Orthopedic Surgery for Friedreich Ataxia

Friedreich ataxia (FA) is the prototype of all forms of progressive ataxia, and it accounts for approximately one half of all cases of hereditary ataxia. FA is an autosomal recessive spinocerebellar disorder that has a slow but relentlessly degenerative course.[1, 2]

Guidelines for the clinical management of FA were published in November 2022 by an expert panel using the Grading of Recommendations Assessment and Evaluation (GRADE) framework for rare diseases developed by the RARE-Bestpractices Working Group.[3]

FA is an autosomal recessive disorder caused by a mutation and abnormal expansion of a GAA repeat in intron 1 of the FXN gene, which is located on chromosome 9. This gene encodes a 210-amino-acid protein called frataxin. The pathology in FA results from lack of frataxin or its function.

Certain nerve and muscle cells cannot function properly with a shortage of frataxin, leading to the signs and symptoms of FA. Approximately 98% of mutant alleles have an expansion of a gossypol acetic acid (GAA) trinucleotide repeat in intron 1 of the gene, leading to reduced levels of frataxin.[4, 5, 6, 7, 8, 9, 10, 11]

It has been hypothesized that frataxin is a mitochondrial protein important for normal production of cellular energy and that a defect in its action may result in abnormal accumulation of iron in mitochondria, leading to excess production of free radicals, which then results in cellular damage and death.[12]  The neural pathways affected in FA are those associated with large neuronal cell bodies and extensive axon elongations, which are the long tracts of the dorsal columns, pyramidal system, and peripheral nerves.

FA occurs in 1-2 per 100,000 of the US population. Its international prevalence is also 1-2 per 100,000; prevalence appears to be slightly higher in Quebec, Canada.

Symptoms may begin in infancy or in the third decade; however, symptoms usually begin when an individual is aged 8-15 years. Men and women are affected equally. All races are affected.

The rate of progression of FA is variable. The rate of progression of FA is variable, but more than 95% of individuals with FA cannot ambulate by the time they are aged 45 years, and on average, patients lose the ability to walk 15 years following onset of symptoms. The mean age of loss of ambulation is 25 years. 

Age at death is rather variable. Death usually occurs in the middle of the fourth decade of life. However, survival into the sixth and seventh decades of life has been documented. Death often is related to cardiomyopathy and diabetes and tends to occur earleir when these conditions are present, but aspiration pneumonia due to dysphagia also may shorten the lifespan of patients with FA.

Patients and their parents must be provided with information on the nature, inheritance, and implications of the genetic disorder to help them make informed medical and personal decisions.

FA is inherited in an autosomal recessive manner. Parents of a child diagnosed with FA are both obligate carriers of an FXN gene mutation. Siblings of patients with FA have a 25% risk of being affected. Offspring of patients with FA all inherit one mutant allele from the affected parent. However, these children only have a risk of being affected if the unaffected parent is a carrier of a mutation in the FXN gene. The carrier status of the unaffected parent can be determined by DNA testing.

Patients should be instructed as to the importance of maintaining an active lifestyle.

The essential criteria for diagnosis of Friedreich ataxia (FA) are progressive limb and gait ataxia developing before the patient is aged 25 years. Ataxia of gait is the most frequent presenting symptom, but this occasionally is preceded by scoliosis or cardiac symptoms.

Difficulty in standing steadily and in running are early symptoms of FA. Children are slow in learning to walk, their gait is clumsy and awkward, and they are not as agile as other children.

Occasionally, it begins rather abruptly following a febrile illness, and one leg may become clumsy before the other.

Although a hemiplegic pattern (ie, the arm and leg on one side become ataxic before those on the other side) has been discussed, it is exceptional; usually, both legs are affected simultaneously.

The hands usually become clumsy months or years after the gait disorder, and dysarthric speech appears after the arms are involved (rarely is it an early symptom).

In some patients with FA, pes cavus and kyphoscoliosis precede the neurologic symptoms. In others, these follow by several years.

Mode of inheritance is autosomal recessive.

Diabetes mellitus occurs in 10% of patients with FA, and an additional 10-20% have impaired glucose tolerance. Most patients with diabetes require insulin therapy, but some achieve reasonable control with oral hypoglycemic drugs. Diabetes tends to cluster within families. Heart disease is present in at least two thirds of patients with FA. Palpitations and angina sometimes occur.

Patients with very early onset of FA tend to be rather short, but growth and development are normal in those who are ambulant throughout adolescence.

Optic atrophy occurs in approximately 25% of persons with FA. Nystagmus is observed only in approximately 20% of individuals with FA; however, extraocular movements are nearly always abnormal, with broken-up pursuit, dysmetric saccades, square-wave jerks, and failure of fixation and suppression of the vestibuloocular reflex.

Significant sensorineural deafness occurs in 10% of persons with FA.

Heart disease is found in more than 75% of patients. Clinical evidence of ventricular hypertrophy, systolic ejection murmurs, and third or fourth heart sounds may be observed. Signs of heart failure occur late in the disease, often as a preterminal event. This usually is associated with arrhythmias such as atrial fibrillation. Peripheral cyanosis and edema in the lower limbs are very common.

Distal wasting, particularly in the upper limbs, is observed in approximately 50% of patients with FA. Flexor spasms are common. Weakness of the legs is severe in late disease. It rarely involves the arms before the patient is chair bound. Deep tendon reflexes are absent. Plantar responses are extensor in 90% of patients.

Ataxia usually is present at the time of diagnosis.

Loss of vibration and position sense occurs in most persons with established FA. Two-point discrimination may be increased in individuals with early FA.

Sphincter dysfunction, particularly urgency of micturition and constipation, occurs but is not usually severe.

Scoliosis is frequent and may be severe and associated with increased cardiopulmonary morbidity.

Approximately 50% of patients have pes cavus and/or equinovarus deformity of the feet.

Potential complications of FA include the following:

• Cardiac arrhythmias, angina, heart failure
• Respiratory failure
• Dysphagia

The diagnosis of Friedreich ataxia (FA) essentially is a clinical one. Confirmation of the diagnosis by DNA testing is recommended for all patients in whom FA is clinically suspected.[13]

Polymerase chain reaction (PCR) with nucleotide primers spanning the repeated region is used to amplify the DNA in intron 1. The products then are fractionated on an agarose or polyacrylamide gel. On normal chromosomes, the number of GAA repeats ranges from 7 to 22 units, whereas on disease chromosomes, the number ranges from approximately 100 to 2000 repeats. A normal-sized repeat length on both chromosomes argues strongly against a diagnosis of FA.

Findings from computed tomography (CT) and magnetic resonance imaging (MRI) are normal or show mild cerebellar atrophy (usually observed late in the disease). The cervical spinal cord often is atrophied.

Echocardiography reveals evidence of hypertrophic cardiomyopathy in approximately 40% of patients. The severity of left ventricular hypertrophy is related to the number of GAA repeats.

Electrocardiography (ECG) yields abnormal results in approximately two thirds of patients, most distinctively with widespread T-wave inversion. If this is present in this context, it is virtually diagnostic of FA.

Electromyography (EMG) and nerve conduction study (NCS) may be helpful. Electrodiagnostic findings that support the diagnosis of FA include the following:

• Median motor conduction velocity higher than 40 ms; absent or reduced amplitude of sensory nerve action potential
• Absent H-reflex
• Abnormal central motor conduction time after transcranial magnetic stimulation

The spinal cord exhibits loss of axons and gliosis in the posterior columns, the distal portions of corticospinal tracts, and the spinocerebellar tracts. Degeneration of neurons is present in the spinal cord (Clarke column), brain stem (cranial nerve nuclei VIII, X, and XII), cerebellum (dentate nucleus and the Purkinje cells of the superior vermis), and, to some extent, the Betz cells of the motor cortex.

Large dorsal root ganglion neurons also are decreased in number, their large myelinated axons traveling first in the dorsal root ganglion and then in dorsal columns, thereby undergoing secondary degeneration. The heart is enlarged and may have pericardial adhesions. Multifocal destruction of myocardial fibers with inflammation and fibrosis is detectable in about one half of the patients who come to autopsy examination.

As previously discussed, GAA repeat expansion along with the reduced effect on frataxin expression is the main known cause of Friedreich ataxia (FA). No approved therapy to delay, stop, or reverse the progression of FA is available in the United States. Free radical scavengers, specific inhibitors of histone deacetylases, and antioxidants (eg, coenzyme Q, N-acetylcysteine, vitamin E) are being studied.[14]

Antioxidant therapy with idebenone, in particular, has been extensively studied for the treatment of FA.[15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30] Idebenone potentially improves mitochondrial function and decreases production of reactive oxygen species. However, it has not been shown to increase exercise capacity or significantly alter neurologic function.[31, 32]

Supportive treatment should be provided as needed. Diabetes must be managed. Cardiac failure and arrhythmias should be treated as they arise.

Surgery for foot deformity and scoliosis may be of benefit in selected patients. Current guidelines should provide assistance in making this determination (see Guidelines).[3]

Prenatal testing is clinically available for couples at a 25% risk of having a child with FA and in whom both disease-causing mutations are known.[33] DNA extracted from cells obtained from amniocentesis at 16-18 weeks of gestation or chorionic villus sampling at 9-11 weeks of gestation can be analyzed.

Consultations that may be helpful include the following:

• Genetic counselor for DNA testing
• Orthopedic surgeon for scoliosis and cavovarus foot deformities ^{[34, 35]}
• Cardiologist for evaluation of cardiomyopathy
• Endocrinologist for diabetes mellitus management
• Rehabilitation medicine therapist for prostheses, walking aids, wheelchairs, and physical, occupational, and speech therapy

In November 2022, guidelines for the clinical management of Friedreich ataxia (FA) were published by an expert panel using the Grading of Recommendations Assessment and Evaluation (GRADE) framework for rare diseases developed by the RARE-Bestpractices Working Group.[3] The following recommendations and suggestions were made regarding orthopedic issues (ie, scoliosis and foot deformity) in patients with FA:

• Spinal examination must be part of the multidisciplinary approach for individuals with FA and should be performed regularly
• Individuals with FA who have a spinal curve between 20° and 40° and/or are between the ages of 10 and 16 years should be observed for curve progression; bracing may not reduce or stop curve progression, but it may be valuable in delaying surgical correction in young children
• Patients with scoliosis >40° may be considered appropriate for surgical correction
• Delay of surgical intervention should be considered in ambulant individuals with FA
• For all FA patients being considered for scoliosis surgery, extensive preoperative evaluation and planning regarding cardiac and pulmonary function are required
• It is suggested that surgery not be used over conservative therapy for individuals with scoliosis and FA
• Age should be considered when scoliosis surgery is contemplated for individuals with FA
• Stratification according to cardiac status is recommended when scoliosis surgery is contemplated for individuals with FA
• Orthopedic surgery is conditionally recommended for FA patients with foot issues if it is considered that such surgery would assist in foot alignment to facilitate mobility and/or safe and effective transfers
• Orthotics are conditionally recommended for FA patients with foot issues 
• It is not possible to recommend either physiotherapy or no physiotherapy for FA patients with foot issues