain-of-function Charcot Marie Tooth Syndrome type IA (CMT1A) o PMP22 protein is an integral membrane glycoprotein in nerves o Clinically: ♣ Demyelinating motor and sensory neuropathy ♣ Often presents in lower extremities with weakness and muscle atrophy and mild sensory loss ♣ Progressive; typical patterns on nerve conduction studies ♣ Autosomal Dominant

Answer 41

With these different types, will have point-mutations These point mutations in Osteogenisis Imperfect Type II, III, and IV will lead to new proteins/ Chains made for the procollagen o In Osteogenesis type I, loss of function mutations ½ the amount of total collagen trimers, but it is all normal mild phenotype ♣ Osteogensis type 1 is less severe, still have some functional collagen (not causing problems) o In Osteogenesis types II, III, IV novel property mutations relatively ‘normal’ amount of total collagen trimers, but ½ is abnormal severe phenotype ♣ The abnormal collagen causes more abnormal/bad effects o Lesson: better to have ½ the amount of normal collagen, than produce abnormal collagen trimers

Answer 42

Huntington Disease Having more than 50 of CAG tri nucleotide repeats will lead to Huntington Disease for sure appearing Will lead to expanded polyglutamine tracts in the Huntington protein Anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase of severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders, such as Huntington's disease

Answer 43

o The α-thalassemias involve the genes HBA1[11] and HBA2,[12] inherited in a Mendelian recessive fashion. Two gene loci and so four alleles exist. It is also connected to the deletion of the 16p chromosome. α Thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns. o Beta thalassemias are due to mutations in the HBB gene on chromosome 11, also inherited in an autosomal, recessive fashion. The severity of the disease depends on the nature of the mutation. Mutations are characterized as either βo or β thalassemia major if they prevent any formation of β chains, the most severe form of β-thalassemia; as either β+ or β thalassemia intermedia if they allow some β chain formation to occur; or as β thalassemia minor if only one of the two β globin alleles contains a mutation, so that β chain production is not terribly compromised and patients may be relatively asymptomatic.

Answer 44

Qualitative Hemoglobinopathies---> Usually changes in structure (a change in amino acid) Hb S (sickle cell) a valine replacing a glutamine in the 6th position of the beta chain of globin Hb C which substitution of a glutamic acid residue with a lysine residue at the 6th position of the β-globin chain has occurred Hb E At position 26 there is a change in the amino acid, from glutamic acid to lysine.

Answer 45

Quantitative Hemoglobinopathies Thalassemia (these are changes in the gene) ♣ α thalassemia s a form of thalassemia involving the genes HBA1[1] and HBA2.[2] Alpha-thalassemia is due to impaired production of alpha chains from 1,2,3, or all 4 of the alpha globin genes, leading to a relative excess of beta globin chains. On chromosome 16 ♣ β thalassemia Beta thalassemia (β thalassemia) is a form of thalassemia caused by mutations in the HBB gene on chromosome 11, inherited in an autosomal recessive fashion. The severity of the disease depends on the nature of the mutation. HBB blockage over time leads to decreased Beta-chain synthesis. ♣ γ thalassemia ♣ Δ thalassemia

Answer 46

Hemoglobin S The most common type of abnormal hemoglobin and the basis of sickle cell trait and sickle cell anemia.Hemoglobin S differs from normal adult hemoglobin (called hemoglobin A) only by a single amino acid substitution (a valine replacing a glutamine in the 6th position of the beta chain of globin). o Homozygous SS disease “Sickle Cell Anemia” o S heterozygous: AS, sickle trait ♣ Sickle cell trait (or sicklemia) describes a condition in which a person has one abnormal allele of the hemoglobin beta gene (is heterozygous), but does not display the severe symptoms of sickle cell disease that occur in a person who has two copies of that allele (is homozygous).

Answer 47

No alles:The fetus cannot live once outside the uterus and may not survive gestation: most such infants are stillborn with hydrops fetalis, and those who are born alive die shortly after birth. They are edematous and have little circulating hemoglobin, and the hemoglobin that is present is all tetrameric γ chains (hemoglobin Barts). 3 Alleles affected: The condition is called Hemoglobin H disease. Two unstable hemoglobins are present in the blood: Hemoglobin Barts (tetrameric γ chains) and Hemoglobin H (tetrameric β chains). Both of these unstable hemoglobins have a higher affinity for oxygen than normal hemoglobin, resulting in poor oxygen delivery to tissues. The disease may first be noticed in childhood or in early adult life, when the anemia and hepatosplenomegaly are noted. Two Alleles Effected: he condition is called alpha thalassemia minor. Two α genes permit nearly normal production of red blood cells, but there is a mild microcytic hypochromic anemia. The disease in this form can be mistaken for iron deficiency anemia and treated inappropriately with iron. Alpha thalassemia minor can exist in two forms: • alpha-thal-1 (αα/--), associated with Asians, involves cis deletion of both alpha genes on the same chromosome; • alpha-thal-2 (α-/α-), associated with Africans, involves trans deletion of alpha genes on different (homologous) chromosomes One allele Effected: This is known as alpha thalassemia minima and with this type there is minimal effect on hemoglobin synthesis. Three α-globin genes are enough to permit normal hemoglobin production, and there are no clinical symptoms. They have been called silent carriers. They may have a slightly reduced mean corpuscular volume and mean corpuscular hemoglobin.

Answer 48

The Xist RNA, a large (17 kb in humans) transcript, is expressed on the inactive chromosome and not on the active one. The genes on the inactive chromosome will become methylated XIST – gene located on the X chromosome ♣ Expressed only from the inactive X ♣ X inactivation can’t occur in it’s absence Unclear mode of action

Answer 49

Nonrandom X chromosome inactivation ♣ Occurs when there is a structurally abnormal X chromosome • more of the normal Xs are turned on ♣ This occurs to inactivate a defunct X chromosome o Skewed X inactivation occurs when the inactivation of one X chromosome is favored over the other, leading to an uneven number of cells with each chromosome inactivated. It is usually defined as one allele being found on the active X chromosome in over 75% of cells, and extreme skewing is when over 90% of cells have inactivated the same X chromosome ♣ This is of medical significance due to the potential for the expression of disease genes present on the X chromosome that are normally not expressed due to random X inactivation. ♣ Observed when a female shows signs or symptoms of an X-linked recessive condition, such as Duchene Muscular Dystrophy ♣ Instead of a random inactivation pattern more of the X chromosome with normal gene is turned off

Answer 50

Hypophosphatemic Rickets An X-linked dominant form of rickets that differs from most cases of rickets in that ingestion of vitamin D is relatively ineffective. It can cause bone deformity including short stature and genu varum (bow leggedness). It is associated with a mutation in the PHEX gene sequence (Xp.22) and subsequent inactivity of the PHEX protein ♣ X-linked Dominant ♣ 1 in 20,000 o Clinical Manifestation of Hypophosphatemia Rickets ♣ Hypophosphatemia low levels of phosphate ♣ Short stature ♣ Bone deformity Mutation in Hypophasphatemic rickets a mutation in the PHEX gene sequence, located on the human X chromosome at location Xp22.The PHEX protein regulates another protein called fibroblast growth factor 23 (produced from the FGF23 gene). Fibroblast growth factor 23 normally inhibits the kidneys' ability to reabsorb phosphate into the bloodstream. ♣ Gene: PHEX ♣ Regulates fibroblast growth factor ♣ Inhibits the kidneys ability to reabsorb phosphate into the blood stream

Answer 51

Fragile X Syndrome a genetic syndrome. Nearly half of all children with fragile X syndrome meet the criteria for a diagnosis of autism.[1] It is an inherited cause of intellectual disability especially among boys. It results in a spectrum of intellectual disabilities ranging from mild to severe as well as physical characteristics such as an elongated face, large or protruding ears, and large testes X-linked dominant Gene: FMR1 Trinucleotide repeat disorder- CGG (will have anticipation) ♣ 1 in 2500-4000 males more predominant in males ♣ 1 in 7000-8000 females Most common cause of inherited developmental delay ♣ Anticipation ♣ Maternal transmission bias ``` Clinical Manifestation ♣ Intellectual disabilities ♣ Dysmorphic features: large ears, long face, macroorchidism ♣ Autistic behavior ♣ Social anxiety ♣ Hand flapping/biting ♣ Aggression ``` Genetic composition Fragile X Fragile X syndrome is a genetic disorder which occurs as a result of a mutation of the fragile X mental retardation 1 (FMR1) gene on the X chromosome, most commonly an increase in the number of CGG trinucleotide repeats in the 5' untranslated region of FMR1. Fragile X Associated Tremor Ataxia Syndrome(FXTAS) • White matter lesions on MRI • Intention tremor, Gait ataxia FMR1- related Primary Ovarian Insufficiency • Cessation of menses before age 40 o CPG repeats for Fragile X 6-45 Normal range 46-55 Grey Zone • Grey Zone – can expand when passed onto the mother – do not expand to full mutation but can to premutation 56-200 Premutation • Premutation – Causes FXTAS and POI ♣ >200 Full Mutation

Answer 52

Genetic composition Fragile X Fragile X syndrome is a genetic disorder which occurs as a result of a mutation of the fragile X mental retardation 1 (FMR1) gene on the X chromosome, most commonly an increase in the number of CGG trinucleotide repeats in the 5' untranslated region of FMR1. Fragile X Associated Tremor Ataxia Syndrome(FXTAS) • White matter lesions on MRI • Intention tremor, Gait ataxia FMR1- related Primary Ovarian Insufficiency • Cessation of menses before age 40 ``` CPG repeats for Fragile X 6-45 Normal range 46-55 Grey Zone • Grey Zone – can expand when passed onto the mother – do not expand to full mutation but can to premutation 56-200 Premutation • Premutation – Causes FXTAS and POI ♣ >200 Full Mutation ```

Answer 53

``` Rett Syndrome is a rare genetic postnatal neurological disorder of the grey matter of the brain[2] that almost exclusively affects females but has also been found in male patients. The clinical features include small hands and feet and a deceleration of the rate of head growth (including microcephaly in some). Repetitive stereotyped hand movements, such as wringing and/or repeatedly putting hands into the mouth, are also noted.[3] People with Rett syndrome are prone to gastrointestinal disorders and up to 80% have seizures.[4] They typically have no verbal skills, and about 50% of affected individuals do not walk. Scoliosis, growth failure, and constipation are very common and can be problematic. ♣ X-linked Dominant ♣ 1 in 10,000 females ♣ 95% new mutation rate o Clinical manifestations ♣ Loss of normal movement and coordination ♣ Acquired microcephaly ♣ Loss of communication skills ♣ Failure to thrive ♣ Seizures ♣ Abnormal hand movements ``` Mutation of Rett is caused by mutations in the gene MECP2 located on the X chromosome (which is involved in transcriptional silencing and epigenetic regulation of methylated DNA), need these proteins for normal nerve cell function ♣ Gene: MECP2 ♣ Methyl CpG binding protein ♣ Essential for the normal function of nerve cells

Answer 54

``` Lesch-Nyhan Syndrome s a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT), produced by mutations in the HPRT gene located on the X chromosome. ♣ X-linked recessive ♣ 1 in 380,000 o Clinical Manifestations of Lesch-Nyhan Syndrome ♣ Cerebral palsy ♣ Cognitive and behavioral disturbances ♣ Overproduction of uric acid ♣ Self injury o Mutation on Lesch-Nyhan ♣ Gene: HPRT1 ♣ Hypoxanthine phosphoribosyltransferase 1 • Recycling of purines ```

Answer 55

``` Dystrophinopathies -X-linked recessive Spectrum of muscle disease from mild to severe • Duchenne Muscular Dystrophy • Becker Muscular Dystrophy • DMD-associated dilated cardiomyopathy ``` Mutation Gene: DMD Chromosome Xp21-21.1 Dystrophin Dystrophin is a protein located between the sarcolemma and the outermost layer of myofilaments in the muscle fiber (myofiber). It is a cohesive protein, linking actin filaments to another support protein that resides on the inside surface of each muscle fiber’s plasma membrane Largest human gene, located on the x-chromosome o Early onset and late onset of different muscular dystrophy ♣ Early= Duchenne Muscular Dystrophy ♣ Later =Becker Muscular Dystrophy DMD (the mutated Gene)-associated Dilated Cardiomyopathy for both Duchenne and Becker Muscular Dystrophy o Dilated cardiomyopathy presenting between 20-40 years of age o Early death o No skeletal muscle involvement o No Dystrophin in the myocardium

Answer 56

Becker Muscular Dystrophy is an X-linked recessive inherited disorder characterized by slowly progressive muscle weakness of the legs and pelvis. It is a type of dystrophinopathy, which includes a spectrum of muscle diseases in which there is insufficient dystrophin produced in the muscle cells, resulting in instability in the structure of muscle cell membrane. This is caused by mutations in the dystrophin gene, which encodes the protein dystrophin. ♣ Progressive muscular weakness proximal > distal ♣ Dilated cardiomyopathy ♣ CK levels 5x normal ♣ Later onset • Wheelchair bound after 16 • Death in their 40’s Abnormal quantity or quality of Dystrophin

Answer 57

``` Duchenne Muscular Dystrophy a recessive X-linked form of muscular dystrophy, affecting around 1 in 3,600 boys, which results in muscle degeneration and premature death.[1] The disorder is caused by a mutation in the gene dystrophin, located on the human X chromosome, which codes for the protein dystrophin. Dystrophin is an important component within muscle tissue that provides structural stability to the dystroglycan complex (DGC) of the cell membrane. ♣ Progressive muscular weakness proximal > distal ♣ Calf hypertrophy ♣ Dilated cardiomyopathy • CK levels 10x normal ♣ Onset before the age of 5 • Wheelchair bound before 13 • Death in their 30’s ♣ Absence of Dystrophin ```

Answer 58

``` Hemophilia A is a genetic deficiency in clotting factor VIII,[1] which causes increased bleeding and usually affects males. About 70% of the time it is inherited as an X-linked recessive trait, but around 30% of cases arise from spontaneous mutations. ♣ X-linked recessive ♣ I in 4000 male births ♣ 10% carrier females affected ``` Clinical Manifestations Blood disorder where blood fails to clot appropriately due to a deficiency of Factor VIII ♣ Spontaneous bleeds into joints, muscles or intracranial ♣ Excessive bruising ♣ Prolonged bleeding after injury or incision ♣ Delayed wound healing ♣ Royal family ``` Mutation in Hemophilia A ♣ Gene: F8 ♣ Chromosome: Xq28 ♣ Deficiency of Factor VIII ♣ 22A inversion causes 50% ```

Answer 59

``` Mitochondrial Disease o Group of disorders caused by dysfunction of the respiratory chain o These disorders tend to affect tissues that heavily rely on oxidative phosphorylation, brain, retina, skeletal muscle and heart Examples: • Kearns-Sayre Syndrome • MELAS • MERRF • Leber Hereditary Optic Neuropathy ```

Answer 60

Kearns-Sayre Syndrome is a mitochondrial myopathy with a typical onset before 20 years of age. KSS is a more severe syndromic variant of chronic progressive external ophthalmoplegia (abbreviated CPEO), a syndrome that is characterized by isolated involvement of the muscles controlling movement of the eyelid ♣ Mitochondrial inheritance ♣ 1-3 in 100,000 ♣ Most commonly caused by a somatic mutation ``` Clinical Manifestation Kears-Sare Syndrome ♣ Triad • Pigmentary Retinopathy • Progressive External Ophthalmoplegia • And onset before age 20y ♣ Cardiac conduction defects ♣ Ataxia ♣ Deafness ♣ Kidney problems ``` Mutation of Kearns-Sayre Syndrome ♣ Single large deletion of mtDNA (mitochondrial) ♣ Most common deletion removes twelve genes

Answer 61

MELAS Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes ♣ Mitochondrial inheritance ♣ 1 in 300,000 ♣ Low new mutation rate ``` o Melas clinical manifestation ♣ Starts between age 2 & 10 y ♣ Muscle weakness ♣ Seizures ♣ Repetitive stroke-like episodes ♣ Elevated lactic acidosis ``` ``` o Mutation of Melas caused my mutations in the mtDNA, ome of the genes (MT-ND1, MT-ND5) affected in MELAS encode proteins that are part of NADH dehydrogenase (also called complex I) in mitochondria, that helps convert oxygen and simple sugars to energy. ♣ Mitochondrial genes • MT-ND1 • MT-ND5 • MT-TH • MT-TL1 (80%) • MT-TV ```

Answer 62

MERRF (or Myoclonic Epilepsy with Ragged Red Fibers) is a mitochondrial disease. It is extremely rare ♣ Myoclonic epilepsy with ragged-red fibers ♣ Mitochondrial inheritance ♣ 1 in 400,000 ♣ Low new mutation rate ``` o Clinical Manifestations of MERRF ♣ Muscle symptoms ♣ Seizures ♣ Ataxia ♣ Dementia ♣ Ragged-red fibers ``` o Mutation for MERRF ♣ Mitochondrial genes ♣ MT-TK gene is mutated

Answer 63

Leber Hereditary Optic Neuropathy is a mitochondrially inherited (transmitted from mother to offspring) degeneration of retinal ganglion cells (RGCs) and their axons that leads to an acute or subacute loss of central vision; this affects predominantly young adult males. ♣ Mitochondrial inheritance ♣ 1 in 30,000-50,000 Europeans ``` o Clinical Manifestation ♣ Bilateral subacute vision failure ♣ Occurs during young adulthood o Mutation of Leber Hereditary Optic Neuropathy These genes code for the NADH dehydrogenase protein involved in the normal mitochondrial function of oxidative phosphorylation. ♣ mtDNA • m.3460G>A • m.1178G>A • m.14484T>C ```

Answer 64

Short stature, midface hypoplasia, small ears, hearing loss, upslanted palpebral fissures, epicanthal folds, protruding tongue, heart disease, ‘Brushfield Spots”, duodenal atresia, C1-2 instability, 5th finger hypoplasia, single palmar crease (Simian), mental retardation, Leukemia, Dementia. While normaly chromosome 21 nondisjunction is the cause…. Trisomies of 13 and 18 also liveborns o Detecting Trisomy 21 Downs Syndrome: ♣ Chromosome analysis is useful for identifying aneuploidies, like trisomy 21 ♣ Also suitable for identifying large chromosomal structural changes (duplication, deletion, rearrangements) ♣ Resolution of about 3-5 Mb

Answer 65

WAGR Syndome WAGR syndrome is a rare genetic syndrome in which affected children are predisposed to develop Wilms tumour (a tumour of the kidneys), Aniridia (absence of the coloured part of the eye, the iris), Genitourinary anomalies, and Retardation.[1] The G is sometimes instead given as "gonadoblastoma," since the genitourinary anomalies are tumours of the gonads (testes or ovaries). The condition results from a deletion on chromosome 11 resulting in the loss of several genes. As such, it is one of the best studied examples of a condition caused by loss of neighbouring (contiguous) genes. o Wilms Tumor, Aniridia (black eye), malformation, retardation o A Deletion of chromosome 11 o Detecting: FISH for PAX6 Locus in Child with WAGR and normal chromosomes Use a FISH probe to see the deletion of PAX6 for WAGR syndrome o Some individuals with isolated Aniridia have PAX6 mutations ♣ Black eyes with no oether syndromes ♣ Isolated Aniridia is familial ~70% of the time 80% of Aniridia without PAX6 deletion have detectable mutations in PAX6 by DNA sequence analysis o Micro Array and Fish cannot detect this, too small ♣ Use Sanger Sequencing to find this small gene DNA Sequencing: Mutations in known genes (mutation can be previously reported or can be novel), polymorphic variants, small (1 to ~100 nucleotide) deletion/insertions. Can find and sequence small, specific changes

Answer 66

PKU Disease Young baby is lacking the phenylalanine, mostly survive on mother Knowing the Diagnosis, able to give necessary low Phenylalanine diet to prevent the harshness of the symptoms ♣ Usually Autosomal Recessive ♣ Usually due to enzyme deficiency ♣ Some amenable to dietary and/or pharmacological manipulation. ♣ Newborn screening (heel stick) done for early diagnosis early treatment less morbidity.

Answer 67

``` Alpha-1 AT a disease that leads to lung and liver problems (early emphysemia) ♣ Autosomal recessive ♣ Deficiency of alpha-1 antitrypsin Elastases unchecked • Early empysema • Hepatic fibrosis / cirrhosis Recombinant AT1 therapy • Is a protein infusion therapy that works okay • AT1 inhibits elastase ```

Answer 68

Fabry Disease X-linked disorder Deficiency of alpha-galactosidase A enzyme activity will build up the Gl3 glucolipid • Microvascular Disease • Neuropathy • Nephropathy • Cardiomyopathy Mean survival 40 years prior to dialysis and renal transplantation Recombination Alpha-Gal •Can have Alpha-Galactosidase A enzyme transfusions

Answer 69

FGFR3 Gly380Arg gain of function mutation leads to achondroplasia, Spinal cord compression (apnea/death) is the most feared complication, paternal age effect PRINCIPLES: Gain-of-function mutations ♣ Advanced paternal age ♣ De novo mutation o MAJOR PHENOTYPIC FEATURES ♣ Age at onset: prenatal ♣ Rhizomelic short stature ♣ Megalencephaly ♣ Spinal cord compression ♣ (trident hand) o Skull growth abnormal: midface hypoplasia (otits, sleep apnea)…small cranial foramina (hydrocephalus, brainstem compression (10% of patients), increased frequency of hypotonia, quadriparesis, failure to thrive, central apnea, and sudden death). ♣ Between 3% and 7% of patients die unexpectedly during their first year of life because of brainstem compression (central apnea) or obstructive apnea o Genetic component of Achondroplasia ♣ Autosomal dominant disorder ♣ Caused by specific mutations in Fibroblast Growth Factor Receptor 3 (FGFR3); ♣ Two mutations, 1138G>A (∼98%) and 1138G>C (1% to 2%), account for more than 99% of cases of achondroplasia, and both result in the Gly380Arg substitution. Pathogensis of Anchondroplasia ♣ FGFR3 is a transmembrane tyrosine kinase receptor binds fibroblast growth factors initiates a signaling cascade ~ inhibits bone growth (over-simplified) ♣ FGFR3 c.1138 G>A Gly380Arg = gain-of-function mutations that cause ligand-independent activation of FGFR3. FGFR3 turned ON inappropriately inhibits bony growth ♣ c.1138G is ~#1 most mutable nucleotide in human gene nearly 100% of achondroplasia (single gene / single nucleotide) ♣ De novo mutations of FGFR3 guanine 1138 occur exclusively in the father's germline and increase in frequency with advanced paternal age (>35 years) Summary of Achondroplasia ♣ FGFR3 Gly380Arg gain of function mutation leads to achondroplasia ♣ Spinal cord compression (apnea/death) is the most feared complication ♣ Paternal age effect

Answer 70

Fragile X Syndrome Fragile X syndrome is hypermethylated loss of function, Premature Ovarian Failure and FXTAS occur with premutations and a gain of transcript / gain of function, Fragile X triplet repeat is in 5’ UTR region ``` o X-Linked PRINCIPLES ♣ Full Triplet repeat expansion ♣ Somatic mosaicism ♣ Sex-specific anticipation ♣ DNA methylation ♣ Haplotype effect ``` ``` MAJOR PHENOTYPIC FEATURES ♣ Age at onset: childhood ♣ Mental deficiency ♣ Dysmorphic facies ♣ Male postpubertal macroorchidism ``` o fragile X-associated tremor/ataxia syndrome (FXTAS) ♣ X-Linked ♣ Premutation Triplet repeat expansion ♣ Age at onset: Adulthood ♣ Ataxia, tremor ♣ Memory loss, parkinsonism, peripheral neuropathy ♣ Men >> women o Premature Ovarian Failure ♣ X-linked ♣ Premutation Triplet repeat expansion ♣ Women (not men) o FMR1 (Gene) and FMRP (protein): ♣ FMRP expressed most abundantly in neurons, may chaperone mRNAs from nucleus to translational machinery. (mRNA and protein have function) ♣ 99% of FMR1 mutations are 5’ CGG expansions ♣ Normal: 6-50 CGG repeats ♣ Normal FMRP protein amount Fragile X: Premutations and Full Mutations ♣ The molecular pathogenesis is different in the premutation diseases, compared with the full mutation that leads to FXS. FMR1 mRNA expression levels are increased with the premutation and decreased or absent with the full mutation. FMRP levels are absent or decreased with the full mutation and normal or close to normal with the premutation. ♣ The CGG repeat in the Methylation due to extensive elongation of the CGG repeat in the 5′-ÚTR of the FMR1 gene is depicted as a lock Summary of Fragile X syndrome ♣ Fragile X syndrome is hypermethylated loss of function ♣ Premature Ovarian Failure and FXTAS occur with premutations and a gain of transcript / gain of function ♣ Fragile X triplet repeat is in 5’ UTR region

Answer 71

The three major causes of Down’s syndrome: o 1) Trisomy 21 An extra copy of the third chromosome ♣ is in 95% of the patients ♣ Risk increases drastically with mother in mid 30’s, more likely of disjunction o 2) Unbalanced Translocation unbalanced translocation between chromosome 21 and some other acrocentric chromosome ♣ 3-4% of patients with down’s syndrome ♣ Important to check karyotype of parents o 3) Mosaic Trisomy 21 -->mixture of cells that have trisomy 21 and other cells with Down’s Syndrome ♣ Due to many of the cells not being Trisomy, much of the phenotype will be normal • Depends on what cells have Trisomy

Answer 72

Sandhoff disease, also known as Sandhoff-Jatzkewitz disease, variant 0 of GM2-Gangliosidosis or Hexosaminidase A and B deficiency, is a lysosomal genetic, lipid storage disorder caused by the inherited deficiency to create functional beta-hexosaminidases A and B.[1][2] These catabolic enzymes are needed to degrade the neuronal membrane components, ganglioside GM2, its derivative GA2, the glycolipid globoside in visceral tissues,[1] and some oligosaccharides. Accumulation of these metabolites leads to a progressive destruction of the central nervous system and eventually to death

Answer 73

Tuberous sclerosis or tuberous sclerosis complex (TSC) is a rare multi-system genetic disease that causes benign tumors to grow in the brain and on other vital organs such as the kidneys, heart, eyes, lungs, and skin. A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung 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. These proteins act as tumor growth suppressors, agents that regulate cell proliferation and differentiation.

Diseases and Drugs 2nd M2M Flashcards

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