HUNTINGTON DISEASE AND SPINOCEREBELLAR ATAXIAS Flashcards
What type of disorders are Huntington disease and spinocerebellar ataxias examples of?
Dynamic repeat disorders
These are important genetic neurodegenerative disorders.
What are the key clinical features of Huntington disease?
Progressive neurodegenerative disorder characterized by:
* Motor disturbance
* Cognitive disturbance
* Psychiatric disturbance
* Choreiform movements
* Subcortical dementia
* Onset in third or fourth decade
* Mean age of onset 40 years
* Death occurs 15-20 years after onset
Marked clinical variability exists, including a juvenile form.
What is the typical age of onset for spinocerebellar ataxias?
Typically 30-40 years, but can be as young as 2 years
Most forms are clinically indistinguishable.
What inheritance pattern do Huntington disease and spinocerebellar ataxias follow?
Autosomal dominant inheritance
This results in a 50% risk to siblings and children.
What phenomenon describes the increased severity and earlier onset of disease in successive generations?
Anticipation
This occurs in dynamic repeat disorders.
What is the molecular basis of dynamic repeat disorders?
Involves a specific arrangement of DNA with a 3-nucleotide DNA sequence repeated a number of times
Examples include Huntington disease and various spinocerebellar ataxias.
What are the characteristics of dynamic repeat disorders?
Characterized by:
* Varying number of repeats
* Variable age of onset
* Variable severity
* Increased severity in successive generations (anticipation)
Parent of origin can influence repeat instability.
What are the repeat numbers associated with normal, intermediate, and mutated Huntington disease?
Normal: 5-26 repeats
Intermediate: 27-35 repeats
Mutation: 40-200 repeats
The mutation is inherited from the father.
What is the significance of the CAG repeat in Huntington disease?
It is a trinucleotide repeat that indicates the presence of the disorder when the repeat number exceeds 40
The polyglutamine tract is important in disease pathogenesis.
What genetic testing principles are important for Huntington disease and spinocerebellar ataxias?
Testing should be based on:
* Reason for testing
* Type of testing (diagnostic, predictive, prenatal)
* Ethical practice
Awareness of conditions and appropriateness of testing is critical.
What is the role of predictive testing?
Used for asymptomatic individuals with a positive family history to determine risk of developing the disease
Requires a complete predictive protocol including genetic counseling.
What is the importance of a negative test result in genetic testing?
Indicates that the specific mutation is not present, but does not rule out other potential gene mutations causing the phenotype
Essential for accurate diagnosis and counseling.
What is the relationship between Huntington disease and HDL2?
HDL2 is a different gene with a different repeat sequence that causes a similar disease phenotype, particularly significant in Africa
It has a reduced penetrance with 29-39 repeats.
What are the common genetic subtypes of spinocerebellar ataxias?
Over 40 genetic subtypes exist, including:
* 8 trinucleotide repeat disorders
* 1 pentanucleotide disorder
Most mutations occur across all population groups.
What is the threshold concept in dynamic repeat disorders?
Repeat number above a certain threshold leads to instability and the manifestation of a dynamic mutation
This concept explains increasing number of repeats across generations.
What are the implications of dynamic repeat disorders on disease progression?
Associated with:
* Increasing disease severity
* Decreased age of onset
* More rapid disease progression
Greater instability is often linked to the parent of one sex.
