Lecturer: Dr Lucy Patston [email protected]. Thank you to the following 2013 Year Two students who devoted their time and effort to developing the.

Week beginningMonday 21 October 2013

Lecture 21d

Huntington’s Disease

Lecturer: Dr Lucy [email protected]

Thank you to the following 2013 Year Two students who devoted their time and effort to developing the following seminar topic:

Kaspara Chaise Matthew Selby Bryan Ellis

Some content may differ from that originally created by these students

Acknowledgements

WHAT IS HUNTINGTON’S

Named after George Huntington◦ Published a paper in 1872 comprehensively

describing the disease

Autosomal Dominant Disease

Primarily affects neurologic function

Caused by gene mutation

INHERITANCE

Huntington’s disease (HD) is an inherited disorder and is not contagious

HD is a dominant disease; A person needs only to inherit one copy of the mutated Huntington gene to develop HD

Consequently every child of a person with HD has a 50% chance of inheriting the gene and developing the disease. (fig. 1.)

INHERITANCE

CLINICAL MANIFESTATIONS

Psychiatric & Behavioral disturbance Mood swings, irritability and depression (these

eventually decline into Dementia) Involuntary movement of arms and legs

Formally called Huntington Chorea from the Greek Khoreia, “dance” because of the uncontrolled (twitching, jerking, writhing) movement of the limbs and dystonia (muscle contractions that lead to twisting movements and abnormal postures)

INCIDENCE

1 in 20 000 born with mutated gene in western European decent populations

Approximately 1 in 1 million in Asian and African populations

Video clip of HD sufferer ◦ http://www.youtube.com/watch?v=JzAPh2v-SCQ

ONSET

Symptoms do not commonly appear until

approximately 40 years of age Symptoms can appear as early as one year

of age and manifest different features such as: lack of movement, a rigid body and seizures

Age of onset can decrease with each successive generation

PHENOTYPE

Born carrying mutation

Initially live with no ill effects

Effects accumulate in brain over time

PHENOTYPE

As the disease progresses, walking and

speech become more difficult, and memory

and intellectual functions continue to

decline

High risk of suicide and suicidal thoughts

HD causes death usually 20 years after

onset

Affected gene causing HD is called IT15◦ Found on short arm of chromosome 4 (autosomal

rather than being on a sex chrosome)

HD mutations are dominant◦ Those who inherit the mutation will develop the

disease if they live long enough

HD gene is expressed as the protien Huntingtin in all mammalian cells

GENOTYPE

All IT15 alleles have a section of trinucleotide repeats of cytosine-adenine-guanine (CAG)

Repeats always number <36 in a normal allele, triplet repeats of <39 are reliably associated with development of the disease (fig.2.)

GENOTYPE

CAG REPEATS

HUNTINGTIN PROTEIN CODING

Coding of CAG forms the amino acid glutamine During protein synthesis IT15 is transcribed

into mRNA and translated into amino acids forming a polypeptide chain

CAG creates a polyglutamate section within the polypeptide

Normal Huntingtin proteins interact with other proteins in the brain to support healthy brain cells and brain function

MUTATION CHANGES THE PROTEIN

Protein transcribed from mutated allele has extra long polyglutamate chains

The chains fold and alter the tertiary structure of the protein resulting in alterd function (fig. 3.)

SYNTHESIS OF HUNTINGTIN PROTEIN

NORMAL HUNTINGTIN PROTEINSMaintain brain cell health

Essential for: ◦ Proper cell division◦ Programmed cell death (a normal part of cell

lifecycle)

Interacts with many other proteins in the brain◦ Including those involved in:

Transcription Cell signalling Intra-cellular transportation

EFFECTS OF HD IN THE BRAIN Mutated huntingtin protein causes neurons in

the brain to malfunction and die First target is always the striatum (part of the

basal ganglia)◦ Severe atrophy of the striatum and its projections is

observed in HD patients post mortem (fig. 4.) With progression, no brain structure is spared As an area is damaged, symptoms associated

with the function of that area appear

STRIATUM

Responsible for planning, habit-learning and modulating movement (often inhibiting it)◦ The loss of its neurons leaves uninhibited,

inappropriate movement Has links to mood neurons

◦ With mood disturbance being a characteristic of the disease

EFFECTS OF HD IN THE BRAIN

4

DAMAGE AND DEATH OF BRAIN CELLS Caused by extra long polyglutamate chains of

mutant protein that break off easily Glutamine is a charged molecule

◦ Excess causes proteins to link and ‘clump’ instead of taking normal folded form

◦ Resulting tangled masses are called protein aggregates

Both huntingtin and the proteins it interacts with become caught up in the aggregates resulting in:◦ Loss of proper protein function◦ Proteins become toxic to brain cells causing loss of

brain tissue (fig. 4.)

ONE GENE MUTATION BUT VARIABLE DISEASE

The extent of brain cell death increases with the number of CAG repeats, which explains the earlier onset of the disease (phenotype variation) with longer CAG repeats (genotype variation) (Fig. 5.)

VARIABILITY OF AGE

Fig. 5.

GENETIC TESTING FOR HD IN NZ

Genetic testing is available in New

Zealand but strict conditions apply

Only people over 18 years of age are

eligible◦ counselling is required before and after testing

◦ less than 5% of those concerned actually carry

out the test (mostly because there is no cure)

GENETIC TESTING FOR HD IN NZ

Fetuses can be tested, allowing parents the option of termination if the baby is found to carriy the HD mutation

In vetro fertilization (IVF) embryos can also be tested, allowing implants free from mutation◦ Funded in a limited way◦ At risk parent generally tested first

GENETIC TESTING AND ETHICS

Would it be for the baby's own good? Can people chose their children's genetic

characteristics? ◦ May set presedents leading to selective

implantation based on non-medical features? ('I want a baby with blue eyes!')

Would you want to know at what age you are most likely to die?

If you knew, would getting life insurance be a problem?

THE SEARCH FOR A CURE

Currently there is no cure for HD

Neurogenesis◦ New replacement brain cells in a diseased adult

human brain

Stem cells◦ Neural stem cells

THE SEARCH FOR A CURE Stem cells

◦ Embryonic stem cells◦ Embryonic germ cells◦ Adult stem cells

THE FUTURE

In theory◦ Stem cells from the same person◦ Avoids rejection

REFERENCE

http://lens.auckland.ac.nz/images/7/72/Huntington's_Disease_2011.pdf

http://www.yourgenesyourhealth.org/hd/whatisit.htm

Marieb, E. N., & Hoehn, K. (2007). Human anatomy & physiology (7th ed.). San Francisco, CA: Pearson Benjamin Cummings.