Differential diagnosis in Friedreich’s ataxia

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

Reaching a Friedreich’s ataxia (FA) diagnosis can be challenging. Numerous disorders lead to gait and motor difficulties in childhood, and FA may be a rarer cause of these symptoms. Thus, it may not be as readily considered during the diagnostic process, leading to diagnostic delays and misdiagnoses.

Importance of early diagnosis

Despite improvements in recent years, there remains a substantial delay in the FA diagnostic process, with a median time to diagnosis after symptom onset of around three years. For patients with an atypical presentation, including non-neurological symptoms or later age at onset, this delay may be significantly longer. Patients commonly see several healthcare providers before an accurate diagnosis is achieved.

As disease-modifying therapies for FA emerge, it becomes increasingly critical to reach an early, accurate diagnosis. A sooner start to treatment may help to substantially slow disease progression, prevent or ease the severity of comorbidities, and improve the quality of life for FA patients.

Differential diagnosis

FA has clinical overlap with a range of other conditions, including peripheral neuropathies, inherited ataxias, and other neurological conditions, driving its misdiagnosis. Still, FA has defining clinical, imaging, and laboratory characteristics that can differentiate it from these other disorders.

Other ataxias

A number of inherited progressive ataxias may resemble FA with symptoms of progressive ataxia, neuropathy, and reflex loss that are evident in childhood or adolescence, but can mostly be distinguished on the basis of clinical history, genetic testing, MRI evaluations, and blood tests.

Inherited ataxias with possible clinical overlap to FA include:

• Spinocerebellar ataxia (SCA): distinguished from FA by MRI imaging, where significant cerebellar atrophy is observed in SCA and not in FA. More importantly, most SCAs have dominant inheritance so a family history is almost always present.
• Ataxia with vitamin E deficiency: with a very similar clinical presentation to FA, this form of ataxia is distinguished by low blood vitamin E levels and neurological improvement upon vitamin E supplementation. It is also far less common than FA.
• Ataxia with oculomotor apraxia types 1 and 2: this form of ataxia shows cerebellar atrophy on MRI, and is also less common than FA.
• Abetalipoproteinemia (Bassen-Kornzweig disease): distinguished from FA by abnormal lipid levels and neurological improvements with fat-soluble vitamin supplementation. It also has clinical aspects not seen in FA – including retinal degeneration, for example – and is extremely rare.
• Refsum disease: differentiated from FA by elevated phytanic acid levels and improvements with dietary restrictions. Again, it is far less common than FA and lacks cardiac manifestations.
• Ataxia-telangiectasia: distinguished from FA by elevated blood alpha-fetoprotein levels and the presence of many different clinical features, namely an earlier age of onset usually, presence of telangiectasias, loss of cerebellar volume early on MRI, hematologic abnormalities, and predisposition to cancer.

Peripheral neuropathies

Inherited neuropathies, particularly Charcot-Marie-Tooth (CMT) disease types 1 and 2, account for a significant number of misdiagnoses in FA patients. CMT can lead to ataxia and areflexia that may resemble FA early, but lacks any changes in electrocardiogram. It is also usually autosomal dominant, so a family history is present. Genetic testing readily differentiates CMT and FA.

Electrodiagnostic tests can be used if genetic testing does not confirm the difference, as CMT presents with a severe slowing of motor nerve velocities reflective of demyelinating neuropathy whereas FA is characterized by axonal sensory changes without slowed motor nerve velocities. FA may likewise be distinguished from other demyelinating forms of peripheral neuropathy.

Other conditions

Cerebral palsy (CP) can cause symptoms of ataxia. In CP, symptoms typically emerge before age 2, leading to delays in motor and cognitive skill development, whereas motor and cognitive milestones are not delayed in FA. Spasticity and muscle weakness are common in CP, but not in children with FA.

Developmental coordination disorder (DCD) is characterized by impaired motor coordination with onset ranging from 5-18 years, and thus has significant overlap with FA. While symptoms progress in FA, DCD tends to improve or stabilize over time.

Unsteady stance and fidgety body movements in FA patients can also result in a misdiagnosis of chorea. These decrease over time and are never present in isolation as areflexia and gait difficulties are uniformly found in FA.

Combating delayed diagnosis/misdiagnosis

While many disorders lead to overlapping symptoms with FA, a careful physical examination and thorough laboratory workup should enable FA to be distinguished, avoiding delays or mistakes in the diagnostic process.

FA should be suspected as the most likely diagnosis in children or adolescents without a dominant family history presenting with slowly progressive ataxia, deep tendon reflex loss, and sensory axonal neuropathy, particularly when substantial cerebellar atrophy is not observed.

Prompt genetic testing for mutations in the FXN gene once FA is suspected can definitively establish an FA diagnosis and avoid an unnecessarily lengthy diagnostic process; it should probably be the first test in most children presenting in this way. Blood tests can rule out other hereditary causes of ataxia if needed (no such conditions are acute) if genetic testing is negative.

As orthopedic problems could be the presenting symptom of FA in a minority of cases, a neurological examination should be conducted in children with idiopathic scoliosis, particularly ages 10-18, with referral to a neurologist if evidence of FA or other neurological conditions are observed. Similarly, a few children with FA (usually less than age 10) present with cardiac dysfunction or asymptomatic murmurs. If cardiac evaluation demonstrates cardiac hypertrophy, FA should be considered among possible genetic causes.

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