Friedreich's ataxia(FA)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. It gets its name from German physician Nikolaus Friedreich, who first described it in the 1860s.
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).
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.
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, 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.
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.
