Slide Hunting Ton Disease[1],Edit

7/31/2019 Slide Hunting Ton Disease[1],Edit

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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
http://www.stanford.edu/group/hopes/causes/neuro/f_d07hunhap.jpg


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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
http://hopes.stanford.edu/diagnsis/motorsymptoms/mss4.htmlhttp://hopes.stanford.edu/diagnsis/motorsymptoms/mss4.html


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