Why do trinucleotide repeats cause Spinocerebellar Ataxia (SCA)?

From the Guidelines

Trinucleotide repeats cause spinocerebellar ataxia (SCA) through a genetic mechanism where specific three-nucleotide sequences in DNA abnormally expand beyond their normal length, leading to the production of abnormal proteins with extended polyglutamine tracts that form toxic aggregates within neurons, as supported by the most recent study 1.

Mechanism of SCA

The expansions of trinucleotide repeats, such as CAG repeats, occur in genes important for cerebellar function. When these repeats expand beyond a threshold number, they produce abnormal proteins that disrupt normal cellular functions, particularly in the cerebellum and brainstem, leading to progressive neurodegeneration.

Clinical Presentation

The severity and age of onset of SCA often correlate with the length of the repeat expansion - longer repeats typically cause earlier onset and more severe disease. This phenomenon, known as anticipation, explains why SCA can worsen in successive generations of affected families. Different SCA subtypes (SCA1, SCA2, SCA3, etc.) result from trinucleotide expansions in different genes, each affecting specific neuronal populations and producing somewhat distinct clinical presentations, though all share the common feature of progressive ataxia.

Diagnosis and Imaging

Imaging, particularly MRI, plays a crucial role in the diagnosis of SCA, allowing for the evaluation of parenchymal injury in the form of volume loss or alterations in signal intensity. Patterns of parenchymal injury may suggest a certain ataxia subtype, and the detection of abnormal iron deposition or calcification may also be helpful in some forms of ataxia. However, diagnosis relies on the combination of history, a thorough clinical neurologic examination, and imaging with confirmatory laboratory and/or genetic testing based on these findings, as noted in 1.

Key Points

• Trinucleotide repeats cause SCA through the production of abnormal proteins with extended polyglutamine tracts.
• The severity and age of onset of SCA correlate with the length of the repeat expansion.
• Different SCA subtypes result from trinucleotide expansions in different genes, each affecting specific neuronal populations.
• Imaging, particularly MRI, is crucial in the diagnosis of SCA, but diagnosis relies on a combination of clinical examination, imaging, and laboratory/genetic testing.

From the Research

Trinucleotide Repeats and Spinocerebellar Ataxia (SCA)

• Trinucleotide repeats are a major cause of neurological disease, including Spinocerebellar Ataxia (SCA) 2
• The expansion of trinucleotide repeats leads to the formation of unusual DNA structures during replication, resulting in dynamic mutations 3
• In SCA, the expansion of CAG repeats within the protein coding portion of the gene leads to the formation of polyglutamine tracts, which is thought to be a common mechanism of inherited neurodegenerative disease 2

Mechanism of Trinucleotide Repeat Expansion

• The expansion of trinucleotide repeats is unstable and can lead to anticipation, where the disease phenotype worsens over successive generations 2
• The CAG repeat expansion in the TBP gene is thought to be the cause of SCA17, and the organization of the repeats is proposed to be an alternative scheme [(CAG)3 (CAA)2] [CAA (CAG)n CAA CAG] [CAA (CAG)n CAA CAG] 3
• The mechanism of trinucleotide repeat expansion is not fully understood, but it is thought to involve the formation of unusual DNA structures during replication 3

Clinical and Molecular Characteristics of SCA

• SCA is a group of degenerative ataxias with autosomal dominant inheritance, and the most common form of mutation is the expansion of trinucleotide (CAG) repeat encoding polyglutamine 4
• The clinical and molecular characteristics of SCA vary depending on the specific type, but all forms are characterized by ataxia and degeneration of the cerebellum 5
• The pathogenesis of SCA is thought to involve the formation of polyglutamine-containing intranuclear and cytoplasmic inclusion bodies, which may lead to protein aggregation and neuronal degeneration 5

Types of SCA

• There are several types of SCA, including SCA1, SCA2, SCA3/Machado-Joseph disease, SCA6, SCA7, and SCA17, each with distinct clinical and molecular characteristics 2, 4, 6, 5
• SCA6 is the prototype of "pure" cerebellar cortical or cerebello-olivary atrophy, while SCA1, SCA2, and SCA7 are characterized by olivopontocerebellar atrophy (OPCA) 5