AUTHOR INFORMATION

Section 1 of 10

Authored by N K Nikhar, MD, Assistant Professor, Department of Neurology, George Washington University School of Medicine

N K Nikhar, MD, is a member of the following medical societies: American Academy of Neurology

Edited by Paul E Barkhaus, MD, Professor, Department of Neurology, Medical College of Wisconsin; Director of Neuromuscular Diseases, Milwaukee Veterans Administration Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Chief of Neurology, St Louis ConnectCar; Consulting Staff, Barnes Jewish Hospital; Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital; and Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Author's Email:	N K Nikhar, MD
Editor's Email:	Paul E Barkhaus, MD

eMedicine Journal, February 27 2007, VOLUME 8, Number 2

INTRODUCTION

Section 2 of 10

Background: Named after Friedreich from Heidelberg, who reported cases of nonsyphilitic ataxia in the 1860s, Friedreich ataxia (FA) is the most common inherited cause of ataxia. It is an autosomal recessive multisystem disorder, characterized by early onset and progressive ataxia, ataxic dysarthria, musculoskeletal deformities (eg, scoliosis, pes cavus), a predominantly sensory polyneuropathy, and cardiac conduction disturbances. A significant number of patients with advanced disease develop optic atrophy and diabetes mellitus.

Genetic studies have identified the pericentric region of the long arm of chromosome 9, where the X25 gene codes for the 210-amino-acid protein frataxin, as a critical area for FA. Frataxin's function is unknown, but low levels of mRNA transcribed from X25 have been found in tissues undergoing degeneration in FA. Frataxin is increasingly being recognized to be involved in the regulation of the mitochondrial iron/sulfur clusters. While some cases can result from a point mutation, most cases are homozygous for an unstable intronic GAA-repeat expansion.

Pathophysiology: FA is a neurodegenerative disorder that is characterized by degeneration of numerous spinal cord tracts, dorsal roots, and peripheral nerves. Degeneration is noticed particularly in the Clark column, fasciculi gracilis and cuneatus, and ascending and descending spinocerebellar tracts. Anterior and lateral horn cells are spared. Dorsal root ganglia are severely atrophic, and loss of large-diameter myelinated sensory fibers is noted.

While the responsible gene and its related protein have been identified, the mechanism by which they induce multiple tract and extraneural degeneration is unknown. However, the current belief is one of oxidative stress brought about by excessive accumulation of intramitochondrial iron content

All patients with FA eventually develop a peripheral neuropathy. The neuropathy is primarily sensory in the early stages, but in advanced stages, a motor component can be noted. The pattern of sensory loss is due to a central neuronopathy, but in later stages, a distal sensorimotor neuropathy may be noted.

Frequency:

• Internationally: Prevalence of the disease is similar across Europe and the United States. A large Italian study suggested a prevalence between 0.4 case and 4.7 cases per 100,000 population (Filla, 1992). Swedish studies have suggested a prevalence of 1 case per 100,000. While the majority of phenotype correlation is with an unstable GAA expansion of the first intron of the gene encoding for frataxin, this genotype for a FRDA phenotype is uncommon in Japan.

Mortality/Morbidity: The morbidity associated with FA is primarily secondary to cerebellar and pyramidal tract dysfunction. FA is insidiously progressive, and most patients are wheelchair bound 15 years after the onset.

• Peripheral neuropathy is neither the presenting nor the predominant feature. However, it does contribute to disability in advanced cases.

• Although overshadowed by the long-tract signs and symptoms, polyneuropathy is invariably present.

• Early and increased rate of mortality occurs from a combination of cardiomyopathy with cardiac dysrhythmia and respiratory compromise from scoliosis.

Race: No racial predilection is known, although the genetic makeup of patients with Friedreich ataxia seems to be different in the Japanese population.

Sex: FA is an autosomal recessive trait, and thus no gender predilection is seen.

Age: Symptoms and signs present early in life. Most patients present between ages 10 and 15 years, although the age of presentation varies from 18 months to 30 years.

CLINICAL

Section 3 of 10

History: Symptoms that bring attention to FA are ataxic gait, hand incoordination, or dysarthria.

• Occasionally, the presenting symptom is scoliosis.



• At presentation, sensory dysfunction may not be apparent; however, sensory ataxia develops at some stage in almost all patients.



• In well-established cases, impairments of touch, pain, and temperature may develop.

Physical:

• Clinical findings are uniform in most patients.


• • Age of onset is early adolescence.
  
  
  
  • Most present with limb and/or gait ataxia; others, with scoliosis.
  
  
  
  • Scanning speech, extraocular movement abnormalities with impaired smooth pursuit, square wave jerks, and failure of fixation suppression of the vestibuloocular reflex are noted.
  
  
  
  • Nystagmus is seen in a minority of patients.
  
  
  
  • Some patients may have optic atrophy or sensorineural deafness.
  
  
  
• Motor examination reveals mild distal weakness. In advanced cases, atrophy of the small muscles of the hands and feet may be noted.


• • Upper extremities usually are involved earlier than lower extremities. However, lower extremities are involved more severely in the latter half of the disease course from a combination of pyramidal tract dysfunction and peripheral neuropathy.
  
  
  
  • Lower-limb areflexia and extensor plantar responses are seen commonly. Preserved deep tendon reflexes are rare.
  
  
  
• Sensory examination reveals impairment of proprioception and vibration.


• • Impairment of pain and temperature sensations is seen later in the disease.
  
  
  
  • Romberg sign is often positive but is hard to interpret in the presence of the marked cerebellar ataxia.
  
  
  
  • Cognitive function is preserved until late in the disease.
  
  
  
  • On average, patients become nonambulatory 15 years after presentation.
  
  
  
• The following are established criteria for diagnosis as outlined by Harding in 1984:


• • Progressive gait and limb ataxia developing before age 30 years
  
  
  
  • Autosomal recessive pattern of inheritance
  
  
  
  • Generalized areflexia
  
  
  
  • Sensory neuropathy (neuronopathy) on electrophysiological tests
  
  
  
• Cardiac conduction defects with characteristic early T-wave inversion and cardiac myopathy, particularly hypertrophic obstructive cardiomyopathy, are some nonneurologic findings. Diabetes mellitus develops later in about 10% of patients.

Causes:

• FA is caused by a mutation in the X25 gene (in the pericentric region of the long arm of chromosome 9), which codes for the protein frataxin.


• • The mutation is an unstable intronic GAA-repeat expansion. The exact function of frataxin is unknown, but patients with FA are known to show deficiency in linoleic acid in plasma and diminished mitochondrial enzyme activity. Frataxin is considered to have a regulatory function in the iron/sulfur clustering within the mitochondrion.
  
  
  
  • Affected individuals are homozygous for the trinucleotide repeat. Occasionally, a heterozygous GAA repeat may be noted in one allele of the frataxin gene and a point mutation in the other.
  
  
  
  • The number of repeats in the mutation has a parallel correlation with the phenotypic expression; thus, patients with a large number of repeats generally have an earlier onset of presentation and more severe manifestations than those with small increases in the number of repeats. Cardiomyopathy has been shown to have a strong correlation to the GAA expansion genotype than to the point mutations.
  
  
  
• Hereditary causes of ataxia


• • Autosomal recessive ataxias such as ataxia telangiectasia and ataxia with vitamin E deficiency
  
  
  
  • Autosomal dominant cerebellar ataxias (ADCA type I-III), more recently classified as spinocerebellar ataxias (SCA I-XII), dentatorubropallidoluysian atrophy, or episodic ataxia I and II
  
  
  
  • Hereditary motor and sensory neuropathies (especially type II): Abnormal ocular and cerebellar findings are not seen in these patients.
  
  
  
• Acquired causes of ataxia


• • B-12 deficiency, vitamin E deficiency
  
  
  
  • Toxins such as alcohol, diphenylhydantoin
  
  
  
  • Infections, syphilis (ie, tabes dorsalis)
  
  
  
  • Malignancy (ie, paraneoplastic cerebellar degeneration)
  
  
  
• Diagnosis of FA is largely clinical, and the neuropathy features are a small part of the presentation.


• • The electrophysiological abnormalities are striking, with complete loss of sensory potentials even in the early stages, when the clinical symptoms and signs are mild.
  
  
  
  • Consider other causes of severe sensory neuropathy or sensory neuronopathy, including hereditary sensory and autonomic neuropathies, abetalipoproteinemia, Refsum disease, vitamin E deficiency, carcinomatous sensory neuropathies, and autoimmune diseases such as Sjögren disease.
  
  
  

DIFFERENTIALS

Section 4 of 10

Diabetic Neuropathy
Friedreich Ataxia
Inherited Metabolic Disorders
Paraneoplastic Autonomic Neuropathy
Paraneoplastic Cerebellar Degeneration
Persistent Idiopathic Facial Pain
Sarcoidosis and Neuropathy

Other Problems to be Considered:

Ataxia telangiectasia
Vitamin B-12 deficiency
Dentatorubropallidoluysian atrophy
Paraproteinemic neuropathy
Phenytoin toxicity
Syphilis (ie, tabes dorsalis)
Sjögren disease
Vitamin E deficiency

WORKUP

Section 5 of 10

Lab Studies:

• Genetic test to verify the GAA repeat expansion on chromosome 9: This test, which can be performed on a sample of EDTA-anticoagulated blood, has greater than 98% accuracy in prenatal diagnosis for couples with one child with FA.



• Fasting serum glucose: Ten percent of patients with FA develop diabetes mellitus, and significantly more have impaired glucose tolerance.



• Other tests should be ordered to rule out alternative causes of ataxia.


• • Complete blood cell (CBC) count with differential: Normochromic, normocytic anemia of chronic disease (eg, Sjögren disease) or megaloblastic changes of B-12 deficiency may be seen.
  
  
  
  • Erythrocyte sedimentation rate (ESR) may be elevated in Sjögren disease.
  
  
  
  • BUN and creatinine, serum calcium, and liver function tests (alanine aminotransferase, aspartate aminotransferase, bilirubin, alkaline phosphatase, and gamma-glutamyl transpeptidase)
    • Long-standing metabolic upsets may result in neuropathy; these would be important to exclude.

    • Abnormalities of renal and liver function tests may reflect systemic involvement from either a toxin or a systemic disease.
  
  
  
  • Serum B-12 and thyroid studies (thyroid-stimulating hormone, T4)
  
  
  
  • Vitamin E, serum lipid electrophoresis, and phytanic acid: These tests rule out vitamin E deficiency, abetalipoproteinemia, and Refsum disease, respectively.
  
  
  

Imaging Studies:

• Chest radiography may confirm scoliosis. Rarely, a bronchial tumor may be seen on chest x-ray; this can cause a carcinomatous ganglioneuritis with a profound sensory neuropathy.



• Magnetic resonance imaging (MRI) of the brain and cervical cord shows atrophy of the cervical cord and may demonstrate atrophy of the brain stem or cerebellum as part of a more diffuse process.

Other Tests:

• Electrodiagnostic testing


• • Nerve conduction studies (NCS) show absent or markedly attenuated sensory potentials with normal velocities. The motor nerve conduction velocities are always greater than 40 m/s. Distal motor latency may be mildly prolonged with normal amplitudes and conduction velocities.
  
  
  
  • Follow-up electrophysiological studies by Santoro on 15 patients with FA in Italy did not reveal any worsening of the NCS after 6 to 7 years of disease.
  
  
  
• Electrocardiogram


• • Over 65% of patients with FA have abnormal electrocardiogram.
  
  
  
  • Most of these show widespread T-wave inversion in inferior and lateral leads.
  
  
  
  • Ambulatory monitoring may reveal supraventricular dysrhythmias such as sinus arrest and tachycardias.
  
  
  
• The diagnosis of FA is a clinical diagnosis; however, when the level of clinical suspicion is high, almost all affected patients show some of the test result abnormalities mentioned here.

TREATMENT

Section 6 of 10

Medical Care: No cure for FA is known. A number of medications (eg, 5-hydroxytryptophan, amantadine, buspirone, benserazide) have been tried without proven benefit. Medical management centers on identifying potentially treatable problems.

• Patients may develop cardiac dysrhythmia, for which beta-blockers and/or calcium channel blockers (among other anti-arrhythmics) are appropriate.



• Infrequently, oral hypoglycemic agents or even insulin for diabetes mellitus may be required.



• Most patients become wheelchair bound within 15 years from disease onset.

Surgical Care:

• Rarely, corrective surgery for scoliosis may be performed.



• Surgery does not have an impact on morbidity, longevity, or the underlying disease process.

Consultations: Depending on the clinical situation, the following consultations may be appropriate: physical medicine and rehabilitation, cardiology, ophthalmology, and/or orthopedic surgery.

Activity:

• No specific limitations are necessary.



• The progressive disability invariably leads to a wheelchair-bound existence.

FOLLOW-UP

Section 7 of 10

Further Outpatient Care:

• Treatment is determined by physical disabilities. Physical therapy is recommended to prevent contractures and to maintain limb mobility.

Prognosis:

• FA is steadily progressive.



• Disability occurs from a combination of cerebellar dysfunction, peripheral neuropathy, and pyramidal tract involvement. Most patients become wheelchair bound by 15 years from onset.



• Death occurs early from a combination of cardiac and respiratory dysfunction.

MISCELLANEOUS

Section 8 of 10

Medical/Legal Pitfalls:

• The diagnosis is essentially a clinical one.



• The confirmatory test is DNA analysis to look for the GAA-repeat expansion.


• • This has implications in insurance concerns for siblings or immediate relatives.
  
  
  
  • The utility of the DNA test also has a decision-making effect on family planning.
  
  
  

TEST QUESTIONS

Section 9 of 10

CME Question 1: What is the earliest clinical presentation of Friedreich ataxia (FA)?

A: Double vision
B: Dysarthria
C: Change in handwriting
D: Gait difficulty
E: Tinnitus

The correct answer is D: Double vision is caused by a separation of the visual axis subtended by the 2 eyes. Nystagmus, which may be seen in cerebellar disorders, is not usually associated with diplopia. Dysarthria is a common finding in FA but is usually not the earliest disability noted. Change in handwriting often occurs with upper limb dysmetria, but gait instability in the form of increased falls is the earliest difficulty noticed by these patients. Tinnitus is a symptom produced by involvement of the auditory pathways. Sensorineural deafness has been described in patients with FA, but tinnitus is not a feature.

CME Question 2: Which neurophysiological abnormality is seen early in Friedreich ataxia (FA)?

A: Absent sensory potentials
B: Absent compound motor action potentials
C: Prolonged distal motor latency
D: Slow sensory and motor conduction velocities
E: Normal conductions

The correct answer is A: On neurophysiological studies, FA neuropathy in the early stages is almost entirely sensory. Prolonged distal motor latency may be seen later in the course of the disease. In advanced cases, the motor conduction velocity may show mild slowing. Most patients show either absent or markedly attenuated sensory potentials.

Pearl Question 1 (T/F): No confirmatory tests are available for diagnosing Friedreich ataxia (FA).

The correct answer is False: DNA analysis detects GAA repeat expansion. If supported by the clinical findings or a family history of FA, DNA analysis virtually confirms the disease.

Pearl Question 2 (T/F): An extensive diagnostic workup is warranted in patients in whom Friedreich ataxia (FA) is suspected.

The correct answer is True: The differential diagnosis list for ataxias and predominantly sensory neuropathies is long. Vitamin E, phytanic acid, and lipoprotein assays are useful tests, since the electrophysiological and clinical features of diseases associated with metabolic abnormalities may mimic FA.

Pearl Question 3 (T/F): No specific treatment exists for Friedreich ataxia.

The correct answer is True: Like most neurodegenerative disorders, no specific treatment is available for the underlying disease.

Pearl Question 4 (T/F): The long-term prognosis in Friedreich ataxia is good to excellent.

The correct answer is False: The long-term prognosis is poor. Most patients become wheelchair bound within 15 years from the time of presentation.

BIBLIOGRAPHY

Section 10 of 10

• Albano LM, Nishioka SA, Moyses RL, et al: Friedreich's ataxia: cardiac evaluation of 25 patients with clinical diagnosis and literature review. Arq Bras Cardiol 2002 May; 78(5): 444-51[Medline].
• Caruso G, Santoro L, Perretti A, et al: Friedreich's ataxia: electrophysiological and histological findings. Acta Neurol Scand 1983 Jan; 67(1): 26-40[Medline].
• Filla A, De Michele G, Marconi R, et al: Prevalence of hereditary ataxias and spastic paraplegias in Molise, a region of Italy. J Neurol 1992 Jul; 239(6): 351-3[Medline].
• Harding A: Cerebellar and spinocerebellar disorders. In: Bradley WG et al, eds. Neurology in Clinical Practice, 2nd ed. Boston: Butterworth-Heinemann; 1996: 1782-1785.
• Klockgether T: Ataxias. In: Goetz CJ, Pappert EJ, eds. Textbook of Clinical Neurology. Philadelphia: WB Saunders; 1999: 680-682.
• Lowe J, Lennox G, Leigh PN: Disorders of movement and system degenerations. In: Graham DI, Lantos PL, eds. Greenfield's Neuropathology, 6th ed. New York: Oxford University Press; 1997: 314-315.
• McLeod JG: Electrophysiological and sural nerve biopsy studies in patients with Freidreich's ataxia and Charcot-Marie-Tooth disease. Proc Aust Assoc Neurol 1970; 7: 89-95[Medline].
• Mondelli M, Decchi B, Parlanti S, et al: Nerve conduction study, electromyography and somatosensory evoked potentials in non-Friedreich early onset cerebellar ataxia. A comparative study with Friedreich's ataxia and late onset cerebellar ataxia. Electromyogr Clin Neurophysiol 1992 Apr-May; 32(4-5): 207-14[Medline].
• Ouvrier RA, McLeod JG, Conchin TE: Friedreich's ataxia. Early detection and progression of peripheral nerve abnormalities. J Neurol Sci 1982 Aug; 55(2): 137-45[Medline].
• Salih MA, Ahlsten G, Stalberg E, et al: Friedreich's ataxia in 13 children: presentation and evolution with neurophysiologic, electrocardiographic, and echocardiographic features. J Child Neurol 1990 Oct; 5(4): 321-6[Medline].
• Santoro L, Perretti A, Crisci C, et al: Electrophysiological and histological follow-up study in 15 Friedreich's ataxia patients. Muscle Nerve 1990 Jun; 13(6): 536-40[Medline].
• Victor M, Adams W: Adams and Victor's Principles of Neurology, 5th ed. New York: McGraw-Hill; 1993: 987-988.

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