Friedreich's ataxia
Encyclopedia
Friedreich's ataxia is an inherited disease that causes progressive damage
to the nervous system
, resulting in symptoms ranging from gait disturbance to speech problems; it can also lead to heart disease
and diabetes
.
The ataxia
of Friedreich's ataxia results from the degeneration
of nerve tissue in the spinal cord
, in particular sensory neurons essential (through connections with the cerebellum
) for directing muscle movement of the arms and legs. The spinal cord becomes thinner and nerve cells lose some of their myelin sheath (the insulating covering on some nerve cells that helps conduct nerve impulses).
The condition is named after the German
physician Nikolaus Friedreich
, who first described it in the 1860s.
It presents before 25 years of age with progressive staggering or stumbling gait and frequent falling. Lower extremities are more severely involved. The symptoms are slow and progressive. Long-term observation shows that many patients reach a plateau in symptoms in the patient's early adulthood.
The following physical signs may be detected on physical examination
:
20% of cases are found in association with diabetes mellitus
.
Friedreich's ataxia is an autosomal
recessive
congenital ataxia and is caused by a mutation
in gene
FXN (formerly known as X25) that codes for frataxin
, located on chromosome
9. This protein is essential for proper functioning of mitochondria (it has been shown to be connected with the removal of iron from the cytoplasm
surrounding the mitochondria, and in the absence of frataxin, the iron builds up and causes free radical damage). Nerve and muscle
cells appear to be particularly sensitive to the deleterious effects of this type of mitochondrial dysfunction.
The classic form of Friedreich's ataxia has been mapped to a gene on 9q13-q21 that affects production of the protein frataxin. In most cases, the mutant gene contains expanded GAA triplet repeats
in the first intron
; in a few pedigrees, point mutations have been detected. Because the defect is located on an intron
(which is removed from the mRNA transcript between transcription
and translation
), this mutation does not result in the production of abnormal frataxin proteins. Instead, the mutation causes gene silencing
(i.e., the mutation decreases the transcription of the gene) through induction of a heterochromatin
structure in a manner similar to position-effect variegation
.
Besides expression of frataxin, long tracts of GAA repeats induce chromosome breaks in in vivo yeast studies.
and degeneration
of dorsal root ganglion, spinocerebellar tracts, lateral corticospinal tract
s, and posterior columns. In peripheral nerves there is a loss of large myelinated fibres.
. This prescription medicine is also under regulatory review in the European Union and Switzerland. In both the United States and in Europe there are two Phase III clinical trials on-going with idebenone. As of 2009 the FDA has denied the distribution of idebenone in the United States and has discontinued the clinical trials.
A person suffering from Friedreich's Ataxia may require some surgical interventions (mainly for the spine and heart). Often a metal rod is inserted in the spine to help prevent or slow the progression of scoliosis. As progression of ataxia occurs, assistive devices such as a cane, walker, or wheelchair are required for mobility and independence. Other
assistive technology
, such as a standing frame
, can help reduce the secondary complications of prolonged use of a wheelchair
.
In many cases, patients experience significant heart conditions as well. These conditions, fortunately, are much more treatable, and are often countered with ACE inhibitor
s such as enalapril or lisinopril and other heart medications such as digoxin
.
Erythropoietin
has also been investigated.
Persons with Friedreich’s ataxia may also benefit from a conservative treatment approach for the management of symptoms. Health professionals educated in neurological conditions, such as physical therapists, can prescribe an exercise program tailored to maximize function and independence. To address the ataxic gait pattern and loss of proprioception
typically seen in persons with Friedreich’s ataxia, physical therapists can use visual cueing during gait
training to help facilitate a more efficient gait
pattern. The prescription of an assistive device along with gait
training can also prolong independent ambulation.
Low intensity strengthening exercises should also be incorporated to maintain functional use of the upper and lower extremities. Fatigability should be monitored closely. Stabilization exercises of the trunk and low back can help with postural control and the management of scoliosis
. This is especially indicative if the person is non-ambulatory and requires the use of a wheelchair. Balance and coordination training using visual feedback can also be incorporated into activities of daily living. Exercises should reflect functional tasks such as cooking, transfers and self-care. Along with gait training, balance and coordination training should be developed to help minimize the risk of falls.
Stretching exercises can be prescribed to help relieve tight musculature due to scoliosis
and pes cavus
deformities.
A 1984 Canadian study was able to trace 40 cases of classical Friedreich's disease from 14 French-Canadian kindreds previously thought to be unrelated to one common ancestral couple arriving in New France
in 1634: Jean Guyon
and Mathurine Robin.
at the University of Heidelberg, reported five patients with the condition in a series of three papers in 1863. Further observations appeared in a further paper in 1876.
Progressive illness
The term progressive illness describes the course of an illness that gradually progresses and changes mode, generally to the worse. In contrast, non-progressive or chronic illnesses are relatively constant.-Examples:...
to the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
, resulting in symptoms ranging from gait disturbance to speech problems; it can also lead to heart disease
Heart disease
Heart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...
and diabetes
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
.
The ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
of Friedreich's ataxia results from the degeneration
Degeneration
The idea of degeneration had significant influence on science, art and politics from the 1850s to the 1950s. The social theory developed consequently from Charles Darwin's Theory of Evolution...
of nerve tissue in the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
, in particular sensory neurons essential (through connections with the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
) for directing muscle movement of the arms and legs. The spinal cord becomes thinner and nerve cells lose some of their myelin sheath (the insulating covering on some nerve cells that helps conduct nerve impulses).
The condition is named after the German
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
physician Nikolaus Friedreich
Nikolaus Friedreich
Nikolaus Friedreich was a German pathologist and neurologist, and a third generation physician in the Friedreich family...
, who first described it in the 1860s.
Signs and symptoms
Symptoms typically begin sometime between the ages of 5 to 15 years, but in Late Onset FA may occur in the 20s or 30s. Symptoms include any combination, but not necessarily all, of the following:- Muscle weakness in the arms and legs
- Loss of coordination
- Vision impairment
- Hearing impairmentHearing impairment-Definition:Deafness is the inability for the ear to interpret certain or all frequencies of sound.-Environmental Situations:Deafness can be caused by environmental situations such as noise, trauma, or other ear defections...
- Slurred speechSpeechSpeech is the human faculty of speaking.It may also refer to:* Public speaking, the process of speaking to a group of people* Manner of articulation, how the body parts involved in making speech are manipulated...
- Curvature of the spine (scoliosisScoliosisScoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...
) - High plantar archPlantar archThe plantar arch is formed from:* deep plantar artery, from the dorsalis pedis - aka dorsal artery of the foot* lateral plantar arteryThe plantar arch supplies the underside, or sole, of the foot....
es (pes cavusPes cavusHigh arch is a human foot type in which the sole of the foot is distinctly hollow when bearing weight. That is, there is a fixed plantar flexion of the foot...
deformity of the foot) - Diabetes (about 20% of people with Friedreich's ataxia develop carbohydrate intolerance and 10% develop diabetes mellitus)
- Heart disorders (e.g., atrial fibrillationAtrial fibrillationAtrial fibrillation is the most common cardiac arrhythmia . It is a common cause of irregular heart beat, identified clinically by taking a pulse. Chaotic electrical activity in the two upper chambers of the heart result in the muscle fibrillating , instead of achieving coordinated contraction...
, and resultant tachycardiaTachycardiaTachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
(fast heart rate) and hypertrophic cardiomyopathyCardiomyopathyCardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
)
It presents before 25 years of age with progressive staggering or stumbling gait and frequent falling. Lower extremities are more severely involved. The symptoms are slow and progressive. Long-term observation shows that many patients reach a plateau in symptoms in the patient's early adulthood.
The following physical signs may be detected on physical examination
Physical examination
Physical examination or clinical examination is the process by which a doctor investigates the body of a patient for signs of disease. It generally follows the taking of the medical history — an account of the symptoms as experienced by the patient...
:
- Cerebellar: Nystagmus, fast saccadic eye movements, truncal ataxia, dysarthriaDysarthriaDysarthria is a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes...
, dysmetriaDysmetriaDysmetria refers to a lack of coordination of movement typified by the undershoot or overshoot of intended position with the hand, arm, leg, or eye...
. - Pyramidal: absent deep tendon reflexes, extensor plantar responses, and distal weakness are commonly found.
- Dorsal column: Loss of vibratory and proprioceptive sensation occurs.
- Cardiac involvement occurs in 91% of patients, including cardiomegalyCardiomegalyCardiomegaly is a medical condition wherein the heart is enlarged. It is generally categorized in the following manner:* Cardiomegaly due to dilation* Cardiomegaly due to ventricular hypertrophy** Left ventricular hypertrophy...
(up to dilated cardiomyopathyCardiomyopathyCardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
), symmetrical hypertrophyHypertrophyHypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It should be distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number...
, heart murmurs, and conduction defects. Median age of death is 35 years, while females have better prognosis with a 20-year survival of 100% as compared to 63% in men.
20% of cases are found in association with diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
.
Genetics
Autosome
An autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
recessive
Recessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
congenital ataxia and is caused by a mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
in gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
FXN (formerly known as X25) that codes for frataxin
Frataxin
Frataxin is a protein that in humans is encoded by the FXN gene.Frataxin is localized to the mitochondrion. The function of frataxin is not entirely clear, but it seems to be involved in assembly of iron-sulfur clusters...
, located on chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
9. This protein is essential for proper functioning of mitochondria (it has been shown to be connected with the removal of iron from the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
surrounding the mitochondria, and in the absence of frataxin, the iron builds up and causes free radical damage). Nerve and muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
cells appear to be particularly sensitive to the deleterious effects of this type of mitochondrial dysfunction.
The classic form of Friedreich's ataxia has been mapped to a gene on 9q13-q21 that affects production of the protein frataxin. In most cases, the mutant gene contains expanded GAA triplet repeats
Trinucleotide repeat disorders
Trinucleotide repeat disorders are a set of genetic disorders caused by trinucleotide repeat expansion, a kind of mutation where trinucleotide repeats in certain genes exceeding the normal, stable, threshold, which differs per gene...
in the first intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
; in a few pedigrees, point mutations have been detected. Because the defect is located on an intron
Intron
An intron is any nucleotide sequence within a gene that is removed by RNA splicing to generate the final mature RNA product of a gene. The term intron refers to both the DNA sequence within a gene, and the corresponding sequence in RNA transcripts. Sequences that are joined together in the final...
(which is removed from the mRNA transcript between transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
and translation
Translation (genetics)
In molecular biology and genetics, translation is the third stage of protein biosynthesis . In translation, messenger RNA produced by transcription is decoded by the ribosome to produce a specific amino acid chain, or polypeptide, that will later fold into an active protein...
), this mutation does not result in the production of abnormal frataxin proteins. Instead, the mutation causes gene silencing
Gene silencing
Gene silencing is a general term describing epigenetic processes of gene regulation. The term gene silencing is generally used to describe the "switching off" of a gene by a mechanism other than genetic modification...
(i.e., the mutation decreases the transcription of the gene) through induction of a heterochromatin
Heterochromatin
Heterochromatin is a tightly packed form of DNA, which comes in different varieties. These varieties lie on a continuum between the two extremes of constitutive and facultative heterochromatin...
structure in a manner similar to position-effect variegation
Position-effect variegation
Position-effect variegation is a variegation caused by the inactivation of a gene in some cells through its abnormal juxtaposition with heterochromatin....
.
Besides expression of frataxin, long tracts of GAA repeats induce chromosome breaks in in vivo yeast studies.
Pathogenesis
The primary site of pathology is spinal cord and peripheral nerves. SclerosisSclerosis (medicine)
In medicine, sclerosis refers to the stiffening of a structure, usually caused by a replacement of the normal organ-specific tissue with connective tissue.Types include:...
and degeneration
Degeneration
The idea of degeneration had significant influence on science, art and politics from the 1850s to the 1950s. The social theory developed consequently from Charles Darwin's Theory of Evolution...
of dorsal root ganglion, spinocerebellar tracts, lateral corticospinal tract
Corticospinal tract
The corticospinal or pyramidal tract is a collection of axons that travel between the cerebral cortex of the brain and the spinal cord....
s, and posterior columns. In peripheral nerves there is a loss of large myelinated fibres.
Treatment
Currently, there is a treatment approved in Canada called idebenoneIdebenone
Idebenone is an experimental drug, initially developed by Takeda Pharmaceutical Company for the treatment of Alzheimer's disease and other cognitive defects. This has been met with limited success. The Swiss company Santhera Pharmaceuticals has started to investigate it for the treatment of...
. This prescription medicine is also under regulatory review in the European Union and Switzerland. In both the United States and in Europe there are two Phase III clinical trials on-going with idebenone. As of 2009 the FDA has denied the distribution of idebenone in the United States and has discontinued the clinical trials.
A person suffering from Friedreich's Ataxia may require some surgical interventions (mainly for the spine and heart). Often a metal rod is inserted in the spine to help prevent or slow the progression of scoliosis. As progression of ataxia occurs, assistive devices such as a cane, walker, or wheelchair are required for mobility and independence. Other
assistive technology
Assistive technology
Assistive technology or adaptive technology is an umbrella term that includes assistive, adaptive, and rehabilitative devices for people with disabilities and also includes the process used in selecting, locating, and using them...
, such as a standing frame
Standing frame
A standing frame is assistive technology that can be used by a person who relies on a wheelchair for mobility...
, can help reduce the secondary complications of prolonged use of a wheelchair
Wheelchair
A wheelchair is a chair with wheels, designed to be a replacement for walking. The device comes in variations where it is propelled by motors or by the seated occupant turning the rear wheels by hand. Often there are handles behind the seat for someone else to do the pushing...
.
In many cases, patients experience significant heart conditions as well. These conditions, fortunately, are much more treatable, and are often countered with ACE inhibitor
ACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...
s such as enalapril or lisinopril and other heart medications such as digoxin
Digoxin
Digoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin...
.
Erythropoietin
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
has also been investigated.
Persons with Friedreich’s ataxia may also benefit from a conservative treatment approach for the management of symptoms. Health professionals educated in neurological conditions, such as physical therapists, can prescribe an exercise program tailored to maximize function and independence. To address the ataxic gait pattern and loss of proprioception
Proprioception
Proprioception , from Latin proprius, meaning "one's own" and perception, is the sense of the relative position of neighbouring parts of the body and strength of effort being employed in movement...
typically seen in persons with Friedreich’s ataxia, physical therapists can use visual cueing during gait
Gait
Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency...
training to help facilitate a more efficient gait
Gait
Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency...
pattern. The prescription of an assistive device along with gait
Gait
Gait is the pattern of movement of the limbs of animals, including humans, during locomotion over a solid substrate. Most animals use a variety of gaits, selecting gait based on speed, terrain, the need to maneuver, and energetic efficiency...
training can also prolong independent ambulation.
Low intensity strengthening exercises should also be incorporated to maintain functional use of the upper and lower extremities. Fatigability should be monitored closely. Stabilization exercises of the trunk and low back can help with postural control and the management of scoliosis
Scoliosis
Scoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...
. This is especially indicative if the person is non-ambulatory and requires the use of a wheelchair. Balance and coordination training using visual feedback can also be incorporated into activities of daily living. Exercises should reflect functional tasks such as cooking, transfers and self-care. Along with gait training, balance and coordination training should be developed to help minimize the risk of falls.
Stretching exercises can be prescribed to help relieve tight musculature due to scoliosis
Scoliosis
Scoliosis is a medical condition in which a person's spine is curved from side to side. Although it is a complex three-dimensional deformity, on an X-ray, viewed from the rear, the spine of an individual with scoliosis may look more like an "S" or a "C" than a straight line...
and pes cavus
Pes cavus
High arch is a human foot type in which the sole of the foot is distinctly hollow when bearing weight. That is, there is a fixed plantar flexion of the foot...
deformities.
Epidemiology
Friedreich's ataxia is the most prevalent inherited ataxia, affecting about 1 in 50,000 people in the United States. Males and females are affected equally. The estimated carrier prevalence is 1:110.A 1984 Canadian study was able to trace 40 cases of classical Friedreich's disease from 14 French-Canadian kindreds previously thought to be unrelated to one common ancestral couple arriving in New France
New France
New France was the area colonized by France in North America during a period beginning with the exploration of the Saint Lawrence River by Jacques Cartier in 1534 and ending with the cession of New France to Spain and Great Britain in 1763...
in 1634: Jean Guyon
Jean Guyon
Jean Guyon du Buisson was born at the Saint-Aubin parish in Tourouvre, Orne, France on September 18, 1592...
and Mathurine Robin.
History
Friedreich, working as a professor of pathologyPathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
at the University of Heidelberg, reported five patients with the condition in a series of three papers in 1863. Further observations appeared in a further paper in 1876.
External links
- FARA The Friedreich's Ataxia Research Alliance at www.cureFA.org
- Asks the Experts - Responses: Friedreich's Ataxia at Muscular Dystrophy AssociationMuscular Dystrophy AssociationThe Muscular Dystrophy Association is an American organization which combats muscular dystrophy and diseases of the nervous system and muscular system in general by funding research, providing medical and community services, and educating health professionals and the general public...
- NCBI Genes and Disease: Friedreich's ataxia at National Center for Biotechnology InformationNational Center for Biotechnology InformationThe National Center for Biotechnology Information is part of the United States National Library of Medicine , a branch of the National Institutes of Health. The NCBI is located in Bethesda, Maryland and was founded in 1988 through legislation sponsored by Senator Claude Pepper...
- Canadian Association for Familial Ataxias - Claude St-Jean Foundation
- British Columbia (BC) Ataxia Society