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151 Cards in this Set

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  • Back
What is osteogenesis imperfecta?
inherited disorder of type I collagen with wide range of clinical heterogeniety
What chromosome is responsible for proalpha-1?
Type I OI
Type I-fractures during early childhood, normal stature, blue sclera, exaggerated post menopausal bone loss and fractures
Type II OI
severe congenital bone deformities and fractures, usually lethal in perinatal period
congenital fractures with progressive bone failure, gractures and deformity, variable bluish sclera, possible hearing loss
Type IV OI
mild or moderate bone fragility and deformity, normal or grayish sclera, possible hearing loss
What types of mutations cause Type I OI?
null mutation, usually in proalpha-1 chain which reduces procollagen production
What types of mutations cause Type II,III,IV OI?
AA sub in either chain
dominant negative-produces structurally defective collagen
What amount of collagen helices are defective in proalpha-1 mutations in Type II,III,IV?
What is the major treatment of OI?
management of fractures
promote mobility
monitor hearing
What is Marfan's syndrome?
Multisystem disorder affecting the musculoskeletal, ocular, and cardiovascular systems
What are the musculoskeletal symtoms of Marfans?
Musculoskeletal-tall, long limbs, and fingers, arachnodactyly, pectus deformities, joint laxity, high narrow palate
What are the ocular symtoms of Marfans?
lens dislocation, flat cornea, myopia
What are the cardiovascular symtoms of Marfans?
mitral valve prolapse, aortic regurgitation and dilatation and dissection of the aorta
Explain the genetic basis for Marfan's.
Fibrillin 1(15q21) is a glycoprotein that is mutated in Marfans
What is the Tx for Marfans?
Therapy focuses on prevention and symtomatic management--eye exams, ortho, CV
What disorders result from mutations in fibroblasts growth factor receptor 3(FGFR3)?
skeletal dysplasias
Most frequent form of short imbed dwarfism
Delayed motor development
What fraction of surviving babies have achondroplasia if both parents are affected?
2/3 bc AA result in neonatal death.
Explain the mutations behind Achondroplasia.
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.
What most likely explains variations within the same disease?
postion of the mutation.
Why are metabolic disorders present in infancy or early childhood?
In utero there are alot of things the baby doesn't have to do
What is the major inheritance for metabolic disorders?
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?
Newborn appears normal up to 3 months but later experiences stunted growth and MR. Whats the Dx?
congenital hypothyroidism
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?
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.
What are the 5 options for treating metabolic disorders?
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
What enzyme is involved in Tay-Sachs and what does this impairment lead to?
Hexosaminidase A-leads to GM2 ganglioside accumulation in lysosomes
Describe how Tay-Sachs progress.
3-6 mos- lose milestones
8-10 mos-motor development plateaus
1 yr- blind
2 yr-loss of voluntary movement
What is a tell-tale sign of Tay Sachs when examining the eye?
cherry-red spot-normal retina of the fovea surrounded by macular retina may whitish due to accumulation of GM2 ganglioside.
What is the carrier frequency for tay sachs?
1/300 north america
1/30 ashkenzi jew
How do you test for tay-Sachs and how can you get a misdiagnosis?
Enzymatic assays for HexA(αβ) from blood, CVS, or amniocytes--BEWARE two psuedodeficiency genes exists
What is the most common mutation in the ashkenzi jewish population?
4 bp insertion in exon 11 causing a premature stop codon represents 80% of the A-jew population
What are FODs/FOAs?
Fatty acid oxidation disorders are a family of genetic diseases that result from impaired ability to oxidize fatty acids
What is fatty acid oxidation so important?
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.
What is the inheritance for FOD?
mostly autosomal recessive
What are the steps of fatty acid oxidation?
1. transport of activated fatty acid into mitochodrial matrix
3.Breaking the carbon backbone
What are the 4 hydrogenases mentioned? How many carbons do they deal with?
MCAD 6-14
LCAD >12 but usually >17
What is ALD?
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.
What is the clinical presentation of MCAD in adults and children?
Adults/Child-hypoketotic hypoglycemia, vomiting, lethargy, seizures, coma, death
What is the clinical presentation of MCAD in newborns?
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
What are some of the misdiagnoses of MCAD?
SIDS 1-10%
Reye's Syndrome
Explain the biochemical diagnosis of MCAD?
Plasma acylcarnitines
plasma fatty acid profile
urine organic acids
urine acylglycines(can detect symptomatic and asymtomatic)
How is MCAD diagnosis confirmed?
enzymatic assay of fibroblasts, leukocytes, or other tissues

less than 10% activity=affected
Explain the molecular diagnosis of MCAD.
vast majority of mutations are point mutations of ACADM
What is the prognosis for MCAD?
Good if detected early. Although ADD, cerebral palsy, behavioral/developmental diabilities reported.

18% mortality in first metabolic crises if not detected early.
What is the treatment for MCAD?
Avoid fasting
Give toddlers cornstarch bfore bed
High carb intake
L-carnitine supplements (100/200)
In ER, start 10% glucose ASAP after blood draw!
What are the benefits of genetic testing for MCAD?
1. can detect carrier status
2. fast, easy, can be done pre-natally.
Generally, what causes thalassemia?
impaired production of either alpha or beta globin chains.
what is the basis of BMD?
BMD-partial loss or impairment of dystrophin

DMD-complete loss of dystrophin
What is the difference between BMD and DMD genetically?
BMD has mostly in frame deletions whereas DMD mutations causes a frameshift
What is the biochemical basis for BMD/DMD?
loss of structural intergrity and connections at the cell membrane
Descrbe how BMD presents clinically.
Onset greater than 7 yrs
severity ranges
slowly progressive myopathy
calf pain
muscle hypertrophy
failure to walk 16-80
joint contractures
cognitive deficits
Descrbe how DMD presents clinically.
Same as BMD except
onset 2-5 years
failure to walk 8-14 years
night blindness
death at 15-25 yrs from resp/cardiac failure****
How is BMD/DMD diagnosed?
biochemical-increased serum CPK/CK

Histopathological-muscle biopsy shows endomysial fibrosis, muscle finer degernation and regeneration, absent dystrophin staining

DNA Analysis for common mut.
What is the treatment of BMD/DMD?
tissue transplant/gene therapy
What is imprinting?
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.
What are the strutural changes associated with imprinting?
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.
What is the result of the structural changes of imprinting?
Loss of transcription: Due to the structural modifications, the transcriptional machinery cannot bind to imprinted gene--imprinted gene is effectively silenced.
Describe the life cycle of an imprint
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.
What are imprinting centers?
Imprinting centers: regions of DNA near imprinted genes that control selective silencing of particular genes depending on gender of fetus.
What is the theoretical purpose of imprinting?
genes that are paternally expressed tend to enhance fetal growth and genes that are maternally expressed tend to suppress fetal growth
What is the incidence of Angelmann syndrome?
What is the incidence of prader-willi?
Incidence: 1/15,000
What is the connection between Angelmann and imprinting?
Angelman and imprinting: The Angelman gene is expressed only in the egg (paternally imprinted)
What is the clinical presentation of prader-willi?
Birth and infancy:
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
What is the connection between PW and imprinting?
Prader-Willi gene is expressed only in the sperm (maternally imprinted)
What is the clinical presentation of Angelmann?
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
How can PWS and AS be detected?
-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.
results from impaired production of either alpha or beta globin chains
What is the genetic basis of alpha thalassemia?
mostly deletions--likely caused by unequal crossovers.
Other causes are large or LCR mutations, or Hb constant spring
What is consequence of the different genetic mutations of alpha thalassemia?
A2-silent carrier
A1,A2-mild microxytic anemia
A1,A2,A2-severe hemolytic anemia
A1,A1,A2,A2-Bart hydrops fatalis
Why is hydrops fatalis restricted to southeast asia?
more deletions in A1-A2 together;usually cis mutations
What is the genetic basis of beta thalassemia?
mostly point mutations
What are the possible alleles for beta thalassemia?
b+ - reduced function, only some b globin produced
b0 – non-functioning, no b globin produced
What is the range of disease for beta thalassemia?
b thalassemia minor – one normal allele, one b+ or b0 – mild
b thalassemia major – 2 non-functioning or reduced function (b+/b0) alleles – severe
What is the clinical picture of alpha thalassemia?
ranges from mild microcytic anemia to severe MA to hydrops fatalis
What is the clinical picture of beta thalassemia?
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
What is a side effect of transfusion therapy for both thalassemias?
iron overload
What is the ethnic distribution of thalassemia alleles?
Meditteranean, african, middle easternm indian, chinese, and SE asian
What are the ranges of alpha thalassemia trait around the world?
UK, japan, iceland-.01%
SW pacific islands-49%
What are the ranges of beta thalassemia trait around the world?
What are two ways to diagnose thlassemia?
HB protein
What are heinz bodies?
in beta thalassemia, excess alpha chains precipitate as heinz bodies in RBC
What method would you use to detect alpha thalassemia?
Southern blot-deletions in alpha globin account for 85 percent
What method would you use to detect beta thalassemia?
PCR, ASO/microarray-only about 15 mutations account for more than 90% of the cases
What is the treatment of thalassemia?
supportive(transfusions, antibiotics;risk of iron overload)
allogenic bone marrow transplantation
gene therapy?
what is the carrier status of thalassemia in cyprus?
What is thrombophilia?
group of conditions characterized by tendency for excessive or inappropriate clotting
What is the clinical significance of thrombophilia?
can lead to pulmonary embolism, stroke, DVT, etc.
In US, affects about 1/1000 and kills 100,000
What is the genetic basis for thrombophilia?
factor V leiden
protein C deficiency
protein S deficiency
antithrombin mutation
prothrombin mutation
What is the most common cause of thrombophilia?
Factor V leiden-1/20 carrier rate
-caused by a mutation that disrupts one of 3 activated protein C cleavage sites in factor 5
Antithrombin deficiency
-AT is a serine protease inhibtor
-mutations impact either expression or binding
-carrier rate of 1/100
-accounts for 4% of VT
Prothrombin mutation
results in increased steady state level of circulating prothrombin
carrier rate is 1-2% of general population
Protein C deficiency
-protein C normally inhibits thrombin formation
-heterozygous in 1/200-500 normal and 5% of VT
Protein S deficiency
-vit K dependent enzyme so can be genetic or vit K def.
-normally activates factor 5a,8a
-1-5% of VT
-inhibits incativation of 5a by activated protein C
-mutations impact MTHFR, CBS(B6, folate), or MS(B12,folate)
What are the enviornmental risk factors for excess or inappropriate clotting?
smoking, oral contraceptives, pregnancy, surgery, prolonged lack of physical activity
What are the treatment options?
-Lifestyle changes
-folate and B12 supplementation for hyperhomocysteinemia
-anticoagulants for other thrombophilias
List unstable trinucleotide repeat disorders in humans.
fragile x
myotonic dystrophy
a bunch of ataxias
What the common features of trinucleotide repeats?
-neurological disease
-usually AD--can be X-linked of AR
-exhibit reduced penetrance or genetic anticipation
What is genetic anticipation?
age of onset decreases
severity and incidence increases
Myotonic dystrophy
AD 1/8000
myotonia, muscle wasting, cataracts, testicular atrophy, male baldness
What are the three forms of myotonia dystrophy?
-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
What type of repeat causes myotonic dystrophy?
-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
What is a possible pathophysiology of myotonic dystrophy?
depletion of CUG binding protein from the total mRNA population may affect processing of other mRNAs
Fragile X
-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
Clinical features of fragile X
large head, long face, large ears, macroorchism, hyperextensible joint, pectus excavatum, mitral prolapse, mental impairment, ADHD, autistic like behavior
What causes fragile x?
-CGG repeat in FMR1
-normal(7-40), premutation(60-200), disease(200+)
-loss of function
-expansion mostly in female gam.
Where does FMRP function?
-neurons-plays a role in spine maturation and synaptic plasticity
Trinucleotide repeats
-novel mechanism
-can occur anywhere
-show evidence of anticipation
-loss or gain of function
What 3 tasks does the mitochondria fulfill?
1.oxidative phosphorylation
2.produces ROS
3.regulates apoptosis
How many genes in the mitochondria?
37--polypeptides of oxphos, rRNAs, tRNAs

-have modified codon usage rules
Heteroplasmy and Replicative Segregation
Heteroplasmy-mixed intracellular population of mutant and normal mtDNA develops;makes prenatal diagnosis difficult
RS-cell linages can drift to mutant and normal
Threshold Expression
phenotypes normal until cirtical threshold of mutants is exceeded.
varies depending on type and tissue demands
Why does mtDNA have a high mutation rate?
-lack efficient repair systems
-lack histones
-association with inner membrane where ROS develops
-accumulations of polymorphisms 10x faster
Leber Hereditary Optic Neuropathy(LHON)
-painless subacute bilateral vision failure
-typically presents in young adults; males over females
What is the genetic basis for LHON?
-4 primary point mutations
What is the suggested pathophysiology of LHON?
-inhibition of e transport chain between complex 1 and Q10
-leads to increase ROS leading to apoptosis
Myoclonic Epilepsy with Ragged Red Fibers (MERRF)
-myoclonic epilepsy
-fibers are abnorma deposits of mitochondria in muscle
-other relatives may have ataxia, renal dysfunction, diabetes, dementia
What causes MERRF?
frequently associated with mutations in the tRNA(Lys) gene which results in reduction of mitochondrial protein synthesis
Leigh's Syndrome
-subacute necrotizeing encephalomyopathy
-average age 1-2
-duration 5 yrs
-ataxia, hypotonia, spasticity, developmental delay,etc.
What causes leighs syndrome?
-18% due to mtDNA mutations
-remaining are nuclear mutations in genes that function in mtOXPHOS
-x-linked or AR
What are some other disorders that mtDNA may be involved?
Novel issues associated with mitochondria.
-maternal inheritance
-threshold of expression
-high rate of mutation
mtDNA mutations
-point affecting oxphos
-deletions that remove several mt genes
-point that alter usage of mt tRNAs
Name the two reproductive duct systems.
1. mesonephric (wolffian)
2. paramesonephric(mullerian)
Sex development in males.
-leydig cells produce testosterone that stimulates mesonephros to form vas, epidid., and seminal vesicles
-sertoli cells secrete MIS that stimulates regression of the paramesonephros
Sex development in females.
no leydig, no test., mesonephros regression
no sertoli, no MIS, paramesonephros becomes oviduct, fallopian, uterus, upper third of vagina
Formation of external genitals in males.
-test to DHT by 5alpha reductase
-DHT is required for differentiation of genital tubercle to penis and genital swellings to scrotum
Formation of external genitals in females.
-absence of DHT, the genital tubercle forms clit while swellings and urethral fold form labia
What are the key genes for sex dtermination?
required for conversion of genital ridge into bipotential gonad--loss of function mutation reults in loss of gonads and kidneys
-master male regulatory swith
-expressed briefly early in development
-encodes DNA binding protein
-located just below the Yp pseudosomal region
-direct target of SRY
-fetal expression increased in testis
-haploinsufficiency leads to campomelic dysplasia(lethal skeletal formation with sex reversal)
What causes XX males and XY females?
-aberrant X/Y recombination
-XX male posess SRY but lack genes for sperm
-XY female lack SRY and produce few oocytes
-xlinked gene that encodes TF
-expression reduced in testis
-anti male gene
-46 XY with DAX1 mutation inhibit SRY leading to XY females
-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.
Which two genes compete to control SF-1?
DAX-1-promotes ovary
SRY-promotes testis
-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
What causes Hermaphroditism?
-mosaicism(mitotic NDJ from a 47XXY)
-chimerism(dual fertilization of the ovum and one of it's polar bodies)
What can cause primary sex reversal?
SRY mutations-XYF
SRY translocation-XXM
Duplications of DAX1-XYF
SOX9 mutaions-XYF
What is primary vs secondary sex reversal?
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
What are examples of secondary sex reversals?
Androgen insensitivity
5 alpha reductase 2 mutations
-AR due to defects in enzymes required for cortisol biosynthesis, produced by adrenal cortex
-hallmark-inadequate production of glucocorticoids
CAH pathophysiology
-cortisol levels fall
-results in accumulation of hormones upstream from block
-hormones shunted to form androgens which virilize females
Clinical presentation of CAH.
-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
Androgen Insensitivity
-associated with x-linke androgen receptor
-XY females
What are the degrees of AI?
Mild-near normal
Moderate-ambiguous gent.
Severe-clitoromegaly, post labial fusion
Complete-external completely female;no internal genitalia
5 alpha reductase 2 mutations
-AR 1/100,000
-enzyme convers test to DHT
-mutation results in failure to synthesize DHT
What is the presentation of 5 alpha reductase 2 mutations?
-variable ext female phenotype: small phallus, bilateral testis, normally developed mesonephric ducts that term into blind vag.
-partial virilization in affected males at puberty