Purkinje Cells and Ataxia

Purkinje Cells and Ataxia

• Degeneration of Purkinje cells correlates strongly with ataxia.
• Purkinje cells are notably vulnerable due to their large cell bodies with abundant cytoplasm.

Mitochondrial Dysfunction

• Proper mitochondrial function is crucial for the survival and conduction of Purkinje cells.
• Impaired mitochondrial performance leads to the degeneration of these cells.

Channelopathies

• Mutations in voltage-gated calcium channels result in excessive calcium release from stores, leading to degeneration in spinocerebellar ataxias (SCA) 15, 16, and 29.
• Increased mitochondrial calcium influx is implicated in SCA28, promoting apoptosis of Purkinje cells.

Autophagy and Proteostasis

• Loss of autophagy and accumulation of misfolded long polyglutamine peptide contribute to neurodegeneration.

Family and Patient History

• Family history is critical; onset and progression of symptoms can vary, often gradually manifesting over years.
• The size of triplet repeat expansions has a direct relationship with the severity and pace of disease onset.

Clinical Features

• There is a significant phenotypic overlap among various SCA subtypes, even within families.
• Pediatric cases tend to present more severely and at an earlier age.

Central Nervous System Involvement

• Most hereditary ataxias affect not only the cerebellum but also the brainstem and spinal cord.
• Symptoms may include tongue atrophy, fasciculations, spasticity, and hyperreflexia.

Genetic Testing in Diagnosis

• Definition of SCA subtypes requires clinical manifestations followed by genetic analysis as the gold standard.
• Advances in molecular genetic testing enable earlier classification and diagnosis of SCAs.

Scenarios for Genetic Testing

• Multiple testing types include diagnostic, predictive, prenatal, carrier tests, and risk factor assessments.
• Genetic testing in families with positive histories is crucial for identifying specific SCA subtypes.

Neuroimaging Findings

• Neuroimaging reveals cerebellar atrophy, notably prominent in SCA2; other SCAs may show regional differences.
• Specific atrophies are seen in different SCAs, such as pontocerebellar atrophy in SCA3.

Management of Spinocerebellar Ataxia

• Spinocerebellar ataxia is a genetic disorder with no definitive cure; treatment focuses on symptom relief.
• Common treatments include antiepileptic drugs, botulinum toxin for dystonia, beta-blockers, and antidepressants.

Prognosis of Spinocerebellar Ataxia

• Full symptoms often take years to develop and are typically irreversible once evident.
• Most patients may require wheelchair support within 10 to 15 years; physical therapy can help delay this need.

Inherited Neurological Disorders

• Ataxia is a neurological sign indicating lack of coordination in muscle movements, often presenting with abnormal gait, speech changes, and eye movement disorders.
• Three main types of ataxia: cerebellar, sensory, and vestibular, each affecting different coordination systems.
• Ataxia can be classified as sporadic (without family history), genetic (hereditary), or acquired (due to environmental factors).

Types of Ataxia

• Sporadic Ataxia: Develops in adulthood due to factors like head trauma, tumors, or toxin exposure.
• Genetic Ataxia: Inherited, showing clear patterns such as autosomal dominant, autosomal recessive, or X-linked inheritance.
• Acquired Ataxia: Resulting from structural conditions, inflammation, or toxicity, usually not inherited.

Genetic Ataxia Examples

• Friedreich’s Ataxia (FRDA): Autosomal recessive; onset typically before age 20, requiring abnormal genes from both parents.
• Fragile X–Associated Tremor/Ataxia Syndrome (FXTAS): X-linked inheritance, risk increases with age.

Spinocerebellar Ataxia (SCA)

• SCA is a hereditary, progressive neurodegenerative disorder primarily affecting the cerebellum, with over 40 distinct genetic subtypes known.
• Major types include SCA1, SCA2, SCA3, and SCA6, accounting for most cases.
• CAG repeat expansions are common mechanisms in several types of SCA, leading to neurodegeneration.

Etiology and Epidemiology

• SCA has a global prevalence of 1 to 5 per 100,000 people.
• SCA3 is most prevalent (25-50%), followed by SCA2 (13-18%), SCA6 (13-15%), and SCA7.
• Genetic anticipation observed with increasing CAG repeats in successive generations.

Pathophysiology

• Pathogenesis involves genetic mutations leading to abnormal proteins that cause neurodegeneration through mechanisms like transcriptional dysregulation and mitochondrial dysfunction.
• Purkinje cells are primarily affected; their degeneration correlates with the symptoms of ataxia.
• Mitochondrial dysfunction and channelopathies contribute to the progression of SCA.

Family and Patient History

• Family history is crucial for diagnosis; gradual onset and slow progression are typical.
• Clinical manifestations vary among family members, with early onset often observed in pediatric cases.
• The severity of the disease may correlate with the size of triplet repeat expansions.

Management and Prognosis

• Management of ataxia usually focuses on symptomatic relief and support, as many genetic ataxias are progressive and lack curative treatments.
• Prognosis varies widely depending on the type of ataxia and individual patient factors, including genetic background and family history.

Explore the critical relationship between Purkinje cell degeneration and ataxia. This quiz covers mitochondrial dysfunction, channelopathies, and the role of autophagy in neurodegeneration, along with the importance of family history in symptom progression.