Huntington's Flashcards
What is Huntington’s disease
Degeneration of the striatum and later cortex and other areas
What are the clinical signs of Huntington’s disease - motor symptoms
Chorea: Involuntary, jerky, and uncoordinated movements.
Dystonia: Sustained or repetitive muscle contractions causing abnormal postures or movements.
Bradykinesia: Slowed voluntary movement.
Rigidity: Stiffness in muscles.
Impaired balance and coordination, leading to frequent falls.
Difficulty swallowing (dysphagia) and speech impairments (dysarthria).
What are the clinical signs of Huntington’s disease - cognitive symptoms
Memory impairments: Difficulty recalling information or learning new things.
Reduced ability to plan and organize: Challenges with executive functioning.
Difficulty concentrating and short attention span.
Impaired judgment and decision-making abilities.
Progressive dementia in later stages.
What are the clinical signs of Huntington’s disease - psychiatric symptoms
Depression: Persistent sadness, lack of motivation, and suicidal thoughts.
Irritability and mood swings.
Obsessive-compulsive behaviours: Repeated, intrusive thoughts and ritualistic actions.
Anxiety disorders.
Psychosis: Rare, but may involve hallucinations or delusions.
What are the clinical signs of Huntington’s disease - other features
Sleep disturbances.
Weight loss: Despite adequate or increased food intake, due to metabolic and physical challenges.
What is the purpose of palliative treatment
Palliative treatment focuses on:
- relieving symptoms,
- improving quality of life, and
- addressing the emotional, psychological, and social needs of patients with chronic or incurable conditions.
Unlike curative treatments, palliative care does not aim to cure the underlying disease
What are the options for palliative treatment in HD
Physical therapy
- Swallowing
- Involuntary movements
- Cognition
Tetrabenazine (dopamine reducing agent)
- Involuntary movements
Selective serotonin reuptake inhibitors + cognitive behavioural therapy
- depression
What type of disease is Huntington’s and what causes it genetically
Monogenic disease
Expansion of a CAG/CTG repeat in the Huntingtin gene
Caused by multiple molecular mechanisms
- Tackling any one of them individually is not going to be enough
What is the main modifiers of the severity of the disease
Repeat size
- Motor and neurological symptoms correlate with repeat size
Somatic expansion - measured with small-pool PCR
- Genome wide association finds genes that modify disease severity
- Most loci are genes involved in mismatch repair, which changes the rates of somatic expansions
- Removing mismatch repair improves molecular signs of HD
What are the 3 types of ATMPs (advanced therapy medicinal products)
- Cell therapy
- These contain cells or tissues that have been manipulated to change their biological characteristics or cells or tissues not intended to be used for the same essential functions in the body
- Gene therapy
- They work by inserting ‘recombinant’ genes into the body, usually to treat a variety of diseases, including genetic disorders, cancer or long-term diseases
- A recombinant gene is a stretch of DNA that is created in the laboratory, bringing together DNA from different sources
- Tissue engineering
- These contain cells or tissues that have been modified so they can be used to repair, regenerate or replace human tissue
What are the 3 forms of gene therapy
Supplementation - e.g. overexpressing a gene that is missing
Downregulation - e.g. silencing a faulty gene
Gene editing - e.g. mutate or correct a faulty gene
What kind of inheritance leads to what type of mutation
Recessive
- Loss of function
Dominant
- Haploinsufficient
- Dominant negative
- Gain of function
What is a recessive mutation
Recessive if one copy of the protein is enough for normal activity
When this is not the case, then the mutations are dominant and this is called haploinsufficiency
What are gain of function mutations
Mutant protein has a new toxic function in addition to the normal function but it retains the normal function
What are dominant negative mutations
The mutant protein interferes with the function of the normal protein
What type of ATMP can be used to treat each mutation type
Supplementation
- Recessive
- Haploinsufficient
- Dominant negative
Downregulation
- Dominant negative
- Toxic gain of function
Gene editing
- Dominant negative
- Toxic gain of function
How do you show that a gene is haploinsufficient
Prediction: heterozygotes knockout mice will develop the disease
They do not -> disease is not haploinsufficient
How to show that it is a gain of function mutation
Prediction: adding the mutation to a mouse would cause the disease
Mouse gains the disease and retains its normal function but also acquires a harmful new activity.
Cellular assays can be used to show abnormal interactions or toxic effects unique to the mutant protein
What are some examples of ATMPs for Huntington’s disease
Zinc Finger Transcriptional Repressors: Suppress mutant huntingtin (mHTT) gene expression.
CRISPR/Cas9 Gene Editing: Specifically targets and edits the expanded CAG repeats in the HTT gene.
- CRISPR/Cas9 + allele - specific SNP
- CRISPR/Cas9 to introduce DNA break
Antisense Oligonucleotides (ASOs): Bind to mRNA to reduce mutant huntingtin protein production.
RNA Interference (RNAi): Silences the mHTT gene by degrading its RNA transcripts.
Stem Cell Therapy: Replaces damaged neurons and supports neuroprotection.
Gene Therapy via Viral Vectors: Delivers therapeutic genes to modify or reduce mHTT expression.
Small molecules to disrupt pre-mRNA splicing
What are the cellular consequences of mHTT presence
Transcriptional dysregulation
Dysregulation proteosome and autophagy systems
Disruption of BDNF-mediated functions
Mitochondrial dysfunction
Endoplasmic reticulum stress
Excitotoxicity
Synaptic dysfunction
Cholesterol metabolism
What are the 3 main challenges of gene editing
Efficiency
Delivery
Safety
What is the main gene editing treatment in HD and how does it work
CRISPR/Cas9 nickase for the treatment of HD
Targeting the Mutant Allele: The nickase is engineered to specifically recognize and bind the expanded CAG repeat in the mutant HTT gene.
Creating a Single-Strand Break: Instead of cutting both DNA strands, the nickase makes a precise nick (single-strand cut) at the target site.
Promoting Repair or Contraction: The cell’s repair mechanisms are triggered, leading to the contraction of the expanded CAG repeat in the mutant allele while sparing the normal allele
