Friedreich Ataxia (FRDA)

Genetic disorder characterized by progressive dysfunction of the posterior spinal cord, cerebellum (ataxia, nystagmus), and peripheral nerves. It typically becomes apparent before adolescence. Clinical features include unsteady posture, frequent falling, progressive ataxia, characteristic foot deformities, increasing incoordination of the arms and hands, dysarthria, and nystagmus. It may be associated with cardiomyopathy, chest pain, arrhythmias, and diabetes mellitus. All patients have normal intelligence.

FRDA I; Spinocerebellar Degeneration; Hereditofamilial Spinal Ataxia; Friedreich Tabes.

First described in 1863 by the German neurologist Nicholaus Friedreich.

Degeneration of the posterior spinal column, corticospinal, spinocerebellar, and pyramidal tracts. Mixed upper and lower motor neuron disease. Loss of ambulation typically occurs 15 years after disease onset. More than 95% of patients are wheelchair bound by age 45 years.

Estimated 1:30,000-50,000 in the general population. Carrier frequency is 1:60-110 with a disease prevalence of 1:29,000. Incidence is low in Africans and Asians.

Autosomal recessive. Gene map locus is 9q13. FRDA is associated with a mutation that consists of unstable expansion of GAA repeats on chromosome 9. FRDA alleles are found in approximately 11.4% of apparently recessive patients and 5.2% of apparently sporadic patients.

Spinocerebellar degeneration involving the spinocerebellar tracts, dorsal columns, pyramidal tracts, and, to a lesser extent, the cerebellum and medulla. Frataxin, the protein produced by the FRDA gene, which is part of the cellular energy of mitochondria, is severely reduced in the nervous system, heart, and pancreas of patients with FRDA. Patients have abnormally high levels of iron in their heart tissue and it is believed that the nervous system, heart, and pancreas may be particularly susceptible to damage from the free radicals produced when the excess iron reacts with oxygen. Many enzymatic activities are defective, but reduced activity of FE-S cluster-containing subunits (located in mitochondrial complexes I, II, and III and in aconitase) play a major role in disease progression.

Neurologic examination, EMG, muscle biopsies, and measurement of nerve conduction. Direct molecular test of GAA expansion is useful for the diagnosis, prognosis (size of GAA expansion is associated with the frequency of cardiomyopathy and loss of reflexes in the upper limbs), and genetic counseling. Prenatal diagnosis is available.

Symptoms usually begin between the ages of 5 and 15 years but can appear earlier. The first sign is usually difficulty in walking. The ataxia gradually worsens and slowly spreads to the arms and trunk. Foot deformities, such as clubfoot, flexion of the toes, hammertoes, or foot inversion, may be early signs. Rapid, rhythmic, involuntary movements of the eyeball are common. Most people with FRDA develop scoliosis, which may be extremely severe. Hypertrophic cardiomyopathy and congestive heart failure (often a cause of death) are usual. Of patients with FRDA, 25% have diabetes mellitus; diabetic ketosis is not infrequent.

For elective surgery, an anesthesiology consultation is highly recommended. Evaluate neurologic status (preferably with the help of an independent neurologist), cardiac status (ECG tracings, echocardiography aimed at grading the severity of cardiomyopathy and risks of cardiac failure), and metabolic status (diabetes). Check for scoliosis, possible associated difficult airway, and restrictive lung disease. Plan adequate postoperative analgesia and postoperative ECG monitoring. Depending on the physical status of the patient and the severity of surgery, postoperative transfer to the intensive care unit may be mandatory. Neurologic signs may be enhanced during the postoperative period, with spasticity that may become a sustained tetanus. Consider preoperative treatment with vitamin E and idebenone (antioxidants to decrease sensitivity to catecholamines, limit the cardiomegaly, and probably improve myocardial function).

Regional anesthetic techniques have long been denied in these patients, even though no scientific data are available. As for all demyelinating disorders, as the disease progresses, nerve stimulation becomes technically more difficult, thus making nerve location more unreliable, and less concentrated local anesthetic solutions are sufficient. Epidural and spinal anesthesias have been performed without adverse effects in many patients. FRDA patients have a marked sensitivity to depolarizing muscle relaxants, which induces hyperkalemia. The sensitivity to nondepolarizing muscle relaxants is increased, and proper neuromuscular monitoring is essential. However, monitoring of muscle relaxation may be difficult, depending on the progress of the disease. If general anesthesia is used, transesophageal echocardiographic monitoring is helpful to maintain continuous evaluation of cardiac contraction. As with any hypertrophic cardiomyopathy, maintain adequate volume status and avoid tachycardia, vasoplegia, and adrenergic stimulation during the intraoperative and postoperative periods. Postoperative supervision must emphasize hemodynamic and cardiac rhythm monitoring, adequate analgesia, and careful clinical muscular monitoring, especially of the pharyngeal and respiratory muscle. Postoperative mechanical ventilation must be considered to ensure adequate ventilation and facilitates adequate pain management.

Marked sensitivity but also normal response to nondepolarizing muscle relaxants have been reported. Succinylcholine can induce hyperkalemia in these patients and result in cardiac arrhythmias. Because of the potential risk of cardiac arrhythmias, halothane should be used with caution and combined with adequate analgesia, limiting the potential for sympathomimetic responses. Propofol, fentanyl, and low doses of cis-atracurium is probably a good anesthetic regimen. Short-acting beta-blockers (esmolol, atenolol) may be useful to blunt adrenergic responses on the heart.

Spinocerebellar Ataxia (SCA): An Overview: Characterized by degeneration of the cerebellum and its afferent and efferent connections. Clinical features include ataxia, cerebellar dysarthria, oculomotor disturbances, retinopathy, optic nerve atrophy, spasticity, extrapyramidal movement disorders, peripheral neuropathy, sphincter disturbances, and epilepsy. More than 25 variants of the spinocerebellar ataxia exist, and an overview is available under Spinocerebellar Ataxia.

Friedreich Ataxia Type II (FRDA II): Clinical features similar to Friedreich ataxia type I but with frataxin gene mutations (at a different locus than in FRDA1). Slow progression of the degeneration.

Familial Episodic Cerebellar Ataxia (Episodic Ataxia Type II): Characterized by episodic cerebellar ataxia, particularly in children, followed by amelioration of symptoms later in life with no permanent or progressive cerebellar abnormalities. Autosomal dominant pattern of inheritance. It is believed to be a variant of episodic ataxia syndrome, called EA1 (resulting from mutations of the potassium channel gene KCNA1 on 12p13) and EA2 (resulting from mutations of the calcium channel gene CACNL1A4 on 19p, which is highly expressed in the cerebellum).

Periodic Vestibulocerebellar Ataxia (Episodic Ataxia Type III): Characterized by recurrent attacks of vertigo, diplopia, and ataxia beginning in early adulthood. Slowly progressive cerebellar ataxia occurred in some patients. Assumed to be an autosomal dominant ataxia.

Roussy-Levy Syndrome: Hereditary disease inherited as autosomal dominant characterized by spinocerebellar degeneration. Not usually associated with motor ataxia and gait problems. Other features include lower limb muscular atrophy, bilateral pes cavus, and loss of deep reflexes. Severe scoliosis, camptodactyly, and clubfeet have been associated. Distinguished from FRDA by the absence of cerebellar and pyramidal signs and from Charcot-Marie-Tooth disease by the absence of sensory and vasomotor changes.

Foix Alajouanine Syndrome: Rare entity presenting as a subacute myelopathy evolving over 1 to 5 years as a result of an arteriovenous malformation of the spinal cord predominantly affecting the lower thoracic and/or lumbosacral levels.

Gordon-Holmes Syndrome: Characterized by late-onset cerebellar ataxia and hypogonadotropic hypogonadism. Hypogonadotropism was reflected in failure of secondary sexual characteristics, eunuchoidism, absence of libido, and infertility.

Marie Ataxia: Characterized by progressive degeneration of spinal nerves causing tremors and severe muscle atrophy in the arms, legs, head, and neck. It can appear in either early adulthood or middle age. Clinical features include abnormal reflexes, muscle contractions, and decreased pain or touch perception.

Charcot-Marie-Tooth Disease: Characterized by muscle weakness and atrophy, primarily in the legs. Type I Charcot-Marie-Tooth disease usually begins in middle childhood or teenage years and is associated with a deformity of the foot often referred to as gampsodactyly or clawfoot, which produces a “stork leg” deformity. With time, it spreads to the upper extremities and produces a “stocking-glove" pattern of diminished sensitivity. There is decreased sensitivity to vibration, pain, and temperature. There are several other types of this genetic condition.

Louis-Bar Syndrome: Progressive cerebellar ataxia characterized by the loss of motor coordination in the limbs and head. The onset of disease is usually in infancy. Impaired muscle coordination is an early sign of the disease that becomes most evident when walking. At age 3 to 6 years, telangiectasias appear in the eyes and on the face and palate. Other clinical features include an increased risk of sinus and respiratory infections, neoplasms, and premature aging. It has been associated with an immune deficiency (IgA or IgE). Mental development may be normal in the early stages, but loss of intellectual capacities may occur during the second decade of life. It is often misdiagnosed as FRDA until the telangiectasias appear.

Hereditary Olivopontocerebellar Atrophy (OPCA): Rare group of disorders characterized by a progressive sense of disequilibrium, cerebellar ataxia, and dysarthria. There are at least five distinct forms of hereditary OPCA. Most forms of hereditary OPCA are inherited as autosomal dominant traits.