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Huntington Disease
Pathology
Huntington's Disease (HD) is a progressive neurodegenerative disorder caused by an autosomal dominant mutation in the HTT gene, which encodes the huntingtin protein. The mutation involves an abnormal expansion of CAG trinucleotide repeats, leading to a polyglutamine tract in the huntingtin protein. This protein becomes toxic, resulting in neuronal dysfunction and death, primarily affecting the striatum and cerebral cortex
Symptoms
HD is characterized by a triad of symptoms:
Motor dysfunction: Chorea (involuntary, jerky movements), dystonia, bradykinesia, and eventual rigidity.
Cognitive decline: Impaired executive functions, memory disturbances, and dementia in later stages.
Psychiatric symptoms: Depression, anxiety, irritability, and psychosis.
Primary Mechanism
The primary mechanism involves widespread neuronal dysfunction and selective neurodegeneration, particularly in the striatum and cerebral cortex. Key cellular processes affected include proteostasis, mitochondrial energy production, and synaptic transmission. Mutant huntingtin also disrupts transcriptional regulation and enhances glutamate excitotoxicity via NMDA receptor overactivation, leading to neuronal apoptosis and death.
The primary pathological injury in HD involves the accumulation of mutant huntingtin protein, which leads to:
Neuronal loss: Predominantly in the caudate nucleus and putamen of the basal ganglia.
Glutamate excitotoxicity: Overactivation of NMDA receptors contributes to neuronal death.
Mitochondrial dysfunction: Energy deficits exacerbate neuronal damage
Secondary Mechanism
The secondary mechanisms of HD result from the cascading effects of the primary pathology. Neuroinflammation, driven by activated microglia and astrocytes, amplifies neuronal injury through the release of pro-inflammatory cytokines and oxidative stress. The loss of striatal neurons further disrupts motor and cognitive pathways, leading to abnormal cortical-striatal-thalamic loops and secondary neuronal damage in connected regions. Systemic effects, including metabolic dysfunction, weight loss, and muscle wasting, emerge as secondary consequences of mitochondrial impairments and catabolic changes induced by the disease. Together, these mechanisms contribute to the progressive and multisystem nature of HD, culminating in severe disability and mortality.
Secondary injuries arise from the ongoing neurodegeneration:
Neuroinflammation: Microglial activation and astrocyte dysfunction exacerbate damage.
Loss of connectivity: Degeneration of white matter tracts disrupts communication between brain regions.
Systemic effects: Weight loss and muscle wasting occur despite adequate caloric intake, possibly due to metabolic dysfunction
Outcome
The progressive nature of HD results in severe disability and death. Patients often lose independence, requiring full-time care. Death typically occurs 15-20 years after symptom onset, often due to complications like aspiration pneumonia, falls, or infections.
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