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3. Week 1 - Medical Genetics > Commoner (non-cancer) genetic disorders > Flashcards

Commoner (non-cancer) genetic disorders Flashcards

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1
Q

What is the average onset for Huntington disease?

A

between 30-50 years

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2
Q

What are the symptoms of Huntington disease?

A
  • progressive chorea
  • dementia
  • psychiatric symptoms
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3
Q

What is chorea?

A

involuntary movements

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4
Q

What is the inheritance pattern of Huntington disease?

A

Autosomal dominant with genetic anticipation

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5
Q

What gene is implicated in Huntington disease?

A

Huntingtin (HTT)

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6
Q

What mutation is present in Huntington disease?

A

unstable length mutation in HTT gene

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7
Q

What happens to the length mutation in HTT?

A

Mutation length prone to expansion during meiosis, especially from the father

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8
Q

What is the clinical relevance of the number of repeats in the HTT gene?

A

<35 repeats = unaffected
36-39 repeats = incomplete penetrance
>40 repeats = affected

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9
Q

What is the genetic code of the repeat unit in HTT?

A

CAG repeat unit - encodes polyglutamine tract

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10
Q

What is the physiological outcome of expansion of the tract in Huntington disease?

A

Expansion causes insoluble protein aggregates and neurotoxicity

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11
Q

What are the treatment options for Huntington disease?

A

No cure

DNA testing possible

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12
Q

When would DNA testing be used for Huntington disease?

A
  • testing unaffected family members

- presymptomatic test (predictive)

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13
Q

What is the inheritance pattern of myotonic dystrophy?

A

Autosomal dominant with genetic anticipation

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14
Q

What are the symptoms of myotonic dystrophy?

A
  • progressive muscle weakness in early adulthood
  • myotonia
  • cataracts
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15
Q

What is the genetic basis of myotonic dystrophy?

A

unstable length mutation of a CTG repeat in the transcribed but not translated region of the DMPK gene

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16
Q

Which gene is implicated in myotonic dystrophy?

A

DMPK gene

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17
Q

What is the clinical relevance of the length mutation for myotonic dystrophy?

A
  • Normal = 4-37 repeats
  • Affected = 50- >2000 repeats

N.B general correlation between number of repeats and clinical severity

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18
Q

What is the pathogenic mechanism in myotonic dystrophy?

A

Abnormal DMPK mrna indirectly affects adjacent genes, making their products appear reduced

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19
Q

Give examples of genes affected by a mutation in DMPK

A
  • chloride channel 1 gene
  • SIX5
  • DMWD
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20
Q

What is the inheritance pattern of cystic fibrosis?

A

Autosomal recessive inheritance

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21
Q

What is the carrier frequency of cystic fibrosis?

A

1 in 20-25

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22
Q

What are the clinical manifestations of cystic fibrosis?

A
  • recurrent lung infections with bronchiectasis and obstructive lung disease
  • exocrine pancreatic insufficiency
  • male infertility
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23
Q

How is cystic fibrosis diagnosed?

A
  • newborn screening
  • genetic testing
  • sweat test
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24
Q

How is newborn screening used to diagnose cystic fibrosis?

A

looking for elevated immunoreactive trypsin (IRT) level

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25
Q

How is genetic testing used to diagnose cystic fibrosis?

A

Looking for common genetic mutations

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26
Q

How is sweat testing used to diagnose cystic fibrosis?

A

Increased concentration of chloride on two occasions

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27
Q

What is the underlying cellular abnormality in cystic fibrosis?

A

defective chloride ion channel resulting in increased thickness of secretions

28
Q

Which gene is responsible in cystic fibrosis?

A

Cystic fibrosis transmembrane conductance regulator (CFTR)

29
Q

What are the chances of a sibling of someone affected with cystic fibrosis being a carrier?

A

2 in 3

30
Q

What is the most common mutation found in the CFTR gene?

A

F508del

N.B - over 1000 different mutations known

31
Q

What affect does the F508del have?

A
  • in frame deletion of phenylalamine

- prevents the normal folding of a protein and insertion into the plasma membrane

32
Q

What is cascade screening?

A

indentification of mutations permits prenatal diagnosis if desires and the subsequent identification of carrier relatives

33
Q

What is the inheritance pattern of neurofibromatosis type 1?

A

Autosomal dominant inheritance

34
Q

What is affected in neurofibromatosis type 1?

A

Typically cells derived from the neural crest

  • melanocytes
  • bone
  • connective tissue
  • neurons
35
Q

What are the common features of neurofibromatosis type 1?

A
  • cafe au lait macules
  • neurofibromas (from teens)
  • short stature
  • macrocephaly
  • learning difficulties (in 30%)
  • Lisch nodules

N.B - very variable expressivity

36
Q

What are lisch nodules?

A

dome shaped gelatinous masses developing on the surface of the iris. Gold tan-brown colour

37
Q

What other conditions is an individual with neurofibromatosis type 1 at risk of?

A
  • hypertension
  • scoliosis requiring surgery
  • pathological tibial fractures
  • Signficant tumours
38
Q

What tumous are associated with neurofibromatosis type 1?

A
  • phaeochomocytomas
  • sarcomas
  • optic pathway gliomas
39
Q

Which gene is involved in neurofibromatosis type 1?

A

NF1 encoding neurofibromin

40
Q

What is the normal role of neurofibromin?

A

prevent ras signallying proteins overactivity in the cellular signalling pathway, which promotes cell proliferation

41
Q

What are the chances of offspring being affected if their parent has neurofibromatosis type 1?

A
  • 50% chance of being affected
  • 100% penetrance
  • clinical severity is variable
42
Q

What is the inheritance pattern of Duchenne muscular dystrophy?

A

X-linked recessive inheritance

43
Q

What are the symptoms of Duchenne muscular dystrophy?

A 
symptoms usually manifest <5years:
- delayed walking
- progressive proximal weakness
By 7-13:
- unable to walk
44
Q

What serum changes can be seen in Duchenne muscular dystrophy?

A

Marked elevation of serum creatinine kinase (from birth as CK leaks out of damaged muscle fibers

45
Q

What are other features of Duchenne muscular dystrophy?

A
  • respiratory failure
  • cardiomyopathy
  • scoliosis
  • non-progressive learning disability
46
Q

What is the average lifespan for someone with Duchenne muscular dystrophy?

A

25

47
Q

What features can been seen on muscle biopsy from someone with Duchenne muscular dystrophy?

A

absence of dystrophin protein

48
Q

What is the normal role of dystrophin protein?

A

crucial in linking the muscle fiber inner structural cytoskeleton (composed of f-actin) to the extracellular matrix proteins (via binding to the dystroglycan proteins)

49
Q

What is the implicated gene in Duchenne muscular dystrophy?

A

DMD gene encoding dystrophin protein

- mutation usually frame shift

50
Q

What are the features of Becker muscular dystrophy?

A
  • milder
  • onset ~11years
  • wheelchair much later if at all
  • learning disability less common
  • lifespan may be normal
51
Q

Which gene is implicated in Becker muscular dystrophy?

A

Caused by same mutation as DMD:

  • DMD gene encoding dystrophin
  • mutation usually in frame
52
Q

What is the inheritance pattern of fragile X syndrome?

A

X-linked recessive with genetic anticipation

N.B - can also effect female carriers, with milder learning disability

53
Q

Which gene is implicated in fragile X syndrome?

A

FMR1 gene encoding FMRP

54
Q

What are the features of fragile X syndrome?

A
  • significant learning diability
  • enlarged testes after puberty
  • large ears
  • long face
  • prognathism
55
Q

Describe the consequences of a mutation of FMR1

A
  • hypermethylation of FMR1, leading to suppresion of transcription
  • loss of production of FMRP
56
Q

What is the normal role of FMRP

A

regulates transcription by binding to mRNA molecules

- though to be necessary for normal learning and memory

57
Q

What is the clinical significance of the repeat tract in the FMR1 gene?

A
  • affected = full mutaion of >200 repeats

- unaffected = ~ 55-200 repeats (premutation)

58
Q

What condition is linked to the FMR1 premutation?

A

Fragile X associated tremor/ataxia syndrome (FXTAS)

  • affects 40% males with premutation
  • 20 % females affected
59
Q

What are the features of Fragile X associated tremor/ataxia syndrome (FXTAS)

A
  • late onset
  • progressive intention tremor
  • subsequent cerebellar ataxia
60
Q

Describe the morphological features of Down syndrome

A 
Facial features:
- upslanting palpebral features
- small nose
- flat facial profile
- epicanthal folds
- small, low-set, folded ears
Additionally:
- single palmar crease
- sandal gap
61
Q

What are common conditions associated with Down syndrome?

A
  • learning disability
  • congenital heart defects
  • hypothyroidism
62
Q

What are the features of trisomy 18?

A
  • small chin
  • clenched hands with overlapping fingers
  • malformations of heart, kidney and other organs
  • if survive past first year - profound learning difficulties
63
Q

What are the features of trisomy 13

A
  • cleft lip palate
  • abnormal ears
  • scalp defects
  • redundant skin around nape
  • clenched fists
  • single palmar creases
  • postaxial polydactyly
  • cryptorchidism
  • hypotelorism
  • micropthalmia
  • congenital heart defect
  • normally fatal ~ 1month
  • profound learning disability

N.B - remember baby born @RHF with Patau’s!

64
Q

What is hypotelorism?

A

increased distance between the eyes

65
Q

What is micropthalmia?

A

abnormally small eyes

66
Q

what is postaxial polydactyly?

A

Extra digit on little finger side

3. Week 1 - Medical Genetics (7 decks)

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