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M2MWeek4 > Day 1-2 through autosomal recessive disorders > Flashcards

Day 1-2 through autosomal recessive disorders Flashcards

1
Q

lS

A

risk of disease in siblins of affected/risk of disease in gen. pop. Risk of disease in relatives

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2
Q

heritability

A

Proportion of variance in trait that is due to genetic variation

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3
Q

Heterogeneity

A

The “same” disease can be caused by different alleles at one location or by alleles at different locations in the genome. (Locus vs. allelic)

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4
Q

Phenocopy

A

environmentally caused phenotype that mimics the genetic version of the trait (Ex. Thalidomide vs. genetics)

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5
Q

Odds Ratio (OR)

A

Risk of disease if carrying a given gene variant/Risk of disease if not carrying a given gene variant

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6
Q

haplotype

A

a set of DNA variations (polymorphisms) that tend to be inherited together. A set of SNPs found on the same chromosome

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7
Q

linkage disequilibrium

A

the non random association of alleles at different loci

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8
Q

What is the karyotype of a Pt wth Turners Syndrome?

A

XO

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9
Q

What abnormalities of the CVS are present in a Pt with TS?

A

Bicuspid Aortic Valve; Coarctation of the aorta; Systemic Hypertension; Prolonged QTc Syndrome; Partial anomalous pulmonary venous connection; Persistent left SVC; systemic hypertension

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10
Q

Abnormalities of the eye with TS?

A

Inner canthal folds; ptosis; blue sclera

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11
Q

Abnormalities of the skeleton system with TS?

A

Cubitus Valgus; Short 4th metacarpal/metatarsal; Short stature; madelung deformtiy; scoliosis

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12
Q

Abnormalities of the neck with TS?

A

Web Neck; Lower Hairline; cystic hygroma

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13
Q

Learning abnormalities associated with TS?

A

Difficulty in math; visual spatial skills; low nonverbal scores

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14
Q

Describe ear; nose; mouth of Pt with TS

A

Prominent Auricles; lowset; high narrow mouth palate; small mandible

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15
Q

Describe chest of Pt with TS?

A

Broad widely spaced Nipples; pectus excavatum

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16
Q

Abnormalities with endocrine system in Pts with TS

A

Hypothyroidism; gonadal dysgenesis

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17
Q

Abnormalities of reproductive system in TS

A

Non functioning ovaries; infertility

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18
Q

Allelic heterogeneity

A

the existence of multiple mutant alleles of a single gene

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19
Q

Compound heterozygote

A

one who carries two different mutant alleles of the same gene

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20
Q

Phenylketonuria (PKU) phenotype

A

Microcephaly; profound mental retardation if untreated. Neurobehavioral symptoms (hyperactivity; seizure; tremor; and gait disorders). High phenylalanine/low tyrosine levels in the plasma (conversion from Phe to Tyr is impaired). High phenylalanine metabolites in urine and sweat > characteristic �mousy� odor.

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21
Q

What leads to PKU?

A

Defects in PAH gene(phenylalanine hydroxylase) ~98%. Defects in PAH cofactor BH4 (tetrahydrobiopterin) ~1 to 2%

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22
Q

If a Pt has PKU b/c of defect in BH4; what other effects will they have?

A

Issues making dopamine (BH4 also a cofactor tyr hydroxylase); issues making seratonin (BH4 is also a cofactor for trp hydroxylase)

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23
Q

Where is PAH gene?

A

12q22 to 24.

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24
Q

How many alleles have been identified at the PAH gene? How does this relate to most PKU Pts?

A

Over 400 (high allelic heterogeneity). Most PKU patients are compound heterozygotes

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25
Q

What are two methods of newborn screening for PKU? (old and current)

A

Guthrie test (old) and Mass Spectrometry (current)

26
Q

How did a guthrie test work?

A

Based on the findings that thienylalanine inhibits growth of B. subtilis and that such inhibition can be overcome by high level of phenylalanine in blood sample of a PKU baby

27
Q

How does Mass Spectrometry work?

A

Sorts many molecules in a blood specimen by mass and measures the quantity of each molecule

28
Q

Why is the timing of test important for PKU diagnosis?

A

A newborn level of phenylalanine is typicallly normal bc mom had normal PAH. Must test after baby begins eating/metabolizing on its own; but before irreversible damage is done.

29
Q

What are treatments for PKU?

A

Low phenylalaine diet; BH4 supplements if they are BH4 deficient and also supplements to balance neurotransmitters. Gene therapy? Enzyme therapy?

30
Q

Why must a woman stay on a low-phenylalanine diet throughout child bearing years?

A

No matter the genotype of the child; if the mother has elevated phenylalanine levvels during fetal development there is a very high risk of miscarriage and congential malformations; mental retardation; growth impairment

31
Q

What is the phenotype of alpha1 Antitrypsin Deficieny (ATD) Pts?

A

20x increased risk of emphysema (worse with smokers). Late onset; but 80 to 90% will develop symptoms. Also; liver cirrhosis/liver carcinoma

32
Q

What is frequency of alpha1 ATD?

A

Occurrence ~ 1/2500; carrier frequency ~ 1/25. Most common among Northern European Caucasians

33
Q

What does alpha1 antitrypsin normally do?

A

Normally inhibits elastase; a serine protease. AKA SERPINA1 (SERPIN = SErineProteaseINhibitor)

34
Q

What type of cells release elastase? What does elastase do?

A

Activated neutrophils at the airway release it. It destroys elastin in connective tissues

35
Q

Why is it bad to have ATD?

A

Without antitrypsin; elastase runs wild and destroys all the elastin. This is bad for the avleoli

36
Q

Where is alpha1 antitrypsin made and secreted?

A

Made in the liver; secreted into plasma

37
Q

Where is SERPINA1 gene located?

A

On chromosome 14 (14q32.13)

38
Q

Which alleles encode functional AT proteins?

A

3 common M alleles

39
Q

Which allele is the most common mutant allele? What does it change?

A

Z allele. Glu342Lys

40
Q

What is so bad about the Z allele?

A

Make a protein that is not folded properly; tends to accumulate in the ER of liver cells > cell damage. Z/Z genotypes have ~15% of normal SERPINA1 level

41
Q

What is another common mutant allele in ATD? What does it change?

A

S allele. Glu264Val

42
Q

How does the S allele lead to ATD?

A

Make an unstable/less effective SERPINA1 protein. S/S genotypes have 50 to 60% of normal SERPINA1 level

43
Q

Describe the ecognetics of ATD

A

Smoking accelerates onset of emphysema in ATD Pts. Damage to lungs from smoking >> body sends more neutrophils to lung -> more neutrophils release more elastase -> more severe damage

44
Q

Describe phenotype of Tay Sachs Disease (aka Gm2 gangliosidosis type I)?

A

Progressive destruction of CNS. Starts at 3-6 mo. And is fatal by 2 to 4 years. Begins with muscle weakness and increased starle response. Advanced symptoms include seizures; loss of voluntary movement; mental retardation; vegetative state. “Cerry-red spot” in eyes.

45
Q

What are the biochemical defects in T S disease?

A

A lysosomal storage disorder with (>300x) accumulation of GM2 ganglioside in the lysosome. Pts are unable to degrade GM2 ganglioside b/c of a defective hexosaminidase A. Pts usually have mutations in the HEXA gene

46
Q

What are the two subunits of the enzyme hexosaminidase A (HexA)? What genes encode for the two subunits?

A

Alpha and beta subunits. Encoded by HEXA and HEXB genes; respectively.

47
Q

What do mutations in HEXA gene lead to?

A

Tay Sachs

48
Q

What do mutations in HEXB gene lead to?

A

Sandhoff disease (GM2 gangliosidosis II)

49
Q

Where is the Gm2 ganglioside primarily sythesized? What system is primarily affected by T S?

A

Primarily synthesized in the neurons of the brain and a component of neuron cell membrane. Impact is mostly in the brain.

50
Q

Which subunit is defective in T S? Which gene encodes for that? Which enzyme is affected?

A

The alpha subunit is defective. Encoded for the HEXA gene. The HexA (hexosaminidase A) enzyme is affected because it has both alpha and beta subunits

51
Q

What are the two subunit of the enzyme hexosaminidase B (Hex B)?

A

HexB is a homodimer of beta-beta

52
Q

Which subunit is defective in Sandhoff disease? Which gene encodes for that? Which enzyme(s) is affected?

A

andhoff disease is caused by a defective ? subunit. Encoded for by HEXB gene. Both HexA and HexB activities are affected.

53
Q

On which chromosome is the HEXA gene? (Encodes for alpha subunit)

A

Chromosome 15 (Chr 15q23-24)

54
Q

On which chromosome is the HEXB gene? (Encodes for beta subunit)

A

Chromosome 5 (Chr5q13)

55
Q

What is defective in the AB-variant of Tay-Sachs?

A

GM2-AP (GM2 activator protein). **Note the HExA and HexB enzyme are totally fine; but GM2 still accumulates**

56
Q

What does the GM2-AP do?

A

Facilitates interaction between the lipid substrate and the HexA enzyme (alpha subunit) within the cell. Brings the lipid from the cell to the alpha subunit

57
Q

On which chromosome is the GM2AP gene?

A

Chr 5q32-33

58
Q

What is the most common HEXA mutant allele? What does it do on a molecular basis?

A

A 4bp insertion in exon 11 of HEXA. Causes a frameshift and a premature stop codon (it’s a null allele).

59
Q

What are the 4 types of screening that can be done for Tay-Sachs?

A

Enzymatic activity assay; Carrier Screening; Prenatal screening; DNA testing

60
Q

Describe enzymatic activity assay for Tay-Sachs

A

Both HexA and HexB enzymes are present in the serum. Their activities can be distinguished in such assays because only HexA is inactivated by heat

61
Q

Describe carrier screening for Tay-Sachs

A

Has 97% accuracy because carriers have lower HexA enzyme levels in the blood. Primarily done among Ashkenazi Jewish population

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