Review Question - QID 221259

This patient with progressive ataxia with loss of vibratory sense, decreased deep tendon reflexes and motor strength, diabetes mellitus, cardiomyopathy, and pes cavus, most likely has Friedreich ataxia. Friedreich ataxia is caused by a trinucleotide (GAA) repeat mutation in tocopherol transfer protein that is inherited in an autosomal recessive fashion.

Friedreich ataxia is an autosomal recessive genetic disease that is the most common type of hereditary ataxia. The disease is caused by a repeating trinucleotide (GAA) leading to a loss-of-function mutation in the frataxin gene. This gene encodes a mitochondrial protein involved in the synthesis of iron-sulfur clusters that are critical for the functioning of enzymes in the electron transport chain. FTX deficiency leads to mitochondrial dysfunction impaired energy production, and iron accumulation. Friedreich ataxia is characterized by progressive spinocerebellar ataxia, impaired speech, and loss of muscle strength that eventually leads to loss of ambulation and independence. Other symptoms include cardiomegaly, nystagmus, pes cavus, frontal balding, diabetes mellitus, and kyphoscoliosis. Patients often present with symptoms during adolescence and lose the ability to ambulate within 11-25 years. Diagnosis is based on clinical findings and confirmed via genetic testing. Neuroimaging of the brain and spinal cord is recommended to rule out other disease processes. Management is mainly supportive and requires a multidisciplinary approach. Gene therapy is currently being explored as a potential treatment.

Shinnick et al. review information regarding Friedreich ataxia and concomitant symptoms. They found that this disease sometimes has a co-occurrence with nephrotic syndrome. They recommend that further research is needed to understand the pathophysiology and implications of this rare comorbidity.

Figure/Illustration A is a clinical photograph demonstrating a girl with very high arched feet (blue circles). This finding of pes cavus is classically seen in patients with Friedreich ataxia.

Incorrect Answers:
Answer 1: An autoimmune attack of the peripheral nervous system describes Guillian-Barre syndrome (GBS), a rare disorder characterized by rapid-onset ascending muscle weakness. Symptoms typically develop over the course of hours to weeks. The condition can be life-threatening, as patients may develop respiratory distress requiring mechanical ventilation. Pes cavus, diabetes, and cardiomyopathy are more consistent with Friedreich ataxia.

Answer 3: Defects in superoxide dismutase 1 are one of the proposed pathogenic mechanisms of amyotrophic lateral sclerosis (ALS), a motor neuron disease. The disease is characterized by combined upper motor neuron and lower motor neuron deficits with no sensory, bowel, or bladder defects. It is extremely rare for this disease to occur in adolescents; the majority of cases occur between the 5th and 7th decades of life.

Answer 4: Defects in the ataxia telangiectasia mutated (ATM) gene cause ataxia-telangiectasia syndrome, a rare neurodegenerative disorder characterized by ataxia and telangiectasias. ATM codes for ATM kinase, which is involved in detecting and repairing DNA double-strand breaks. Patients will also have frequent infections of the upper and lower respiratory tracts due to low IgA levels.

Answer 5: Vitamin E deficiency is a cause of ataxia. It is frequently caused by an autosomal recessive disease caused by mutations in the alpha-tocopherol transfer protein gene. Patients present with slowly progressive ataxia with neuropathy. Some patients also develop retinitis pigmentosa. It is important to test for vitamin E levels in patients with progressive ataxia as high-dose vitamin E replacement typically leads to improvement.

Bullet Summary:
Friedreich ataxia is an autosomal recessive disease caused by a GAA trinucleotide repeat leading to a loss-of-function mutation in the frataxin gene.