Neuro-Ophthalmic Manifestations of Friedreich Ataxia
Friedreich ataxia (FA) is the most common autosomal recessive genetic ataxia in the Caucasian population. It affects the central and peripheral nervous system, causing a variety of different manifestations. FA may affect all four limbs and typically presents with progressive dysarthria, pyramidal signs, sensory disturbances, and loss of reflexes in the lower extremities. Most patients start experiencing symptoms under the age of 20, and the disease is progressive throughout life.
History and Epidemiology:
Nikolaus Friedreich described the disorder in 1863 in patients with early onset ataxia, kyphoscoliosis, and familial heart degeneration. Although Friedreich’s work was not well recognized at the time of publication, his work was highlighted several decades later when Pierre Marie distinguished FA from other forms of ataxia.The prevalence of FA varies depending on geographic location ranging from 1:20,000 to 1:750,000 with higher prevalence in European populations (e.g., Southern France, Northern Spain and Ireland); lesser rates in Scandinavia and Russia ; and even lower rates in Sub-Saharan Africa and the Eastern hemisphere.
FA is a progressive genetic disorder. Typically, patients will experience symptoms in adolescence, on average at 15.5 years old, with gait disturbances. Independent gait loss occurs about 8 years (on average) following initial symptoms with the need for wheelchair after 11-15 years. Generally, dysarthria occurs in 10-15 years, diabetes in 16 years, and proprioception loss within 40 years. Patients may also later suffer from visual disturbances, scoliosis, dysarthria, and cardiac sequelae. FA has an autosomal recessive inheritance and is characterized by a homozygous GAA triplet repeat expansion in intron 1 of the frataxin gene located on chromosome 9. Females and males are equally affected. Frataxin is a protein located in the inner mitochondrial membrane and is responsible for normal mitochondrial respiration. However, triplet repeat expansions interfere with the normal function of the frataxin gene.
Neurologically, patients with FA have smaller dorsal root ganglia with thin and gray dorsal roots. Across the length of the spinal cord, the diameter is less than normal, particularly in the thoracic area. For the heart, the weight is increased in patients with FA due to hypertrophic cardiomyopathy, and on gross appearance, the myocardial tissue has a “marble-like” appearance that has been previously described in patients with FA.
The pathophysiology of FA involves shifting levels of intracellular iron that leads to vulnerability of the central and peripheral nervous system to oxidative stress, including retinal ganglion cells. FA has also been observed to be present with ocular manifestations in up to 30% of patients with involvement of the brainstem-cerebellar circuit and optic nerves. Recent studies suggest that patients with FA may have a reduced retinal nerve fiber layer (RNFL) thickness that is directly correlated with visual acuity and contrast sensitivity based on optical coherence tomography (OCT) imaging. Interestingly, recent studies have revealed initial visual field defects in the periphery that progress concentrically, relating to OCT documented RNFL loss of the optic nerve.
Typically, the age of the average patient with FA will have onset of symptoms around 15.5 years of age, with most patients being diagnosed prior to age 25.Parents or educational providers will notice children having abnormal motor skills. There may be a history of cardiomyopathy earlier in the clinical course (up to 63%), with diabetes occurring later in the disease process (8-32% of FA patients). Patients may have difficulty sitting down easily or with comfort, due to scoliosis. Despite the findings of optic atrophy in some patients (described in Examination section below), most patients are not visually symptomatic.
Patients most commonly have ataxic gait, dysmetria of upper and lower extremities, dysarthria, lack of deep tendon reflexes, Babinski signs, and atrophy and weakness of distal extremities. Patients may present with scoliosis or foot deformity characteristic of pes cavus earlier than other manifestations. On neuro-ophthalmic exam, there may be nystagmus, unstable fixation, square-wave jerks, impaired pursuit movement, or saccadic dysmetria. On fundus exam, patients may have optic atrophy, and less commonly a retinitis pigmentosa like syndrome.
FA can be diagnosed clinically on the patient’s history and physical exam, with genetic testing. Through studies by Harding, a set of various symptoms have been compiled (Table 1) that describe criteria for making a diagnosis.
Table 1. Harding's Criteria Featured in Wood
|Essential||-Age of onset before 25 years
-Progressive ataxia of gait and limbs
-Absent knee and ankle jerks
-Axonal picture on neurophysiology
-Dysarthria (if after five years from onset)
|Additional (present in over 66%)||-Scoliosis
-Pyramidal weakness in lower limbs
-Absent reflexes in arms
-Large fiber sensory loss on examination -Abnormal ECG
|Others (less than 50%)||-Nystagmus
Assessment of progression can be monitored with multiple different clinical rating scales, including the FARS (Friedreich Ataxia Rating Scale), a combination of ataxia, activities of daily living, and a neurological examination.
With regards to the diagnosis, nerve conduction studies may show sensory neuronopathy and absent sensory nerve action potentials in patients, a characteristic finding of FA. Genetic diagnosis can be made using polymerase chain reaction (PCR), which will amplify the repeat expansions of intron 1.
Patients suspected of FA also may require other workup to look for other involved organ systems. An electrocardiogram (ECG) and echocardiogram can assess for cardiomyopathy and left ventricular wall thickness, which has been correlated with GAA trinucleotide repeat expansion. Blood glucose levels may be measured, since a small percentage of FA patients have diabetes.
In recent studies, OCT has been assessed for optic neuropathy, with decreased RNFL thickness. Magnetic resonance imaging may show abnormalities in the optic apparatus and some FA patients have higher apparent diffusion coefficient values than controls in some trials.
Although there is no approved specific treatment for FA , a multi-disciplinary approach to care is recommended including genetic counselors, neurology, ophthalmology, orthopedic surgery, and occupational, physical, and speech therapy.  Orthopedic surgery or bracing may be necessary for patients with scoliosis. Patients who are affected by pes cavus may be treated with botulinum toxin injections in the gastrocnemius muscle or stretching of their Achilles tendon to facilitate mobility in the legs. Low vision services might be helpful in visually symptomatic patients with optic nerve or retinal atrophy.
The prognosis for FA may be more favorable for females with an older onset of symptoms (>20 years). However, in general the prognosis is worse for patients with diabetes, dilated cardiomyopathy or other cardiac disease, and for patients with an earlier onset. Most of the mortality in FA arises from aspiration pneumonia, stroke, or cardiac complications.
In summary, FA is a progressive, triplet repeat, genetic disorder that may manifest neuro-ophthalmic symptoms and signs including optic atrophy or retinopathy. Although there is no cure, a multidisciplinary approach to care is recommended.
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