AUTOSOMAL DOMINANT DISORDERS Flashcards

Question 1

Q

Achondroplasia
- Mechanism
  - What gene?
  - What kind of genetic change?
  - Protein result of that change?
  - How it affects the human body - clinical features?
- Screening and diagnosis
  - Is it screened for at birth?
  - Or does it require specialist testing?
- Management
  - Medication?
  - Lifestyle changes?
  - Exclusion diets?
  - Is there no treatment?
- Quality of life and outlook
  - Are they able to function?
  - Impairment adjustments?
  - Life span?
  - Cures/treatments being trailed?

Answer

A

Overview
- Gain of function - decreased endochondral ossification, inhibited proliferation of chondrocytes in growth plate cartilage and decreased cartilage matrix production
- Has autosomal dominant inheritance, but 80% of cases are de novo mutations
Mechanism - chromosome affected and mutation
- 99% are cause by g.1138G>A and g.1138G>C
  - Causes p.Gly380Arg
Clinical features
- Abnormal bone growth that results in short stature with disproportionally short arms and legs, a large head and characteristic facial features
  - Trident hands
- Intelligence and life span are usually normal, although an increased risk is present for death in infancy from compression of the spinal cord and/or upper airway obstruction
- Motor development is somewhat delayed
Screening and diagnosis
- Lack of growth/delayed physical development
Treatment
- Can be treated with growth hormone - used to augment the height, especially if introduced early on
The mating between two individuals who have this form of dwarfism generates about 2/3 children who are dwarf and 1/3 of normal height
There is also a higher than normal frequency of miscarriages and stillbirths
The most reasonable explanation is that homozygosity for the mutant allele is not compatible with life

Question 2

Q

Hypochondroplasia
- Mechanism
  - What gene?
  - What kind of genetic change?
  - Protein result of that change?
  - How it affects the human body - clinical features?
- Screening and diagnosis
  - Is it screened for at birth?
  - Or does it require specialist testing?
- Management
  - Medication?
  - Lifestyle changes?
  - Exclusion diets?
  - Is there no treatment?
- Quality of life and outlook
  - Are they able to function?
  - Impairment adjustments?
  - Life span?
  - Cures/treatments being trailed?

Answer

A

Overview
- Gain of function - milder phenotype when compared to achondroplasia
- 80% are de novo mutations
Mechanism - chromosome affected and mutation
- 70% are associated with 20 FGFR3 mutations
- Most common - missense mutation p.ASN540Lys
  - p.Lys650Met is also observed
Clinical features
- Low birth weight and length
- Disproportional limb to trunk ratio
- Short stature
Screening and diagnosis
- Present to paediatricians when they are toddlers/school aged children who fail to grow
- No trident hands or facial features like achondroplasia
- Milestones are usually normal

Question 3

Q

Huntington’s disease
- Mechanism
  - What gene?
  - What kind of genetic change?
  - Protein result of that change?
  - How it affects the human body - clinical features?
- Screening and diagnosis
  - Is it screened for at birth?
  - Or does it require specialist testing?
- Management
  - Medication?
  - Lifestyle changes?
  - Exclusion diets?
  - Is there no treatment?
- Quality of life and outlook
  - Are they able to function?
  - Impairment adjustments?
  - Life span?
  - Cures/treatments being trailed?

Answer

A

Overview
- Neurological disease that impairs motor skills and mental disturbances due to an aggregation of Huntington proteins in the brain
- Causes the cells in the caudate nucleus of the brain to begin to die, causing a relentless deterioration over a 10-25 year period
Mechanism - chromosome affected and mutation
- HTT gene defect where there is an expansion of a run of glutamine repeats within the Huntington protein
- The number of CAG repeats in a normal allele range from 10-26
- Huntington’s disease patients have 36-121 CAG repeats
Clinical features
- Progressive motor disability featuring chorea
  - A neurological disorder characterized by jerky involuntary movements affecting especially the shoulders, hips and face
- Voluntary movement may also be affected
- Mental disturbances including cognitive decline, changes in personality and/or depression
- Family history consistent with autosomal dominant inheritance
- Incidence
  - 3-7 per 100,000 people with European ancestry
Screening and diagnosis
- Usually onsets at about 30-50 years
- Earliest reported - 2 years
- Each child of a Huntington’s disease parent has a 50% chance of inheriting the disorder
- The number of CAG repeats ranges from 10 to 26 in normal alleles
- In patients with Huntington’s disease, the CAG repeat number ranges from 36-121
- 27-41 repeats need cautious interpretation
  - 27-35 - intermediate alleles
    - May be at risk of having a child with the allele in the abnormal range due to anticipation
  - 36-41 - reduced penetrance
    - May or may not develop Huntington’s disease
- Patients with adult onset usually have an expression that ranges from 40-55 repeats
- With juvenile onset symptoms (12-13 years old) - usually have expansions above 60 CAG repeats
- If you carry the disease, you will eventually develop the condition
- Symptoms often appear after reproductive age
Treatment
- No treatment and no cure
- 179 clinical trials are being undertaken to determine the mechanism of the disease
  - There are some indications about what it does
    - Normal Huntington protein
      - Dynamically moves between the nucleus and cytoplasm
    - Mutant Huntington protein
      - Causes cytoplasmic and nuclear aggregation that accumulate in neuronal cells

Question 4

Q

Myotonic dystrophy
- Mechanism
  - What gene?
  - What kind of genetic change?
  - Protein result of that change?
  - How it affects the human body - clinical features?
- Screening and diagnosis
  - Is it screened for at birth?
  - Or does it require specialist testing?
- Management
  - Medication?
  - Lifestyle changes?
  - Exclusion diets?
  - Is there no treatment?
- Quality of life and outlook
  - Are they able to function?
  - Impairment adjustments?
  - Life span?
  - Cures/treatments being trailed?

Answer

A

Overview
- Myotonic dystrophy (DM = Dystrophia myotonica) is a multisystem disorder that affects skeletal muscle (Progressive muscle wasting and weakness), smooth muscle, and the eye, heart, endocrine system and CNS
- Three different phenotypes - mild, classical, and congenital
- The most common form of muscular dystrophy and begins in adulthood
Mechanism - chromosome affected and mutation
- Expansion of CTG trinucleotide repeats in the DMPK gene
- Exceeds normal 37 length repeat
- Affects about 1 in 8,000 people
- Types
  - Mild - 50-150 repeats (onset at 20-70, average life span of 60 years)
  - Classic - 100-1,000 (onset 10-30 years, 48-55 year life span)
  - Congenital - >1000 (onset 0-10 years, 45 year life span)
Clinical features
- Muscular dystrophy - degrading muscles
Treatment
- Use of ankle-foot orthoses, wheelchairs or other assistive devices
- Treatment of hypothyroidism
- Management of pain
- Consultation with cardiologist for symptoms or RCG evidence of arrythmia
- Removal of cataracts if vision is impaired
- Hormonal replacement therapy for males with hypogonadism
- Surgical excision of pilomatricoma
Quality of life and outlook
- Severity of disease is related to the number of CTG repeats
  - Types
    - Mild - 50-150 repeats (onset at 20-70, average life span of 60 years)
    - Classic - 100-1,000 (onset 10-30 years, 48-55 year life span)
    - Congenital - >1000 (onset 0-10 years, 45 year life span

Question 5

Q

Retinoblastoma
- Mechanism
  - What gene?
  - What kind of genetic change?
  - Protein result of that change?
  - How it affects the human body - clinical features?
- Screening and diagnosis
  - Is it screened for at birth?
  - Or does it require specialist testing?
- Management
  - Medication?
  - Lifestyle changes?
  - Exclusion diets?
  - Is there no treatment?
- Quality of life and outlook
  - Are they able to function?
  - Impairment adjustments?
  - Life span?
  - Cures/treatments being trailed?

Answer

A

Overview
- Malignant tumour arising in the retina of one (Or both) eyes during infancy or early childhood
- Frequency of 1 in 12-20,000
- Starts during foetal development, when retinal cells are rapidly developing
Mechanism - chromosome affected and mutation
- Loss of tumour suppressor gene
- Rb protein protects cell from going through cell division inappropriately
  - Checkpoint in the cell cycle with other mechanisms
    - Makes sure the cell is ready to divide
    - Absence causes cell to replicate, regardless of signal
  - 30% of all retinoblastoma cases are due to inherited disease allele
- Occurs in a loss of function of both alleles of the gene
  - Still dominant - as in hereditary retinoblastoma, the affected individual already carries a chromosome with the mutant form of the retinoblastoma gene
    - Sporadic form of cancer - Knudson’s two hit hypothesis
      - “Two hits” will ensure the disease as they are required for loss of tumour suppressor function
    - Familial form of cancer - Knudson’s two-hit hypothesis
      - Two mutations (two hits) are required for loss of tumour suppressor function
      - The first “hit” is inherited and the second “hit” is somatic
    - “One hit” will greatly increase chances of contracting the disease
    - Clinical features
      - Expressed by 5 years of age in nearly all cases
      - Leukocoria
        Is an abnormal white reflection from the retina of the eye

Question 6

Q

Neurofibromatosis
- Mechanism
  - What gene?
  - What kind of genetic change?
  - Protein result of that change?
  - How it affects the human body - clinical features?
- Screening and diagnosis
  - Is it screened for at birth?
  - Or does it require specialist testing?
- Management
  - Medication?
  - Lifestyle changes?
  - Exclusion diets?
  - Is there no treatment?
- Quality of life and outlook
  - Are they able to function?
  - Impairment adjustments?
  - Life span?
  - Cures/treatments being trailed?

Answer

A

Overview
- Neurofibroma is a swelling of a peripheral nerve that is caused by thickening of the nerve sheath or connective tissue
- Two types
  - Type 1 is characterized by skin colour change and growth of tumours along nerves in the skin, brain and other parts of the body
  - Type 2 is the growth of noncancerous tumours in the nervous system - leads to deafness
    - Most common are vestibular schwannomas or acoustic neuromas
Mechanism - chromosome affected and mutation
- Type 1 - mutation in NF1 gene (tumour suppressor gene) causing neurofibromin (50% inherited, 50% de novo)
  - NF1 - Ch17q.12
  - 1 in 3-4,000 worldwide
  - 50% of affected have learning difficulties and/or ADHD
  - Associated with missense, nonsense, insertion and deletion mutations
    - Suggest alleles cause partial or complete loss-of-function
- Type 2 - mutations in NF2 gene - tumour suppressor protein merlin
  - NF2 - Ch22q.12.2
  - 1 in 33,000 worldwide
- Associated with missense, nonsense and frame-shift mutations
  - Suggest NF2 alleles cause partial/complete loss-of-function
Clinical features
- Type 1 - visible tumours, skin colour changes (Café-au-lait macules)
- Type 2 - tumours, hearing loss in teens with tinnitus and balance problems
  - Tumours usually develop in both ears by 30
  - Can develop in other parts of the nervous system
NF1 and NF2 are unrelated proteins encoded by separate genes of different chromosomes
- NF1 - Prevents cell growth through inhibiting the oncogene Ras
- NF2 - Thought to prevent cell growth through contact-mediated growth inhibitors
Screening and diagnosis
- First mutated allele is inherited from parents and the second allele has been somatically inactivated
Treatment
- NF1 - 100% penetrance
  - Surgical removal of disfiguring or uncomfortable discrete cutaneous or subcutaneous neurofibromas
  - Surgical treatment has to be complete or will have to be repeated
  - Life span - 8 years of less in general populations
- NF2 - 100% penetrance
  - Treatment of vestibular schwannoma is primarily surgical
  - Individuals with vestibular tumours need to be aware of insidious problems with balance and underwater disorientation which can result in drowning
  - Normal life span

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AUTOSOMAL DOMINANT DISORDERS Flashcards

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