INTRODUCTION:
Huntington’s disease is a hereditary disorder caused by an autosomal dominant mutation that usually begins causing symptoms at age 30 to 40 years. It is characterized by first by flicking movements in individual muscles and then progressive severe distortion movements of the entire body. In addition, severe dementia develops along with motor dysfunction.
The abnormal movements of HD are believed to be caused by the loss of most of the cell bodies of GABA-secreting neurons in the caudate nucleus and putamen and of acetylcholine secreting neurons in many parts of the brain. The axons terminal of the GABA neurons normally inhibit portions of the globus pallidus and substantia nigra. The loss of inhibition is believed to allow spontaneous outbursts of global pallidum and substantia nigra activity that cause the distortion movements.
Dementia in HD probably does not result from the loss of GABA neurons but from the loss of acetylcholine secreting neurons, perhaps especially in the thinking areas of the cerebral cortex.
Mechanism of Huntington:
Huntington protein interacts with 100 other proteins. It is toxic to certain cell types particular in the brain. Early damage is most evident in the striatum but as the disease progresses other areas of the brain are also affected. Early symptoms are attributable to the function of the striatum and its cortical connection mainly control over movement, mood, and higher cognitive functions.
HTT gene is expressed in all mammalian cells. Higher concentration is found in brain and testis, with moderate amount found in liver, heart, and lungs. It interacts with protein which is involved in transcription, cell signaling and intracellular transporting. It also acts as an antiapoptotic agent, control production of brain-derived neurotrophic factors, a protein which protects neurons and regulates their creation during neurogenesis. HTT also facilitate vesicular transport and synaptic transmission and controls neuronal gene transcription.
Signs and symptoms become noticeable at the age of 35-44 years but can begin at any age from infancy to old age. The most characteristic physical symptoms are:
Jerky, random, uncontrollable movements called ‘chorea’.
Psycho-motor functions become increasingly impaired. Abnormal facial expressions and difficulties in chewing, speaking and swallowing. Sleep disturbances are also associated symptoms.
Cognitive abilities are progressively impaired- e.g., executive function (planning cognitive thinking, abstract thinking inhibition of inappropriate actions). As the disease progresses, memory deficits tend to appear. Suicidal attempts or thoughts are more common than in the general population.
Mutant huntingtin is expressed throughout the body and associated with abnormalities in peripheral tissues that are directly caused by site expression outside the brain. These abnormalities include muscle atrophy, cardiac failure, impaired glucose tolerance, weight loss, osteoporosis, and testicular atrophy.
In humans, the disease is not caused by inadequate production of HTT but by a gain of toxic function of HTT gene (mutated HTT); it has much time repeating codon, CAG, that codes for more glutamine residues in the molecular structure of an abnormal neuronal cell protein called huntingtin that causes the symptoms.
Cellular changes and pathology due to mutated HTT: there are multiple cellular changes through which toxic function of mutant HTT may manifest and produce the disease HD pathology. During the biological process of post-translational modification of mutant HTT, cleavage of protein can cleave behind shorter fragments constitutive the parts of the polyglutamine expansion. The polar nature of glutamine causes interaction with other protein. When it is overabundant in unmodified HTT proteins or the HTT fragments created from HTT cleavage. Thus the mutant HTT molecule strand form H-bonds with one another, forming a protein aggregate rather than folding into functional proteins. Over time the aggregates accumulate, ultimately interfering with neuron function. Because these fragments can then misfold and coils in a process called protein aggregation, to form inclusion bodies, within the cells.
Neuronal inclusions are one of the earliest pathological changes which are toxic and result in neuronal cell death. Several pathways by which HTT may cause cell death have been identified, these include- effect on chaperone proteins, which help in protein folding and remove misfolded one, interact with caspases which play a role in process of removing cells, the toxic effect of glutamine on nerve cells, impairment of energy production within cells and effects on expression of genes.
Another way function of cell disrupted is due to damage of mitochondria in striatal cells of the brain, interaction of altered HTT protein with numerous protein in neurons leads to an increased vulnerability of glutamine which in larger amounts have been found to be an excitotoxin.
HD affects the whole brain, but certain areas are more vulnerable than others. The most prominent early effect on parts of basal ganglia called neostriatum which is composed of the caudate nucleus and tamin. Other areas affected include substantial Niagra of the cerebral cortex. Some part of cerebral i.e, hippocampus, Purkinje cells, lateral tuberal nuclei of hypothalamus and parts of the thalamus. The basal ganglia which are most prominent effected in HD play a key role in movement and behavioral control. Since they are part of the cognitive executive system and motor circuit. The basal ganglia orderly inhibit a large number of circuits that generate specific movements. To initiate a particular movement, the cerebral cortex sends a signal to basal ganglia that cause the inhibition to be released. Damage to the basal ganglia can cause the release or reinstatement of the inhibitions to be erratic and uncontrolled which results in an awkward start to the motion to be unintentionally initiated, or a motion to be halted before or beyond its intended completion.
The accumulating damage to this area causes the characteristic erratic movements associated with HD. Because of the basal ganglia inability to inhibit movement individuals affected by it will experience a reduced ability to produce speech and swallow food and liquids.
Diagnosis:
Medical diagnosis of the onset of HD can be made by the appearance of the disease-specific to the disease.
Genetic testing: if no family history
Physical and psychological examination
Medical imaging- CT, MRI of the brain which can show atrophy of coordinate nuclei early in the disease
PET scan
Pre implantation genetic testing/ diagnosis (PGD)
Embryos produced using in-vitro fertilization may be genetically tested using PGD. One or more cells are extracted from a typical 4-8 cell embryo and then tested for genetic abnormality can then be used to ensure embryos affected with HT gene is not implanted, and therefore any offspring will not inherit the disease.
Pre-natal testing: it can be done for embryo and fetus in the womb, using fetal genetic material. Amniocentesis test can be performed if the pregnancy is further along within 14-18 weeks.
Management:
There is no cure for HD but treatment are available.
To reduce the severity of its symptoms:
Tetrabenazine is an approved compound for the management of chorea.
Exercises and therapies – help rehabilitate cognitive symptoms of HD.
There is some evidence for the usefulness of physical therapies, occasional therapies and speech therapies.
Other drugs that help to reduce chorea include neuroleptics and benzodiazepines.
Nutrition management is very important as the disease advances. Thickening agents can be added to liquids as thicker fluids are easier and safer to swallow. The effective person if eating becomes too hazardous or uncomfortable, the option of using percutaneous endoscopic gastrostomy (feeding tube) is available. This reduces the risk of aspirating food and provides better nutritional management.
Physical therapies result in stunting stretching and cardiovascular exercises, walking aids are prescribed. These patients die due to infection like pneumonia. They have a greater risk of heart disease and suicidal temptation.
