Neurogenetics Flashcards
What is the inheritance pattern of Duchenne muscular dystrophy?
X-linked recessive
What is the presentation of Duchenne Muscular Dystrophy?
Delay in motor development Onset of weakness - 3-4 years Wheelchair bound by 10-12 years Death from involvement of respiratory and cardiac muscles in 20s
What are some characteristic features of DMD?
Calf hypertrophy
Gowers sign
Toe walking
What causes DMD?
Genetic abnormalities of the dystrophin gene
- large scale deletion in 70%
- point mutations, small insertion and deletion in remaining 30%
How is DMD diagnosed?
- raised serum creatine kinase (CK)
- electromyography (EMG)
- muscle biopsy
- molecular genetic testing
> screen for deletions
What is the differential diagnosis of DMD?
Autosomal recessive limb girdle muscular dystrophies (some caused by sarcoglycan deficiencies)
DMD is caused by de novo mutations in what proportion of boys?
1/3
Describe carrier testing for DMD?
mutation testing
- identify mutation in affected boy
- test for mutation in female relatives wishing to know carrier status
- female carriers of known dystrophin mutations can be offered pre-natal testing
What is the incidence of DMD and huntingtons?
DMD: 1/3000 males
Huntingtons disease: 1/20,000
What is the presentation of huntingtons disease?
- onset usually between 30 and 50 years
- involuntary movements
- dementia
- progression to severe dependency and death over 15-20 years
What is the inheritance pattern of huntingons disease?
Autosomal dominant trait
Age dependant penetrance
What are the early clinical signs of huntingtons disease?
- clumsiness
- agitation
- irritability
- apathy
- anxiety
- disinhibition
- delusions
- hallucinations
- abnormal eye movements
- depression
What are the later clinical signs of huntingtons disease?
- dystonia
- involuntary movements
- trouble with balance and walking
- trouble with activities that require manual dexterity
- slow voluntary movments
- difficult initiating movement
- inability to control speed and force of movement
- weight loss
- speech difficulties
- stubbornness
What are the late clinical signs of huntingtons disease?
- ridigity
- bradykinesia
- severe chorea
- serious weight loss
- inability to walk
- inability to speak
- swallowing problems
- inability to care for onself
What is the molecular defect in the huntington gene?
CAG repeats
What testing can be offered to pregnant women for huntingtons disease?
Pre-natal testing
Pre-gestational testing
What is spinal muscular atrophy?
Progressive loss of anterior horn cells in spinal cord and brainstem nuclei
What is the presentation of SMA?
- hypotonia
- proximal muscle weakness
- tongue fasciculaiton
What are the types of SMA?
What is the inheritance pattern of SMA?
- 0, I, II, III, IV
- autosomal recessive
What causes SMA?
SMN1 deficiency
How can SMA be treated?
BY synthetic oligonucleotide (nusinersin)
Binding of synthetic oligonucleotide results in retention of exon 7 in SMN2 mRNA
What causes 50-70% of cases of dementia?
Alzheimers disease
Describe the pathology of alzheimers disease?
- loss of cortical neurones
- neurofibrillary tangles (intracellular)
- senile plaques (Extracellular)
What are senile plaques?
Extracellular protein deposits containing amyloid B protein
Amyloid B protein is a fragment of which gene?
the APP (amyloid precursor protein) gene (chromosome 21)
Describe the genetic aetiology of alzheimers disease
An autosomal dominant trait in 5-10% of cases (early onset)
Down syndrome (trisomy 21) (onset in 3rd or 4th decade)
What causes autosomal dominant alzheimers disease?
- APP mutations (chromosome 21)
- Presenilin 1 (chromosome 14)
- presenilin 2 (chromosome 1)
e4 allele confers what prognosis?
Predisposes to alzheimers disease with some clustering in families
e2 allele confers what prognosis?
Associated with longevity
e4/e4 genotype means __% are affected by alzheimers at 80 years
e4/e4 genotype means 55% are affected by alzheimers 80 years
e3/e4 genotype means __% are affected by alzheimers at 85 years
e3/e4 genotype means 27% are affected by alzheimers at 85 years
no e4 genotype means _% are affected by alzheimers at 85 years
no e4 genotype means 9% are affected by alzheimers at 85 years
Alzheimers disease is _____genous with rare ______ ______ forms and common _______ forms
Alzheimers disease is heterogenous with rare autosomal dominant forms and common multifactorial forms
Multiple scleosis is ______ with some clustering in families
Multiple scleosis is multifactorial with some clustering in families
Multiple sclerosis risk is;
_% in first degree relatives
_% in second degree relatives
_% population risk
Multiple sclerosis risk is;
3% in first degree relatives
1% in second degree relatives
0.2% population risk
MS is more common in individuals with certain ___ haplotypes
MS is more common in individuals with certain MHC haplotypes
