What is Trinucleotide Repeat Disorders?
Trinucleotide repeat disorders are a set of human diseases caused by an unusual increase of repeated sequences primarily impacting the nervous system. These can develop at any stage in a person’s life.
Repetitve sequences, located in parts of our DNA called microsatellite regions, make up about 30% of our genetic information. In a healthy person, these sections of repeated DNA with varying lengths are meant to provide flexibility for evolution. Yet, when these repeated sequences go beyond a certain limit, producing an irregular protein, their expression is kept under check. When this limit is passed, the control is lost, and an unusual protein is produced. This can result in either a functional or non-functional protein, causing either a ‘gain of function’ or ‘loss of function’ mutation.
With each new generation, the number of these repeats increases significantly, and the age at which a patient starts showing symptoms is directly related to the number of these irregular expansions. The severity of the disorder becomes worse with every generation due to a longer repeat sequence. Because of this, the inheritance pattern of these diseases indicates the changing nature of these mutations, and is known as ‘anticipation’.
Disorders such as Myotonic dystrophy, Huntington’s disease, spinocerebellar ataxia, Friedreich’s ataxia, and fragile X syndrome are all considered trinucleotide repeat disorders. This information focuses on the features of trinucleotide repeat disorders by closely analyzing these five common disorders.
What Causes Trinucleotide Repeat Disorders?
It is well-known that certain disorders, which involve repetition of three molecules, or ‘trinucleotide repeats,’ can be inherited within families. Scientists have extensively researched the main event that causes these disorders to begin.
It’s thought that various environmental factors may trigger complex reactions in our cells that ultimately help those cells survive. Some of these factors include exposure to cold, heat, low oxygen, and harmful substances. One unintentional result of these reactions is that they may lessen the accuracy of DNA repair processes. When a cell’s DNA is damaged, the cell naturally tries to repair it. However, under certain conditions, these repair processes may actually increase the chances of new changes occurring in the cell’s DNA. These changes often happen specifically in areas of the DNA that are very prone to mutation.
When subjected to such conditions, these highly mutable areas in our DNA may start to repeat certain sequences of three molecules; this is known as a ‘trinucleotide repeat expansion.’ It is believed that such repeats can ultimately lead to the development of certain disorders.
Risk Factors and Frequency for Trinucleotide Repeat Disorders
Trinucleotide repeat disorders are a group of conditions that vary in prevalence and can be more common in certain regions or amongst specific populations. Here’s a break down of several such disorders:
- Friedreich ataxia is the most common autosomal recessive ataxia, making up half of all hereditary ataxia cases. It occurs between 1 in 22,000 to 2 in 100,000 individuals, specifically among Europeans and those of European descent in North America. On average, 1 out of 60 to 90 people are carriers of FA, and the disease prevalence is roughly 1 per 29,000.
- Fragile X syndrome frequency varies among different populations. For instance, Tunisian Jews have 10 times the number of cases as the White population. Native Americans and the Spanish Basque population exhibit a lower prevalence of the syndrome due to fewer CGG repeat sequences. Conversely, the Afro-Caribbean and African-American populations in Atlanta, Georgia, USA have an estimated disease point of 1 in 2,500, which is higher than in the White population. The prevalence among White males is around 1 in 4,000 and among females it is approximately 1 in 8,000 to 9,000.
- Spinocerebellar ataxias have a global prevalence of 3 in 100,000, but this varies significantly by region. SCA3 is the most common type worldwide, but in Cuba, SCA2 is more common. SCA7 is most common in Venezuela, while SCA6 is prevalent in Northern England. Each SCA subtype accounts for less than 1% of undiagnosed autosomal dominant cerebellar ataxia (ADCA).
- Huntington disease, an autosomal dominant disorder, is most prevalent among Hispanic Americans and Northern Europeans and least common among black Africans and East Asians. The prevalence is linked to the frequency of intermediate alleles (‘borderline alleles’) in the specific population.
- Myotonic dystrophy has a frequency of 1 in 1,100 in the Finnish population, and is equally prevalent in DM1 and DM2 forms. In fact, DM1 is the most common genetic disease of skeletal muscle in England. In Europe, the gene frequency is about 1 in 7,400. A high frequency of DM1 (1 in 550) is found in Northeastern Quebec. The relationship between disease severity and expansion size is weak in DM2, leading to less anticipation in DM2 than in DM1.
Signs and Symptoms of Trinucleotide Repeat Disorders
Below are some easier explanations of five medical disorders, along with the main signs and symptoms that doctors use to diagnose them:
- Friedrich Ataxia (FA):
This is a disease that progressively affects a person’s movement. Common symptoms include walking difficulties, loss of reflexes in the lower body, speech impairment, and loss of certain sensory perceptions like vibration detection. Some may also have heart disease, spine curvatures, and foot abnormalities. Tests often show issues with nerve conduction. - Fragile X Syndrome:
This is a genetic disorder that often leads to learning disabilities and cognitive impairment. Physical signs often include facial changes, enlarged testicles after puberty, and seizures in about 20% of affected male children. They might also have relatively large heads compared to their body. Some show signs of scoliosis, flat feet, and heart valve problems. - Spinocerebellar Ataxias (SCA):
This group of disorders is characterized by problems with movement and coordination, eye movement issues, and speech difficulties. Some types also show other symptoms like muscle rigidity, paralysis, and cognitive problems. - Huntington Disease (HD):
This inherited disease causes gradual mental decline and loss of bodily control. Three significant symptoms include movement disorders mainly chorea, a decline in thinking (cognitive) skills, and behavior changes. HD patients often experience severe mood swings and hallucinations. - Myotonic Dystrophy (DM):
This is a type of muscular dystrophy that affects muscles and other body organs. It can range from a severe infantile form to a mild adult form. Symptoms can include involuntary muscle tightening (myotonia), muscle weakness, difficulty thinking and reasoning (cognitive difficulties), and excessive sleepiness.
Testing for Trinucleotide Repeat Disorders
: Doctors can’t make a diagnosis of repeat disorders, a type of genetic abnormality, purely based on a patient’s family medical history. This is why, if a patient shows signs that suggest a repeat disorder, they still need further evaluation – having symptoms of these disorders doesn’t necessarily mean that they inherited it from their parents, and they could be an isolated case.
Genetic testing is needed to confirm or rule out the diagnosis. One common technique used in genetic testing is the polymerase chain reaction (PCR). This method helps to identify the presence and measure the size of repeat sequences – the hallmark of these disorders. However, sometimes, the repeat sequences give a tricky reading and show multiple shadows, compromising the accuracy of the results in these cases.
This led scientists to develop new techniques including small pool PCRs, which are more precise in quantifying the changes in repeat sequences. However, for disorders involving specific types of repeats known as CGG repeats, southern blotting is usually the preferred method. This is an older, more traditional lab technique, but it’s better in these cases because the enzymes used in PCR have a hard time working accurately on long CGG sequences.
Overall, these methods offer a high level of diagnostic accuracy, accounting for 99% of the clinical accuracy. It’s important to remember that although we may have a good grasp of how to detect these disorders, diagnosing a patient should never be solely based on their family history or genetic testing results, and must always consider the patient’s symptoms and overall health.
Treatment Options for Trinucleotide Repeat Disorders
Trinucleotide repeat disorders, a group of genetic disorders, have different characteristics and treatment approaches. Let’s take a look at some of these:
Friedrich Ataxia: This condition is often managed with antioxidants which are substances that limit cell damage. Commonly used antioxidants include coenzyme Q, vitamin E, high-dose vitamin C (also known as ascorbic acid), and others, like idebenone and N-acetylcysteine. These compounds are considered useful because they can help to reduce the cell damage seen in Friedrich Ataxia.
Fragile X syndrome: For patients with Fragile X syndrome, the approach to treatment varies as their physical and behavioral symptoms change over time. Around one in five males and one in twenty females could experience seizures, which require quick diagnosis and treatment. Behavioral issues might be addressed through behavioral therapy, medication, or both. Other symptoms might require the assistance of specialists like speech therapists and physiotherapists. Some patients might face challenges with connective tissue related abnormalities, such as hip dislocations and hernias, which might require surgery. Some could experience issues with digestion and these cases may be aided by suitable nutrition advice and medication.
Spinocerebellar Ataxia: There isn’t confirmed treatment for spinocerebellar ataxia (SCA). Genetic testing can confirm the diagnosis and can help provide answers and aid in understanding what the future might look like. It might not seem like much, but for some patients, simply having a name for their condition can provide a psychological boost. At present, some treatments are currently being explored. For example, a 24-week program focusing on balance, coordination, and muscle strengthening has shown positive effects in reducing symptoms in a type of SCA.
Huntington’s Disease: The primary focus in managing Huntington’s disease is managing each individual symptom rather than addressing the root cause of the disease. Some common treatment medications include newer antipsychotic drugs to manage severe chorea (a symptom of Huntington’s) and other psychiatric symptoms. Depression, which often arises with Huntington’s, is typically treated with newer forms of antidepressants. In specific cases, some medications commonly used in treating Alzheimer’s disease have shown modest benefits.
Muscular Dystrophy: The key aspects of treating muscular dystrophy involve genetic counseling, helping the patient maintain their physical function and independence, and preventing complications. In one type of muscular dystrophy – DM1 – there is often a focus on monitoring and managing breathing complications due to muscle weakness. Some patients might need nighttime ventilatory support. Regular heart monitoring is also necessary as the placement of a pacemaker or cardiac defibrillator could be a life-saving intervention.
What else can Trinucleotide Repeat Disorders be?
There are several conditions with similar symptoms that can be mistaken for various diseases. Here are some conditions that might be confused with others:
Friedreich Ataxia:
- Abetalipoproteinemia
- Ataxia with isolated vitamin E deficiency
- Dentatorubropallidoluysian atrophy
- Hereditary motor and sensory neuropathies
- Refsum disease
- Spinocerebellar ataxia types 1, 2, 3
Fragile X Syndrome:
- Autism spectrum disorders
- Genetics of Marfan syndrome
- Gigantism and acromegaly
- Pediatric attention deficit hyperactivity disorder (ADHD)
- Pervasive developmental disorder
- Prader-Willi syndrome
- Rett syndrome
- Asperger syndrome
Spinocerebellar ataxia:
- Abetalipoproteinemia
- Ataxia with isolated vitamin E deficiency
- Dentatorubropallidoluysian atrophy
- Hereditary motor and sensory neuropathies
- Refsum disease
Huntington Disease:
Even though Huntington’s disease has specific symptoms, some conditions mimic its appearance and can be confused with it. When there’s uncertainty, doctors use molecular testing to confirm or rule out Huntington’s disease. Conditions that mimic Huntington disease include:
- Polyglutamine diseases
- Dentatorubral-pallidoluysian atrophy (DRPLA)
- SCA17
- Huntington disease-like 2
- Neuroferritinopathy
- Neuroacanthocytosis family of diseases
Myotonic Dystrophy:
Other disorders might seem like myotonic dystrophy because they share similar symptoms. They include:
- Recessive generalized myotonia
- Limb-Girdle muscular dystrophy
- Duchenne muscular dystrophy
- Myotonia congenita (Thomsen disease)
- Paramyotonia congenita (Eulenburg disease)
What to expect with Trinucleotide Repeat Disorders
Friedreich’s ataxia, a disorder affecting nerve fibers, tends to have a more severe impact when it’s associated with a heart condition known as dilated cardiomyopathy, as it often necessitates a transplant. On the other hand, patients merely experiencing ataxia (loss of body movement control) and diabetes, while hindered by the condition, aren’t facing a life-threatening situation.
In the case of Fragile X syndrome, patients generally have a nearly regular lifespan. The average age of death was found to be about 12 years less than the general population for both men and women, but this discrepancy could be more to do with the study than actual facts. Like the general population, the most frequent causes of death were heart disease, strokes, and cancers. However, Fragile X patients may face issues with aging due to the lack of a specific protein, FMRP. Further studies are needed to understand which groups of Fragile X patients are more prone to aging problems and how treatment could assist them.
For patients suffering from spinocerebellar ataxias, a group of inherited disorders that damage the part of the brain controlling movement, complete physical dependency is not the average experience. Though these disorders frequently shorten life, it’s challenging to predict life expectancy due to the diverse symptoms and severity. In extreme cases, patients may need continuous professional care in a healthcare facility during the last stages of their illness.
In the case of Huntington’s disease, a genetic disorder that causes the progressive breakdown of nerve cells in the brain, it frequently triggers severe depression, leading to a suicide rate up to four times higher than in the general population.
Lastly, adults with myotonic dystrophy, a type of muscular dystrophy affecting muscle function, show a drastically reduced survival rate – from an expected rate of 78% down to an observed rate of 18%. There does appear to be a link between the length of a certain genetic repeat (CTG) and younger age at death. The most common causes of death were noted to be pneumonia and irregular heartbeats.
Possible Complications When Diagnosed with Trinucleotide Repeat Disorders
Trinucleotide repeat disorders can cause a vast array of health problems, ranging from physical disabilities to lethal complications. The type and severity of complications depend on the specific disorder. Here are several disorders and their associated complications:
- Fragile X syndrome – This disorder is linked with seizures, middle ear infection (otitis media), behavior and speech disorders.
- Friedreich’s ataxia – Associated complications may include diabetes, abnormal spine curvature (scoliosis), heart enlargement (dilated cardiomyopathy), foot deformity, and sensory impairment.
- Spinocerebellar ataxia – This condition can lead to exhaustion (fatigue), pain, dysautonomia — a condition that affects the nervous system, affecting heart rate, blood pressure, and sweating, and a sleep disorder where you act out your dreams (REM sleep behavioral disorder).
- Huntington disease – Complications can range from mood disorders, including mania and depression, trouble swallowing, choking, and loss of control over bladder and bowel (incontinence).
- Myotonic dystrophy – This disorder may cause muscle weakness, muscle stiffness (myotonia), difficulty swallowing (dysphagia), high blood sugar (hyperglycemia), female infertility, male pattern baldness, underactivity of the mumps gland (hypogonadotropic hypogonadism), eye clouding (cataracts), learning disabilities, abnormal heart rhythm (QT lengthening), slowed or blocked electric signalling in the heart (AV block), immune deficiency.
Preventing Trinucleotide Repeat Disorders
People with trinucleotide repeat disorders, a type of genetic disorder, will have this condition throughout their entire lives. The complications with these disorders can vary from mild to severe. So, it’s important that they receive counseling and clear explanations about the disorder. This will help patients and their families better understand and accept their health situation.
Consistent mental health check-ups and emotional support are also important for these patients. The limitations caused by their condition can sometimes lead to depression. In addition, different types of these genetic disorders have been linked to various mental health conditions. For instance, patients with Huntington’s disease may experience both highs (mania) and lows (depression); some people with types of ataxia (a group of disorders that affect co-ordination, balance and speech) may develop dementia. Other conditions like Friedreich’s ataxia are linked to major depressive disorder (MDD), and those with fragile X syndrome – a genetic condition causing learning problems and cognitive impairment – may experience a range of issues like anxiety, attention deficit hyperactivity disorder, mood swings, and aggressive behavior. Personality changes like increased aggression, depression, and heightened sensitivity to interpersonal relations have also been found in patients with myotonic dystrophy (a type of muscular dystrophy).
Alongside a correct diagnosis, it’s also important for the patients with these conditions to have access to genetic counseling and information about family planning. Conditions like fragile X-related mental retardation, Huntington’s disease, certain ataxias, and myotonic dystrophy are connected with a phenomenon known as ‘anticipation’, which means that the disease can appear earlier and more severe in their children. Moreover, the likelihood of these disorders being passed on, called the penetrance, is usually high. Therefore, educating and informing patients about the potential risks for their children is vital.
