Friedreich's ataxia

Friedreich's ataxia
Classification and external resources
Frataxin
ICD-10	G11.1
ICD-9	334.0
OMIM	229300
DiseasesDB	4980
MedlinePlus	001411
eMedicine	article/1150420
MeSH	D005621
GeneReviews	Friedreich Ataxia

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.

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 impairment
• Slurred speech
• Curvature of the spine (scoliosis)
• High plantar arches (pes cavus 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 fibrillation, and resultant tachycardia (fast heart rate) and hypertrophic cardiomyopathy )

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:

• Cerebellar: Nystagmus, fast saccadic eye movements, truncal ataxia, dysarthria, dysmetria.
• Lower motor neuron lesion: absent deep tendon reflexes.
• Pyramidal: 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, 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.^{[citation needed]}

20% of cases are found in association with diabetes mellitus.

Genetics

Friedreich's ataxia has an autosomal recessive pattern of inheritance.

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.

Pathogenesis

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

Treatment

Currently, there is a treatment approved in Canada called idebenone. 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 inhibitors 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.

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 in 1634: Jean Guyon and Mathurine Robin.

History

Friedreich, working as a professor of pathology 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

• friedreichs_ataxia at NINDS
• friedreich at NIH/UW GeneTests
• FARA The Friedreich's Ataxia Research Alliance at www.cureFA.org
• Asks the Experts - Responses: Friedreich's Ataxia at Muscular Dystrophy Association
• NCBI Genes and Disease: Friedreich's ataxia at National Center for Biotechnology Information
• Canadian Association for Familial Ataxias - Claude St-Jean Foundation
• British Columbia (BC) Ataxia Society