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151 Cards in this Set
- Front
- Back
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What is osteogenesis imperfecta?
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inherited disorder of type I collagen with wide range of clinical heterogeniety
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What chromosome is responsible for proalpha-1?
proalpha-2? |
1-17
2-7 |
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Type I OI
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Type I-fractures during early childhood, normal stature, blue sclera, exaggerated post menopausal bone loss and fractures
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Type II OI
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severe congenital bone deformities and fractures, usually lethal in perinatal period
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Type III OI
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congenital fractures with progressive bone failure, gractures and deformity, variable bluish sclera, possible hearing loss
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Type IV OI
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mild or moderate bone fragility and deformity, normal or grayish sclera, possible hearing loss
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What types of mutations cause Type I OI?
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null mutation, usually in proalpha-1 chain which reduces procollagen production
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What types of mutations cause Type II,III,IV OI?
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AA sub in either chain
dominant negative-produces structurally defective collagen |
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What amount of collagen helices are defective in proalpha-1 mutations in Type II,III,IV?
proalpha-2? |
1-75%
2-50% |
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What is the major treatment of OI?
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management of fractures
surgery-rodding promote mobility monitor hearing medication-bisphosphates |
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What is Marfan's syndrome?
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Multisystem disorder affecting the musculoskeletal, ocular, and cardiovascular systems
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What are the musculoskeletal symtoms of Marfans?
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Musculoskeletal-tall, long limbs, and fingers, arachnodactyly, pectus deformities, joint laxity, high narrow palate
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What are the ocular symtoms of Marfans?
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lens dislocation, flat cornea, myopia
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What are the cardiovascular symtoms of Marfans?
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mitral valve prolapse, aortic regurgitation and dilatation and dissection of the aorta
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Explain the genetic basis for Marfan's.
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Fibrillin 1(15q21) is a glycoprotein that is mutated in Marfans
ADom. |
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What is the Tx for Marfans?
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Therapy focuses on prevention and symtomatic management--eye exams, ortho, CV
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What disorders result from mutations in fibroblasts growth factor receptor 3(FGFR3)?
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skeletal dysplasias
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Achondroplasia
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Most frequent form of short imbed dwarfism
Rhizomelia Delayed motor development ADom. |
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What fraction of surviving babies have achondroplasia if both parents are affected?
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2/3 bc AA result in neonatal death.
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Explain the mutations behind Achondroplasia.
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Most mutations are de novo related to increasing paternal age at position 1138. 97% are G to A with 2.5% G to C. This results in a gain of function evident in inappropriate inhibition of chondrocyte proliferation.
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What most likely explains variations within the same disease?
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postion of the mutation.
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Why are metabolic disorders present in infancy or early childhood?
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In utero there are alot of things the baby doesn't have to do
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What is the major inheritance for metabolic disorders?
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ARecessive
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Infant appears normal in the first few months of life but later experiences severe MR and motor retardation, microcephaly, poor growth rate, and siezures. Whats the Dx?
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PKU
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Newborn appears normal up to 3 months but later experiences stunted growth and MR. Whats the Dx?
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congenital hypothyroidism
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Within a few days, newborn becomes irritated after milk feedings with vomiting, diarhea, lethargy, jaundice and liver damge. Eventually, developmental retardation, hepatomegaly, growth retardaion, cataracts, and death occurs. Whats the Dx?
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galactosemia
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Newborn presents in the first week of life with feding difficulties, lethargym and fialure to thrive. Eventually, the disorder leads to progressive neuro problems, acidosis, siezures, and sudden apnea that can rapidly lead to coma or death.
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MSUD
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What are the 5 options for treating metabolic disorders?
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1. restrict intake
2. alt. metabolic pathways to remove toxic products 3. coax additional activity out of impaired enzyme 4. supplement deficiencies 5. supportive treatment |
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What enzyme is involved in Tay-Sachs and what does this impairment lead to?
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Hexosaminidase A-leads to GM2 ganglioside accumulation in lysosomes
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Describe how Tay-Sachs progress.
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3-6 mos- lose milestones
8-10 mos-motor development plateaus 1 yr- blind 2 yr-loss of voluntary movement 4yr-death |
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What is a tell-tale sign of Tay Sachs when examining the eye?
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cherry-red spot-normal retina of the fovea surrounded by macular retina may whitish due to accumulation of GM2 ganglioside.
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What is the carrier frequency for tay sachs?
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1/300 north america
1/30 ashkenzi jew |
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How do you test for tay-Sachs and how can you get a misdiagnosis?
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Enzymatic assays for HexA(αβ) from blood, CVS, or amniocytes--BEWARE two psuedodeficiency genes exists
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What is the most common mutation in the ashkenzi jewish population?
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4 bp insertion in exon 11 causing a premature stop codon represents 80% of the A-jew population
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What are FODs/FOAs?
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Fatty acid oxidation disorders are a family of genetic diseases that result from impaired ability to oxidize fatty acids
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What is fatty acid oxidation so important?
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NADH + FADH2 and acetyl CoA--once glucose and glycogen run out these are replaced by fatty acid breakdown. w/o leads to hypoglycemia, coma, death.
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What is the inheritance for FOD?
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mostly autosomal recessive
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What are the steps of fatty acid oxidation?
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1. transport of activated fatty acid into mitochodrial matrix
2.Dehydrogenation 3.Breaking the carbon backbone |
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What are the 4 hydrogenases mentioned? How many carbons do they deal with?
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SCAD <8
MCAD 6-14 LCAD >12 but usually >17 VLCAD |
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What is ALD?
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Adrenoleukodystrophy-results from mutations that impact the function of very long chain acyl-coA synthetase, the enzyme that primes very long chain fatty acids for beta oxidation.
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What is the clinical presentation of MCAD in adults and children?
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1:20,000
Adults/Child-hypoketotic hypoglycemia, vomiting, lethargy, seizures, coma, death |
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What is the clinical presentation of MCAD in newborns?
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NEWBORN-feeding difficulties in first week of life, lethargy and failure to thrive. Can progress to neurological problems, acidosis, seizures, profound hypoglycemia, sudden apnea leading to coma/death
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What are some of the misdiagnoses of MCAD?
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SIDS 1-10%
Reye's Syndrome Diabetes |
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Explain the biochemical diagnosis of MCAD?
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Plasma acylcarnitines
plasma fatty acid profile urine organic acids urine acylglycines(can detect symptomatic and asymtomatic) |
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How is MCAD diagnosis confirmed?
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enzymatic assay of fibroblasts, leukocytes, or other tissues
less than 10% activity=affected |
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Explain the molecular diagnosis of MCAD.
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vast majority of mutations are point mutations of ACADM
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What is the prognosis for MCAD?
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Good if detected early. Although ADD, cerebral palsy, behavioral/developmental diabilities reported.
18% mortality in first metabolic crises if not detected early. |
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What is the treatment for MCAD?
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Avoid fasting
Give toddlers cornstarch bfore bed High carb intake L-carnitine supplements (100/200) In ER, start 10% glucose ASAP after blood draw! |
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What are the benefits of genetic testing for MCAD?
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1. can detect carrier status
2. fast, easy, can be done pre-natally. |
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Generally, what causes thalassemia?
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impaired production of either alpha or beta globin chains.
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what is the basis of BMD?
DMD? |
BMD-partial loss or impairment of dystrophin
DMD-complete loss of dystrophin |
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What is the difference between BMD and DMD genetically?
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BMD has mostly in frame deletions whereas DMD mutations causes a frameshift
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What is the biochemical basis for BMD/DMD?
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loss of structural intergrity and connections at the cell membrane
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Descrbe how BMD presents clinically.
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Onset greater than 7 yrs
severity ranges slowly progressive myopathy calf pain muscle hypertrophy failure to walk 16-80 joint contractures cardiomyopathy cognitive deficits |
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Descrbe how DMD presents clinically.
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Same as BMD except
onset 2-5 years failure to walk 8-14 years scoliosis night blindness death at 15-25 yrs from resp/cardiac failure**** |
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How is BMD/DMD diagnosed?
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biochemical-increased serum CPK/CK
Histopathological-muscle biopsy shows endomysial fibrosis, muscle finer degernation and regeneration, absent dystrophin staining DNA Analysis for common mut. |
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What is the treatment of BMD/DMD?
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supportive
prednisone tissue transplant/gene therapy |
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What is imprinting?
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Genes are expressed differently depending upon the parent of origin. For imprinted genes expression only occurs from one parent's allele. The relevant DNA is marked in a gender specific manner that determines whither or not that gene is expressed.
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What are the strutural changes associated with imprinting?
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1. Gene methylation: gene is methylated in CpG islands (region of DNA with lots of C and G).
2. Promotor methylation: promoter of gene can also be methylated 3. Methyl CpG binding proteins: further structural modification of imprinted gene. |
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What is the result of the structural changes of imprinting?
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Loss of transcription: Due to the structural modifications, the transcriptional machinery cannot bind to imprinted gene--imprinted gene is effectively silenced.
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Describe the life cycle of an imprint
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Fertilization:Maternal gamete (with genes silenced due to maternal imprinting). Paternal gamete (with genes silenced due to paternal imprinting).
Zygote:Original imprinting is maintained Somatic development:Original imprinting is maintained Germ line development:the original imprints from parents are erased and new imprints established based on gender. |
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What are imprinting centers?
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Imprinting centers: regions of DNA near imprinted genes that control selective silencing of particular genes depending on gender of fetus.
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What is the theoretical purpose of imprinting?
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genes that are paternally expressed tend to enhance fetal growth and genes that are maternally expressed tend to suppress fetal growth
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What is the incidence of Angelmann syndrome?
What is the incidence of prader-willi? |
Incidence: 1/15,000
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What is the connection between Angelmann and imprinting?
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Angelman and imprinting: The Angelman gene is expressed only in the egg (paternally imprinted)
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What is the clinical presentation of prader-willi?
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Birth and infancy:
hypotonia poor suck reflex: difficulty gaining weight until age 3. failure to thrive Early childhood Hyperphagia: will often go foraging for food in all places à obesity Hypogonadism à delayed puberty Small hands and feet Mild mental impairment |
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What is the connection between PW and imprinting?
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Prader-Willi gene is expressed only in the sperm (maternally imprinted)
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What is the clinical presentation of Angelmann?
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Clinical presentatation:
Neuological:Severe mental impairment, Seizures Gait: stiff-legged with flexed arms Personality:very happy, frequent outbursts of laughter fyi: many children are misdiagnosed as having cerebral palsy |
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How can PWS and AS be detected?
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-methylation status of region
-FISH of 15q11-q13 -PCR studies to detect UPD -If deletion, examine chromosomes of parents -Testing of imprinting and UBE3A for mutations. |
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Thalassemia
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results from impaired production of either alpha or beta globin chains
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What is the genetic basis of alpha thalassemia?
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mostly deletions--likely caused by unequal crossovers.
Other causes are large or LCR mutations, or Hb constant spring |
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What is consequence of the different genetic mutations of alpha thalassemia?
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A2-silent carrier
A1,A2-mild microxytic anemia A1,A2,A2-severe hemolytic anemia A1,A1,A2,A2-Bart hydrops fatalis |
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Why is hydrops fatalis restricted to southeast asia?
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more deletions in A1-A2 together;usually cis mutations
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What is the genetic basis of beta thalassemia?
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mostly point mutations
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What are the possible alleles for beta thalassemia?
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normal
b+ - reduced function, only some b globin produced b0 – non-functioning, no b globin produced |
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What is the range of disease for beta thalassemia?
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b thalassemia minor – one normal allele, one b+ or b0 – mild
b thalassemia major – 2 non-functioning or reduced function (b+/b0) alleles – severe |
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What is the clinical picture of alpha thalassemia?
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ranges from mild microcytic anemia to severe MA to hydrops fatalis
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What is the clinical picture of beta thalassemia?
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Cooley's anemia-range of severity from mild MA with mild bone marrow hyperplasia to severe hemolytic anemia with GR, jaundice, hepatosplenomegaly, and bone marrow expansion leading to bone defomities
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What is a side effect of transfusion therapy for both thalassemias?
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iron overload
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What is the ethnic distribution of thalassemia alleles?
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Meditteranean, african, middle easternm indian, chinese, and SE asian
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What are the ranges of alpha thalassemia trait around the world?
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UK, japan, iceland-.01%
SW pacific islands-49% |
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What are the ranges of beta thalassemia trait around the world?
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Afican/American-1.5%
Sardina-30% |
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What are two ways to diagnose thlassemia?
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HB protein
DNA |
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What are heinz bodies?
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in beta thalassemia, excess alpha chains precipitate as heinz bodies in RBC
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What method would you use to detect alpha thalassemia?
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Southern blot-deletions in alpha globin account for 85 percent
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What method would you use to detect beta thalassemia?
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PCR, ASO/microarray-only about 15 mutations account for more than 90% of the cases
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What is the treatment of thalassemia?
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supportive(transfusions, antibiotics;risk of iron overload)
allogenic bone marrow transplantation gene therapy? |
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what is the carrier status of thalassemia in cyprus?
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1/7
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What is thrombophilia?
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group of conditions characterized by tendency for excessive or inappropriate clotting
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What is the clinical significance of thrombophilia?
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can lead to pulmonary embolism, stroke, DVT, etc.
In US, affects about 1/1000 and kills 100,000 |
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What is the genetic basis for thrombophilia?
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factor V leiden
protein C deficiency protein S deficiency antithrombin mutation prothrombin mutation hyperhomocysteinemia |
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What is the most common cause of thrombophilia?
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Factor V leiden-1/20 carrier rate
-caused by a mutation that disrupts one of 3 activated protein C cleavage sites in factor 5 |
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Antithrombin deficiency
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-AT is a serine protease inhibtor
-mutations impact either expression or binding -carrier rate of 1/100 -accounts for 4% of VT |
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Prothrombin mutation
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results in increased steady state level of circulating prothrombin
carrier rate is 1-2% of general population |
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Protein C deficiency
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-protein C normally inhibits thrombin formation
-heterozygous in 1/200-500 normal and 5% of VT |
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Protein S deficiency
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-vit K dependent enzyme so can be genetic or vit K def.
-normally activates factor 5a,8a -1-5% of VT |
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Hyperhomocysteinemia
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-inhibits incativation of 5a by activated protein C
-mutations impact MTHFR, CBS(B6, folate), or MS(B12,folate) |
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What are the enviornmental risk factors for excess or inappropriate clotting?
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smoking, oral contraceptives, pregnancy, surgery, prolonged lack of physical activity
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What are the treatment options?
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-Lifestyle changes
-folate and B12 supplementation for hyperhomocysteinemia -anticoagulants for other thrombophilias |
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List unstable trinucleotide repeat disorders in humans.
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fragile x
huntingdons myotonic dystrophy a bunch of ataxias |
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What the common features of trinucleotide repeats?
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-neurological disease
-usually AD--can be X-linked of AR -exhibit reduced penetrance or genetic anticipation |
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What is genetic anticipation?
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age of onset decreases
severity and incidence increases |
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Myotonic dystrophy
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AD 1/8000
myotonia, muscle wasting, cataracts, testicular atrophy, male baldness |
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What are the three forms of myotonia dystrophy?
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-mild-late age of onset, cataracts, little or no wasting
-classic-early adulthood, myotonia, muscle weakness and wasting -congenital-onset at birth, generalized muscle hypolasia, sever mental retardation |
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What type of repeat causes myotonic dystrophy?
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-CTG of DMPK, a protein kinase
-normal(5-30), mild(50-80), classic(80-150), congenital(2000+) -massive expansions(thousands) are almost always maternal in origin |
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What is a possible pathophysiology of myotonic dystrophy?
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depletion of CUG binding protein from the total mRNA population may affect processing of other mRNAs
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Fragile X
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-xlinked dominant with reduced penetrance
-most common heritable form of MR(M 1/4000;F 1/8000) -name refers to a marker of X where chromatin fails to condense properly |
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Clinical features of fragile X
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large head, long face, large ears, macroorchism, hyperextensible joint, pectus excavatum, mitral prolapse, mental impairment, ADHD, autistic like behavior
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What causes fragile x?
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-CGG repeat in FMR1
-normal(7-40), premutation(60-200), disease(200+) -loss of function -expansion mostly in female gam. |
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Where does FMRP function?
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-neurons-plays a role in spine maturation and synaptic plasticity
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Trinucleotide repeats
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-novel mechanism
-can occur anywhere -show evidence of anticipation -loss or gain of function |
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What 3 tasks does the mitochondria fulfill?
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1.oxidative phosphorylation
2.produces ROS 3.regulates apoptosis |
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How many genes in the mitochondria?
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37--polypeptides of oxphos, rRNAs, tRNAs
-have modified codon usage rules |
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Heteroplasmy and Replicative Segregation
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Heteroplasmy-mixed intracellular population of mutant and normal mtDNA develops;makes prenatal diagnosis difficult
RS-cell linages can drift to mutant and normal |
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Threshold Expression
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phenotypes normal until cirtical threshold of mutants is exceeded.
varies depending on type and tissue demands |
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Why does mtDNA have a high mutation rate?
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-lack efficient repair systems
-lack histones -association with inner membrane where ROS develops -accumulations of polymorphisms 10x faster |
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Leber Hereditary Optic Neuropathy(LHON)
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-painless subacute bilateral vision failure
-typically presents in young adults; males over females |
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What is the genetic basis for LHON?
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-4 primary point mutations
-homoplasmic |
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What is the suggested pathophysiology of LHON?
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-inhibition of e transport chain between complex 1 and Q10
-leads to increase ROS leading to apoptosis |
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Myoclonic Epilepsy with Ragged Red Fibers (MERRF)
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-myoclonic epilepsy
-fibers are abnorma deposits of mitochondria in muscle -other relatives may have ataxia, renal dysfunction, diabetes, dementia |
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What causes MERRF?
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frequently associated with mutations in the tRNA(Lys) gene which results in reduction of mitochondrial protein synthesis
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Leigh's Syndrome
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-subacute necrotizeing encephalomyopathy
-average age 1-2 -duration 5 yrs -ataxia, hypotonia, spasticity, developmental delay,etc. |
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What causes leighs syndrome?
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-18% due to mtDNA mutations
-remaining are nuclear mutations in genes that function in mtOXPHOS -x-linked or AR |
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What are some other disorders that mtDNA may be involved?
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-dementias
-cancers -aging |
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Novel issues associated with mitochondria.
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-maternal inheritance
-heteroplasmy -RS -threshold of expression -high rate of mutation |
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mtDNA mutations
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-point affecting oxphos
-deletions that remove several mt genes -point that alter usage of mt tRNAs |
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Name the two reproductive duct systems.
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1. mesonephric (wolffian)
2. paramesonephric(mullerian) |
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Sex development in males.
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-leydig cells produce testosterone that stimulates mesonephros to form vas, epidid., and seminal vesicles
-sertoli cells secrete MIS that stimulates regression of the paramesonephros |
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Sex development in females.
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no leydig, no test., mesonephros regression
no sertoli, no MIS, paramesonephros becomes oviduct, fallopian, uterus, upper third of vagina |
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Formation of external genitals in males.
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-test to DHT by 5alpha reductase
-DHT is required for differentiation of genital tubercle to penis and genital swellings to scrotum |
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Formation of external genitals in females.
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-absence of DHT, the genital tubercle forms clit while swellings and urethral fold form labia
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What are the key genes for sex dtermination?
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WT-1
SRY SOX9 DAX1 MIS SF-1 |
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WT1
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required for conversion of genital ridge into bipotential gonad--loss of function mutation reults in loss of gonads and kidneys
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SRY
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-master male regulatory swith
-expressed briefly early in development -encodes DNA binding protein -located just below the Yp pseudosomal region |
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SOX9
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-TF
-direct target of SRY -fetal expression increased in testis -haploinsufficiency leads to campomelic dysplasia(lethal skeletal formation with sex reversal) |
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What causes XX males and XY females?
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-aberrant X/Y recombination
-XX male posess SRY but lack genes for sperm -XY female lack SRY and produce few oocytes |
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DAX1
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-xlinked gene that encodes TF
-expression reduced in testis -anti male gene -46 XY with DAX1 mutation inhibit SRY leading to XY females |
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SF1
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-TF modulates transcription of genes involved in steroidogenesis(test/MIS)
-involved in ovarian granulosa cells for estrogens -also play role in early dev. in transforming the bipotential gonad. |
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Which two genes compete to control SF-1?
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DAX-1-promotes ovary
SRY-promotes testis |
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Hermaphroditism
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-most common finding is testis on one side and ovary on other
-next is unilateral ovary/ovo-testis -may have incomplete closure of scrotum and penis |
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What causes Hermaphroditism?
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-mosaicism(mitotic NDJ from a 47XXY)
-chimerism(dual fertilization of the ovum and one of it's polar bodies) |
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What can cause primary sex reversal?
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SRY mutations-XYF
SRY translocation-XXM Duplications of DAX1-XYF SOX9 mutaions-XYF 1/20000 |
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What is primary vs secondary sex reversal?
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primary-sex chromosome content is reversed from both gonadal and exta gonadal phenotype
secondary-sex chromosome content is consistent with gonadal sex but ext or int gent. are reversed relative to sex chromosome content |
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What are examples of secondary sex reversals?
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CAH
Androgen insensitivity 5 alpha reductase 2 mutations |
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CAH
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-AR due to defects in enzymes required for cortisol biosynthesis, produced by adrenal cortex
-hallmark-inadequate production of glucocorticoids |
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CAH pathophysiology
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-cortisol levels fall
-results in accumulation of hormones upstream from block -hormones shunted to form androgens which virilize females |
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Clinical presentation of CAH.
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-masculinization of ext gent.
-irregular menstral periods -classic(1/15000), nonclassic(1/1000) -degree of enzyme deficiency dictates symtoms -90% due to mutation of CYP21 |
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Androgen Insensitivity
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-associated with x-linke androgen receptor
-1/20,000 -XY females |
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What are the degrees of AI?
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Mild-near normal
Moderate-ambiguous gent. Severe-clitoromegaly, post labial fusion Complete-external completely female;no internal genitalia |
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5 alpha reductase 2 mutations
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-AR 1/100,000
-enzyme convers test to DHT -mutation results in failure to synthesize DHT |
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What is the presentation of 5 alpha reductase 2 mutations?
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-variable ext female phenotype: small phallus, bilateral testis, normally developed mesonephric ducts that term into blind vag.
-partial virilization in affected males at puberty |
