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M2MWeek4 > Autosomal Dominant Diseases > Flashcards

Autosomal Dominant Diseases Flashcards

1
Q

What are the clinical manifestations of achondroplasia?

A

Small stature (4’ female - 4’3 male); rhizomelic limb shortening; short fingers; genu varum; trident hands; midfacial retrusion; small foramen magnum

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2
Q

What is the mutation seen in achondroplasia?

A

Mutation on FGFR3 (fibroblast growth factor receptor 3) on chr. 4p16.3; nucleotide 1138. Amino acid substitution-missense mutation; Gly380Arg. Mutation increases the activity of the protein interfering with skeletal development

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3
Q

Which nucleotide on which gene has the highest mutation rate known in man?

A

Nucleotide 1138 of the FGFR3 gene

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4
Q

Are Pts with achondroplasia heterozygotes or homozygotes?

A

Must be heterozygotes b/c homozygotes are incompatible with life (incompletely dominant).

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5
Q

Which gene on which chromosome is mutated in retinoblastoma?

A

RB1 gene on chromosome 13 (90% penetrance)

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6
Q

Pts must have 2 or more of the following to be diagnosed with Neurofibromatosis Type I

A

6 or more cafe-au-lait spots; 2 or more neurofibromas; 1 plexiform neurofibroma; Freckling in the axillary or inguinal area; Optic glioma; 2 or more Lisch Nodules; Distinctive osseous lesions; Affected first degree relative

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7
Q

What is the mutation seen in neurofribromatosis type I (gene and chromosome)? What type of mutation is this?

A

NF1 (neurobibromin-tumor suppressor gene) on chr.17q11.2. Since this is a tumor supressor gene; this is a loss of function mutation

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8
Q

Is neurofibromatosis dominant or recessive? Why is this kind of weird?

A

Dominant but weird because the Pt must also have a mutation in the cells involved to show the phenotype

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9
Q

What does locus heterogeneity mean?

A

A mutation in more than one locus causing the same clinical condition

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10
Q

Describe inheritance; rate; expressivity; penetrance of tuberous sclerosis

A

Autosomal dominant; 1/6000; variable expressivity; fully penetrant; 1/3 inherited 2/3 d novo

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11
Q

What skin findings might you expect with tuberous sclerosis?

A

Hypopigmented Patches; Angiofibroma; Shagreen Patch; Ungual fibroma

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12
Q

What kindey findings are expected with tuberous sclerosis?

A

Renal cysts; renal angiomyolipomas

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13
Q

What lung findings are expected with tuberous sclerosis?

A

lympangioleiomyomatosis

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14
Q

What heart findings are expected with tuberous sclerosis?

A

Cardiac rhabdomyoma (in infants)

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15
Q

What CNS findings are expected with tuberous sclerosis?

A

Subependymal nodules; Subependymal giant cell astrocytomas (SEGAs); Other cortical dysplasias; seizures

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16
Q

What neuropsychiatric disorders are expected with tuberous sclerosis?

A

Cognitive impairment; Autism; ADHD; Other behavioral and emotional problems

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17
Q

What are the clinical criteria to be diagnosed with tuberous sclerosis?

A

Two major features or 1 major feature with 2 minor features

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18
Q

What are the major features with tuberous sclerosis (11)?

A

Angiofibromas; Cardiac rhabodmyoma; Cortical dysplasias; Hypomelanotic macules; Lymphangioleiomyomatosis; Multiple retinal nodular hamartomas; Renal angiomyolipoma; Shagreen Patch; Subependymal nodule; SEGA; Ungual Fibroma

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19
Q

What are the minor features with tuberous sclerosis (6)?

A

Confetti skin lesions; Dental Enamel pits (>3); Intraoral fibromas; Multiple renal cysts; Nonrenal hamartomas; Retinal achromic patch

20
Q

What is the mutation in tuberous sclerosis (gene and chromosome)? There are 2 possible

A

TSC1; TSC2 genes. On chromosome 9 and 16. Only need a mutation in 1 of the genes; but a mutation in either gene will cause disease

21
Q

What do TSC1 and TSC2 do? What type of mutation is there is tuberous sclerosis?

A

Encode hamartin and tuberin proteins; Regulate cell growth and proliferation. Loss of function mutations

22
Q

What are the clinical manifestations of osteogenesis imperfecta type 1?

A

Multiple fractures; Mild short stature; Adult onset hearing loss; Blue sclera

23
Q

What is the mutation seen with osteogenesis imperfecta type 1 (gene and chromosome)?

A

COL1A1 (collagen type 1 alpha 1) on chr. 7q21.3

24
Q

What occurs with the mutation seen in osteogenesis imperfecta type 1?

A

Reduced production of pro-alpha 1 chains that reduces the type 1 collagen production by half

25
Q

What are the clinical manifestations in marfan syndrome?

A

Systemic disorder of connective tissue; Ocular; Skeletal; Cardiovascular. Note that connective tissues are also part of the vascular system; most importantly in the large arteries

26
Q

What is needed to make a diagnosis of Marfan syndrome with and without a family history?

A

No family history: Aortic root enlargement + ectopia lentis; FBN1 mutation; or sytemic score >7. Positive family history only need 1 out of: ectopia lentis; systemic score >7; aortic root enlargement

27
Q

What is the mutation seen in marfan syndrome (gene and chromosome)?

A

FBN1 (fibrillin-extracellular matrix protein) on chr. 15q21.1

28
Q

What is the immediate effect of the mutation seen in marfan syndrome?

A

Severe reduction in the number of microfibrils

29
Q

What is a trinucleotide repeat disorder?

A

Expansion of a segment of DNA consisting of three or more nucleotides

30
Q

What kind of transmission is seen in a trinucleotide repeat disorder?

A

AD; AR; and X-linked transmission

31
Q

What is slipped mispairing?

A

Mispairing of bases in regions of repetitie DNA replication plus inadequate DNA repair systems

32
Q

What is anticipation?

A

When the severity and/or onset of disease increases in the next generation. Seen in trinucleotide repeat disorders

33
Q

What is parental transmission bias?

A

When the trinucleotide expansion is more prone to occur in gametogenesis of the male or female

34
Q

What kind of inheritance is seen in huntington disease? Rate?

A

AD; 1 in 10;000

35
Q

What kind of mutation is huntington disease?

A

It is a trinucleotide repeat disorder (CAG)

36
Q

What does the parent of origin have to do with the expression of the disease in huntingtons?

A

If inherited through father more likely to be early onset; if inherited through mother more likely to be later onset

37
Q

What are the clinical manifestations of huntington disease?

A

Progressive neuronal degeneration. Causes motor; cognitive; psychiatric distrubances. Age of onset 35-44. Death about 15 years after onset

38
Q

On which gene/chromosome is the hungtington mutation?

A

HTT (Huntington gene) on chr. 4p16.3

39
Q

What may cause the biochemical property/altered structure of the protein in Hungtinton?

A

The expansion of glutamine

40
Q

What is the repeat count and classification/disease status for CAG repeat disorders (huntington)?

A

39: full penetrance and affected. >60: juvenile onset and affected

41
Q

What other AD trinucleotide repeated disorder did we learn about besides Huntingtons?

A

Myotonic Dystrophy Type 1

42
Q

Which trinucleotide sequence is repeated in Myotonic Dystrophy Type 1?

A

CTG

43
Q

What is the rate and type of transmission seen in MD type 1?

A

1 in 20000. Maternal transmission. Seen with anticipation

44
Q

What are the clinical manifestations of myotonic dystrophy type 1?

A

Adult onset muscular dystrophy; Progressive muscle wasting and weakness; Myotonia; Cataracts; Cardiac conduction defects

45
Q

Where is the mutation seen in myotonic dystrophy type 1? Gene and chromosome?

A

DMPK gene (myotonic dystrophy protein kinase) on chr. 19q13.3. Plays important role in muscle; heart; brain cells

46
Q

What is the CTG repeat count and range of disease seen with myotonic dystrophy type 1?

A

5-34: Normal. 34-49: premutation range. >50 full mutation with 100% penetrance

M2MWeek4 (4 decks)

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