HUNTINGTON’S DISEASE- No Panacea (Cure) yet!
V. Ravi Chandra
B.Pharmacy from Priyadarshini College of pharmacy,
Hyderabad, AP, INDIA
Huntington's disease is an intricate illness. It is a neurodegenerative, insidious disorder-which means it is harmful and fatal but gradually. The onset of the disease is very late to diagnose the disease. Huntington's disease (HD) also called as ‘Huntington’s Chorea’. Chorea means dance in Greek, which is aftereffect of genetically programmed degeneration of brain cells, called neurons, in certain areas of the brain. This degeneration causes uncontrolled movements, loss of intellectual faculties, and emotional disturbance. By choreic movement physically we can diagnose HD. HD is also a familial disease, passed from parent to child through a mutation in the normal gene. Attempts to study early disease are not unique in neurology (e.g., mild cognitive impairment and vascular cognitive impairment), but studying otherwise healthy-appearing individuals who have nearly 99% certainty of manifesting the symptoms of brain disease does provide distinct but valuable information about the true natural history of the disease. A genetic test, coupled with a complete medical history and neurological and laboratory tests, helps physicians diagnose HD. Presymptomic testing is available for individuals who are at risk for carrying the HD gene. HD occurs in about one out of every 10,000 Caucasian individuals. In India, the cases are unknown because of failure of doctors to diagnose HD as they never seen HD in their practice. Approximately 2.5 times more individuals are at risk for the disorder because of the midlife peak in age at onset.
Reference Id: PHARMATUTOR-ART-1222
Huntington’s disease is an autosomal-dominant, progressive neurodegenerative disorder with a distinct phenotype, including chorea and dystonia, in coordination, cognitive decline, and behavioral difficulties. Typically, onset of symptoms is in middle age after affected individuals have had children, but the disorder can manifest at any time between infancy and senescence. The mutant protein in Huntington’s disease—huntingtin—results from and expanded CAG repeat leading to a polyglutamine strand of variable length at the N-terminus. Evidence suggests that this tail confers a toxic gain of function. The precise pathophysiological mechanisms of Huntington’s disease are poorly understood, but research in transgenic animal models of the disorder is providing insight into causative factors and potential treatments. Several doctors, but George Huntington’s vivid description led to the eponymous designation of the disorder as Huntington’s disease. Over the next, few decades noted the hereditary nature of chorea in the 19thcentury, the worldwide distribution of the disorder and its juvenile form were recorded. The discovery of the causal HDgene has stimulated research, and work is now focusing on molecular mechanisms of disease.
Huntington’s disease was given different names throughout this history as understanding of the disease changed. Originally called simply 'chorea' for the jerky dance-like movements associated with the disease, HD has also been called 'hereditary chorea' and 'chronic progressive chorea'.
The first thorough description of the disease was by George Huntington in 1872. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked; he presented his detailed and accurate definition of the disease as his first paper.
The most striking pathology in HD occurs within the neostriatum, in which gross atrophy of the caudate nucleus and putamen is accompanied by selective neuronal loss and astrogliosis. Marked neuronal loss also is seen in deep layers of the cerebral cortex. Other regions, including the globus pallidus, thalamus, sub thalamic nucleus, substantia nigra, and cerebellum, show varying degrees of atrophy depending on the pathologic grade. The extent of gross striatal pathology, neuronal loss, and gliosis provides a basis for grading the severity of HD pathology. No gross striatal atrophy is observed in grades 0 and 1. Grade 0 cases have no detectable histologic neuropathology in the presence of a typical clinical picture and positive family history suggesting HD. Grade 1 cases have neuropathologic changes that can be detected microscopically but without gross atrophy. In grade 2, striatal atrophy is present, but the caudate nucleus remains convex. In grade 3, striatal atrophy is more severe, and the caudate nucleus is flat. In grade 4, striatal atrophy is most severe, and the medial surface of the caudate nucleus is concave.
The genetic basis of HD is the expansion of a cysteine-adenosine-guanine (CAG) repeat encoding a polyglutamine tract in the N -terminus of the protein product called huntingtin. The function of huntingtin is not known. Normally, it is located in the cytoplasm. The association of huntingtin with the cytoplasmic surface of a variety of organelles, including transport vesicles, synaptic vesicles, microtubules, and mitochondria, raises the possibility of the occurrence of normal cellular interactions that might be relevant to neuro-degeneration. N-terminal fragments of mutant huntingtin accumulate and form inclusions in the cell nucleus in the brains of patients with HD, as well as in various animal and cell models of HD. The presence of neuronal intranuclear inclusions (NIIs) initially led to the view that they are toxic and, hence, pathogenic.More recent data from striatal neuronal cultures transfected with mutant huntingtin and transgenic mice carrying the spinocerebellar ataxia-1 (SCA-1) gene (another CAG repeat disorder) suggest that NIIs may not be necessary or sufficient to cause neuronal cell death, but translocation into the nucleus is sufficient to cause neuronal cell death.Caspase inhibition in clonal striatal cells showed no correlation between the reduction of aggregates in the cells and increased survival.
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