Friedreich ataxia was first described by Nikolaus Friedreich in 1863 and belongs to the group of spinocerebellar heredodegenerative diseases, which progresses to a spinal ataxic syndrome similar to funicular myelosis and spinal syphilis. It is a hereditary, autosomal recessive disease, defect consists of a mutation located on chromosome 9.
Friedrich ataxia is considered to be the most common autosomal recessive ataxia, representing 50% of all cases of hereditary ataxias. Carrier testing and prenatal diagnosis of Friedreich ataxia are possible, due to the progress of molecular genetic.
Friedreich ataxia is characterized by degradation and demyelination of posterior cords of the spinal cord, spinocerebellar tracts and pyramidal tracts, associated with loss of thick, myelinated nerve fibers and fibrous gliosis. The spinal cord becomes thinner, transverse diameter of thoracic region is reduced.
Ataxia Freidreich is a relatively common disease, the incidence varies between 1 case in 22,000 inhabitants and 2 cases per 100,000 inhabitants. The disease produces significant morbidity, loss of mobility occurring in 15 years after disease onset. Around the age of 45 years, 95% of patients are immobilized.
Friedreich Ataxia Causes
Friedreich ataxia is the result of a gene mutation located on chromosome 9. This gene is encoding a protein called frataxin. The result of the mutation is an excessive number of repeats of the GAA (guanine adenine adenine) trinucleotide DNA sequence in the first intron of the gene that encodes frataxin. Friedreich ataxia is the only disease known to be a result of GAA trinucleotide repeat. This expansion of trinucleotid repeat alters the expression of the gene, decreasing the synthesis of frataxin protein.
Decreased synthesis of frataxin protein induce major pathophysiological changes. In Friedreich ataxia, the major pathological process consists of a retrograde degeneration (dying back phenomena) of axons beginning from the periphery and neuronal loss with gliosis, affecting spinal cord and spinal nerve roots. The pathological process is leading to loss of thick, myelinated axons of the peripheral nerves, while unmyelinated nerve fibers and sensory peripheral nerves are spared. Posterior columns of spinal cord, corticospinal and spinocerebellar tracts are showing demyelination and depletion of large myelinated nerve fibers, accompanied by a fibrous gliosis. Overall, the spinal cord becomes thin, anteroposterior and transverse diameters of the thoracic cord being reduced. Dorsal spinal ganglia show shrinkage and the posterior column and Clarke column degeneration is leading to loss of position and vibration senses and to a sensory ataxia. Large neurons loss in the sensory ganglia causes extinction of tendon reflexes. Neuronal loss also appear in dentate nuclei, superior vermis, bulbar and pontine nuclei, and in optic tracts.
The degenerative process can also reach myocardium (heart muscle), leading to a chronic interstitial myocarditis with hypertrophy of cardiac fibers, accompanied by vacuolation of muscle fibers and interstitial fibrosis.
Friedreich Ataxia Symptoms
Friedreich ataxia debuts between 8 and 15 years, almost always before the age of 20 years, presenting the following symptoms:
- Gait ataxia, the patient presents a tabetocerbellar gait, due to mixed sensory and cerebellar ataxia associated with impaired balance. Patient present a wide-based gait with constant shifting of position to maintain balance. Sitting and standing are associated with titubation (swaying motion of the trunk or head ). Gait ataxia may be associated with difficulty standing and running;
- Dysarthric and explosive speech, in evolution speech will become slow, slurred and incomprehensible. Incoordination of speaking, swallowing, laughing and breathing may lead to the impression that patient is choking while speaking;
- Loss of position and vibratory senses appears initially in the hands and feet, then in evolution light touch, pain and temperature sensation may be diminished;
- Reflexes are abolished, especially rotulian and Achilles reflex and plantar cutaneous reflex is positive in over 90% of cases.
Muscle tone is normal or decreased, distal muscular atrophies may affect the upper limbs and appear initially to 50% of cases. Sfincetrian control is usually kept;
- Trophic disorders are characteristic and consist of kyphoscoliosis which can be severe, producing significant cardiopulmonary impairment and death by respiratory failure. Legs cyanosis may occur. High plantar arches, foot inversion, hammertoes are characteristic for the disease and are present in 50% of cases;
- Nystagmus occurs in 20% of patients, especially horizontal nystagmus;
- Visual acuity is rarely affected, but optic atrophy occurs in 25% of patients, leading to blindness;
- Deafness may be associated with vertigo;
- Hypertrophic cardiomyopathy occurs in more than 50% of patients, myocarditis, myocardial fibrosis, progressive heart failure, tachycardia and arrhythmia are common in the evolution of the disease. Cardiac arrhythmia and congestive heart failure can represent a cause of death in patients with Friedreich ataxia;
- Diabetes mellitus or impaired glucose tolerance are found in 10% of cases;
- Mental retardation, psychosis and dementia are less common, but cognitive impairment occur more frequently in disease evolution.
Friedreich Ataxia Diagnosis
Magnetic resonance imaging (MRI) is very useful in evaluation of atrophic changes seen in Friedreich ataxia. MRI of the brain and spinal cord shows atrophy of the cervical spinal cord and minimal cerebellar atrophy.
Transcranial sonography is useful in highlighting dentate nucleus hyperechogenicity, which represents a characteristic for the disease.
Echocardiography may reveals concentric ventricular hypertrophyor septal hypertrophy. Approximately 65% of patients present abnormal ECG findings, such as T-wave inversion and ECG aspects of ventricular hypertrophy.
Nerve conduction velocity is usually normal or can be mildly reduced.
Histologic findings show loss of thick, myelinated axons of the peripheral nerves, while unmyelinated nerve fibers and sensory peripheral nerves are spared. Posterior columns of spinal cord, corticospinal and spinocerebellar tracts are showing demyelination and depletion of large myelinated nerve fibers, accompanied by a fibrous gliosis.
Friedreich Ataxia Treatment
No medical treatment is useful in slowing the natural evolution of neurological impairments for patients with Friedreich ataxia. Medical treatment is only administered for heart failure, arrhythmias and diabetes mellitus.
Surgical procedures for scoliosis and foot deformities may be helpful in selected cases of Friedreich ataxia.