Predisposition Testing for Neurodegenerative Disease I Flashcards
What is Huntington Disease?
100% inherited AD
CAG repeat expansion in HTT on 4p16.3
leads to polyglutamine repeat in mHTT causing neurodegeneration
Describe the repeat lengths for Huntington disease.
Normal: <26
Intermediate (may expand): 27-35
HD (reduced penetrance): 36-39
HD (full penetrance): 40+
What is meiotic instability?
the ability o fan allele to increase or decrease CAG repeat length during meiosis so that the modal GAC repeat number in an individual’s somatic cells is not the same as the repeat number present in the same allele in his or her gametes
uncommon in normal alleles (<1%)
2% maternal expansion 21% paternal expansion
Describe the impact of repeat length on presentation in Huntington disease.
inverse correlation between the age of onset and the number of repeats
CAG repeat length accounts for approximately 50% of the variation in age of onset (modifier genes yet to be determined; age of onset can vary even among families)
BUT clearly advise patient that this correlation does NOT inform about types of symptoms and the course of disease (no correlation with duration OR symptoms)
CAA repeats can also be present among CAG repeats (NOT the number of Gln in the protein that determines age of onset but the amount of CAG repeats specifically
What is the Unified HD Rating Scale (UHDRS)?
four domains of clinical performance and capacity: motor function cognitive function behavioral abnormalities functional capacity
What are the statistics of Huntington disease.
1-10 per 100,000
pan-ethnic
mean age of onset 36-45 years (as early as 2 as late as 90; 6% present before the age of 20)
10% have no family history
death occurs on average 15-25 years after onset of motor signs (most commonly from aspiration)
Describe the kind of neurodegeneration present in Huntington disease.
neurodegeneration of striatum in basal ganglia Corpus Striatum (striatum) is an important nucleus present in the forebrain part of the brain that controls cognition, reward, and coordinated movements (being a part of basal ganglia, it controls many important functions)
What are the core symptoms of Huntington disease?
impaired speech chorea slow eye movements restless fidgets slowness of movement trouble swallowing trouble with fine motor tasks
What is chorea?
a neurological disorder characterized by jerky involuntary movements affecting especially the shoulders, hips, and face
What is the pathophysiology of Huntington disease?
loss of striatum neurons results in too little GABA which causes over-stimulation of motor cortex and bursts of excitatory discharges causing chorea but also causes under-stimulation of the thalamus which causes slowness later in disease
What kinds of motor impairment are common in Huntington disease?
involuntary- chorea, tics, rigidity, dystonia (muscles contract uncontrollably), tremor and myoclonus (muscle fatigue)
voluntary- gait, eye movements, swallowing and speech
What psychiatric disorders are common with Huntington disease?
affective disorders/depression suicidal ideation (3-13%) irritability apathy anxiety psychosis OCD
Describe the cognitive impairment in patients with Huntington disease.
cognitive and psychiatric symptoms begin 7-15 years before onset of motor symptoms
includes forgetfulness, slow thought processing, attention and concentration deficits, word-finding, and dementia (particularly impaired executive function)
What disorders are Huntington-like?
HDLI: PRNP (prion gene-associated with GSS; fatal familial insomnia)
HDL2: JPH3 gene
HLD3: Childhood onset, recessive
HDL4/SCA17: spinous cerebellar ataxia 17 (presents with ataxia, chorea, psychiatric symptoms)
C9orf72: responsible for the greatest number of familial ALS and dementias
What conditions (other than Huntington disease) cause chorea?
neuroacanthocytosis (Wilson's disease) sydenham's chorea from rheumatic fever drug-induced metabolic and endocrine anomalies stroke
How do you counsel for Huntington disease?
discussion of the diagnosis and how PD could be an incorrect diagnosis
possibility of anticipation
preparation for both positive AND negative results
What is Juvenile Huntington disease?
family history (usually paternal)
>60 CAG repeats
stiffness of the legs, clumsiness of arms and legs, decline in cognitive function, changes in behavior, seizures, changes in oral motor function
death within 15 years
DONT test unless progressively symptomatic
DONT test a child for an adult onset disease (AAP guidelines)
juvenile (under 20)
What is important to discuss when giving Huntington disease results and conversations?
discussion about the end of diagnostic odyssey, now focus on treatment (importance of good nutrition, guided exercise, treatment for depression or anxiety)
possibility of research and hope for the future
discussion of children and whether information will be communicated
discussion of sibling risk and whether they might wish to pursue predictive testing
What is the protocol for predictive genetic testing for Huntington disease?
telephone screen
genetic counseling
psych assessment
neuro evaluation
results session
support people are strongly encouraged for genetic counseling and results
children should not have presymptomatic testing for adult-onset disease (emancipated minor evaluated case by case)
only 5-10% of the at-risk population go through testing
What family planning options are available for patients with Huntington disease?
natural pregnancy and take changes (put a time perspective on what patient is saying- many years before symptoms may start, child may not get it for 30-50 years, discuss clinical trials, symptomatic treatment)
no children
adoption
sperm/oocyte donation
preimplantation genetic diagnosis (disclosing/non-disclosing)
prenatal testing
What are some reasons for predictive Huntington disease testing?
reproductive options
life planning
discomfort with uncertainty
What is the role of a genetic counselor when counseling for Huntington disease?
Devil’s advocate
one has to assume a carrier status
someone should NOT pursue genetic testing if it is going to worsen their quality of life
refer back to the protocol for testing
What trials for disease modifying therapies are available for Huntington disease?
antisense oligonucleotides (ASOs)- similar trials with SMA, ALS, etc. based on mechanism, ASOs can alter mRNA to reduce, modify or restore protein expression HD: Ionis_roche trial for early manifesting patients- mean reduction of 40% in mutant huntingtin protein at the two highest doses of therapy; an open label extension of the study; HTTRx is a 20 nucleotide ASO that reduces the amount of HTT mRNA by forming a hybrid region which activates Rnase H1 to degrade HTT mRNA
