Neurogenetics Flashcards
(25 cards)
Inheritance of Duchenne Muscular Dystrophy (DMD)?
X-linked recessive inheritance, so it mainly occurs in boys
Recall that males inherit their X-chromosome from their mother; females inherit from both mother and father
Rarely, female carriers can experience symptoms due to X-inactivation
Consequences of DMD?
Delay in motor development with an onset of weakness at 3-4 years, of the pelvic and shoulder girdles
Wheelchair bound by 10-12 years
Death from cardiorespiratory muscle inv. in 20s
Characteristic signs of DMD?
Characteristic posture with exaggerated lumbar lordosis
Proximal muscle wasting with pseudohypertrophy of calf muscles
Patient toe walk (on tip toes)
Gower’s sign +ve
Underlying pathology of DMD?
Mutation leads to dystrophin deficiency; these mutations can be:
• Large scale deletions in the gene (70%)
• Point mutations, small insertions and deletion (30%)
Ix of DMD?
Screening test:
• Raised serum creatine kinase (CK)
Electromyography (AMG)
Muscle biopsy
Molecular genetic testing (screen for deletions)
Differentials of DMD?
Becker muscular dystrophy - milder form of DMD where the dystrophin is not as deficient; it is an X-linked condition
Autosomal recessive limb girdle muscular dystrophies - caused by sarcoglycan deficiency
NOTE - this is autosomal, not X-linked
Offering mutation testing to patients?
Identify mutation in the affected boy and then test for mutations in female relatives wishing to know their carrier status
Female carriers of known dystrophin mutations can be offered prenatal / pre-gestational testing
Risk to family members of an affected male?
High recurrence risk for male siblings and male relatives on mother’s side of the family; offer carrier testing and prenatal diagnosis
Occurrence of Huntington’s disease?
Fairly common
Onset typically between 30 aand 50 years
What is Huntington’s disease?
Autosomal dominant, progressive neurodegenerative disorderv where there is abnormal glutamine (protein) production; grossly, there is atrophy of the basal ganglia
It involves involuntary movements and dementia;
Penetrance is age-dependent (i.e: it is variable)
Consequences of Huntington’s disease?
Progression to severe dependency and death over 15-20 years
Early clinical signs of Huntington’s disease?
Clumsiness
Agitation, irritability, apathy, anxiety, disinhibition (personality change)
Delusions, hallucinations
Abnormal eye movements
Depression
Later clinical signs of Huntington’s disease?
Dystonia
Involuntary movements
Trouble with balance and walking, with activities that require manual dexterity
Slow voluntary movements and difficulty initiating movements
Inability to control speed and force of movement
Weight loss
Speech difficulties
Stubbornness
Late clinical signs in Huntington’s disease?
Rigidity
Bradykinesia (difficulty initiating and continuing movement)
Severe chorea (less common)
Serious weight loss
Inability to walk and speak
Swallowing problems (risk of choking)
Loss of independence
Molecular genetic defect in Huntington’s disease?
Look at no. of CAG repeats:
• 40+ repeats have full penetrance and the patient will be affected; there is a 50% risk to offspring
• 36-39 repeats have reduced penetrance and patient may/may not be affected; there is a 50% risk to offspring
• 27-35 repeats is intermediate and patient will not be affected; but there is still an elevated (<50%) risk to offspring
• <26 repeats is normal and patient will not be affected; there is no risk to offspring
Treatment of HD?
Underlying pathology is currently untreatable
What is Alzheimer’s disease?
Most common cause of dementia and it may cause pre-senile dementia
Typically occurs in older age
Genetics associated with Alzheimer’s disease?
Displays genetic heterogeneity and can cluster in families
Commonly, it is a multifactorial disorder but, in ~5-10% of cases, it is an autosomal dominant trait
Pathology of Alzheimer’s disease?
There is a loss of cortical neurones
Presence of intracellular neurofibrillary tangles and extracellular senile plaques
What are senile plaques?
Extracellular protein deposits containing amyloid β protein (fragment of the product of the APP, amyloid precursor protein, gene on chromosome 21)
Assoc. of Down syndrome with Alzheimer’s disease?
AKA trisomy 21
Onset tends to be in the 3rd/4th decade, likely due to extra chromosome 21 (contains the APP gene)
Autosomal dominant mutations in Alzheimer’s disease?
APP mutations (on chromosome 21)
Presenilin 1 (on chromosome 14)
Presenilin 2 (on chromosome 1)
What are presenilins?
Components of gamma-secretase
Secretases are involved with cleavage of APP
Explain the significance of apolipoprotein E (ApoE) in Alzheimer’s disease
There are 3 alleles:
• e4 (this allele predisposes to Alzheimer’s disease, with some clustering in families)
• e3
• e2 (assoc. with longevity)
