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.
Main points
  • Autosomal dominant. Anticipation.
  • Gene: ATN1
    • Normal: 6-35 repeats
    • Premutated: 35-47 repeats. unstable, but rarely expands
    • Mutated: > 48 repeats
  • Protein: Atrophin-1
  • Statistics: 5-7 per 1 million in Japan. Rarer in other places of the world.
  • Symptoms: Symptom start average at 30 years (range 1 to 70 years).
      All ages present with ataxia and cognitive decline.
    • < 20 years: Seizures
    • > 20 years: choreoathetosis and psychiatric disturbances
  • Treatment: Symptomatic.
  • Diagnosis: Triple-primed PCR, Southern Blot.


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.
Main points
  • X-linked dominant
  • Gene: FMR1 (CGG repeats), 1% of affected individuals has a partial or full deletion of the gene.
    • Normal: 6-40 repeats
    • Intermediate: 41-60 repeats. Offsprings NOT at increased risk
    • Premutation: 61-200 repeats
    • Full mutation: >200-230 repeats
  • Protein: Fragile-X Messenger Ribonucleoprotein 1
  • Statistics:
    • Premutation: 1/200 women carriers. 1/400 male carriers.
    • Full mutation: 1/5000 women. 1/3600 males.
  • Symptoms: Intellectual disability (moderate to severe, can be mild in females) and autistic features. Long and narrow face with a prominent jaw and broad forehead with large ears (face symptoms become more prominant with age). Macroorchidism (congenital or postpubertal). Joint laxity.
  • Treatment: Symptomatic.
  • Diagnosis: Triple-primed PCR, Southern Blot.


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.
Main points
  • Autosomal recessive
  • Gene: FXN
    • Normal: 5-33 repeats
    • Premutation: 34-65
    • Full mutation: >66 repeats
  • Protein: Frataxin
  • Statistics:
    • Premutation: 1/60 to 1/100
    • Full mutation: 2-4/100.000 (Europe)
  • Symptoms: Frequent falling and clumsiness caused by gait ataxia, loss of proprioception and muscle weakness. Dysarthria. Loss of deep tendon reflexes, and vibratory sense. Hypertrophic cardiomyopathy and diabetes mellitus. Kyphoscoliosis.
  • Treatment: Symptomatic.
  • Diagnosis: Triple-primed PCR, Southern Blot.


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.
Main points
  • Autosomal dominant
  • Gene: HHT
    • Normal: < 26 repeats
    • Intermediate: 27-35 repeats (unstable repeats, prone to expansion in the next generation, particularly if passed down by a male)
    • Full mutated: > 35 repeats (Full penetrance of symptoms with repeats equal or over 40)
  • Protein: Huntingtin
  • Statistics:
    • Median survival: 15-18 years
    • Mean age of symptom start: 40 years
  • Symptoms: Progressive cognitive and motorfunction decline. First minor twitching occurs that later develops into chorea, that with time is replaced with rigidity and bradykinesia. This eventually makes individuals unable to take care of themselves as walking, swallowing and speaking becomes more difficult.
  • Treatment: first and foremost supportive. Tetrabenazine and Deutetrabenazine is sometime used to treat symptoms of chorea.
  • Diagnosis: Triple-primed PCR, Southern Blot.


Myotonic dystrophy type 1 (CTG)

is the most common form of adult-onset muscular dystrophy. It is caused by a CTG repeat expansion in the 3' untranslated region of the DMPK gene located on chromosome 19. This gene codes for a protein kinase that is involved in muscle function (DM1 protein kinase, also expressed in heart and brain and is vital for their normal function as it phosphorylates several proteins involved in muscle contraction). When the CTG repeats are over 50, the gene expression is altered which leads to muscle fiber atrophy and muscle weakness. The disease is characterized by myotonia (delayed muscle relaxation after contraction), muscle weakness and wasting, cataracts, cardiac conduction defects and endocrine changes. Symptoms can start at any age, from birth to late adulthood, and the severity of symptoms often correlates with the number of CTG repeats. The congenital form is the most severe, with symptoms present at birth or in early infancy. These individuals often have severe muscle weakness, respiratory difficulties and cognitive impairment. The adult form typically presents with myotonia, muscle weakness and cataracts in early adulthood. Cardiac conduction defects are common and can lead to sudden death if not monitored and treated. Other symptoms include endocrine changes such as insulin resistance and thyroid dysfunction.
The disease is progressive, with symptoms worsening over time. There is currently no cure for myotonic dystrophy type 1, and treatment is focused on managing symptoms and preventing complications. This may include physical therapy, medications to manage myotonia and cardiac conduction defects, and regular monitoring for respiratory and endocrine complications.
Main points
  • Autosomal dominant
  • Gene: DMPK
    • Normal: 5-34 repeats
    • Premutated(normal): 35-49 repeats
    • Mutated: >50 repeats
      • Mild symptoms: 50-150 repeats (cataracts, mild myotonia with onset from 20-70 years)
      • Classic symptoms: 100-1.000 repeats (cataracts, myotonia, frontal boldness, arrhythmia with onset from 10-30 years)
      • Congenital form: >1.000 repeats (hypotonia, respiration affected, myotonia, cataracts, arrhythmia with onset from birth to 10 years)
  • Protein: DM1 protein kinase
  • Statistics: 1:20.000 (worldwide)
  • Treatment: Symptomatic.
  • Diagnosis: Triple-primed PCR, Southern Blot.


Myotonic dystrophy type 2

is a multisystemic disorder caused by a CCTG repeat expansion in the CNBP gene located on chromosome 3. This gene codes for a zinc finger protein that is involved in transcriptional regulation. When the CCTG repeats are over 75, the gene expression is altered which leads to muscle fiber atrophy and muscle weakness. The disease is characterized by myotonia (delayed muscle relaxation after contraction), muscle weakness and wasting, cataracts, cardiac conduction defects and endocrine changes. Symptoms typically start in adulthood and are generally milder than those seen in myotonic dystrophy type 1. Myotonia is often less severe, and muscle weakness is more proximal (closer to the center of the body) than distal. Cataracts are common, but cardiac conduction defects are less frequent than in type 1. Endocrine changes such as insulin resistance and thyroid dysfunction can also occur.
The disease is progressive, with symptoms worsening over time. There is currently no cure for myotonic dystrophy type 2, and treatment is focused on managing symptoms and preventing complications. This may include physical therapy, medications to manage myotonia and cardiac conduction defects, and regular monitoring for respiratory and endocrine complications.
Main points
  • Autosomal dominant
  • Gene: CNBP
    • Normal: 11-26 repeats (no symptoms)
    • Premutated: 27-74 repeats (no symptoms)
    • Mutated: >75 repeats (symptoms present)
  • Protein: CCHC-type zinc finger nucleic acid binding protein (important for transcriptional regulation as it binds to DNA and RNA)
  • Statistics: 1:100.000 (worldwide)
  • Symptoms:
    • Myotonia (delayed muscle relaxation after contraction), muscle weakness and wasting, cataracts, cardiac conduction defects and endocrine changes.
  • Treatment: Symptomatic.
  • Diagnosis: Triple-primed PCR, Southern Blot.


Spinal and bulbar muscular atrophy (SBMA)

also known as Kennedy's disease, is a rare X-linked recessive neurodegenerative disorder caused by a CAG repeat expansion in the androgen receptor (AR) gene located on the X-chromosome. This gene codes for the androgen receptor protein, which is involved in the development and maintenance of male characteristics. When the CAG repeats are over 38, the androgen receptor protein becomes toxic to motor neurons, leading to their degeneration. The disease is characterized by progressive muscle weakness and atrophy, particularly in the proximal muscles (those closest to the center of the body). Other symptoms include fasciculations (muscle twitching), cramps, and difficulty swallowing and speaking. Gynecomastia (enlarged breast tissue in males) is also common. Symptoms typically start in adulthood, usually between the ages of 30 and 50. The disease is progressive, with symptoms worsening over time. There is currently no cure for SBMA, and treatment is focused on managing symptoms and preventing complications. This may include physical therapy, medications to manage muscle cramps and fasciculations, and regular monitoring for respiratory complications.
Main points
  • X-linked recessive
  • Gene: AR
    • Normal: 9-36 repeats
    • Mutated: >38 repeats
  • Protein: Androgen receptor protein
  • Statistics: varies between populations from 1:40.000 to 1:300.000
  • Symptoms: Progressive muscle weakness and atrophy, particularly in the proximal muscles. Fasciculations, cramps, and difficulty swallowing and speaking. Gynecomastia.
  • Treatment: Symptomatic.
  • Diagnosis: Triple-primed PCR, Southern Blot.


Spinocerebellar Ataxia

is a group of hereditary ataxias that are characterized by progressive cerebellar ataxia with variable involvement of other neurological systems. They are caused by CAG repeat expansions in various genes, leading to the production of abnormal proteins that accumulate in neurons and cause neurodegeneration. The most common types of spinocerebellar ataxia include SCA1, SCA2, SCA3 (Machado-Joseph disease), SCA6, SCA7, and SCA17. Each type is associated with a specific gene and has its own characteristic clinical features, although there is considerable overlap between the different types. Common symptoms include progressive ataxia, dysarthria, nystagmus, and peripheral neuropathy. Some types may also be associated with cognitive decline, ophthalmoplegia, and other neurological symptoms. The age of onset and rate of progression can vary widely, even within the same type of spinocerebellar ataxia. Diagnosis is typically made through genetic testing to identify the specific CAG repeat expansion. There is currently no cure for spinocerebellar ataxia, and treatment is focused on managing symptoms and providing supportive care.
Main points
  • autosomal dominant, autosomal recessive and X-linked forms also exist. Anticipation in some types.
  • Gene: varies depending on the type of SCA
    • SCA1: ATXN1
    • SCA2: ATXN2
    • SCA3: ATXN3
    • SCA6: CACNA1A
    • SCA7: ATXN7
    • SCA17: TBP
  • Protein: varies depending on the type of SCA
  • Statistics: varies depending on the type of SCA, most common is SCA3 with a prevalence of 1-2 per 100.000.
  • Symptoms: Progressive cerebellar ataxia, dysarthria, nystagmus, and peripheral neuropathy. Some types may also be associated with cognitive decline, ophthalmoplegia, and other neurological symptoms.
  • Treatment: Symptomatic.
  • Diagnosis: Triple-primed PCR, Southern Blot.