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Venty Muliana Sari
Zukhrofi Muzar
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Prevalence 1/10,000-1/20,000(Caucasian).
Mean age at onset is 30-50 years.
10% of all patients < 20 yo (Juvenile
Huntingtons disease ;JHD)
However, it has been seen in persons asyoung as 5 yo & as old as 90 yo.
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The clinical symptoms : (Craufurd, 1994)
Motor dysfunction,
Behavioural disturbances and
Cognitive decline (learning difficulties at
school in JHD).
The classic sign is chorea (spreads to all
muscles)
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Usually start with chorea, involuntary &low-amplitude movements in distalextremities, continuous jerky movements,
affect all parts of the body ~ dancingmovements.
Chorea progressively in the initial years later replaced by bradykinesiaand rigidity
confined to a wheelchair (Craufurd, 1996).Patients also develop dysarthria, dysphagia,
balance problems, and incoordination.
In JHD patients, rigidity >> chorea.
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Irritability 3873%Apathy 3476%Anxiety 3461%Depressed mood 3369%Obsessive and compulsive 1052%
Psychotic 311% Behavioral abnormalities usually precede the
motor symptoms, (James et al., 1994).
Huntingtons Disease patients show overallimpairment in recognizing facial expressions(Scott et al., 1997)
Suicide is more common in HD patients, 3rd mostcommon cause of death (Craufurd, 1994; Farrer etal,1986).
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In the very late stages of the disease, mental
activities become slower and patients
develop dementia, characterized with poor
concentration, inefficient use of memory,and impairment of executive functions
(Craufurd, 1996).
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The pathology of HD is restricted to thebrain, especially in basal ganglia and the
predominant neuropathological hallmark isselective loss of neurons (atrophy) of thestriatum.
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The Basal Ganglia consist of :
caudate,
putamen,
globus pallidus,
substantia nigra,
subthalamus.
HD specifically degeneratesthe caudate nucleus foundwithin the basal ganglia
Striatum
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The medium-sized spiny GABAergic neurons
of the striatum (caudate nucleus and
putamen) degenerate in HD, atrophy of
the caudate and putamen Striatal degeneration is the first and most
obvious neuropathology in the early-grade
HD brain. However, later, profound loss of
neurons in other regions (particularly theneocortex) is also seen.
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Striatum is GABA-releasing. The striatum isstimulated by the cortex to release GABA.
By the indirect pathway, this GABA will hitthe GPe.
By the direct pathway, the GABA will hit GPi.
GPe inhibition leads to inhibition of thesubthalamic nucleus, which leads todisinhibition of the GPi and thus inhibition of
motion through GPi's suppressive action onthe thalamus. GPi inhibition (through thedirect pathway) leads to disinhibition ofthalamus, allowing motion
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The neurotransmitters gamma amino butyric acid(GABA), acetylcholine and dopamine were found to bedecreased in HD basal ganglia (Bier et al., 1997).
Glutamic acid decarboxylase (GAD) levels, the enzymeinvolved in GABA biosynthesis, was also found to bereduced in the caudate, putamen and globus pallidus(Graybi et al., 1990). GABA is one of theneurotransmitters found in spiny neurons, so thefinding of significantly reduced levels of GABA is
consistent with the morphological observations. Depletion of GABA within the basal ganglia and the
substantia nigra causes the alteration in motor andmental function ultimately producing involuntarymovements
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Gusella et al, Nature 1983; 306:234-238
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Huntingtons Disease Collaborative Research
Group, Cell 1993; 72: 971-983
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The human HD gene (IT-15) was localized to
chromosome 4p16.3 and consists of 67 exons
spanning 180 kb of DNA. codes for a protein
called the huntingtin protein
Structure of the Huntington disease gene
Short vertical bars represent exons.
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remain unclear
Essensial for development (absence of huntingtinis lethal in mice)
Upregulates the expression of Brain Derived
Neurotrophic Factor (BDNF) at the transcriptionlevel
BDNF helping to support
survival of existing neurons & encourage the growth
differentiation of new neurons and synapses. active in the hippocampus, cortex, and basal
forebrainareas vital to learning, memory, and higherthinking.
BDNF itself is important for long-term memory
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Potter et al. (2004) Genetics in Medicine6(1) 61-65.
ASHG (1998)American Journal of Human Genetics 62(5) 1243-1247.
CAGrepeats
Classification Disease status
9-26 Normal No risk for HD and no known risk to children
27-35 Intermediate No risk for HD, but a small risk to children
36-39 Reduced penetrance May develop HD and a 50% risk to children
40 Full penetrance Will develop HD and a 50% risk to children
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1 ttg ctg tgt gag gca gaa cct gcg ggg gca
ggg gcg ggc tgg ttc cct ggc cag cca ttg
61 gca gag tcc gca ggc tag ggc tgt caa tca
tgc tgg ccg gcg tgg ccc cgc ctc cgc cgg
121 cgc ggc ccc gcc tcc gcc ggc gca cgt ctg
gga cgc aag gcg ccg tgg ggg ctg ccg gga
181 cgg gtc caa gat gga cgg ccg ctc agg ttc
tgc ttt tac ctg cgg ccc aga gcc cca ttc
241 att gcc ccg gtg ctg agc ggc gcc gcg agt
cgg ccc gag gcc tcc ggg gac tgc cgt gcc
301 ggg cgg gag acc gcc atg gcg acc ctg gaa
aag ctg atg aag gcc ttc gag tcc ctc aag
361 tcc ttc cag cag cag cag cag cag cag cagcag cag cag cag cag cag cag cag cag cag
421 cag cag cagcaa cag ccg cca ccg ccg ccg
ccg ccg ccg ccg cct cct cag ctt cct cag
21 CAG repeats in a normal/usual Huntington disease gene
CAG repeat
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< 35 CAG triplet repeats
are normal: encodes a
run of 11-34 glutamine
amino acid residues in
the protein.
A run of > 34 glutamine
residues the protein to
aggregate in the brain cells
progressive cell death.
CAG repeat
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Excess of Huntingtin(mutant Huntington's
protein) is expressed
together with caveolin-1.
Caveolin-1 is the majorstructural protein called
caveolae capture
cholesterol and move it in
and out of the neuronal
membranes cholesterolaccumulates in membranes
of neurons
This leads to progressive
neuronal degeneration
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Huntingtin reacts withHIP -1 and HAP 1
Amount of C-A-G
repeats determinestheir reactions
If repeat high,Huntingtin binds less toHIP 1 and more to HAP 1
HIP1, when over-expressed in neurons, isneurotoxic
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HAP1 acts as an accessary molecule for
microtubule associated molecular motors
maintaining normal cellular functions suchas calcium homeostasis, neurite growth,
neurotrophic functions, neuronal
differentiation and synaptic transmission and
plasticity.
Huntingtin interacting proteins are geneticmodifiers of neurodegeneration
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A review of the family history pedigree,
Confirmation of the family diagnosis
Explanation of the applicants risk status
ADOften the genetic counselor will explore the
applicants experience with HD and
perceptions of the disease, and discuss the
potential burden of the test results on theindividual and the family.
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None
Medications and drug treatment may relieve some
symptoms (Depression or Psychosis)
Speech, physical, and occupational, therapy mayhelp.
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MayoClinic.com. (2007). Mayo Clinic medical information and tools for healthy living -
MayoClinic.com. 14 Mar. 2009, from.
Huether, Sue E., and Kathryn L. McCance. Understanding Pathophysiology. St. Louis: Mosby,2007.
Huntingtons outreach project for education at Stanford (2008). The Basic Neurobiology of
Huntingtons Disease. Retrieved March 15, 2009, from
http://hopes.stanford.edu/diagnsis/motorsymptoms/mss4.html
Young, J. (2006). Big Step in Understanding the Etiology of Huntingtons Disease. Retrieved
March 13, 2009, from
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