Introduction:
A new type of DNA (deoxyribonucleic acid) mutation, where there are repetitive elements in DNA called trinucleotide repeat (TNR) expansion. The expansion of a trinucleotide repeats DNA sequences in a particular gene and causes genetic defects in inherited diseases. The mutated gene contains more triplets than found in a normal gene, and the number of triplets keeps increasing as it gets inherited. These change the function and expression of the gene. A triplet repeat tract is a type of microsatellite (a repeated segment of DNA that is present in about 30 percent of the genome) due to the unstable nature of the repeats, which leads to mutation and causes neuromuscular or neurodegenerative disorders. There are a number of diseases that occur due to TNR expansion, such as myotonic dystrophy, fragile X syndrome, Huntington’s disease, and many others which are explained below in detail.
What Are Triplet Repeat Disorders?
It is a type of unstable mutation in which there is an expansion of trinucleotide repeat sequences (three nucleotides are repeated consecutively) and form DNA polymerase slippage. These cause neurological diseases. These mutations show the anticipation phenomenon. These mutations become severe as it gets passed down. The age of onset of these diseases is inversely proportional to the number of repeats. Diseases that occur due to trinucleotide repeat expansion are:
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Myotonic Dystrophy: It is an inherited disorder where there is a decrease in muscle size and weakness. This disease has CTG (cytosine, thymine, and guanine) nucleotide repetition in the 3′ untranslated region of the DMPK (DM1 protein kinase) gene at the 19q13 chromosome. In the space of three generations, it can go from mild and late-onset to severe and early onset, and it is mainly associated with transmission from the mother.
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Huntington's Disease: It is a rare disease that causes degeneration of nerve cells which leads to functional disabilities and difficulty in concentrating. It is an autosomal dominant degenerative disorder caused by unstable trinucleotide repeat of CAG (cytosine, adenine, and guanine) in the IT15 (interesting transcript 15) gene at the 4p16.3 chromosome. A normal person has 6 to 29 CAG triplets, and persons with Huntington’s disease have 36 to 100 CAG triplets; as the gene repeats, a gene product called huntingtin is produced, which causes the death of brain cells that control movements. The clinical symptoms are different for adult-onset and juvenile-onset.
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Fragile X Syndrome: Males are severely affected by this disorder, it causes intellectual disability and learning disabilities and affects memory and thinking abilities. This involves mutation of the FMR-1 (fragile X messenger ribonucleoprotein 1) gene at the Xq27.3 chromosome. Unaffected people have six to fifty copies of CGG (one cytosine and two guanine) repeat; people with fifty to two hundred CGG repeats are known as pre-mutation. People with more than two hundred CGG repeats show symptoms of these diseases and have broken X chromosomes.
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Fragile X E Mild Mental Retardation: It affects the intellectual ability and mostly affects males. It is due to CGG repetition on FMR2 (fragile X messenger ribonucleoprotein 2) gene at Xq28 chromosome.
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Spinal And Bulbar Muscular Atrophy (Kennedy Disease): It is a disorder that affects the nerve cells which originate from the spinal cord and brainstem that control muscle movements. This involves the repetition of the CAG nucleotide in the androgen receptor (AR) gene at the Xq13-21 chromosome. Unaffected people have 12 to 33 CAG repeats, but these patients have 40 to 62 repeats.
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Friedreich Ataxia: It is a degenerative disorder that damages the peripheral nerves, spinal cord, and the cerebellum portion of the brain; due to nerve injury, it causes uncontrolled movements and loss of sensation. This is due to the GAA (one guanine and one two adenine) trinucleotide repeat expansion of the X25 gene, which is located on chromosome 9q13 and there are more than 1700 repeats.
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Spinocerebellar Ataxia Type 1 (SCA1): The clinical features include dysarthria, progressive cerebellar ataxia, and eventual bulbar dysfunction. This involves CAG repetition in SCA1 located at the 6p23 chromosome.
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Spinocerebellar Ataxia Type 2: The clinical features include hypo-or areflexia (muscle reflex is decreased or absent), extremely slow saccadic eye movements, and ophthalmoparesis. This causes problems in coordination, movements, and balance and causes difficulty in speech and swallowing. This involves repetition of CAG at the SCA2 gene, which is located at the 12q24.1 chromosome.
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Spinocerebellar Ataxia Type 3 (Machado-Joseph Disease): The clinical features include bulging eyes, rigidity, and facial and lingual fasciculation. This involves repetition of CAG at the SCA3 (MJD1)gene, which is located at the 14q32.1 chromosome.
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Spinocerebellar Ataxia Type 6: This predominantly causes cerebellar dysfunction and is characterized by slow progressive or episodic ataxia. This involves the repetition of CAG at the SCA6 gene in the 19p13 chromosome.
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Spinocerebellar Ataxia Type 7: Patients with this disorder show cerebellar ataxia, visual problems, and pigmentary macular degeneration. This involves CAG repetition at the SCA7 gene in the 3p12-13 chromosome.
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Bipolar Affective Disorder: It is a condition that causes extreme mood swings from mania (high energy level) to depression. This involves CAG repetition.
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Dentatorubral-Pallidoluysian Atrophy: It is a brain disorder that affects thinking ability, causes involuntary movements, and mental and emotional problems. This shows CAG repeat in the DRPLA gene at 12p13.31 chromosome of 49 to 75 repeats.
What Is the Molecular Diagnosis of Triplet Repeat Disorders?
A successive diagnosis depends on the positive family history. With the help of cloning the genes of these disorders, it is possible to study the allelic status of the affected individuals. If the trinucleotide repeat expansion is small (less than 150 repeats) like in spinal and bulbar muscular atrophy, dentatorubral pallidoluysian atrophy, spinocerebellar ataxia type 1, and Huntington’s disease, the allelic status can be determined by polymerase chain reaction (PCR) and amplification at the region of repeats and determining the size by polyacrylamide gel electrophoresis. In the case of large expansion, traditional Southern blot length analysis is used.
Conclusion:
All triplet repeat disorders show the genetic phenomenon called anticipation, where the genetic condition becomes more severe and affects at an early age as the disease is passed down. Molecular analysis of these disorders is a diagnostic tool in identifying. Psychological support and psychiatric evaluation should be offered to all patients with repeat disorders. Genetic counseling should be done, and family planning should be educated in these patients due to the phenomenon of anticipation.
