6. Developmental and Genetic Disease Flashcards
What disease is known as “Brittle Bone Diseaes”?
Osteogenesis Imperfecta
What structural macromolecule is not synthesized correctly in Osteogenesis Imperfecta?
Type I Collagen
Why do patients with Type I OI appear with blue sclera?
A deficiency in collagen fibers seen in this patient prevents the translucence to the sclera
How do OI patients develop hearing loss?
Fractures and fusion of bones of the middle ear restrict their mobility.
What connective tissue protein is lacking in Marfan syndrome patients?
Fibrillin
What gene mutation is found in patients with epidermolytic hyperkeratosis?
Keratin gene
What is Fibrillin?
Large glycoproteins. They are the most common microfibrils needed for elastin assembly.
What is Anencephaly?
congenital absence of the cranial vault, with cerebral hemispheres either missing or reduced to small masses
During what days of gestation does anencephaly occur/
23rd and 26th
What structures are absent due to failure of the neural tube to close?
calvarium (the dome of the skull), skin and subutaneous tissues
What are 3 major phenotypical charactersitics of anencephaly?
Acrania, protruding eyes, long arms
Neurofibromatosis Type 1 is characterized by what clinical manifestations?
- disfiguring neurofibromas 2 . Areas of dark pigmentation of the skin (care au lai spots) 3. Pigmented lesions of the iris (Lisch nodules)
What is the protein product of the NF1 gene? What is its function?
NF1 geene produces the neurofibomin protien which is expressed in many tissues and belongs to a family of GTPase-activating proteins (GAPs) which inactivate ras protein.. NF1 is a tumor suppressor gene
What is he consequence of loss of GAP activity? What is the predisposition of this abnormality when induced by NF1 gene mutation?
Uncontrolled ras p21 activation; formation of benign neurofibromas
Nf1 is associated with the incidence of what class of tumors?
Neurogentic tumors, (ex. Meningioma, optic glioma, pheochromocytoma)
p21 is active in which form: GTP bound or GDPbound?
GTP (p21 is a membrane bound protein that binds GTPase activating protein from the cytosol)
What protein can be screened for to detect an anencephalic fetus?
Alpha-fetoprotein
What gene mutation is seen in Marfan syndrome patients?
Fibrillin-1 missense mutation
What produces the concentric crings of elastin in the aortic wall/
Deposition of elastin on microfibrillar fibers
What gene mutatikons are found in patients with muscular dystrophy?
Dystrophin
What gene mutatikons are found in patients with OI and Ehlers-Danlos syndrome?
Collagen
Marfan Syndrome follows what pattern of inheritance?
Autosomal Dominant
What unmetabolized substrate is accumulated in Tay-Sachs disease?
Gangliosdies
What molecules are neceesary for Ganglioside metabolism to prevent Tay-Sachs disease development?
Beta-hexosaminidases that require the participation of the GM2-activator protien
Tay-Sachs Disaease follows what pattern of inheritance?
Autosomal Recessive
What are 3 major phenotypical charactersitics of Cystic Fibrosis?
- Chronic Pulmonary Disease 2. Dficient exocrine pancreatic function 3. complications of inspissated mucus in a number of organs including the SI, liver, and reproductive tract
What is a key clinical manifestation in the diagnosis of CF? Describe this pathogenesis.
Increased concentrations of electrolytes in the sweat. This is caused by the decreased chloride conductance that results in a filure of Cl reabsorption by sweat gland cut cells causing NaCL to accumulate in thesweat. Other symptooms will be attributed to the presence of abnormally thick mucus.
CFTR stands for what? What membrane transporter famiily does CFTR belong to?
Cystic Fibrosis Transmembrane Conductance Regulator; ATP-binding familyu of membrane transporter proteins that constitues a chloride channel in most epithelia
Familial Hypercholestoreliam is characterized by deposition of cholesterol where?
arteries, tendons, and skin
What cgene is affected in familial hypercholesterolemia?
Genes that encodes the cell surface receptor that removes LDLs from the blood,LDLR
Due to high levels of Phenylalanine in the first few years of life, what pathology occurs?
Mental deterioration/retardation
Why would a PKU patient have fair skin, blonnd hair, and blue eyes?
the inability to convert phenylalanine to tyrosine leads to reduced melanin synthesis
What causes the “mousy” odor in PKU patients?
phenylacacetic acid formation
PKU is caused by what deficiency? What is the urine product?
Phenylalanine hydroxylase (PAH); Phenylpyruvic acid
Ehlers-Danlos syndromes follow what pattern of inheritance?
Autosomal Dominant
What are phenotype of Ehlers-Danlos syndrome patients?
Hyperelasticity, fragility of the skin, joint hypermobility (unusual extension and flexion), and often a bleeding diathesis
What aspect of collagen is defected in Ehlers-Danlos syndrome?
Molecular structure, synthesis, secretion, and degradation
What secondary complication are Ehlers-Danlos patients at risk for when they undergo surgery?
Dehiscence because sutures do not hold well . Patients can stretch skin many centimeters.
What molecule accumulates in Gaucher disease patients? Due to what deficiency?
glucosylceramide ( a common core structure for membrane glychosphingolipids); Glucocerebrosidase ( a type of lysosomal acid beta-glucosidase)
What are Gaucher cells?
Lipid-laden macrophages that are characteristically present in the red pulp of the spleen, liver sinusoids, lymph nodes, lungs, and bone marrow. They are derived from the resident macrophages in the respective organs - ex. Kupferr cells in the liver and alveolar macrophages in the lung
What gene mutation is seen in Fabry Disease?
Galactosidase gene mutations
How does hepatospleomegaly develop in Gaucher patients?
When the degradation of cerebrosides of cell membranes is blocked by the glucocerebrosidase deficiencyk, there ais accumulation in sleen and liver
Name 3 dysraphic disorders
Anencephaly, meningocele, and meningomyelocele
What is Beri-Beri?
Polyneuropathy, edema, and Heart Failure caused by Thiamine deficiency
What mode of inheritance is associated with cleft lip and cleft palate?
Multifactorial Inheritance (multiple genes interact with various environmental factors to produce disease)
During the 35th day of gestation , disturbance in gene expression can lead to interference with proper fusion and cleft lip due to what genetic cause?
Structural Chromosomal Abnormalities
What correlation is there between disease severity and transmission of cleft lip?
More severe anatomical defect, greater probability of transmission. Transmission to a child also increases when one previously child born to a couple has the disease.
What gender is most at risk for cleft lip?
males (sons of women with cleft lip have ffour times higher risk than sons of affected fathers)
What X-linked condition is charecterized by progressive degeneration of muscles, particularly those of the pelvic and shoulder girdles?
Duchenne-Becker Muscular Dystrophy
How does myocyte death occur in Becker Muscular Dystrophy and Ducehenne Muscular Dystrophy?
Dystrophin is absent. It is a member of cytoskeletal porteins (alpa-actinin and spectrin) and is located on the cytoplasmic side of the muscle cell’s plasma membrane. It Is liked to it by dystrophin-associated glycoprotein complex and bound to extracellular laminin. Without dystophin, the membrane is damaged during contrraction causing cell death.
McArdle disease is associated with what gene mutation?
Glycogen phosphorylase gene mutation
What marker is increased in serum for DMD disease patients? What is likely the ultimate cause of death in DMD and at what is the mean age of death?
Creatinine Kinase; Cardiomyopathy is common cause of death at 17 yrs of age in boys
Klinefelter Syndrome aka Testicular Dysgenesis is related to the presence of what abnormality? How does this develop?
O(80%) have an additional X chromosome (47, XXYcomplement) and arises as a result of nondisjunction during gametogenesiss (1/2 cases-paternal meiosis I forming a spermacontianing both a Xand Y chromosome that feritlizes a normal oocyte )
What is atelectasis?
collapse of the alveoli
What causes hypoxia and acidosis in an infant suffering from respiratory distress syndrome?
The infant’s lack of surfactant and subsequent atelectasis causes an alveoli to be perfused without ventilation
Describe the the characteristics of a lung that suffered from surfactant deficiency on gross examination
Lungs are dark red and airless. Alveolar ducts are lined by hyaline membranes ( conspicous, eosinophilic, fibrin-rich, amorphous structures)
What are the most common symptoms found in Respiratory Distress infants beginning within an hour of birth
- Increased respiratory effort (with forceful inspiratory contractions and use of accessory neck muscles) 2. Necrotizing enterocloitis (due to GI mucosal ischemia amd can be pseudomembranous, gangrene, or perforated) 3. Bacterial colonization (Often C. difficile)
Patients with Turner Syndrome have what genetic abnormality? What’s the likely cause
1/2 lack an entire X chromosome, Other 1/2 are mosaics (45, X.46/XX 15% or 45,X/46XY) or display structural aberrations of the X chromosome.; Caused by nondisjunction during mitosis
What is Erythroblastosis fetalis?
A hemolytic disease caused by maternal antibodies that pass through the placenta and attack antigens expressed on fetal RBCs. Severity of erythroblastosis fetalis increases with each succeeding pregnancy and varies from a mild hemolysis to fatal anemia.
When a Rh + fetal erythrocytes more than 1 mL is introduced into the circulation of a Rh - mother, what is the effect?
The mother becomes sensitized to the D antigen and a small concentration of fetal D antigin leads to the mother’s antibody (IgG) production
What occurs when a mother’s IgG crosses the placenta into fetal blood? Why is this possible?
IgG antibodies are small enough o cross the plaent and produces hemolysis in the fetus.
Birth defects such as cleft lip, pyloric stenosis, hypospadias (urethra opens on the ventral aspect of the penis), and congenital heart disese display what type of inheritances?
Multifactorial Inheritance (multiple genes interact with various environmental factors to produce disease)
What is the pirmary causes of Trisomy 21?
Nondisjunction of Meiosis I (92-95%cases), Translocation of a long arm of chromosome 21 to another acrocentric chromosome (5%)
What are the morphological lesions characteristic of Alzheimer disease and Down Syndrome?
- granulovacuolar degeneration. 2. neorfibrillarly tangles 3 . Senile plaques 4. loss of neurons; Plaques are composed of fibrillar protein Beta-amyloid protein
Describe the pathology caused by the mutation seen in Fragile X syndrome
The CGG Trinucletoide repeat is expanded adjacent to the FMR1 and causes the methylation of the promoter located next to the FMR1 which silences the FMR1 gene. The abnormal repeat is associated with an inducivle fragile site on the X chormosome which appears a s a nonsaining gap or chromosomal break on cytogenetic studies
What are the clinical features of a Fragile X patient?
increased head cirucmference, facial coarsening, enlarged testes, and abnormalities of the cardiac valves
What cardiomyopathy is associated with Marfan Syndrome? Fammilial Hypercholesterolemia?
Aortic Dissection; athersclerosis which leads to myocardial infraction
What is TORCH?
a complex of similar signs and symptoms produced by fetal or neonatal infection with a variety of the following microorganisms: Toxoplasma Others Rubella Cytomegalovirus Herpes. Others include congenital syphillis (caused by Treponema Pallidum)
What are common findings of congenital syphillis?
Early finding: A maculopapular rash; Periostitis and an outward curving of the anteriror tibia (saber shins) are also commonly found. Flat raised plaques (condylomata lat) around the anus and female gentalia may develop.
What term refers to defects caused by the incomplete formation of a lumen.
Atresia
Tuberous sclerosis is an example of dysplasia. What occurs in this pathological disease?
the Bran contains aggregrates of normally developed cells arranged into grossly visible “tubers”
Many hollow organs begin as what cell organization pattern?
As strands and cords that are programmed to die t o formal the cavity or lumen
Minute or microscopic aggregates of normal tissue in aberrant locations are known as what?
Choristomas
Focal,, benign overgrowths of one or more of the mature cellular elements of a normal tissue are known as what?
Hamartomas
What tumors are most frequently found in childhood?
Hemangiomas
What is a papilloma?
A benign tumor that outgrows as a nipple like and finger like
What is a teratoma?
an encapsulated tumor with tissue or organ components resembling normal derivatives of more than one germ layer.
What measure is used to determine if an infant will experience respiratory distress syndrome?
A lecithin-to-sphingomyelin ratio above 2:1 implies that the fetus will survive without developirn resp . Distress
When does lecithin concentration rise and peak?
Rise rapidly: 3rd trimester beginning; What is Peak: Near term
What is the composition of surfactant?
A mixture of phospholipids: 75% phosphatidylcholine (lecithin) and 10% phosphatidylglycerol
When does the lining of fetal alveoli differentiate?
late pregnancy
What is the most severe form of Erythroblastosis and what secondary illnesses likely develop?
Hydrops fetalis characterized by severe edema secondary to congestive heart failure caused by severe anemia.
What is dystocia?
delivery or difficult labor
What factors predispose to burth injury?
Cephalopelvic disproportion, dystocia, prematurity, and breech presentation
Define Cephalohematoma
Subperiosteal hemorrhage that is confined to a single cranial bone and becomes apparent within the first few hours after birth
Bilirubin encephalopathy is also known as what? Describe this condition
Kernicterus; Neurological condition associated with severe jaundice and bile staining of the brain (esp. basal ganglia, pontine nuclei, and cerebellar dentate nuclei). Bilirubin is thought o injure brain cells by interferin with mitochondrial function
Which population si vulnerable to hyperbillirubinemai and may develop kerniccterus at levels as low as 12 mg/dL (despite the fact that term infants rarely develop kernicterus at levels below 20 mg/dL)
Premature Infants
Which enzyme is deficienat in the fetal immature liver preventing conjucation of released heme?
glucuronyl transferase
What are two management options for kernicterus?
Exhange transfusion keep maximum serum bilirubin at an acceptable level; Phototherapy converts toxic unconjugated bilirubin into isomers that are nontoxic and excreted into the urine
Do exogenous toxins acting on preimplantation stage embryos produce errosrs of morphogenes and cause malformaitons?
Nondisjunction of Meiosis I (92-95%cases), Translocation of a long arm of chromosome 21 to another acrocentric chromosome (5%)
What is the most commmon consequence of toxic exposure at the preimplantation stage?
Death of the embryo (30% of fertilized ova are aborted spontaneously without the mother being aware)
What is placenta accreta?
Abnormal adherence of the placenta to the uterine wall
