Friedreich's ataxia

Friedreich's ataxia is an inherited disease that causes progressive damage to the nervous system resulting in symptoms ranging from gait disturbance and speech problems to heart disease.

"Ataxia," which refers to coordination problems such as clumsy or awkward movements and unsteadiness, occurs in many different diseases and conditions. The ataxia of Friedreich's ataxia results from the degeneration of nerve tissue in the spinal cord and of nerves that control muscle movement in the arms and legs. The spinal cord becomes thinner and nerve cells lose some of their myelin sheath (the insular covering on all nerve cells that helps conduct nerve impulses).

Eponym
It is named after the German physician Nicholaus Friedreich, who first described the condition in the 1860s.

Prevalence
Friedreich's ataxia, although rare, is the most prevalent inherited ataxia, affecting about 1 in 50,000 people in the United States. Males and females are affected equally.

Due to the relatively heterogenous population of Quebec, a 1984 Canadian study was able to trace 40 cases of classical Friedreich's disease from 14 previously unrelated French-Canadian kindreds to one common ancestral couple arriving in New France in 1634: Jean Guyon and Mathurine Robin.

Delatycki et al. (2000) provided an overview of the clinical features, pathology, molecular genetics, and possible therapeutic options in Friedreich ataxia.

Genetics
Friedreich's ataxia is an autosomal recessive congenital ataxia and is caused by a mutation in Gene X25 that codes for frataxin, located on chromosome 9. This protein is essential in neuronal and muscle cells for proper functioning 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).

The classic form has been mapped to 9q13-q21; the mutant gene contains expanded GAA triplet repeats in the first intron of "frataxin gene". 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 (the mutation decreases the transcription of the gene) through induction of a heterochromatin structure in a manner similar to position-effect variegation.

Relationship to muscular dystrophy
Friedreich's ataxia and muscular dystrophy, though often compared, are completely different diseases. Muscular dystrophy is the result of muscle tissue degeneration whereas Friedreich's ataxia is the result of nerve tissue degeneration caused by a trinucleotide repeat expansion mutation. Both are researched by the Muscular Dystrophy Association.

Types of Friedreich's ataxia
There are two types, the classic form and one in association with a genetic vitamin E deficiency. They cannot be distinguished clinically in lab.

Symptoms
Symptoms typically begin sometime between the ages of 5 to 15 years, but in Late Onset FA may occur in the 20's or 30's. Symptoms include any combination, but not necessarily all of the following:


 * Muscle weakness in the arms and legs
 * Loss of coordination
 * Vision impairment
 * Hearing loss
 * Slurred speech
 * Curvature of the spine (scoliosis)
 * High plantar arches
 * Diabetes
 * Extreme heart conditions (e.g., atrial fibrillation, and resultant tachycardia (fast heart rate) and cardiomyopathy (enlargement of the heart))

It presents before 25 years of age with progressive staggering gait, frequent falling and titubation. Lower extremities are more severely involved.

These symptoms are slow and progressive. Long-term observation shows that many patients reach a plateau in symptoms in the patient's early adulthood. Because of many of these symptoms, a person suffering from Friedrich'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 occurs, assistive devices such as a cane or walker or a wheelchair are required for mobility (independence).

Signs

 * Cerebellar: Nystagmus, fast saccadic eye movements, truncal titubation, dysarthria, dysmetria.
 * 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 cardiomegaly (up to dilated cardiomyopathy), symmetrical hypertrophy, 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% cases are found in association with diabetes mellitus type 1 or 2 or pancreatic β cell dysfunction.

Pathogenesis
The primary site of pathology is spinal cord and peripheral nerves. Sclerosis and degeneration of spinocerebellar tracts, lateral corticospinal tracts, and posterior columns. In peripheral nerves there is a loss of large myelinated fibres.

Treatment
The symptoms can be treated but there is no treatment for Friedrich's Ataxia at this time. There are several clinical trials taking place, including one for idebenone, in the United States. 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 inhibitors such as Lisinopril and other heart medications such as Digoxin.

Current Research
Recent research led by Joel Gottesfeld of The Scripps Research Institute has indicated that Histone Deacetylase Inhibitors are able to reverse the silencing of the frataxin gene in human primary lymphocytes. This class of chemicals is thought to enable DNA transcription of the frataxin gene because the inhibition of histone deacetylation, makes the terminal tails of histones H3 and H4 more likely to remain fully acetylated. Acetylation removes the positive charge from the lysine (an amino acid that is a part of the n-terminal tail of the histone proteins), and thus makes the histones less able to neutralize the charges of the DNA (specifically the negatively charged phosphate backbone). This causes the DNA and the histone proteins to be less condensed (back to the form of euchromatin). This increases the ability of regulatory proteins and RNA polymerases to access the frataxin gene, and therefore returns the transcription (and the overall expression) of the frataxin gene to normal levels.

Because the genetic defect occurs in the intron, the excess nucleotides repeats are removed from the mRNA transcript, and the resulting frataxin proteins are not defective. The HDACi chemicals effect the histone proteins throughout the cell, but gene expression microarray experiments reveal that the effects are limited, and do not appear to be clustered into any family of genes that might cause deleterious side effects. The compounds are not cytotoxic to lymphocytes or to mice when administered at therapeutic doses.

On April 11th, 2007, Repligen Corporation, a biopharmaceutical company, entered into an exclusive commercial license with The Scripps Research Institute for the development of HDACi compounds that could have clinical uses in the treatment of Friedreich's Ataxia.