Friedreich’s ataxia
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Friedreich's ataxia (FRDA or FA) is an autosomal-recessive genetic disease that causes difficulty walking, a loss of sensation in the arms and legs, and impaired speech that worsens over time. Symptoms generally start between 5 and 20 years of age. Many develop
hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM, or HOCM when obstructive) is a condition in which the heart becomes thickened without an obvious cause. The parts of the heart most commonly affected are the interventricular septum and the ventricles. This r ...
and require a mobility aid such as a cane, walker, or wheelchair in their teens. As the disease progresses, some affected people lose their sight and hearing. Other complications may include
scoliosis Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not t ...
and diabetes mellitus. The condition is caused by mutations in the ''FXN'' gene on chromosome 9, which makes a protein called frataxin. In FRDA, cells produce less frataxin. Degeneration of nerve tissue in the spinal cord causes the ataxia; particularly affected are the sensory neurons essential for directing muscle movement of the arms and legs through connections with the
cerebellum The cerebellum (Latin for "little brain") is a major feature of the hindbrain of all vertebrates. Although usually smaller than the cerebrum, in some animals such as the mormyrid fishes it may be as large as or even larger. In humans, the cerebel ...
. The spinal cord becomes thinner, and nerve cells lose some myelin sheath. No effective treatment is known, but several therapies are in trials. FRDA shortens life expectancy due to heart disease, but some people can live into their 60s or older. FRDA affects one in 50,000 people in the United States and is the most common inherited ataxia. Rates are highest in people of Western European descent. The condition is named after German physician
Nikolaus Friedreich Nikolaus Friedreich (1 July 1825 in Würzburg – 6 July 1882 in Heidelberg) was a German pathologist and neurologist, and a third generation physician in the Friedreich family. His father was psychiatrist Johann Baptist Friedreich (1796–1862) ...
, who first described it in the 1860s.


Symptoms

Symptoms typically start between the ages of 5 and 15, but in late-onset FRDA, they may occur after age 25 years. The symptoms are broad, but consistently involve gait and limb ataxia, dysarthria and loss of lower limb reflexes.


Classical symptoms

There is some variability in symptom frequency, onset and progression. All individuals with FRDA develop neurological symptoms, including dysarthria and loss of lower limb reflexes, and more than 90% present with ataxia. Cardiac issues are very common with early onset FRDA . Most individuals develop heart problems such as
enlargement of the heart Cardiomegaly (sometimes megacardia or megalocardia) is a medical condition in which the heart is enlarged. As such, it is more commonly referred to simply as "having an enlarged heart". It is usually the result of underlying conditions that make t ...
, symmetrical hypertrophy,
heart murmurs Heart murmurs are unique heart sounds produced when blood flows across a heart valve or blood vessel. This occurs when turbulent blood flow creates a sound loud enough to hear with a stethoscope. Turbulent blood flow is not smooth. The sound dif ...
, atrial fibrillation, tachycardia,
hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM, or HOCM when obstructive) is a condition in which the heart becomes thickened without an obvious cause. The parts of the heart most commonly affected are the interventricular septum and the ventricles. This r ...
, and conduction defects. Scoliosis is present in about 60%. 7% of people with FRDA also have diabetes and having diabetes has an adverse impact on people with FA, especially those that show symptoms when young.


Other symptoms

People who have been living with FRDA for a long time may develop other complications. 36.8% experience decreased visual acuity, which may be progressive and could lead to functional blindness. Hearing loss is present in about 10.9% of cases. Some patients report bladder and bowel symptoms. Advanced stages of disease are associated with supraventricular
tachyarrhythmias Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...
, most commonly atrial fibrillation. Other later stage symptoms can include, cerebellar effects such as nystagmus, fast
saccadic A saccade ( , French for ''jerk'') is a quick, simultaneous movement of both eyes between two or more phases of fixation in the same direction.Cassin, B. and Solomon, S. ''Dictionary of Eye Terminology''. Gainesville, Florida: Triad Publishi ...
eye movements, dysmetria and loss of coordination ( truncal ataxia, and
stomping gait Stomping gait (or sensory ataxia gait) is a form of gait abnormality. It indicates involvement of posterior column. Posterior column carries proprioception which is essential for coordination of motor movements. __TOC__ Presentation ''Uncoordinated ...
). Symptoms can involve the dorsal column such as the loss of vibratory sensation and proprioceptive sensation. The progressive loss of coordination and muscle strength leads to the full-time use of a wheelchair. Most young people diagnosed with FRDA require mobility aids such as a cane, walker, or wheelchair by early 20s. The disease is progressive, with increasing staggering or stumbling gait and frequent falling. By the third decade, affected people lose the ability to stand or walk without assistance and require a wheelchair for mobility.


Early-onset cases

Non-neurological symptoms such as
scoliosis Scoliosis is a condition in which a person's spine has a sideways curve. The curve is usually "S"- or "C"-shaped over three dimensions. In some, the degree of curve is stable, while in others, it increases over time. Mild scoliosis does not t ...
, pes cavus, cardiomyopathy and diabetes are more frequent amongst the early-onset cases.


Genetics

FRDA is an autosomal-recessive disorder that affects a gene (''FXN'') on chromosome 9, which produces an important protein called frataxin. In 96% of cases, the mutant ''FXN'' gene has 90–1,300 GAA
trinucleotide repeat expansion A trinucleotide repeat expansion, also known as a triplet repeat expansion, is the DNA mutation responsible for causing any type of disorder categorized as a trinucleotide repeat disorder. These are labelled in dynamical genetics as dynamic muta ...
s in
intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...
1 of both alleles. This expansion causes
epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
changes and formation of
heterochromatin Heterochromatin is a tightly packed form of DNA or '' condensed DNA'', which comes in multiple varieties. These varieties lie on a continue between the two extremes of constitutive heterochromatin and facultative heterochromatin. Both play a role ...
near the repeat. The length of the shorter GAA repeat is correlated with the age of onset and disease severity. The formation of heterochromatin results in reduced
transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...
of the gene and low levels of frataxin. People with FDRA might have 5-35% of the frataxin protein compared to healthy individuals. Heterozygous carriers of the mutant FXN gene have 50% lower frataxin levels, but this decrease is not enough to cause symptoms. In about 4% of cases, the disease is caused by a ( missense, nonsense, or intronic) point mutation, with an expansion in one allele and a point mutation in the other. A missense point mutation can have milder symptoms. Depending on the point mutation, cells can produce no frataxin, nonfunctional frataxin, or frataxin that is not properly localized to the mitochondria.


Pathophysiology

FRDA affects the nervous system, heart, pancreas, and other systems. Degeneration of nerve tissue in the spinal cord causes ataxia. The sensory neurons essential for directing muscle movement of the arms and legs through connections with the cerebellum are particularly affected. The disease primarily affects the spinal cord and peripheral nerves. The spinal cord becomes thinner and nerve cells lose some myelin sheath. The diameter of the spinal cord is smaller than that of unaffected individuals mainly due to smaller dorsal root ganglia. The
motor neuron A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirectl ...
s of the spinal cord are affected to a lesser extent than sensory neurons. In peripheral nerves, a loss of large myelinated sensory fibers occurs. Structures in the brain are also affected by FRDA, notably the dentate nucleus of the cerebellum. The heart often develops some fibrosis, and over time, develops left-ventricle hypertrophy and dilatation of the left ventricle.


Frataxin

The exact role of frataxin remains unclear. Frataxin assists iron-sulfur protein synthesis in the electron transport chain to generate adenosine triphosphate, the energy molecule necessary to carry out metabolic functions in cells. It also regulates iron transfer in the mitochondria by providing a proper amount of reactive oxygen species (ROS) to maintain normal processes. One result of frataxin deficiency is mitochondrial iron overload, which damages many proteins due to effects on cellular metabolism. Without frataxin, the energy in the mitochondria falls, and excess iron creates extra ROS, leading to further cell damage. Low frataxin levels lead to insufficient biosynthesis of iron–sulfur clusters that are required for mitochondrial electron transport and assembly of functional
aconitase Aconitase (aconitate hydratase; ) is an enzyme that catalyses the stereo-specific isomerization of citrate to isocitrate via ''cis''- aconitate in the tricarboxylic acid cycle, a non-redox-active process. Image:Citrate wpmp.png, Image:Cis- ...
and iron dysmetabolism of the entire cell.


Diagnosis

Balance difficulty, loss of proprioception, an absence of reflexes, and signs of other neurological problems are common signs from a physical examination. Diagnostic tests are made to confirm a physical examination such as
electromyogram Electromyography (EMG) is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph to produce a record called an electromyogram. An electromyog ...
, nerve conduction studies, electrocardiogram, echocardiogram,
blood test A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a hypodermic needle, or via fingerprick. Multiple tests for specific blood components, such as a glucose test or a cholester ...
s for elevated glucose levels and vitamin E levels, and scans such as
X-ray radiograph An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10 nanometers, corresponding to frequencies in the range 30  ...
for scoliosis. MRI and
CT scans A computed tomography scan (CT scan; formerly called computed axial tomography scan or CAT scan) is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers ...
of brain and spinal cord are done to rule out other neurological conditions. Finally, a genetic test is conducted to confirm. Other diagnoses might include Charcot-Marie-Tooth types 1 and 2, ataxia with vitamin E deficiency, ataxia-oculomotor apraxia types 1 and 2, and other early-onset ataxias.


Management

Physical therapists play a critical role in educating on correct posture, muscle use, and the identification and avoidance of features that aggravate spasticities such as tight clothing, poorly adjusted wheelchairs, pain, and infection.


Rehabilitation

Physical therapy typically includes intensive motor coordination, balance, and stabilization training to preserve gains. Low intensity strengthening exercises are incorporated to maintain functional use of the upper and lower extremities. Stretching and muscle relaxation exercises can be prescribed to help manage spasticity and prevent deformities. Other physical therapy goals include increased transfer and locomotion independence, muscle strengthening, increased physical resilience, "safe fall" strategy, learning to use mobility aids, learning how to reduce the body's energy expenditure, and developing specific breathing patterns. Speech therapy can improve voice quality.


Devices

Well-fitted orthoses can promote correct posture, support normal joint alignment, stabilize joints during walking, improve range of motion and gait, reduce spasticity, and prevent foot deformities and scoliosis. Functional electrical stimulation or
transcutaneous nerve stimulation Transcutaneous electrical nerve stimulation (TENS or TNS) is the use of electric current produced by a device to stimulate the nerves for therapeutic purposes. TENS, by definition, covers the complete range of transcutaneously applied currents ...
devices may alleviate symptoms. As progression of ataxia continues, assistive devices such as a cane, walker, or wheelchair may be required for mobility and independence. A standing frame can help reduce the secondary complications of prolonged use of a wheelchair.


Medication and surgery

Cardiac abnormalities can be controlled with
ACE inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of hypertension, high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease i ...
s such as enalapril, ramipril, lisinopril, or trandolapril, sometimes used in conjunction with beta blockers. Affected people who also have symptomatic congestive heart failure may be prescribed eplerenone or
digoxin Digoxin (better known as Digitalis), sold under the brand name Lanoxin among others, is a medication used to treat various heart conditions. Most frequently it is used for atrial fibrillation, atrial flutter, and heart failure. Digoxin is on ...
to keep cardiac abnormalities under control. Surgery may correct deformities caused by abnormal muscle tone. Titanium screws and rods inserted in the spine help prevent or slow the progression of scoliosis. Surgery to lengthen the Achilles tendon can improve independence and mobility to alleviate
equinus deformity Toe walking refers to a condition where a person walks on their toes without putting much or any weight on the heel or any other part of the foot. This term also includes the inability to connect one's foot fully to the ground while in the standi ...
. An automated implantable cardioverter-defibrillator can be implanted after a severe heart failure.


Prognosis

The disease evolves differently in different people. In general, those diagnosed at a younger age or with longer GAA triplet expansions tend to have more severe symptoms. Congestive heart failure and abnormal heart rhythms are the leading causes of death, but people with fewer symptoms can live into their 60s or older.


Epidemiology

FRDA affects Indo-European populations. It is rare in East Asians, sub-Saharan Africans, and Native Americans. FRDA is the most prevalent inherited ataxia, affecting approximately 1 in 40,000 with European descent. Males and females are affected equally. The estimated carrier prevalence is 1:100. A 1990–1996 study of Europeans calculated the incidence rate was 2.8:100,000. The prevalence rate of FRDA in Japan is 1:1,000,000. FRDA follows the same pattern as
haplogroup R1b Haplogroup R1b (R-M343), previously known as Hg1 and Eu18, is a human Y-chromosome haplogroup. It is the most frequently occurring paternal lineage in Western Europe, as well as some parts of Russia (e.g. the Bashkirs) and pockets of Central A ...
. Haplogroup R1b is the most frequently occurring paternal lineage in Western Europe. FRDA and Haplogroup R1b are more common in northern Spain, Ireland, and France, rare in Russia and Scandinavia, and follow a gradient through central and eastern Europe. A population carrying the disease went through a
population bottleneck A population bottleneck or genetic bottleneck is a sharp reduction in the size of a population due to environmental events such as famines, earthquakes, floods, fires, disease, and droughts; or human activities such as specicide, widespread violen ...
in the Franco-Cantabrian region during the last ice age.


History

The condition is named after the 1860s German pathologist and neurologist,
Nikolaus Friedreich Nikolaus Friedreich (1 July 1825 in Würzburg – 6 July 1882 in Heidelberg) was a German pathologist and neurologist, and a third generation physician in the Friedreich family. His father was psychiatrist Johann Baptist Friedreich (1796–1862) ...
. Friedreich reported the disease in 1863 at the University of Heidelberg. Further observations appeared in a paper in 1876. Frantz Fanon wrote his medical thesis on FRDA, in 1951. A 1984 Canadian study traced 40 cases to one common ancestral couple arriving in New France in 1634. FRDA was first linked to a GAA repeat expansion on chromosome 9 in 1996.


Research

Active research is ongoing to find a treatment. Patients can enroll in a registry to make clinical trial recruiting easier. The Friedreich's Ataxia Global Patient Registry is the only worldwide registry of Friedreich's ataxia patients to characterize the symptoms and establish the rate of disease progression. The Friedreich's Ataxia App is the only global community app which enables novel forms of research. As of May 2021, research continues along the following paths.


Improve mitochondrial function and reduce oxidative stress

*
Reata Pharmaceuticals Reata Pharmaceuticals, Inc. is a pharmaceutical company based in Plano, Texas. Founded in 2002, Reata is primarily focused on investigating experimental oral antioxidative and anti-inflammatory drugs, which dually activate the antioxidative transc ...
developed RTA 408 (
Omaveloxolone Omaveloxolone, sold under the brand name Skyclarys, is a medication used for the treatment of Friedreich's ataxia. It is taken by mouth. The most common side effects include an increase in alanine transaminase and an increase of aspartate am ...
or Omav) to target activation of a transcriptional factor, Nrf2. Nrf2 is decreased in FRDA cells.. * PTC-743 (formerly EPI-743) is being developed by
PTC Therapeutics PTC Therapeutics is a US pharmaceutical company focused on the development of orally administered small molecule drugs and gene therapy which regulate gene expression by targeting post-transcriptional control (PTC) mechanisms in orphan disease ...
. PTC-743 is a para-benzoquinone and targets the
NAD(P)H dehydrogenase (quinone 1) NAD(P)H dehydrogenase uinone1 is an enzyme that in humans is encoded by the ''NQO1'' gene. This protein-coding gene is a member of the NAD(P)H dehydrogenase (quinone) family and encodes a 2-electron reductase (enzyme). This FAD-binding protein fo ...
(NQO1) enzyme to increase the biosynthesis of glutathione. *
Retrotope Retrotope, Inc. is a drug development company advancing the idea that polyunsaturated fatty acids (PUFA) drugs fortified with heavy isotopes (reinforced lipids) protect living cells by making bonds within the delicate molecules inside and around c ...
is advancing
RT001 Di-deuterated ethyl linoleate (also known as RT001, di-deuterated linoleic acid ethyl ester, 11,11-''d2''-ethyl linoleate, or ethyl 11,11-''d2''-linoleate) is an experimental, orally-bioavailable synthetic deuterated polyunsaturated fatty acid (PU ...
. RT001 is a
deuterated Isotopic labeling (or isotopic labelling) is a technique used to track the passage of an isotope (an atom with a detectable variation in neutron count) through a reaction, metabolic pathway, or cell. The reactant is 'labeled' by replacing specific ...
synthetic homologue of ethyl linoleate, an essential omega-6 polyunsaturated fatty acid which is one of the major components of lipid membranes, particularly in
mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
. Oxidation damage might be reduced if the polyunsaturated fatty acids in the lipids were made more rigid and less susceptible to oxidation by the replacement of hydrogen atoms with the heavy hydrogen isotope deuterium.


Modulation of frataxin controlled metabolic pathways

*
Dimethyl fumarate Dimethyl fumarate (DMF) is the methyl ester of fumaric acid and is named after the earth smoke plant (''Fumaria officinalis''). Dimethyl fumarate combined with three other fumaric acid esters (FAEs) is solely licensed in Germany as an oral thera ...
has been shown to increase frataxin levels in FRDA cells, mouse models, and humans. DMF showed an 85% increase in frataxin expression over 3 months in
multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
.


Frataxin replacements or stabilizers

* EPO mimetics are orally available peptide imitations of
erythropoietin Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bo ...
. They are small molecules erythropoietin receptor agonists designed to activate the tissue-protective erythropoietin receptor. * Etravirine, an antiviral drug used to treat HIV, was found in a
drug repositioning Drug repositioning (also called drug repurposing) involves the investigation of existing drugs for new therapeutic purposes. Repurposing achievements A number of successes have been achieved, the foremost including sildenafil (Viagra) for ere ...
screening to increase frataxin levels in peripheral cells. Fratagene Therapeutics is developing a small molecule called RNF126 to inhibit an enzyme which degrades frataxin.


Increase frataxin gene expression

*
Resveratrol Resveratrol (3,5,4′-trihydroxy-''trans''-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens, such as bacteria or fungi. Sources ...
might improve mitochondrial function. * Nicotinamide (vitamin B3) was found effective in preclinical FRDA models and well tolerated. * An
RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
-based approach might unsilence the FXN gene and increase the expression of frataxin. Non-coding RNA (
ncRNA A non-coding RNA (ncRNA) is a functional RNA molecule that is not translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally important types of non-c ...
) could be responsible for directing the localized
epigenetic In biology, epigenetics is the study of stable phenotypic changes (known as ''marks'') that do not involve alterations in the DNA sequence. The Greek prefix '' epi-'' ( "over, outside of, around") in ''epigenetics'' implies features that are "o ...
silencing of the FXN gene. *
Lentivirus ''Lentivirus'' is a genus of retroviruses that cause chronic and deadly diseases characterized by long incubation periods, in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS. Lent ...
-mediated delivery of the FXN gene has been shown to increase frataxin expression and prevent DNA damage in human and mouse fibroblasts. *
CRISPR Therapeutics CRISPR Therapeutics AG is a Swiss–American biotechnology company headquartered in Zug, Switzerland. In fiscal year 2021, the company had revenues of $915 million, with net income of $378 million. By the end of the same year, the num ...
received a grant from the
Friedreich's Ataxia Research Alliance The Friedreich's Ataxia Research Alliance (FARA) is a 501(c)(3), non-profit, tax-exempt organization formed to support the research on Friedreich's ataxia. It was formed in 1998 by Ron and Raychel Bartek. FARA's turnover in 2017 was $7.3 million ...
to investigate gene editing as a potential treatment for the disease in 2017.


Society and culture

''
The Cake Eaters ''The Cake Eaters'' is a 2007 American independent drama film about two small town families who must confront old issues with the return of one family's son. The film was directed by Mary Stuart Masterson (in her feature film directorial debut) ...
'' is a 2007 independent drama film that stars Kristen Stewart as a young woman with FRDA. ''
The Ataxian ''The Ataxian'' is a documentary film of Kyle Bryant, a sufferer of Friedreich's ataxia. The film premiered at the Dances With Films Festival in 2015. Synopsis The movie tells how Bryant lost the ability to play his favorite sports and walk. ...
'' is a documentary that tells the story of
Kyle Bryant Kyle Bryant (October 5, 1981) is an athlete, speaker and the spokesperson for the Friedreich's Ataxia Research Alliance (FARA). Bryant is the founder and event director of rideATAXIA – a nationwide bike ride fundraiser benefiting FARA. Early li ...
, an athlete with FRDA who completes a long-distance bike race in an adaptive "trike" to raise money for research. Dynah Haubert spoke at the
2016 Democratic National Convention The 2016 Democratic National Convention was a presidential nominating convention, held at the Wells Fargo Center in Philadelphia, Pennsylvania, from July 25 to 28, 2016. The convention gathered delegates of the Democratic Party, the majo ...
about supporting Americans with disabilities. Geraint Williams in an athlete affected by FRDA who is known for scaling
Mount Kilimanjaro Mount Kilimanjaro () is a dormant volcano in Tanzania. It has three volcanic cones: Kibo, Mawenzi, and Shira. It is the highest mountain in Africa and the highest free-standing mountain above sea level in the world: above sea level and ab ...
in an adaptive wheelchair. Shobhika Kalra is an activist with FRDA who helped build over 1000 wheelchair ramps across the United Arab Emirates in 2018 to try to make Dubai fully wheelchair-friendly by 2020.


References


External links


Friedreich's Ataxia Global Patient RegistryNIH's FRDA information page
{{DEFAULTSORT:Friedreich's Ataxia Systemic atrophies primarily affecting the central nervous system Autosomal recessive disorders Mitochondrial diseases Trinucleotide repeat disorders Rare diseases