Category: Pathology - kembara Xtra

Pathology- Vasculitis

4/2/2025

Pathology- Vasculitis
Definition: Vasculitis encompasses a group of diseases where inflammation and damage to blood vessels are the primary pathology. This damage can affect vessels of varying sizes, leading to diverse clinical presentations.
Types of Vasculitis:
This guide outlines key features to differentiate between the vasculitides discussed. Remember that overlap exists, and accurate diagnosis often requires biopsy and serological testing (ANCA).
1. Giant Cell (Cranial or Temporal) Arteritis:

Vessel Size: Medium and large arteries.
Location: Primarily head and neck arteries (temporal artery most commonly).
Demographics: Adults >50 years old.
Presentation: Weeks to months of fever, anorexia, weight loss, headache, scalp tenderness, jaw claudication (pain with chewing).
Serious Complications: Ocular involvement (blindness), aortic aneurysm (25% of cases).
Diagnosis: Temporal artery biopsy (positive in only 60% due to focal nature of inflammation); shows lymphohistiocytic infiltrate, media disruption, and often giant cell reaction.

2. Polyarteritis Nodosa:

Vessel Size: Medium-sized arteries.
Presentation: Systemic vasculitis leading to aneurysm formation and vessel narrowing. Relatively rare with strict diagnostic criteria.
Organ Involvement: Gastrointestinal tract (abdominal pain), nervous system (peripheral nerve palsies), muscles (muscle aches).
Diagnosis: Imaging showing vessel narrowing and aneurysms; biopsy confirming necrotizing vasculitis.

3. Wegener's Granulomatosis (Granulomatosis with Polyangiitis - GPA):

Vessel Size: Small vessels.
Presentation: Systemic vasculitis with prominent upper respiratory tract, lung, and kidney involvement. Characterized by c-ANCA positivity.
Symptoms: Nasal symptoms, acute renal failure, pulmonary symptoms.
Diagnosis:
- Renal biopsy: Focal segmental necrotizing glomerulonephritis with crescent formation (identical to microscopic polyangiitis).
- Lung biopsy: Large necrotizing granulomatous inflammation and necrotizing vasculitis.
Treatment: Aggressive immunosuppression is crucial to prevent death.

4. Microscopic Polyangiitis (MPA):

Vessel Size: Small vessels.
Presentation: Systemic vasculitis with significant renal and lung involvement. Characterized by p-ANCA positivity.
Demographics: Adults, median age 55.
Symptoms: Acute renal failure, pulmonary symptoms.
Diagnosis:
- Renal biopsy: Focal segmental necrotizing glomerulonephritis with crescent formation (identical to Wegener's granulomatosis).
- Lung biopsy: Marked alveolar hemorrhage and necrotizing capillaritis within alveolar septa.
Treatment: Aggressive immunosuppression is essential for survival.

Pathology-Sarcoidosis

4/2/2025

Pathology-Sarcoidosis

I. Definition:

Sarcoidosis is a multisystem inflammatory disease of unknown etiology characterized by the formation of granulomas (collections of immune cells) in various tissues.

II. Epidemiology:

Prevalence: 10-20 cases per 100,000 individuals in the UK.
Age of Onset: Peaks between 20-40 years old.
Race: Individuals of African descent tend to experience more severe disease.

III. Etiology:

Unknown. The underlying cause remains unidentified.

IV. Pathogenesis:

The granulomatous inflammation is hypothesized to be a reaction to an unidentified antigen (foreign substance triggering an immune response). The exact antigen remains unknown.

V. Presentation:

Multisystemic: Can affect virtually any organ, but most commonly involves lymph nodes, lungs, and skin.
Acute Sarcoidosis: Sudden onset with symptoms like:
- Erythema nodosum (skin inflammation)
- Anterior uveitis (eye inflammation)
- Seventh cranial nerve palsy (facial weakness)
- Bilateral hilar lymphadenopathy (enlarged lymph nodes in the lungs - visible on chest X-ray)
Chronic Sarcoidosis: Insidious onset with features such as:
- Lupus pernio (facial skin lesions)
- Pulmonary fibrosis (scarring of lung tissue)
- Posterior uveitis (eye inflammation)

VI. Histopathology (Microscopic Examination):

Non-necrotizing granulomas: The hallmark finding is the presence of granulomas that lack central cell death (necrosis).
"Naked" granulomas: Sarcoid granulomas are typically well-circumscribed with minimal surrounding inflammatory cells, appearing "naked" under a microscope.
Fibrosis: Variable degrees of fibrosis (scarring) may accompany the granulomas.
Absence of other causes: Crucially, other explanations for the granulomas (infections, foreign bodies, tumors) must be ruled out.

VII. Prognosis:

Acute Sarcoidosis: Generally has a favorable prognosis with spontaneous resolution within 1-2 years after diagnosis.
Chronic Sarcoidosis: Carries a higher risk of complications, including progressive pulmonary fibrosis, potentially leading to respiratory failure and right ventricular failure (due to increased pressure in the pulmonary circulation).

Key Differences between Acute and Chronic Sarcoidosis: The table below summarizes the key distinctions:

Feature	Acute Sarcoidosis	Chronic Sarcoidosis
Onset	Sudden	Insidious
Course	Self-limiting (often resolves)	Progressive
Skin Manifestations	Erythema nodosum	Lupus pernio
Eye Involvement	Anterior uveitis	Posterior uveitis
Pulmonary Findings	Bilateral hilar lymphadenopathy	Pulmonary fibrosis
Prognosis	Generally favorable	Potential for serious complications

Pathology-Systemic Sclerosis (Scleroderma)

4/2/2025

Pathology-Systemic Sclerosis (Scleroderma)

I. Definition & Epidemiology:

Definition: Systemic sclerosis (SSc) is a rare, multisystem autoimmune disease characterized by excessive fibrous tissue accumulation in various organs. Crucially, this fibrosis leads to organ dysfunction.
Epidemiology:
- Annual incidence: 2-10 per million.
- Predominantly affects women (30-40 years old).

II. Aetiology & Pathogenesis:

Aetiology: The underlying cause of SSc remains unknown.
Pathogenesis: An aberrant immune response to an unidentified trigger leads to cytokine production (e.g., IL-4, TGF-β). These cytokines stimulate fibroblasts, resulting in excessive collagen deposition and fibrosis. This fibrosis affects multiple organ systems.

III. Clinical Presentation:

Two main subtypes exist, differing significantly in presentation and prognosis:

A. Limited Systemic Sclerosis (lSSc):
- Onset: Typically begins with Raynaud's phenomenon (cold-induced vasospasm in fingers and toes).
- Progression: Gradual thickening and tightening of skin (fingers, face, neck).
- Late Complications (after 10-15 years): Calcium deposits (calcinosis) in finger pads, small bowel involvement, and pulmonary hypertension.
B. Diffuse Systemic Sclerosis (dSSc):
- Onset: More rapid onset with widespread skin thickening, contractures, and ulcers.
- Visceral Involvement: Early involvement of internal organs including pulmonary fibrosis (lung scarring).
- Major Complications: Severe hypertension leading to acute renal failure ("scleroderma renal crisis") is a life-threatening complication.

IV. Immunology:

Autoantibodies are frequently present, aiding in diagnosis and subtype classification:
- Anti-nuclear antibodies (ANA): Present in ~65% of patients. Note: ANA is not specific to SSc.
- Anti-centromere antibodies: Found in 70-80% of lSSc patients. Suggestive of limited disease.
- Anti-topoisomerase I (Scl-70) antibodies: Present in ~40% of dSSc patients. Associated with diffuse disease and worse prognosis.

V. Prognosis & Treatment:

Prognosis: Currently incurable.
Treatment: Immunosuppressive therapies are used to manage organ involvement and progressive skin disease.
Causes of Death: Primarily due to renal and lung complications (renal failure and pulmonary fibrosis).

VI. Key Differences between lSSc and dSSc:

Feature	Limited Systemic Sclerosis (lSSc)	Diffuse Systemic Sclerosis (dSSc)
Onset	Gradual	Abrupt
Skin Involvement	Limited (fingers, face, neck)	Widespread
Visceral Involvement	Late (e.g., pulmonary hypertension)	Early (e.g., pulmonary fibrosis)
Major Complications	Calcinosis, small bowel issues	Scleroderma renal crisis, pulmonary fibrosis
Associated Antibody	Anti-centromere antibodies	Anti-topoisomerase I (Scl-70) antibodies

Pathology - Systemic Lupus Erythematosus (SLE)

4/2/2025

Pathology - Systemic Lupus Erythematosus (SLE)
I. Definition & Epidemiology:

Definition: SLE is a multisystem autoimmune disease characterized by the production of autoantibodies targeting nuclear and cytoplasmic antigens. This means the body's immune system mistakenly attacks its own cells.
Epidemiology:

Incidence: 4 per 100,000 people annually.
Predominantly affects women of childbearing age.
Higher prevalence in individuals of African and Asian descent.

II. Etiology & Pathogenesis:

Etiology (Cause): Unknown. A leading hypothesis suggests defective phagocytosis (the process of engulfing and destroying pathogens) of apoptotic bodies (dying cells). This failure to properly clear apoptotic cells exposes intracellular self-antigens, potentially triggering an autoimmune response.
Pathogenesis (Mechanism):

Autoreactive B and T cells (immune cells) become activated.
Immune complexes form: Autoantibodies bind to self-antigens.
These circulating immune complexes deposit in various tissues (skin, joints, kidneys).
Tissue inflammation and damage result from the immune complex deposition. (Visualize this process using Fig 18.1 if available).

III. Clinical Presentation (Symptoms):
SLE's wide-ranging symptoms depend on the affected organs. Remember the diverse nature of its presentations:

Common Symptoms: Fatigue, weight loss, low-grade fever.
Musculoskeletal: Arthralgia (joint pain).
Skin: Scaly red lesions (often on sun-exposed areas).
Pulmonary: Pleuritis (lung inflammation), pleural effusion (fluid buildup around lungs), pneumonitis (lung inflammation), potentially leading to pulmonary fibrosis (scarring).
Renal: Glomerulonephritis (kidney inflammation), leading to chronic kidney disease. This is a serious complication.
Hematological: Anemia (low red blood cell count), lymphopenia (low lymphocyte count), thrombocytopenia (low platelet count).

IV. Immunology (Diagnostic Markers):
Specific autoantibodies are key diagnostic indicators. Note the high prevalence of certain markers:

Anti-nuclear antibodies (ANA): >95% of SLE patients test positive. This is a common, but non-specific, finding.
Anti-double-stranded DNA (dsDNA) antibodies: 60% of patients. More specific to SLE.
Anti-Smith antigen antibodies: 20-30% of patients. Very specific to SLE.
Anti-phospholipid antibodies: 20-30% of patients. These antibodies cause a hypercoagulable state (increased risk of blood clots).

V. Prognosis:

15-year survival rate: Approximately 80% from the time of diagnosis.
Causes of death: Often related to severe renal (kidney) and pulmonary (lung) complications.

Pathology- Myasthenia Gravis

4/2/2025

Pathology- Myasthenia Gravis
I. Definition:

Myasthenia gravis (MG) is an autoimmune disease. This means the body's own immune system mistakenly attacks healthy tissues.
Specifically, autoantibodies (self-attacking antibodies) target the nicotinic acetylcholine receptor (nAChR) at the neuromuscular junction. This is the point where nerves meet muscles.

II. Epidemiology (Disease Frequency and Distribution):

Rare: Annual incidence is low (20 per 100,000).
Age and Gender: More common in women under 50 and men over 50. Note the age difference between genders.

III. Aetiology (Cause):

Unknown Trigger: The precise cause of autoantibody production is unclear. This is a crucial point to remember – we don't fully understand why the immune system attacks the nAChR.
Thymus Involvement: A significant link exists between MG and the thymus gland (located in the chest). Up to 75% of patients have thymus abnormalities:
- Thymoma: A tumor of the thymus.
- Hyperplasia: Enlargement of the thymus.
Thymus as a Source?: It's hypothesized that the abnormal thymus may be the site where these autoantibodies are produced.

IV. Pathogenesis (Mechanism of Disease):

Neuromuscular Junction: Recall that the nAChR is crucial for muscle contraction. Acetylcholine, a neurotransmitter, binds to it, triggering muscle activation.
Autoantibody Interference: The autoantibodies bind to the nAChR, preventing acetylcholine from binding effectively. This reduces the muscle's ability to contract.
Result: Impaired muscle contraction and weakness.

V. Presentation (Symptoms):

Key Symptom: Muscle Fatigue: Weakness that worsens with activity and improves with rest is the hallmark of MG. This is a fundamental characteristic.
Muscle Groups Affected (in order of typical involvement):
1. Extraocular muscles (eye muscles) – leading to diplopia (double vision) and ptosis (drooping eyelids).
2. Bulbar muscles (muscles controlling swallowing and speech) – difficulty swallowing (dysphagia) and speech impairment (dysarthria).
3. Facial muscles
4. Neck muscles
5. Limb girdle muscles (shoulders and hips)
6. Trunk muscles
Diagnostic Challenge: Symptoms can be subtle and easily mistaken for other conditions, making diagnosis difficult. This highlights the importance of considering MG in patients with unexplained muscle weakness.

VI. Prognosis (Outcome):

Generally Favorable: Most patients respond well to treatment. The disease is typically relapsing (symptoms come and go) but not progressive (does not steadily worsen over time).
Thymoma Exception: Patients with aggressive thymoma may have a poorer prognosis due to the cancerous nature of the tumor.

Key Concepts to Master:

Autoimmune nature: MG is caused by the body attacking its own nAChRs.
Neuromuscular junction dysfunction: The problem lies in the communication between nerves and muscles.
Muscle fatigue: The defining symptom.
Thymus gland involvement: A significant association exists between MG and thymic abnormalities.
Variable presentation: Diagnosis can be challenging due to subtle or atypical symptoms.

Pathology-Guillain-Barré Syndrome (GBS)

4/2/2025

Pathology-Guillain-Barré Syndrome (GBS)
I. Definition & Epidemiology:

Definition: Guillain-Barré syndrome (GBS) is an acute demyelinating polyneuropathy. This means it's a rapid onset disorder affecting many nerves, characterized by damage to the myelin sheath (the protective covering around nerves). It typically appears 1-2 weeks after a respiratory or gastrointestinal infection.
Rarity: GBS is a rare disease with an annual incidence of only 1-2 cases per 100,000 people.

II. Etiology (Causes):

Infectious Triggers: The most common triggers are infections caused by:
- Campylobacter jejuni
- Mycoplasma
- Cytomegalovirus (CMV)
- HIV
- Varicella-zoster virus (VZV)
- Epstein-Barr virus (EBV)
Other Associations: GBS can also be associated with:
- Vaccination (although this is rare and the benefits of vaccination far outweigh the risk)
- Surgery
- Malignancy (cancer)
Idiopathic Cases: In a significant number of cases, no clear cause can be identified.

III. Pathogenesis (Mechanism):

Cross-Reactivity: The leading theory suggests that the immune system, while fighting off an infection, mistakenly attacks the myelin sheath of peripheral nerves. This happens because an antigen (a protein on the surface of the pathogen) is similar to an antigen on the nerve myelin, leading to an immune "cross-reaction".
Demyelination & Polyneuropathy: This attack on the myelin causes demyelination (loss of the myelin sheath), resulting in an acute polyneuropathy (a condition affecting many peripheral nerves).

IV. Clinical Presentation:

Initial Symptoms: GBS typically begins with sudden onset of tingling and numbness in the fingers and toes (distal paresthesia).
Progressive Weakness: Over several weeks, the muscle weakness spreads proximally (from the extremities towards the trunk and center of the body), a hallmark characteristic of GBS.
Major Risk: Progressive ventilatory failure (difficulty breathing) is the most serious complication and a leading cause of death. This necessitates close monitoring and potential respiratory support.

V. Prognosis:

Recovery Rate: Approximately 85% of patients make a complete or near-complete recovery.
Long-Term Disability: About 10% of patients are unable to walk without assistance one year after diagnosis.

Key Concepts for Understanding and Studying:

Acute vs. Chronic: GBS is acute, meaning it develops rapidly. Contrast this with chronic conditions which develop slowly over time.
Polyneuropathy: Understand that "poly" means many and "neuropathy" refers to nerve dysfunction. Therefore, polyneuropathy means widespread nerve dysfunction.
Demyelination: Focus on the concept of immune system cross-reactivity leading to damage of the myelin sheath and subsequent nerve dysfunction.
Ascending Weakness: The progressive spread of weakness from the periphery (fingers and toes) to the center of the body is a critical diagnostic feature.
Ventilatory Failure: Recognize this as the most significant threat to life in GBS patients.

Pathology-Central Nervous System (CNS) Neoplasms

4/2/2025

Pathology-Central Nervous System (CNS) Neoplasms

I. Astrocytic Tumors

Most common primary intracranial neoplasms in adults. Unknown etiology. Typically arise in cerebral hemispheres.
Presentation: Headaches, seizures, focal neurological signs.
Histological Spectrum & Grading (WHO): Differentiation dictates grade and prognosis. Higher grade = worse outcome. Key genetic alterations drive progression.

Grade	Tumor Type	Histological Features	Genetic Alterations	Average Survival
II	Diffuse Astrocytoma	Slightly increased glial cellularity, mild atypia	P53 mutation, PDGFR-A overexpression	~5 years
III	Anaplastic Astrocytoma	Increased cellularity, greater atypia, mitotic figures	RB and P16 mutations added	~3 years
IV	Glioblastoma	Highly aggressive; atypical astrocytes, necrosis, vascular proliferation	(Above + more aggressive changes)	<1 year

II. Oligodendroglial Tumors

Usually arise in cerebral hemispheres.
Presentation: Neurological signs or seizures.
Genetic Alterations: Loss of heterozygosity at chromosomes 1p and 19q is common. Progression to anaplastic histology involves loss of 9p and 10q, and CDKN2A mutations.

Grade	Tumor Type	Histological Features	Genetic Alterations	Average Survival
II	Oligodendroglioma	Well-differentiated; round nuclei, clear cytoplasm, calcification common	1p/19q loss	~10 years
III	Anaplastic Oligodendroglioma	Increased cellularity, atypia, increased mitotic activity	1p/19q loss, 9p/10q loss, CDKN2A mutations	2-3 years

III. Ependymal Tumors

Originate from ependymal-lined ventricular system.
Location: Adults – mostly spinal cord; Children – mostly around fourth ventricle.
Histology: Mostly well-differentiated (WHO grade II); regular round nuclei, fibrillary background, glandular structures, perivascular rosettes.
Prognosis: Children (posterior fossa) ~50% 5-year survival; Adult spinal tumors have better outcomes.

IV. Meningiomas

Composed of neoplastic meningothelial cells.
Location & Appearance: Usually smooth, well-circumscribed, adherent to dura mater; can infiltrate skull.
Grading (WHO) & Prognosis: Most are low-grade (I), low recurrence risk post-surgical excision.

Grade	Tumor Type	Histological Features	Prognosis
I	Meningioma	Low mitotic activity, minimal atypia	Low recurrence risk post-surgical excision
II	Atypical Meningioma	Increased mitotic activity, cytological atypia or necrosis	Higher recurrence rate; may require radiotherapy
III	Anaplastic Meningioma	Markedly atypical cells, very high mitotic activity	Aggressive, malignant

V. Medulloblastoma

Predominantly in children. Primitive embryonal tumor, exclusively in cerebellum.
Presentation: Rapid growth, hydrocephalus. Can disseminate via CSF.
Histology: Very cellular; mitotically active small cells, hyperchromatic nuclei, scant cytoplasm.
Prognosis: Rapid growth; fatal without treatment; ~75% 5-year survival with treatment.

VI. Primary CNS Lymphomas

Lymphomas arising in CNS without extra-CNS disease.
Association: Strong association with immunosuppression.
Most common type: Diffuse large B-cell lymphoma; sheets of large atypical B-lymphoid cells.

VII. CNS Metastases

Occur at grey-white matter junction.
Common Primary Cancers: Breast, lung, renal, melanoma.

Pathology- Creutzfeldt-Jakob Disease (CJD)

4/2/2025

Pathology- Creutzfeldt-Jakob Disease (CJD)
I. Definition & Epidemiology:

Definition: CJD is a rare, fatal spongiform encephalopathy caused by the accumulation of misfolded prion protein (PrP) resistant to normal cellular breakdown. It's the most common human prion disease.
Epidemiology: Extremely rare, with an annual incidence of approximately 1 per 1,000,000.

II. Etiology (Causes):

Sporadic CJD: Spontaneous, random misfolding of normal PrP into the abnormal PrP form. The exact mechanism remains unclear.
Familial CJD: Inherited mutations in the PRNP gene increase the likelihood of PrP misfolding.
Variant CJD (vCJD): Believed to be transmitted via consumption of beef contaminated with PrPSc from cattle with bovine spongiform encephalopathy (BSE, "mad cow disease").

III. Pathogenesis (Disease Mechanism):

Misfolded Protein Propagation: The presence of abnormal PrPSc acts as a template, causing normal PrPC to misfold into the abnormal form.
Exponential Growth & Cell Death: This process leads to an exponential increase in PrPSc, ultimately causing neuronal cell death and the characteristic brain damage.

IV. Clinical Presentation:

Sporadic CJD: Typically affects middle-aged and elderly individuals. Onset is marked by rapidly progressing neurological symptoms.
Variant CJD (vCJD): Affects younger individuals (<30 years old). Initially presents with psychiatric symptoms, followed by cerebellar ataxia (problems with coordination and balance) and dementia. Key difference from sporadic CJD.

V. Histopathology (Microscopic Findings):

Sporadic CJD & vCJD: Both show spongiform changes (vacuolation of grey matter), neuronal loss (death of nerve cells), and gliosis (scarring in the brain).
Variant CJD (vCJD only): The presence of numerous "florid plaques" composed of amyloid forms of PrPSc is a key distinguishing neuropathological feature. These are absent in other CJD forms.

VI. Prognosis:

Currently, no effective treatment exists for CJD. The disease is invariably fatal.

Pathology-Motor Neurone Disease (MND)

4/2/2025

Pathology-Motor Neurone Disease (MND)
I. Definition & Epidemiology:

Definition: MND is a group of neurodegenerative diseases causing selective loss of motor neurons. This means the nerve cells that control voluntary muscle movement are progressively destroyed.
Epidemiology:
- Rare disease: Annual incidence 1-5 per 100,000.
- Slight male predominance.
- Typical onset: 50-70 years old.

II. Aetiology (Causes):

Mostly Idiopathic: In most cases (90%), the cause is unknown.
Familial (Inherited): Approximately 10% of cases are inherited, showing a genetic component.
Genetic Links: Several genes associated with familial MND have been identified, including SOD1, TDP-43, and FUS.

III. Pathogenesis (Disease Mechanisms):

Poorly Understood: The precise mechanisms driving MND remain largely unclear, even with insights from familial cases.
RNA Metabolism Dysfunction: A leading hypothesis points to defects in RNA metabolism as a crucial factor in motor neuron degeneration. This is based on the properties of TDP-43 and FUS proteins.
TDP-43 & FUS: Both are RNA/DNA-binding proteins with similar structures. Their dysfunction is strongly implicated in MND development.

IV. Clinical Presentation:

Muscular Symptoms: Asymmetrical muscle weakness and wasting (atrophy), muscle twitching (fasciculations), and muscle stiffness (spasticity) in limbs are common early signs.
Bulbar Symptoms: Difficulty with swallowing (dysphagia), chewing, speaking (dysarthria), coughing, and breathing (dyspnea) are characteristic as the disease progresses and affects the muscles controlling these functions.
Cognitive Changes: Cognitive impairment can also occur in some cases.

V. Macroscopic & Microscopic Findings:

Macroscopy (Gross Examination): The anterior roots of the spinal cord (which carry motor neuron axons) are atrophied (shrunken).
Histopathology (Microscopic Examination):
- Selective loss of motor neurons in the motor cortex (brain) and anterior horns of the spinal cord is the defining feature.
- In sporadic (non-inherited) MND, remaining motor neurons often contain abnormal protein inclusions that include ubiquitin and TDP-43.

VI. Prognosis:

Progressive & Fatal: MND is typically progressive, leading to death within a few years.
Cause of Death: Aspiration pneumonia (lung infection from inhaling food or saliva due to swallowing difficulties) is a frequent cause of death.

Pathology- Huntington's Disease

4/2/2025

Pathology- Huntington's Disease
I. Definition & Epidemiology:

Definition: HD is an inherited, neurodegenerative disorder resulting from a mutation in the HTT gene. This mutation leads to the production of a dysfunctional huntingtin protein.
Epidemiology:
- Prevalence: 5-10 per 100,000 globally, with geographical variation.
- Onset: Typically 35-45 years, but can occur at any age.
- Sex: Affects men and women equally.
- Inheritance: Autosomal dominant (only one affected copy of the gene is needed to develop the disease).

II. Genetics:

HTT Gene: Contains a CAG trinucleotide repeat sequence.
- Normal HTT: Less than 36 CAG repeats.
- Mutant HTT: More than 36 CAG repeats. The number of repeats directly correlates with disease severity and age of onset (more repeats = earlier onset, greater severity).
Anticipation: The number of CAG repeats tends to increase in subsequent generations, leading to earlier onset and more severe disease in offspring. This phenomenon is known as anticipation.

III. Pathogenesis:

Huntingtin Protein (HTT): The protein encoded by the HTT gene has various cellular functions and is expressed throughout the body, but is most concentrated in the brain and testes.
Mechanism of Disease: Mutated huntingtin protein is cytotoxic (toxic to cells), particularly affecting neurons in the caudate nucleus and putamen (basal ganglia structures crucial for movement control).

IV. Clinical Presentation:

Early Symptoms: Uncontrolled, jerky, involuntary movements (chorea).
Progressive Disease: Over time, HD leads to progressive motor, neuropsychiatric (mood disorders, cognitive issues), and cognitive decline, ultimately culminating in dementia.

V. Macroscopic & Microscopic Findings:

Macroscopy: Significant atrophy (shrinking) of the caudate nucleus and putamen. Cortical atrophy may also be present.
Histopathology: Marked neuronal loss in the caudate nucleus. Surviving neurons contain excessive amounts of the mutated huntingtin protein.

VI. Prognosis:

Survival: Average survival is approximately 20 years from symptom onset, but varies depending on the number of CAG repeats (more repeats = shorter survival).
Cause of Death: Often pneumonia or cardiac failure due to mutated huntingtin expression in cardiac muscle.