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98 Cards in this Set

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What are the genetics of Achondroplasia?
Autosomal dominant
Mutation in the FGFR3 receptor, mutations increase with paternal age.
What mutation occurs in Achondroplasia and what is the result?
FGFR3 (fibroblast receptor defect).
Leads to constitutive osteoclast activity which causes short arm/legs, macrocephaly, spinal cord compression, normal IQ, hyperflexible joints and hydrocephalus.
How do you diagnose achondroplasia? Treatment? What is specific to the disease?
Radiographic test of dwarf and DNA test for FGFR mutation.
Surgical intervention for hydrocephalus and spinal cord compression. Growth hormone for height.
Specific to this disease: Worsens with advanced paternal age.
What are the genetics of familial breast cancer?
Autosomal dominant. Mutation in the BRCA1 and BRCA2 genes
What mutation occurs in Familial breast cancer and what is the result?
BRCA1 and BRCA2 mutation which are tumor suppressor genes.
BRCA1 mutations have increased risk for breast, ovarian, prostate and colon cancer.
BRCA2 have increased risk for male and female breast, ovarian, prostate, GB and pancreatic cancer.
What is the treatment for familial breast cancer?
Prevention: Yearly mammograms and male prostate exams. Bilateral mastectomy and salpingo-oophorectomy reduces cancer by 90%.
What is specific to familial breast cancer?
Founder effect and tumor suppressor gene
What are the genetics of chronic myelogenous leukemia?
No germline involvement.
Translocation of the abl gene (9) to brc gene (22) resulting in a Philadelphia chromosome.
What mutation occurs in CML and what is the result?
9-22 translocation to form Philadelphia chromosome. BCR/ABL gene is an oncogene which produces the bcr/abl protein product that causes cell division and proliferation.
Symptoms of CML?
Fatigue, malaise, weight loss and splenomegaly. Millions of blast cells in peripheral blood.
How do you diagnose CML? Treatment?
Diagnosis made with chronic phase blast count in peripheral blood.
Treatment: Imatinib which replaces ATP on bcr/abl protein product inactivating it. Bone marrow transplant. Finally, α-interferon which suppresses the bone marrow.
What type of gene is the bcr/abl gene?
Oncogene
What are the oncogenes that we should know?
BCR/ABL, RAS, MYC and RET
What are the tumor suppressor genes that we should know?
Rb, P53, APC, BRCA1 and BRCA2
What are the genetics of cystic fibrosis?
Autosomal recessive. Trinucleotide deletion of region coding for Phe residue on chromosome 7 (∆F508)
What is the mutation in cystic fibrosis and what does it cause?
Trinucleotide deletion of Phe residue (7) which codes for cystic fibrosis transmembrane receptor (CFTR).
W/o the CFTR, secretions are very thick due to no NaCl. As a result lung infections and pancreatitis occur often.
Sweat is also very salty because the NaCl pump is reversed in the skin so NaCl can't be reabsorbed.
What are the symptoms of CF?
Begins with meconium ileus, poor growth, COPD, chronic infections and malnutrition.
Wolffian ducts fail to develop which causes azoospermia in 95% of males.
What is diagnosis and treatment for CF?
Sweat test is diagnostic
Treatment: Constant pulmonary clearance, management of infections, preventing intestinal obstruction and lung transplant.
What is associated with pancreatic insufficiency in CF patients?
The ∆F508 mutation is closely assoc. with PI.
What are the genetics of Duschenne's muscular dystrophy?
X-linked recessive. The mutation is in the DMD gene which codes for dystrophin. Dystrophin is a protein that stablizes the sarcolemma.
What are the symptoms of DMD?
Presents btw 3-5yrs old with hypotonia and muscle weakness. At age 5, Gower's sign presents with calf pseudohypertrophy. At age 12, they are confined to a wheelchair with scoliosis. 95% of patients have cardiac defects.
Diagnosis for DMD? Treatment?
Muscle biopsy and test for dystrophin protein. DNA test for DMD mutation.
Treatment: No cure. Reduce muscle contractures, maintain mobility, monitor cardiac and pulmonary function.
What are the genetics of familial adenomatous polyposis?
Autosomal dominant with mutation in the APC gene. APC protein is a tumor suppressor gene involved in cell proliferation and division.
Loss of APC function leads to increased levels of β-catenin which stimulates transcription of other genes.
T/F Mutations in both alleles of APC gene causes FAP?
False. Technically, you need mutations in other cell division genes to cause cancer.
Mutations in both alleles of APC causes polyp formation
Presentation of FAP?
Formation of hundreds of polyps in the colon early in life. Some of these will develop into cancer.
Diagnosis and treatment of FAP?
Individuals with >100 polyps or btw 10-100 with family history of FAP are diagnosed.
Treatment: Regular colonoscopies and eventually a colectomy with ileoanal pullthrough.
What type of gene is the FAP gene?
Tumor suppressor gene.
What are the genetics of fragile X syndrome?
X-linked with trinucleotide repeat (CGG) mutation in FMR gene. Mutations decrease with paternal transmission and increase with maternal transmission.
What is the mutation in fragile X and what does it do?
Loss of function mutation in FMR gene which normally codes for chaperone protein to take mRNA from nucleus to ribosomes.
Symptoms of fragile X?
Male: Severe behavioral problems, mild mental retardation, hyperactivity and autism. Large head, long face and MACRO-ORCHIDISM.
What disease is characterized by macro-orchidism?
Fragile X syndrome
What is diagnosis and treatment of fragile X syndrome?
What is specific to the disease?
DNA tests done when symptoms suggest
Treatment: Control the bad behavior.
GENETIC ANTICIPATION
What are the genetics of hemophilia?
X-linked recessive. Mutation in F8C gene or F9 gene causes deficient factor 8 in hemophilia A and factor 9 in hemophilia B.
Symptoms of hemophilia, diagnosis and treatment?
Severe case: Bleeding into joints, soft tissue and muscles. Minor head contusions cause cephalohematomas.
Mild case: Prolonged bleeding after trauma or surgery.
Diagnosis: Measure factor 8 or 9 levels in the blood.
Treatment: Replace missing factors.
What are the genetics of hereditary non-polyposis colon cancer?
Autosomal dominant disorder with mutation in DNA repair genes. 90% have micro-satellite instability.
What is the result of the mutations in HNPCC?
DNA mismatch repair usually reduces mutations by 1000 fold. Missing mismatch repair causes huge increase in cancer risk.
Symptoms of HNPCC? Treatment?
Similar rate of polyp formation compared the normal population except occur much earlier in life. Almost all polyps form proximal to splenic flexure.
Treatment: Regular colonoscopies from age 25 on. Women get regular ultrasounds for ovarian or endometrial cancer.
What is specific to HNPCC?
Micro-satellite instability.
What are the genetics of huntington's disease?
Autosomal dominant trinucleotide repeat (CAG). CAG repeat leads to polyglutamine tract in Huntingtin protein.
Huntingtin protein has unknown function but gain of function causes neostriatal and brain atrophy.
Symptoms of Huntington's disease? Diagnosis? Treatment?
30% of people have psychiatric problems.
66% of people have cognitive and motor problems.
90% of people have chorea.
Diagnosis: DNA test
Treatment: Blocking the gene product in mice has shown promise.
What is specific to Huntington's disease? What is difference between it and Fragile X?
GENETIC ANTICIPATION like Fragile X but this time paternal transmission increases the number of mutations and maternal decreases it.
What are the genetics of Marfan's syndrome?
Autosomal dominant mutation in fibrillin gene. Fibrillin protein is load-bearing protein in structures like the zonular fibers of the lens, aorta and skin.
Symptoms of Marfan's syndrome? Diagnosis? Treatment?
MASS - Mitral valve prolapse, aortic dissection, skeletal deformities, skin problems and lens dislocation.
Diagnosis: Symptoms often lead to diagnosis, DNA test not available.
Treatment: Manage abnormalities with surgical and medical intervention.
What are the genetics of Miller-Dieker syndrome?
80% new mutation. 20% inherited balanced translocation. This mutation is a LIS1 gene hemizygous deletion
What does the missing protein normally do in Miller Dieker syndrome?
LIS1 protein usually helps with neuronal migration. W/o, you develop Lissencephaly (smooth gyri) which is where it gets it's name from.
What are the symptoms of Miller-Dieker syndrome?
Lissencephaly (smooth or few gyri), brain dysgenesis, hypotonia, failure to thrive and death before 2 yrs of age.
Diagnosis of Miller-Dieker syndrome? Treatment?
MRI findings of smooth gyri. FISH test for chromosome 17 LIS1 gene deletion.
Treatment: NG tube for feeding and pharmacological treatment for seizures.
What are the genetics of myoclonic epilepsy with ragged red fibers?
Mitochondrial inheritance. Deletion in genes coding for complex I and IV.
mtDNA more prone to mutations do to exposure to high levels of ROS.
What are the symptoms for myoclonic epilepsy with ragged red fibers? What is the diagnosis?
Presents with worsening epilepsy and muscle weakness as mutations in mtDNA worsen with exposure to ROS.
Diagnosis: Muscle biopsy looking for ragged red fibers.
What is treatment for myoclonic epilepsy with ragged red fibers? What is specific for this disease?
Treatment: Vitamins to improve ox.phos.
MITOCHONDRIAL INHERITANCE.
What are the genetics of non-syndromic deafness?
Autosomal dominant and recessive.
Mutation in the GfB2 gene which normally codes for an ion channel in the cochlea.
What are the symptoms of non-syndromic deafness?
The dominant condition presents with deafness later on in life and with hyperkeratosis of the palms and soles.
Diagnosis of non-syndromic deafness? Treatment?
DNA test to differentiate between syndromic and non-syndromic deafness
Treatment: Cochlear implant
Newborn screening of non-syndromic deafness is now done.
What are the genetics of Prader-Willi syndrome?
Autosomal dominant if due to imprinting. Caused by a mutation in chromosome 15 of paternal chromosome leaving only maternally imprinted 15.
Can also result from maternal disomy in which case paternal 15 is missing.
What are the symptoms of Prader-Willi? Diagnosis?
Infant: Hypotonia, feeding difficulties, hypogonadism and cryptorchidism.
Adolescent: Feeding difficulty flips to overeating and obesity. Also have infertility, behavior problems and MR.
What is the diagnosis for Prader-Willi? Treatment?
DNA test for maternally imprinted chromosome 15.
Treatment: Restrict diet, provide sex hormones for development but this worsens male behavior and predisposes the females to stroke.
What is specific for Prader-willi?
Genetic imprinting
What are the genetics for Retinoblastoma?
Autosomal dominant disorder with RB suppressor gene mutation. RB protein normally sequesters transcription factors for cell division.
What are the symptoms of retinoblastoma? Diagnosis? Treatment?
Present with either bilateral do unilateral retinal tumors. Individuals with bilateral often have other primary cancers.
Diagnosis: With retinoblastomas, a DNA test is done.
Treatment: Enucleation, radiation or chemotherapy, light therapy or cryotherapy.
What type of gene is the RB gene?
Tumor suppressor gene
What are the genetics of sex reversal?
Y-linked
Usually a somatic translocation and so rarely if ever gets passed on. The mutation often causes sterility.
What genetic mutation occurs in sex reversal?
The SRY gene usually fuses onto the X chromosome in males with XX.
There is often an SRY deletion in females with XY.
What are the symptoms of sex reversal?
Female (XY) ovaries do not develop as 2X's are required. Only mimic turner's if there is a large deletion of the Y gene.
Male (XX) sperm do not develop because you need more than the SRY gene. Similar to Kleinfelter's except for MR, behavior problems and these patients enter puberty spontaneously.
Diagnosis for sex reversal? Treatment?
When the phenotype doesn't match the karyotype, run FISH.
Treatment: For males, testosterone for under-virilization and surgical intervention for gynecomastia. For females, estrogen for puberty and removal of ovaries in adulthood to reduce risk of cancer.
What is specific for sex reversal?
Y-linked trait.
What are the genetics of sickle cell anemia?
Autosomal recessive with mutation in the B globin gene at the B6 position. Glutamine is replaced by a valine.
Symptoms of sickle cell anemia?
Anemia, failure to thrive, autolysis of spleen following splenomegaly, increased infections due to missing spleen.
Treatments for sickle cell?
Bone marrow transplant
Hydroxyurea
What are the genetics of Tay-Sachs disease?
Autosomal recessive is a mutation in the Hexosaminidase A enzyme which normally breaks down gangliosides. These accumulate and cause neuro-toxicity.
Symptoms of Tay-Sachs? Diagnosis?
Neurological deficits early in life with death by 2 years. Vision is lost within the first year with cherry red spots on fundoscopic exam.
Diagnosis: Test serum hexosaminidase A and newborn screening.
What is specific about Tay-Sachs?
It is common in Ashkenazic Jews and the Amish
What are the genetics of Thalassemia?
Autosomal recessive with mutation in α or β globin genes
What are the symptoms of Thalassemia? Diagnosis? Treatment?
Microcytic, hypochromic anemia, hemachromatosis and infections
Diagnosis: Hb electrophoresis
Treatment: Bone marrow transplant, folate supplements for RBC synthesis, treatment of infections, iron chelation and supply antioxidants.
What is specific to α or β thal?
α is more prevalent in Japanese people and β is more prevalent in greeks
What are the genetics of thrombophilia?
Autosomal dominant disorder where either factor V or protein C and S are mutated. Factor V leiden is not broken down by protein C in which case predisposes you to clotting. Less common is a mutation in protein C which prevents it from binding factor V.
Symptoms of thrombophilia? Diagnosis? Treatment?
Pulmonary emboli.
Diagnosis: Test serum factor V and serum protein C.
Treatment: Anticoagulation therapy
What is specific to thrombophilia?
Multifactorial disorder
What are the genetics of Turner syndrome?
Missing chromosome (XO), usually sporadic. 50% of the time XO, 25% 2nd X is deficient, 25% of the time patient is mosaic.
What are the symptoms of Turner syndrome?
Ovaries require 2X's to mature so in this case they scar and atrophy.
Main symptoms: Short stature, webbed neck, cystic hygroma, cardiac and renal abnormalities. Reduced estrogen predisposes them to atherosclerosis and heart disease.
What is the treatment for Turner syndrome?
GH to stimulate growth. Estrogen for female characteristics, progesterone for first period and echocardiogram to monitor heart problems.
Diagnosis
Patient has rocker bottom feet, transposition of the great vessels, clenched fists, cleft lip and palate, petite facies and ear malformations
What is the cause?
Trisomy 18
Non-disjunction of chromosome 18
Diagnosis
Holoprosencephaly, polydactyly, congenital heart disease and cutis aplasia of the occiput
What is the cause?
Trisomy 13
Non-disjunction of chromosome 13
Patient has hypotonia, protruding tongues, small ears, medial epicanthal folds, MR, single palmar crease and brushfield spots
What is the disease and what caused it?
Trisomy 21
Non-disjunction of chromosome 21 or Robertsonian translocation
A child has ocular hypertelorism, MR, microcephaly and the cry sounds like a cat.
What is it and what caused it?
Cri du chat
Deletion of the p arm of chromosome 5
Child has thymic aplasia, hypocalcemia, tetralogy of fallot and MR.
What is it and what caused it?
DiGeorge syndrome
Due to failure of neural crest cells to migrate. Deletion is on chromosome 22q11
Male has under-virilization of the genitalia, tall stature, atrophied testes, MR and behavior problems.
Diagnosis? What caused it?
Variant kleinfelter's syndrome due to behavior problems.
Numerous additional X chromosomes and a Y.
Patient has cardiac defects, cleft palate, hyperextensible fingers and abnormal facial characteristics.
Diagnosis?
Velocardiofacial syndrome (less severe than DiGeorge syndrome.
Patient has paroxysms of laughter, seizures, abnormal EEG, severe MR, jerky movements and ataxia
Diagnosis? What type of inheritance is it? What caused it?
Angelmann syndrome
Autosomal dominant
Deletion of maternal chromosome 15q12 or paternal (uniparental) disomy
Patient has black spots in sclera and joints. Urine turns black upon standing
Diagnosis? What caused it?
Alkaptonuria
Lack of homogentisic oxidase needed for breakdown of tyrosine. Increased homogentisic acid in the urine.
Patient has mental retardation, seizures, small head, blond hair and blues eyes and smells musty.
Diagnosis? What caused it? Treatment?
Phenylketonuria. Autosomal recessive disorder.
Lack of the enzyme phe hydroxlase or BH4 in malignant PKU.
Restrict phenyalanine in diet by restricting protein.
Patient has neonatal jaundice, liver disease, cataracts and susceptibility to Ecoli infections.
Diagnosis? How would you confirm? Treatment?
Galatosemia (GALT)
Reducing substance in the urine, serum levels of galactose-1-P uridyltransferase
Treatment: Soy based formula as soon as possible.
Patient has failure to thrive, lethargy, constipation, low body temp and large anterior fontanelle.
Diagnosis? Inheritance pattern?
Congenital hypothyroidism
95% sporadic
Patient has vomiting, lethargy and encephalopathy following a fast. There is hypoglycemia and absence of ketone bodies in the urine.
Diagnosis? Inheritance? Which enzyme is absent? Treatment?
MCADD
Autosomal recessive
Acyl-CoA dehydrogenase preventing ketone formation from medium chain fatty acids.
IV glucose and prevent fasting.
What causes Burkitt's Lymphoma?
A translocation between the c-myc proto-oncogene and the IgH gene. This involves chromosome 8 and 14.
It is autosomal dominant inheritance.
Patient has parathyroid, pancreatic cell and anterior pituitary tumor. Diagnosis?
MEN1 syndrome
Patient has parathyroid tumor, medullary thyroid cancer and pheochromocytoma. Diagnosis? What caused it?
MEN2 syndrome
A mutation in the RET oncogene. YOU ONLY NEED 1 MUTATION HERE.
Inheritance is autosomal dominant.
Patient has brittle bones, wormian bones, short stature, hearing loss and dentinogenesis imperfecta. Diagnosis? Deficiency? Treatment?
Osteogenesis imperfecta
The deficiency is type I collagen
Reduce contact sports, repair broken bones and weight bearing exercises.
Alendronate - bisphosphonates which inhibit osteoclast activity.
Fetus characterized with molar placenta and syndactyly. Diagnosis?
Triploidy (3 sets of all chromosomes).