Huntingtons Disease

Huntingtons DiseaseProgressive autosomal dominant neurodegenerative disorder caused by expansion of a CAG (cytosine ,adenine , guanine ) repeat coding for polyglutamine in the huntingtin protein.

Genetics Review Chromosomes - are located in the nucleus They provide the instructions for all the information necessary for the living organism to grow and function These instructions come in form of a complex molecule called DNA (Deoxyribonucleic Acid).

DNA- Blueprint of life DNA comes in compact form, a twisted ladder shaped molecule called a double helix. Composed of a string of nucleotides. The 4 units are adenine (A), thymine (T), cytosine (C), and guanine (G).

Genes Functional regions of DNA that contain specific instructions are called genes. Example would be regions of DNA that code for making proteins.

Huntingtin Protein Cytoplasmic protein found in almost all tissues of the body and brain Normal function is not well understood, yet implicated in cell membrane recycling and neuroprotection. Studies suggest that huntingtin protein regularly interacts with other proteins found in the brain The altered form of huntingtin protein leads to nerve cell death in brain.

Genetic Mechanism of HD:Unstable Trinucleotide repeat The gene responsible for causing HD is located in chromosome 4. The gene regulates the production of huntingtin protein. Huntingtin protein contains within it the amino acid glutamine (C-A-G). In people with HD, however, there is an excess number of glutamine. That is why HD is often referred to as a trinucleotide repeat disorder

HD = Huntingtin protein with expanded CAG (glutamine) tract

10-35

Proteins must be folded normally to function. Mutant expansion of CAG causes an unusual huntingtin protein which clumps together in the cell and causes neuronal cell death (in the brain only)

How much CAG expansion is too much? People with 10 to about 35 copies of CAG have a normal functioning form of the huntingtin protein. Expansion of 40 or more CAG repeats is often full penetrance and the person will develop HD. For people who have 36 to 39 copies of CAG, the outcome is less clear. Some will develop the symptoms of Huntington's disease and some will not.

Neuropathology of HD HD involve atrophy and cell death of the basal ganglia, the complex subcortical structures involved in control of motor movement, cognition and sensory pathways. Specifically, there is a progressive and marked degeneration of the caudate and putamen (striatum).

Neuropathology

There are different types of neurons and neurotransmitters in the striatum, and the balanced interaction between dopamine, acetylcholine, and GABA play a vital role in regulating motor movements. . Striatal gamma aminobutyric acid (GABAergic) medium spiny neurons are most vulnerable to cell death in HD. . GABA normally has inhibitory effects on the thalamus and tells the cortex to brake movement.

Neuropathology Selective loss of these specialized cells result in decreased inhibition (i.e., increased activity) of the thalamus. Thalamus increases output to certain regions of the cerebral cortex. This may lead to the disorganized, excessive (hyperkinetic) movement patterns of chorea. As disease progresses, damage to other pathways and dopamine receptors causes a decreased stimulation to the cortex and thus rigid bradykinetic features.

Risk factor GENETICS Altered chromosome 4

Overproduction of huntingtin protein Clumping of huntingtin protein Neuronal cell death in the basal ganglia Imbalance of neurotransmitters in striatum (GABA) Decreased inhibition of the thalamus Disrupts critical interneural pathways Thalamus increases output to regions of the cerebral cortex Excessive movement patterns of chorea (Hyperkinesia) Decreased stimulation to the cortex (bradykinesia)

Degeneration of Basal Ganglia

Brain Imaging studies in HD: Striatal degeneration and atrophy Caudate and putamen hypometabolism and volume loss begins before onset of symptoms. Some evidence of patchy cortical thinning are more prominent over the posterior cortical regions and proceed to the anterior cortical regions with disease progression, and more evident in the left striatum. Atrophy of thalamic subnuclei projecting to the prefrontal areas, substantia nigra, nuclei of hypothalamus, small regions of the hippocampus, and Purkinje cells of the cerebellum.

Clinical Features of Huntingtons Disease Progressive neurodegenerative disorder characterized by atrophy of the basal ganglia causing triad of cognitive, motor and psychiatric impairments. There is no cure for HD. Inherited autosomal dominant disorder with a 50% chance of inheriting the mutant gene from an affected parent. In western Europe and USA prevalence is higher at about 7-10 per 100, 000. Lower in Asian and African populations.

Clinical Features Typically an adult onset disorder with a mean age onset of 35-44 years (range 2 to 80 years).