Duplication and Disease: Unstable Trinucleotide Repeats and Neurodegeneration

Neurodegenerative diseases are some of the most challenging conditions in medicine, often progressing slowly and lacking effective cures. While many remain poorly understood, a subset can be traced to a very specific genetic error: the expansion of short, repeating DNA sequences known as trinucleotide repeats. Normally, these repeats are present in small, stable numbers. But when they lengthen beyond a critical threshold, they disrupt how genes are expressed or how proteins fold, setting off a cascade of dysfunction that damages cells and tissues.

What makes trinucleotide repeat disorders particularly striking is their inheritance pattern. Unlike most genetic diseases that stay constant across generations, these repeats can expand when passed from parent to child, a process called anticipation. This means symptoms often appear earlier and with greater severity in each new generation. Depending on where in the gene the expansion occurs, the consequences differ: repeats in non-coding regions can silence a gene or create toxic RNA molecules, while repeats in coding regions alter the protein itself, producing harmful products that poison neurons.

Repeat Expansions in Non-Coding Regions

Fragile X Syndrome and FXTAS

Fragile X syndrome is the most common inherited cause of intellectual disability, affecting about 1 in 2,000 births. It results from expansion of CGG repeats in the 5′ untranslated region of the FMR1 gene on the X chromosome. In healthy individuals, the gene carries about 40 repeats. But, once the number surpasses 200, the gene becomes heavily methylated and silenced. The absence of its protein product, FMRP, disrupts RNA regulation in neurons and impairs brain development.

A related disorder, Fragile X–associated tremor/ataxia syndrome (FXTAS), arises in older adults who carry 50–200 repeats. In this case, the gene is not silenced. Instead, excess RNA containing the repeats accumulates in the nucleus, trapping proteins that normally regulate RNA splicing and transport. This toxic RNA mechanism explains the movement problems, tremors, and cognitive decline seen in FXTAS patients.

Myotonic Dystrophy Type 1 (DM1)

Myotonic dystrophy type 1 affects about 1 in 8,000 people and is inherited in an autosomal dominant fashion. It is caused by expansion of CTG repeats in the 3′ untranslated region of the DMPK gene on chromosome 19. Healthy individuals have fewer than 30 repeats, while patients may carry anywhere from 45 to thousands. The expanded RNA forms hairpin-like structures that bind and trap proteins responsible for splicing. Without these proteins, other genes are processed incorrectly, creating faulty proteins in other regions. This explains why DM1 is a multisystem disorder: it causes progressive muscle weakness, heart conduction problems, cataracts, and, in severe cases, congenital disease in infants.

Friedreich’s Ataxia (FA)

Friedreich’s ataxia, the most common inherited ataxia, follows a recessive inheritance pattern and is caused by a GAA repeat expansion in the first intron of the FXN gene on chromosome 9. Normal alleles have fewer than 34 repeats, while disease alleles can contain hundreds. The expansion reduces expression of frataxin, a mitochondrial protein that helps assemble iron–sulfur clusters, which are essential for energy production and defense against oxidative stress. When frataxin is deficient, iron builds up inside mitochondria, oxidative damage increases, and neurons and muscle cells lose their ability to generate energy efficiently. This mitochondrial dysfunction makes neurons - especially those in the spinal cord and cerebellum - more likely to degenerate and die. Clinically, FA causes progressive loss of coordination, muscle weakness, scoliosis, heart disease, and, in some cases, diabetes.

Repeat Expansions in Coding Regions

Huntington’s Disease (HD)

Huntington’s disease affects about 1 in 20,000 people and is caused by expansion of CAG repeats in the HTT gene on chromosome 4. In healthy individuals, the repeat count ranges from 6–26, while disease occurs with 40 or more. The expansion disrupts normal RNA splicing, causing the ribosome to “read through” into the first intron, where it encounters a premature stop codon. This produces a truncated N-terminal fragment of the huntingtin protein, which is highly toxic to neurons. The fragment misfolds, accumulates, and disrupts transport and energy pathways inside cells. In addition, mutant huntingtin reduces production of brain-derived neurotrophic factor (BDNF), a growth factor critical for synaptic maintenance and neuron survival. Together, these effects lead to progressive degeneration of brain regions controlling movement, emotion, and cognition. Clinically, patients develop involuntary movements, personality and mood changes, and gradual cognitive decline. Larger expansions, often above 60 repeats, cause juvenile-onset disease with faster and more severe progression.

Spinal and Bulbar Muscular Atrophy (SBMA / Kennedy’s Disease)

SBMA is a rare X-linked disorder caused by a CAG repeat expansion in the androgen receptor gene. Normal alleles contain about 17–26 repeats, while disease alleles have 40 or more. The repeat expansion produces a polyglutamine-expanded androgen receptor protein that misfolds and accumulates in motor neurons. This both damages the neurons directly and reduces the receptor’s ability to regulate gene transcription in response to male hormones. As a result, affected men develop progressive muscle weakness, difficulty swallowing and speaking, and partial androgen insensitivity. Women who carry the mutation are usually unaffected or only mildly symptomatic.

"They disrupt how genes are expressed or how proteins fold, setting off a cascade of dysfunction that damages cells and tissues"

Although each of these conditions presents differently, they share the same underlying theme: runaway DNA repeats. In some cases, expanded repeats silence genes entirely, cutting off essential proteins. In others, they create toxic RNA that hijacks proteins needed for splicing and RNA processing. And in coding regions, the repeats alter proteins directly, generating fragments or misfolded molecules that accumulate and poison neurons. These small changes in DNA sequence trigger a chain reaction that leads to widespread dysfunction of neurons and muscles, explaining the devastating nature of these disorders.

By studying trinucleotide repeat diseases, researchers have uncovered not only the unusual inheritance pattern of anticipation but also fundamental insights into how genes, RNA, and proteins interact in healthy cells. This knowledge is guiding new therapies aimed at reducing toxic RNA, restoring normal protein levels, or blocking harmful protein aggregation. Though treatments remain limited, understanding the molecular mechanisms offers hope for interventions that can slow, or even prevent, the relentless progression of these disorders.

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This article was written by Shriya Singh and edited by Julia Dabrowska, with graphics produced by Ishika Joshi. If you enjoyed this article, be the first to be notified about new posts by signing up to become a WiNUK member (top right of this page)! Interested in writing for WiNUK yourself? Contact us through the blog page and the editors will be in touch.