Diseases and Drugs 2nd M2M Flashcards
Down’s syndrome
Down’s syndrome: Down syndrome (trisomy 21) is the most common human chromosomal disorder ascertained in liveborn infants (~1/800). In more than 95% of trisomy 21 cases, the additional chromosome 21 is maternal in origin, and dosage studies indicate that nondisjunction during maternal meiosis I is by far the most common cause.
Turner’s Syndrome
• Turner’s Syndrome 45,X, is a condition in which a female is partly or completely missing an X chromosome.[Signs and symptoms vary among those affected. Often, a short and webbed neck, low-set ears, low hairline at the back of the neck, short stature, and swollen hands and feet are seen at birth. Typically they are without menstrual periods, do not develop breasts, and are unable to have children. Heart defects, diabetes, and low thyroid hormone occur more frequently. Most people with TS have normal intelligence. Many, however, have troubles with spatial visualization such as that needed for mathematics.
o Turner syndrome is not usually inherited from a person’s parents. 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
Common Human Aneuploidy Syndromes:
o Trisomy 21 – Down syndrome Characteristic facies, short stature, hypotonia, moderate intellectual disabilities Cardiac anomalies, leukemia in infancy.
o Trisomy 18 – Edwards syndrome Small for gestational age, small head, clenched fingers, rocker-bottom feet
o Trisomy 13 – Patau syndrome Characteristic facies, severe intellectual disabilities Congenital malformations – holoprosencephaly, facial clefts, polydactyly, renal anomalies
o 45, X -Turner syndrome Short stature, webbed neck, edema of hands and feet, broad shield-like chest, narrow hips, renal and cardiovascular anomalies, gonadal dysgenesis (failure of ovarian maintenance).
o 47, XXY – Klinefelter syndrome Tall stature, hypogonadism, elevated frequency of gynecomastia, high frequency of sterility, language impairment
Trisomy 18
Edwards syndrome Small for gestational age, small head, clenched fingers, rocker-bottom feet
Trisomy 13
Trisomy 13 – Patau syndrome Characteristic facies, severe intellectual disabilities Congenital malformations – holoprosencephaly, facial clefts, polydactyly, renal anomalies
45, X
45, X -Turner syndrome Short stature, webbed neck, edema of hands and feet, broad shield-like chest, narrow hips, renal and cardiovascular anomalies, gonadal dysgenesis (failure of ovarian maintenance).
47, XXY
47, XXY – Klinefelter syndrome Tall stature, hypogonadism, elevated frequency of gynecomastia, high frequency of sterility, language impairment
Acute Myeloid Leukemia
oMore frequently seen in adults, rarely in youth
-Have Auer rods you can see in microscopes
o Cause of Acute Myeloid Leukemia
The Translocation of Chromosome 15 and Chromosome 17 will create a new genetic sequence
The PML section of chromosome 15 and the RARA region of chromosome 17 will translocate, leading to the creation of the PML/RARA transcription factor
-which encodes a putative transcription factor, Differentiation of myeloid hematopoietic precursors past the promyelocytic stage is reportedly inhibited by the actions of a PML-RARA fusion protein.
Vitamin A can combat and ruin the structure of the PML-RARA protein
Chronic Myeloid Leukemia
o Presentation:
- Night sweats, fatigue, weight loss,anemia
- Lab:Peripheral blood smear shows lobulated large cells
o Function: Chromosome 9 and 22 have a translocation, leading to the production of a BCR/ABL protein
-The ABL gene from Chromosome 9 will translocate and mix with the BCR gene with chromosome 22
o ThePhiladelphia chromosomeorPhiladelphia translocationis a specific abnormality of chromosome22, which is unusually short, as an acquired abnormality that is most commonly associated withchronic myelogenous leukemia(CML).[1]It is the result of a reciprocal translocationbetween chromosome 9 and chromosome 22, which is specifically designated t(9;22)(q34;q11). This gives rise to afusion gene,bcr-abl
ThePhiladelphia chromosome
ThePhiladelphia chromosomeorPhiladelphia translocationis a specific abnormality of chromosome22, which is unusually short, as an acquired abnormality that is most commonly associated withchronic myelogenous leukemia(CML).[1]It is the result of a reciprocal translocationbetween chromosome 9 and chromosome 22
Gleevec
Gleevec is atyrosine-kinase inhibitorused in the treatment of multiple cancers, most notablyPhiladelphia chromosome-positive (Ph+)chronic myelogenous leukemia(CML).[1]
o Molecular antagonist: binds at ATP binding site in abl tyrosine kinase and bcr/abl tyrosine kinase
-In order to survive, cells need signaling through proteins (signal cascade) to keep them alive. Some of the proteins in this cascade use aphosphategroup as an “on” switch. This phosphate group isadded by a tyrosine kinase enzyme.
Prader Willi and Angelman Syndrome
Both diseases are based on disorders involving Chromosome 15
o Prader Willi excessive eating, short stature, hypogonadism, a degree of intellectual disability
o Angelman Syndrome short stature, severe intellectual disability, seizures, spasticity
Prader Willi and Angelman Syndrome are based on genetic regions that are methylated on chromosome 15
Prader Willi= PWS gene region
• Has five regions that are only expressed on the paternal chromosomes
Angelman Syndrome= AS gene region
• Has maternal-only expression of 2 genes
Gaucher disease
Red blood Cells are broken down in the vacuoles of the macrophages a portion of the red blood cells is lipid that must be broken down
♣ The macrophages have the extensive enzymatic machinery to break down these lipids and part or this machinery is the enzyme Glucocerebrosidase
o Without the Glucocerebrosidase enzyme, cells will accumulate with the glucose lipid Glucocerbroside Form the cigarette looking cells called Gaucher Cells
♣ These macrophages are then called Gaucher cells which are stored/stuck mainly in liver, spleen and bone marrow.
Without the Glucocerebrosidase enzyme, the cells will accumulate with glucocerebroside
Sighs and Symptoms of Gaucher disease
o Spleen and/or stomach will become swollen
o One of the spleen’s functions is to weed out old blood cells. When the spleen enlarges too much, sometimes to 25 times its normal size, it weeds out too many blood cells, including good ones. This can lead to anemia.
♣ Patients with insufficient blood cells suffer from fatigue, because they are not getting enough oxygen and energy. If the spleen has taken out too many platelets, which are essential for coagulation (clotting), the patient will bleed and bruise more.
Three different Types of Gaucher Disease (I, II, and III)
•Only Gaucher Disease that doesn’t have neurological issues is Type 1
o Can strike at any age
♣ Type 1 will find out anywhere from 6-80 years of age (can develop any time)
♣ Type 2 will always be right at infancy, will probably die within several years
♣ Type 3 will be in the early years (early as 2, possibly as late as 60s)
o Distinguishing symptom
♣ Type 1 will only have the typical enlarged liver/spleen, and have anemia and weakened bones
♣ Type 2 will have type 1 + early onset of neurological problems
♣ Type 3 will have type 1+ Later onset of neurological problems
o Effect of Disease
♣ Type 1 will have mild to moderate conditions
♣ Type 2 will be SEVERE, die in infancy
♣ Type 3 will be moderate to severe
o Glucocerebrosidase Activity
♣ Type 1 Less than 30%
♣ Type2 Very little/least activity
♣ Type 3 little activity
Down’s Syndrome
Also known as trisomy 21, is a genetic disorder caused by the presence of all or part of a third copy of chromosome 21.[1] It is typically associated with physical growth delays, characteristic facial features, and mild to moderate intellectual disability.[2] The average IQ of a young adult with Down syndrome is 50, equivalent to the mental age of an 8- or 9-year-old child, but this varies widely.[3]
Down syndrome can be identified during pregnancy by prenatal screening followed by diagnostic testing, or after birth by direct observation and genetic testing. Since the introduction of screening, pregnancies with the diagnosis are often terminated.[4][5] Regular screening for health problems common in Down syndrome is recommended throughout the person’s life.
CYP450 genes
he CYP450 genes will metabolize many products that arrive in the liver and the small intestines via Phase 1 pharmacokinetics
o Phase 1 Adding a hydroxyl or polar group to make a reactant soluble for the body
o While most CYP genes are important in the rate of inactivation of a drug, in some cases the CYP gene(s) is required to activate a drug.
♣ example of this is CYP2D6 activity being necessary to convert codeine (inactive, almost no analgesic effect) to morphine (active with a potent analgesic effect).
Turner Syndrome
Turner Syndrome 45,XO Signs at birth • Prenatal cystic hygroma • Webbed neck • Puffy hands & feet • Heart defects like coarctation of the aorta • Short stature • Normal intelligence
♣ Infertility due to non-functioning ovaries
♣ Hormone dysfunction Need hormone therapy
♣ Distinctive traits such as low set ears, broad chest
♣ Occurs in 1/2,500 newborn girls
Kleinfelter Syndrome
Kleinfelter Syndrome 47, XXY male has an extra X chromosome ♣ Can be seen in childhood • Learning disabilities • Delayed speech and language • Tendency towards being quiet ♣ Tall stature ♣ Small testes ♣ Reduced facial and body hair ♣ Infertility ♣ Hypospadias ♣ Gynecomastia
Jacobs Syndrome
o Jacobs Syndrome 47,XYY An extra Y disorder ♣ Learning disabilities • Speech delays • Developmental delays ♣ Behavioral and emotional difficulties • Autism spectrum disorders ♣ Tall stature
Triple X Syndrome
o Triple X Syndrome 47,XXX - Extra X chromosome in females ♣ May have tall stature ♣ Increased risk of • Learning disabilities • Delayed speech • Delayed motor milestones • Seizures • Kidney Abnormalities
Congenital Adrenal Hyperplasia
o Ambiguous genitalia in 46, XX
o 21-hydroxylase deficiency
o Complicated by salt wasting in the first few weeks of life and with times of metabolic stress
♣ Decreased sodium and chloride
♣ Increased potassium
Androgen Insensitivity Syndrome (AIS)
o Has the chromosome characteristics: 46, XY (normal)
o AIS is an X-linked gene, Autosomal Recessive
o Mutation causes abnormality of the androgen receptor
♣ Even though the body makes androgens (testosterone), it doesn’t necessarily recognize or respond to it
♣ Phenotypes range from mild under-virilization (Partial AIS) to full sex reversal (Complete AIS)
o Used to be called testicular feminization
5-Alpha Reductase Deficiency
5-Alpha Reductase Deficiency
46, XY
o X-linked gene, AR
o Mutation causes decreased ability of the body to convert testosterone to dihydrotestosterone
o Phenotype shows undervirilized male with increased virilization at the time of puberty
Disorders associated with the SRY gene (on the Y chromosome)
o 46, XY or 46, XX
o Y-linked gene
o Deletion or absence of the gene results in full 46, XY sex reversal and a phenotypically normal female
o Ectopic presence of the SRY gene in a 46, XX individual results in a phenotypically normal male
o Mutations in the SRY gene in a 46, XY individual results in decreased or absent production of Anti Mullerian hormone & under virilization of a male
Denys-Drash & Frasier Syndrome
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
Phenylketonuria
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
1-antitrypsin deficiency (ATD)
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.
1-antitrypsin deficiency (ATD) Treatment and
effects of smoking on ATD
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)
Tay-Sachs Disease (GM2 gangliosidosis type I)
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.
Sandhoff disease
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
Recognize The effects of Tay-Sachs and Sandhoffs Disease
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
Summary of Turner’s Syndrome
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 anondisjunctionin the father.Meioticerrors that lead to the production of X with p arm deletions or abnormal Y chromosomes are also mostly found in the father.[38]IsochromosomeX orring chromosomeX 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 balancedtranslocationof 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]
Turner Syndrome Symptoms and Diagnosing, Treatment
Turner syndrome is due to achromosomal abnormalityin 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 withmosaicism
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.
De novo mutation
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
Achondroplasia
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
Achondroplasia- Dwarfism Genetic component
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
Pure dominant versus Incomplete Dominance
o Pure dominant Homozygotes and Heterozygotes are both equally affected
o Incomplete Dominant Homozygotes are affected more severely
Retinoblastoma
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
