Genetic Neuro Disorders Flashcards
Define chorea
excessive, irregular movements flitting from one body part to another
Define tremor
rhythmic sinusoidal oscillation of a body part
What is Huntingtons disease?
A progressive neurodegenerative disorder characterised by involuntary movements, dementia and progression to severe dependency and death over 15-20 years from onset of first symptoms.
What is the pattern of inheritance with Huntingtons disease?
Autosomal dominant trait with age dependent penetrance
Describe the pathogenesis of Huntingtons disease?
Pathological expansion of a trinucleotide repeat in the Huntingtin gene.
In a normal gene there is around 20 CAG repeats at one position in the gene coding for around 20 glutamine residues.
In Huntingtons disease the number of CAG repeats is expanded so increased glutamines on the protein.
This new protein is actually neurotoxic so causes progressive damage to the nervous system.
Describe what happens to the brain in Huntingtons?
There is loss of cells from the basal ganglia causing flattening of the normal convex curve of the ventricles. The caudate nucleus is usually severely atrophic. There is also loss of cells in the cerebral cortex.
Why does age of onset become earlier as you move down generations of families carrying the Huntingtons gene?
The CAG repeat is highly unstable during meiosis particularly spermatogenesis which often means there are bigger expansions that are passed down. Bigger expansions mean earlier onset of disease.
Describe some early signs of Huntingtons?
subtle fidgetiness, difficulty concentrating, memory lapses, mood swings, clumsiness
Describe some later signs of Huntingtons?
development of chorea (abnormal involuntary movements), inability to walk, speak, swallow, bradykinesia, dementia, ultimately death
Define bradykinesia?
difficulty in initiating and continuing movements
Prognosis of Huntingtons?
Patients usually die 10-20 years after 1st symptoms (1st onset is usually in the 30s or 40s)
2 investigations for Huntingtons disease?
Genetic testing
MRI will show loss of caudate heads
Describe management of Huntingtons disease?
There are no disease modifying drugs
Chorea can improve with treatment such as risperidone or sulpiride
What is Duchenne Muscular Dystrophy?
A genetic disorder that causes loss of muscle cells and therefore muscle wasting and weakness.
What is the pattern of inheritance with Duchenne muscular dystrophy?
X linked recessive disorder (although 1/3 can be spontaneous mutations)
Describe the pathogenesis of Duchenne muscular dystrophy?
Mutation in the dystrophin gene that codes for dystrophin proteins that connect actin filaments to the cell membrane and ECM. The mutation results in progressive loss of muscle cells causing muscle wasting and weakness.
Usually the mutation is a large scale deletion or duplication although about 30% are point mutations.
Describe presentation of Duchenne muscular dystrophy?
Developmental delay in boys (usually a specific motor delay)
Gowers sign (the boy puts hands down to push themselves up)
Toe walking
Exaggerated lumbar lordosis
Calf hypertrophy
Describe some investigations for Duchenne muscular dystrophy?
Initial screening (not v specific but v sensitive): look for raised CK Definitive testing is genetic testing from a blood or saliva sample
Why is it important to distinguish Duchenne Muscular dystrophy from other types of muscular dystrophy?
There are different patterns of inheritance so need to confirm for genetic counselling ie some girls could get, some are x linked
Describe management and prognosis of Duchenne muscular dystrophy?
There is no curative treatment, severely disabled by 10 and usually die in 20s
Sometimes steroids delay progression
Physio can help prevent contractures in later stages
What is spinal muscular atrophy?
A genetic disorder that causes loss of anterior horn cells in the spinal cord
What is the pattern of inheritance with spinal muscular atrophy?
autosomal recessive disorder
Describe the pathogenesis of spinal muscular atrophy?
Most common forms are due to deficiency in SMN1 gene
SMN1 has an essential exon (exon 7) that stops motor neuron loss
Describe presentation of spinal muscular atrophy?
Usually occurs in babies- precise age of onset depends on the type
Hypotonia and muscle weakness (floppy and weak)
Can cause respiratory failure if it affects the muscles of breathing
Describe management of spinal muscular atrophy?
Treatments have been developed that get the similar gene SMN2 to keep this essential exon 7 in its mature mRNA (SMN2 usually splices it out)
This prevents progression of the disease but doesn’t reverse what has happened
Ideally it would be tested for at brith so the baby could be instantly treated
