Clinical features of Friedreich’s ataxia

Last updated March 4, 2024, by Lindsey Shapiro, PhD
Medically reviewed by David Lynch, MD, PhD

Friedreich’s ataxia (FA) is a rare, genetic, neurodegenerative disease characterized mainly by gait and limb ataxia. The most common hereditary cause of ataxia, FA is a multisystemic condition that leads to a range of neurological and non-neurological symptoms.

Causes

Friedreich’s ataxia is inherited in an autosomal recessive pattern, and is caused by loss-of-function variants in the frataxin-encoding FXN gene, located on  chromosome 9. More than 95% of patients are homozygous for a GAA trinucleotide repeat expansion in the first intron of the FXN gene. In cases where GAA expansions are only found in one allele, another deleterious point mutation or variant is found to affect the other.

FA-causing mutations affect FXN transcription, leading to residual levels of the mitochondrial protein frataxin. This is associated with disrupted cellular energy production, affecting particularly cells with high energy demand such as neurons and muscle cells.

Demographics

FA is most commonly found in people of Indo-European ancestry due to inheritance patterns of the GAA repeat expansion. It has a typical age of onset between 10 and 15 years of age.

Cardinal features

FA leads to progressive damage to the peripheral nerves in the spinal cord, driving cardinal neurological symptoms such as ataxia, muscle weakness, and sensory changes that are virtually universal across FA patients.

Ataxia and muscle weakness

Progressive gait unsteadiness is the first complaint for the majority of FA patients. This may include general clumsiness, loss of balance, poor hand function, or loss of athletic abilities that begin to emerge after the normal development of walking.

Lower limb ataxia progresses over time and is eventually accompanied by profound muscle weakness due to spinal cord atrophy. Most patients become wheelchair-reliant within 10-20 years after symptoms first appear. Ataxia affecting the upper limbs and trunk typically develops later in the course of disease.

Dysarthria and dysphagia

Virtually all FA patients will develop dysarthria and dysphagia as the disease progresses due to weakness in the facial muscles. Dysarthria may manifest as slowed speech, poor vocal control, hypernasality, dysphonia, or imprecise consonants. Dysphagia may be characterized by slow oral and pharyngeal transit, poor bolus control, and delayed initiation of swallowing.

Sensory dysfunction

Damage to the peripheral sensory nerves leads to lower limb areflexia, sometimes with arm areflexia, for most patients within five years of disease onset. Patients may also experience sensory impairments such as impaired sense of vibration or of positional sense.

Hearing and vision loss

Neurological changes affecting visual and auditory pathways are seen in nearly all FA patients. Clinically significant vision loss is only observed in a minority of patients, but oculomotor changes, such as optic atrophy, square wave jerks, or difficulty with fixation may be observed. Sound detection is often normal to begin with, but most patients will eventually show evidence of abnormal perception of complex auditory signals including speech.

Orthopedic issues (scoliosis; foot deformities)

Scoliosis is common in FA, affecting about 60%-84% of patients. This may be the presenting symptom for a minority of patients, particularly those who are younger at disease onset. Foot deformities such as pes cavus and equinovarus deformities are also common.

Progression

FA neurological symptoms progress slowly over time, with faster progression typically seen in patients with an earlier age at disease onset and longer GAA expansions.

For patients with disease onset prior to age 15, a loss of ambulation occurs on average 11.5 years after symptom onset; this is typically slower in patients with late-onset (after age 25) or very-late onset disease (after age 40). Non-neurological manifestations, such as cardiac disease and orthopedic issues, may be less common or progress more slowly in patients with late-onset disease.

FARS

The Friedreich’s Ataxia Rating Scale (FARS) is a series of physical assessments to evaluate neurological dysfunction in FA. It encompasses five domains:

• Bulbar function: cough, speech, facial/tongue atrophy
• Upper limb coordination: hand and arm movements
• Lower limb coordination: leg and foot movements, reflexes, vibratory and positional sense
• Peripheral nervous system: muscle atrophy, weakness
• Upright stability: sitting, stance, gait

With a total composite score ranging from 0-125, a higher score reflects greater neurological impairments. A shortened, modified version of FARS (mFARS) without a peripheral nervous system component may also be implemented.

Comorbidities

Heart issues

FA is commonly accompanied by abnormalities in cardiac structure and function, with hypertrophic cardiomyopathy being the most frequent cause of death in FA patients. Other cardiac symptoms may include arrhythmia.

Diabetes

Diabetes is estimated to occur in 8%-32% of FA patients, resulting from frataxin deficiency in the pancreas. Even more patients may demonstrate impaired glucose tolerance.

Neurogenic bladder and gastrointestinal disorders

Symptoms affecting the lower urinary tract, including urinary hesitancy, retention, urgency, and incontinence, are reported in up to about 80% of FA patients. Bowel dysfunction has been reported in more than half of patients, with symptoms including constipation and fecal incontinence.

Mental health issues

Depression, anxiety, and other mental health concerns may arise in FA patients, which may require counseling, medication, and lifestyle changes.

Next: Diagnostic process