Repeat Disorders

Dentatorubral-pallidoluysian atrophy or DRPLA (CAG)

Dentatorubral-pallidoluysian atrophy is a rare progressive brain disorder caused by CAG expansion in the ATN1 gene which codes for a polyglutamine tract in the alpha-1 protein. ATN1 is located on the short arm of chromosome 12 and plays an important role in the development of the brain and other organs as a nuclear transcriptional regulator. When CAG repeats are more than 48, the protein becomes unstable and accumulates in the neural cells.
Symptoms can start anywhere from 1 year of age to the age of 70, with the average symptom start at 30 years of age. The number of repeats in ATN1 correlate with symptom start, meaning that the higher they are the sooner and worse symptoms are. All individuals will show symptoms of progressive ataxia and cognitive decline. Seizures are a more common manifestation in the younger patient, especially under 20 years, and becomes a rarer manifestation as the individuals present older. Those over 20 years are more likely to experience choreoathetosis and psychiatric disturbances, that can range from delusions to psychosis. Brain MRI shows athrophy of the cerebellum and brain stem.
Disease duration can expand to 35 years, though on average it is only 8 years.
When a mutated ATN1 gene is inherited from a father, affected offsprings will normally experience symptoms 26-29 years earlier and 14-15 years earlier of the mutated gene is inherited from their mothers.

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Fragile X (CGG)

Fragile-X syndrome is a intellectual disability syndrome most often (98% of cases) caused by a CGG repeat expansion in the 5' untranslated region of a gene called Fragile X Messenger Ribonucleoprotein 1 (FMR1). The FMR1 gene is located on the X-chromosome and is believed to be involved in mRNA trafficking, moving mRNA from the nucleus to the cytoplasm. When repeats are over 200, the gene is silenced which causes Fragile-X syndrome. As the gene lies on chromosome X, all affected boys have intellectual disability (moderate to severe) and some also autism symptoms that can interfere with communication with others. As females have two X-chromosomes, are not as severly affected, and are more likely to be mildly affected. Theses individuals have long narrow faces with broad forehead, prominent jaw and large ears. These facial features become more apparent with age, and can be hard to notice in infancy. These individuals are known to be hypotonic and suffer from joint hypermobility. Males have machroorchidism, often not present until after puberty.

Healthy carriers are those who are heterozygote for a premutation (50 to 300 repeats of CGG). Most of them will be asymptomatic, but some will develope one of the following syndromes, caused by increased levels of the FMR1 mRNA leading to intranuclear neuronal inclusions.

Fragile X-associated tremor/ataxia syndrome (FXTAS): can be seen in individuals with premutation, and is more commonly seen in male carriers. It is characterized by progressive cerebellar ataxia (can present as frequent falling) and tremor which is then followed by cognitive decline (can result in dementia). Symptoms most often start from the age of 60. (40% of male carriers. 16% of female carriers). On MRI white matter lesions can be seen in the middle cerebellar peduncles, splenium of corpus callosum or in cerebral white matter.

Fragile X-associated primary ovarian insufficiency (FXPOI): can be observed in women with a premutation. This most often presents as infertility or menopause in women younger than 40 years of age (ca. 20% of female carriers).

Fragile X-associated Neuropsychiatric Disorders (FXAND): affects about 50% of individuals with a premutation ({">"}50 repeats). Anxiety and depression is the most common presentation, but OCD, and ADHD is also seen.

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Friedreich Ataxia (GAA)

Friedreich Ataxia is a neurodegenerative disorder mainly caused by a GAA repeat expansion in intron 1 in the gene FXN that is located on chromosome 9. This gene codes for a mitochondrial protein which is thought to be involved in iron-sulfur biogenesis and heme biosyntheses. When the intron 1 repeats are over 66, the transcription of the gene is reduced as the DNA becomes more condensed. This causes iron and ROS overload in the mitochondria, and deficiency of ATP, which is essential for producing cell energy. This reduction in energy will affect cells that require high energy, like neural, muscle and pancreas cells. Most individuals will show symptoms before the age of 25, most between 10-15 years, symptoms can, however, start later in life with some not showing any symptoms until after 40 years of age.
Most cases start with progressive ataxia caused by loss of proprioception and spinocerebellar degeneration. This is followed by disarthria and distal muscle weakness. In majority of cases deep tendon reflexes are lost and babinski reflex is positive. Other symptoms include diabetes mellitus, kyphoscoliosis and hypertrophic cardiomyopathy which is the leading cause of death for these individuals.
As the disease is autosomal recessive, an individual needs to inherit two full mutated genes to show symptoms. These repeats can be of different length, and it seems that the shorter repeats correlates with symptom start and severity of symptoms. Mean life expectancy is about 40 years of age and it is vital that these individuals are diagnosed as soon as possible after symptom start, as correct treatment can increase their lifespan and reduce severity of symptoms.

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Huntington's disease

Huntington's disease start with a prodromal phase where cognitive function is affected. This can appear as lack of emotional recognition, and in executive thought process, which is vital in being able to organize, plan and complete tasks ahead, as well as processing speed and attention can be affected. Mood changes can also be observed in some, like apathy and depression, some with suicidal thoughts. Some even experience affective psychosis or schizophrenic psychosis. These cognitive and personality changes are followed by subtle motor signs like tics or twitches with incordination, restlessness and difficulty with voluntary movement. The prodromal phase can start 15-20 years before early symproms of clinical Hungtington's appear.
After the prodromal phase, symptoms of chorea start appearing with involuntary twitches in fingers, toes and face, and along with it cognitive function is increasingly affected as well. This makes it increasingly hard to complete task and participate in daily life. As the disease progresses, balance is affected, speaking and swallowing. Individuals become more apathetic, losing interest in activies they used to enjoy.
In the late-stage of Hungtington's rigidity and bradykinesia appear and in most cases symptoms of chorea disappears. At this stage, individuals are unable to care for themselves as walking, speaking and swallowing becomes increasingly harder.
The mean age of symptom onset is from 30-50 years of age, however, in 10% of cases symptoms start before the age of 20 (repeats often more than 55). In the juvenile form symptoms can present as progressive parkinsonism, ataxia, dementia with seizures.
Mean survival after the onset of symptoms is 15-18 years. The most common cause of death is aspiration pneumonia, and second suicide.
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Myotonic dystrophy type 1 (CTG)

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Myotonic dystrophy type 2

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Spinal and bulbar muscular atrophy

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Spinocerebellar Ataxia

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