Venty Muliana Sari Zukhrofi Muzar

Huntingtons

Disease (HD)

late-onset and progressive degeneration of cells in the central nervous system

(neurodegenerative disease)
with autosomal dominant inheritance.
Dr. George Huntington (1872)

 Prevalence
Mean

1/10,000-1/20,000(Caucasian).

age at onset is 30-50 years.

10% of all patients < 20 yo (Juvenile

Huntingtons disease ;JHD)

However, it has been seen in persons as young as 5 yo & as old as 90 yo.

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)

start with chorea, involuntary & low-amplitude movements in distal extremities, continuous jerky movements, affect all parts of the body ~ dancing movements. Chorea progressively in the initial years later replaced by bradykinesia and rigidity confined to a wheelchair (Craufurd, 1996). Patients also develop dysarthria, dysphagia, balance problems, and incoordination. In JHD patients, rigidity >> chorea.
Usually

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 overall impairment in recognizing facial expressions

(Scott et al., 1997)

Suicide is more common in HD patients, 3rd most common cause of death (Craufurd, 1994; Farrer et al,1986).

 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).

 The

pathology of HD is restricted to the brain, especially in basal ganglia and the predominant neuropathological hallmark is selective loss of neurons (atrophy) of the striatum.

The Basal Ganglia consist of : caudate, Striatum putamen, globus pallidus, substantia nigra, subthalamus.

HD specifically degenerates the caudate nucleus found within the basal ganglia

 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 the neocortex) is also seen.

 Striatum

is GABA-releasing. The striatum is stimulated by the cortex to release GABA. By the indirect pathway, this GABA will hit the GPe. By the direct pathway, the GABA will hit GPi. GPe inhibition leads to inhibition of the subthalamic nucleus, which leads to disinhibition of the GPi and thus inhibition of motion through GPi's suppressive action on the thalamus. GPi inhibition (through the direct pathway) leads to disinhibition of thalamus, allowing motion

The neurotransmitters gamma amino butyric acid (GABA), acetylcholine and dopamine were found to be decreased in HD basal ganglia (Bier et al., 1997). Glutamic acid decarboxylase (GAD) levels, the enzyme involved in GABA biosynthesis, was also found to be reduced in the caudate, putamen and globus pallidus (Graybi et al., 1990). GABA is one of the neurotransmitters found in spiny neurons, so the finding 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 and mental function ultimately producing involuntary movements

Gusella et al, Nature 1983; 306:234-238

Huntingtons Disease Collaborative Research Group, Cell 1993; 72: 971-983

 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.

remain unclear Essensial for development (absence of huntingtin is lethal in mice) Upregulates the expression of Brain Derived Neurotrophic Factor (BDNF) at the transcription level 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 higher thinking. BDNF itself is important for long-term memory

CAG repeats 9-26

Classification Normal

Disease status 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 40

Reduced penetrance May develop HD and a 50% risk to children Full penetrance Will develop HD and a 50% risk to children

Potter et al. (2004) Genetics in Medicine6(1) 61-65. ASHG (1998) American Journal of Human Genetics 62(5) 1243-1247.

CAG repeat
1 ttg ggg 61 gca tgc 121 cgc gga 181 cgg tgc 241 att cgg 301 ggg aag 361 tcc cag 421 cag ccg ctg gcg gag tgg ggc cgc gtc ttt gcc ccc cgg ctg ttc cag cag ccg tgt ggc tcc ccg ccc aag caa tac ccg gag gag atg cag cag cag ccg gag tgg gca gcg gcc gcg gat ctg gtg gcc acc aag cag cag caa ccg gca ttc ggc tgg tcc ccg gga cgg ctg tcc gcc gcc cag cag cag cct gaa cct tag ccc gcc tgg cgg ccc agc ggg atg ttc cag cag ccg cct cct ggc ggc cgc ggc ggg ccg aga ggc gac gcg gag cag cag cca cag gcg cag tgt ctc gca ctg ctc gcc gcc tgc acc tcc cag cag ccg ctt ggg cca caa cgc cgt ccg agg cca gcg cgt ctg ctc cag cag ccg cct gca ttg tca cgg ctg gga ttc ttc agt gcc gaa aag cag cag ccg cag

21 CAG repeats in a normal/usual Huntington disease gene

CAG repeat
< 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.

Excess of Huntingtin (mutant Huntington's protein) is expressed together with caveolin-1. Caveolin-1 is the major structural protein called caveolae capture cholesterol and move it in and out of the neuronal membranes cholesterol accumulates in membranes of neurons This leads to progressive neuronal degeneration

Huntingtin reacts with HIP -1 and HAP 1 Amount of C-A-G repeats determines their reactions If repeat high, Huntingtin binds less to HIP 1 and more to HAP 1 HIP1, when overexpressed in neurons, is neurotoxic

 HAP1

acts as an accessary molecule for microtubule associated molecular motors maintaining normal cellular functions such as calcium homeostasis, neurite growth, neurotrophic functions, neuronal differentiation and synaptic transmission and plasticity. Huntingtin interacting proteins are genetic modifiers of neurodegeneration

review of the family history pedigree, Confirmation of the family diagnosis Explanation of the applicants risk status AD Often 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 the individual and the family.

None Medications and drug treatment may relieve some symptoms (Depression or Psychosis) Speech, physical, and occupational, therapy may help.

MayoClinic.com. (2007). Mayo Clinic medical information and tools for healthy living MayoClinic.com. 14 Mar. 2009, from <http://www.mayoclinic.com/health/huntingtonsdisease/DS00401>.
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://scienceblogs.com/purepedantry/2006/12/big_step_in_understanding_the.php>