Friedreich Ataxia
Incidence
Friedreich ataxia is transmitted as an autosomal recessive trait.Caused by mutations in the frataxin gene (FRDA). The prevalence of Friedreich ataxia is 2-4 per 100,000. FRDA is the most common inherited ataxia in Europe, the Middle East, South Asia (India), and North Africa. The carrier frequency is 1/60-1/100. FRDA has not been documented in southeast Asia (Japan, Taiwan) and sub-Saharan Africa. In France prevalence is estimated to 1 in 50,000 and males and females are equally affected.
Clinical Characteristics
Friedreich ataxia is transmitted as an autosomal recessive trait. Onset often occurs in childhood or adolescence, but also sometimes in adulthood. In France prevalence is estimated to 1 in 50,000 and males and females are equally affected. Friedreich's ataxia is an inherited disease that causes progressive damage to the nervous system resulting in symptoms ranging from muscle weakness and speech problems to heart disease. Ataxia results from the degeneration of nerve tissue in the spinal cord and of nerves that control muscle movement in the arms and legs. Symptoms usually begin between the ages of 5 and 15 but can appear as early as 18 months or as late as 30 years of age. The first symptom is usually difficulty in walking. The ataxia gradually worsens and slowly spreads to the arms and then the trunk. Foot deformities such as clubfoot, flexion (involuntary bending) of the toes, hammer toes, or foot inversion (turning in) may be early signs. Rapid, rhythmic, involuntary movements of the eyeball are common. Most people with Friedreich's ataxia develop scoliosis (a curving of the spine to one side), which, if severe, may impair breathing. Other symptoms include chest pain, shortness of breath, and heart palpitations. Doctors diagnose Friedreich's ataxia by performing a careful clinical examination, which includes a medical history and a thorough physical examination. Several tests may be performed, including electromyogram (EMG) and genetic testing. The clinical features of Friedreich's ataxia include: males and females equally affected; an ataxic gait is an early sign: upper limbs become ataxic in the later stages, often with an intention tremor; dysarthria is usually a late feature. Features of corticospinal tract involvement include: limb weakness, absent abdominal reflexes and extensor plantars. Features of posterior column involvement are: loss of vibration and joint position sense in the extremities. Dorsal root and peripheral nerve involvement are noted by: loss of lower limb reflexes: ankle before knee and axonal sensory peripheral neuropathy. Musculoskeletal abnormalities present in 80% of cases - pes cavus and kyphoscoliosis. Cardiomyopathy with resultant cardiac failure or dysrhythmias is seen. Nystagmus is common; optic atrophy and retinitis pigmentosa may occur. Diabetes mellitus occurs in 10%. There is no mental retardation. Friedreich ataxia is characterized by difficulties to coordinate movements, associated with neurological signs (dysarthria, loss of reflexes, decrease of deep sensation, pes cavus and scoliosis), cardiomyopathy and sometimes diabetes mellitus. Ataxia is progressive, with an inability to walk alone 10 to 20 years after the disease onset. The causative gene has been identified in 1996 and codes for frataxin. Diagnosis can be made by genetic testing. The disease is due to a frataxin deficiency, which affects the mitochondrial function and the energetic metabolism of the cell. New treatments restoring mitochondrial functions are currently being assessed. Management should address the neurological and cardiological disorders as well as diabetes mellitus. Functional rehabilitation plays a predominant role in the management of the disease.
Precipitants
None.
Provocation Tests
None.
Diagnostic Procedures
Clinical diagnostic criteria for FRDA were established: Obligatory criteria for FRDA: Progressive ataxia of gait and limbs. Absent reflexes in the legs. Onset before age 20 years or before age 25 years. Dysarthria, decrease in position sense and/or vibration sense in lower limbs, muscle weakness. Autosomal recessive inheritance, motor nerve conduction velocity of >40 m/s with reduced or absent sensory nerve action potential. Additional findings described by Harding (1981): Signs present after five years of onset: dysarthria, areflexia, pyramidal weakness of the legs, extensor plantar responses, and distal loss of joint position and vibration sense. Frequent signs: scoliosis, pes cavus, cardiomyopathy of the hypertrophic non-obstructive type, optic atrophy, deafness, glucose intolerance, or diabetes. The vast majority of patients with FRDA have identifiable mutations in the FRDA gene (chromosomal locus 9q13). The most common mutation, seen in >95% of patients, is a GAA triplet-repeat expansion in intron 1 of the FRDA gene. About 75% of patients with FRDA meet most of the previously established obligatory criteria; however, following the identification of the FRDA gene studies have shown that up to 25% of patients homozygous for the GAA expansion in the FRDA gene exhibit atypical clinical findings compared to the previously established clinical diagnostic criteria. Confirmation of the diagnosis by molecular genetic testing is recommended in all patients who are clinically suspected of having FRDA. For more information, please contac www.genetests.org. In this condition there is also Abnormal EKG. Abnormal echocardiogram. Low pyruvate carboxylase activity in liver and cultured fibroblasts. Mitochondrial malic enzyme reduced. GAA trinucleotide repeat, often in intron 1.