Huntingtons Disease

1.​ The cause of Huntington’s disease (HD) is a genetic mutation in the HTT gene, which provides instructions for making a protein called huntingtin. This mutation involves an abnormal expansion of a CAG (cytosine-adenine-guanine) repeat within the gene. This leads to the production of an abnormally long huntingtin protein that is prone to clumping, which is toxic to brain cells. 2.​ The symptoms of Huntington’s disease (HD) include a trade of motor, cognitive, and psychiatric disturbances. Motor symptoms include chorea (involuntary, jerky movements), dystonia (sustained muscle contractions), and rigidity. Cognitive symptoms involve decline in executive functions, such as planning, organization, and decision-making. Psychiatric symptoms can include depression, irritability, anxiety, and in some cases, psychosis. Compared to other neurodegenerative diseases, HD is unique in its combination of these three symptom categories. For example, while Parkinson's disease primarily affects motor functions, and Alzheimer’s disease primarily affects memory, HD affects all three domains significantly. 3.​ As Huntington's disease (HD) progresses, the symptoms worsen. Motor symptoms become more pronounced, leading to increased difficulty with movement, coordination, and balance. Cognitive decline advances, affecting memory, attention, and language skills. Psychiatric symptoms can also intensify, leading to more severe mood disturbances and behavioral problems. Eventually, individuals with HD require assistance with all aspects of daily living. Treatment for HD is primarily symptomatic. Medications can help manage chorea, depression, and psychiatric symptoms. Physical, occupational, and speech therapy can help maintain motor functions and communication skills. There is currently no cure for HD, and treatments do not slow the progression of the disease. 4.​ The classic symptoms of HD include chorea (involuntary, jerky movements), Cognitive decline (problems with memory, planning and decision-making), Psychiatric symptoms (depression, irritability, and sometimes psychosis). Similarities between HD, Parkinson’s and, Alzheimer's include neurodegenerative (all three diseases involve the progressive degeneration of brain cells), cognitive impairment (cognitive decline is a symptom in all three diseases, though it manifests differently), and motor symptoms (Both HD and Parkinson’s disease involve motor symptoms, although the specific types of motor impairments differ). The differences between HD, Parkinson’s, and Alzheimer’s include primary motor symptoms (HD is characterized by chorea, while Parkinson’s is characterized by rigidity, bradykinesia “slowness of movement” and tremor. Alzheimer’s primarily affects memory and cognition, with motor symptoms typically appearing later in the disease. Cognitive profile (Alzheimer’s disease primarily affects memory in its early stages, while HD affects executive functions such as planning and decision-making earlier). Genetic basics (HD is caused by a single dominant gene mutation, whereas Parkinson’s and Alzheumer’s have more complex genetic and environmental risk factors). Specific brain areas affected (HD primarily affects the striatum, Parkinson’s affects the substantia nigra, and Alzheimer’s affects the hippocampus and cerebral cortex). 5.​ GABA (gamma-aminobutyric acid) is the primary inhibitory neurotransmitter in the central nervous system. It reduces neuronal excitability throughout the nervous symptom. GABA typically increases the membrane’s permeability to chloride ions (Cl-) or potassium ions (K+), leading to hyperpolarization. This hyperpolarization makes it more difficult for the neuron to reach the threshold for firing an action potential, thus inhibiting neuronal activity. 6.​ By inhibiting neuronal activity, GABA generally reduces muscle movement. Increased GABA activity can lead to muscle relaxation and decreased responsiveness to stimuli that would normally cause muscle contraction. 7.​ The loss of striatal neurons, many of which are GABAergic (meaning they produce and release GABA), would result in lower GABA levels in the brain. Huntington’s Disease (HD) involves the degeneration of neurons in the striatum, including GABAergic neurons. The reduced GABA levels lead to decreased inhibition of the motor cortex and other brain regions, resulting in the characteristic uncontrolled movements (chorea) seen in HD patients. 8.​ Altered intracellular calcium levels can affect various cellular processes, including enzyme activity, signal transduction, muscle contraction, neurotransmitter release, and gene expression. Dysregulation can lead to apoptosis or necrosis. 9.​ Excitotoxicity is the process by which neurons are damaged or killed by excessive stimulation from excitatory neurotransmitters like glutamate. This overstimulation leads to a large influx of calcium ions into the cell. The excessive calcium activates enzymes that damage cell structures, disrupt mitochondrial function, and trigger apoptosis. In neurodegeneration, chronic excitotoxicity can contribute to the progressive loss of neurons seen in diseases like Alzheimer’s, Parkinson’s, and stroke. 10.​Generation of animal models: (Animal models, such as transgenic mice, are created to express the mutant huntingtin gene, mimicking HD pathology. These models allow researchers to study disease progression and test potential therapies.), Electrophysiology: (Techniques like patch-clamp electrophysiology are used to measure membrane potential and ion channel activity in neurons. This helps understand how mutant huntingtin affects neuronal excitability and firing patterns.), Low concentration measurements: (Ion-selective electrodes are fluorescent dyes that are used to measure intracellular ion concentrations, like calcium or sodium in HD models. This helps reveal disruptions in ion homeostasis caused by mutant huntingtin.), Microscopy and imaging: (Confocal microscopy and other imaging techniques are used to visualize cellular and tissue-level changes in HD models. This includes examining neuronal morphology, synapse density, and the formation of huntingtin aggregates.), Cellular and Tissue assays: ( These assays measure cell viability, apoptosis, and oxidative stress in HD models. They help quantify the extent of neuronal damage and identify potential therapeutic targets.), In vivo imaging: (Techniques like two-photon microscopy allow for real-time imaging of neuronal activity and cellular changes in living animal models of HD. This provides insights into disease progression and the effects of interventions.) 11.​The basic stages of disease progression in Huntington’s disease (HD) are typically described as early, middle, and late stages. Symptoms such as severe motor impairment, cognitive decline, psychiatric disturbances, and difficulties with self-care are likely to require professional care. 12.​Some specific organizations or resources that might be helpful to Amanda’s family in caring for Uncle Gerald include Huntington’s Disease society of America (HDSA) at hdsa.org, the National Institute of Neurological Disorders and Stroke (NINDS) at ninds.nih.gov, and local support groups or care facilities specializing in neurodegenerative diseases.