Trinucleotide Repeat Disorders
Overview
Trinucleotide repeat disorders (TRDs) are a set of genetic disorders caused by trinucleotide repeat expansion, a kind of mutation where trinucleotide sequences in certain genes exceed the normal, stable threshold. This results in diseases which are often neurodegenerative or involve the nervous system.
Genetics of Trinucleotide Repeat Disorders
The human genome is composed of sequences of nucleotides, which are the building blocks of DNA. In some regions of the DNA, certain sequences of three nucleotides, or trinucleotides, are repeated. In most cases, these repeats do not cause any problems. However, when the number of repeats in these regions increases beyond a certain threshold, it can lead to disease. This phenomenon is known as trinucleotide repeat expansion.
The mechanism of trinucleotide repeat expansion is not fully understood, but it is believed to occur during DNA replication, repair, or recombination. It is also known that the likelihood of repeat expansion increases with the number of repeats already present, a phenomenon known as genetic anticipation.
Types of Trinucleotide Repeat Disorders
There are several types of trinucleotide repeat disorders, classified by the specific trinucleotide repeat that is expanded. These include:
Polyglutamine Diseases
Polyglutamine diseases are caused by the expansion of CAG repeats, which code for the amino acid glutamine. This group includes diseases such as Huntington's Disease, Spinocerebellar Ataxia, and Spinal and Bulbar Muscular Atrophy.
Fragile X Syndrome
Fragile X Syndrome is caused by the expansion of CGG repeats in the FMR1 gene. It is the most common inherited cause of intellectual disability and autism.
Friedreich's Ataxia
Friedreich's Ataxia is caused by the expansion of GAA repeats in the FXN gene. It is a neurodegenerative disorder characterized by progressive damage to the nervous system, resulting in symptoms such as gait disturbance, speech problems, and heart disease.
Myotonic Dystrophy
Myotonic Dystrophy is caused by the expansion of CTG repeats in the DMPK gene. It is a multisystem disorder affecting skeletal and smooth muscle, the heart, the endocrine system, and the eye.
Diagnosis and Management
Diagnosis of trinucleotide repeat disorders is usually based on clinical symptoms, family history, and genetic testing. Genetic testing can confirm the diagnosis and identify the specific trinucleotide repeat expansion.
Management of these disorders is largely symptomatic and supportive, as there is currently no cure. Treatment may include physical therapy, medications to manage symptoms, and regular monitoring for complications.
Research and Future Directions
Research into trinucleotide repeat disorders is ongoing, with the aim of better understanding the mechanisms of repeat expansion and developing effective treatments. Potential therapeutic strategies include gene therapy, RNA interference, and small molecule drugs that target the expanded repeat or its downstream effects.