Neurology

Friedreich's Ataxia Image

Friedreich's Ataxia (FA)

FA is an inherited, debilitating, and degenerative neuromuscular disorder. Diagnosis typically occurs by genetic testing, and approximately 75% of people with FA are diagnosed between six and 20 years of age. Childhood-onset FA can occur as early as age five, is more common than later-onset FA, and normally involves more rapid disease progression. Patients experience progressive loss of coordination, muscle weakness, and fatigue, which progresses to motor incapacitation and wheelchair reliance. Most FA patients have disease onset by approximately 13 to 15 years of age and require the use of a wheelchair 10 to 15 years later. The mean life expectancy for FA patients is 35 years. Based on literature and proprietary research, we believe FA affects approximately 5,000 children and adults in the United States and 22,000 individuals globally.

FA is typically caused by a trinucleotide repeat expansion in the first intron of the frataxin gene, which encodes the mitochondrial protein frataxin. Pathogenic repeat expansions reduce frataxin expression, which leads to mitochondrial iron overload and poor cellular iron regulation, increased sensitivity to oxidative stress, and impaired production of mitochondrial adenosine triphosphate (ATP) (1-5). Impaired ATP production likely accounts for many of the symptoms experienced by FA patients, including progressive muscle weakness, decreased coordination, exercise intolerance, and fatigue (2).

In FA patients, mitochondrial function is correlated with measures of neurologic function. Further, data demonstrate that Nrf2 signaling is significantly impaired in FA patients, resulting in insufficient antioxidant defense mechanisms (5, 6).

Follow the links to FA Disease Education sites:

For Healthcare Professionals

For Patients & Caregivers

Diabetic Peripheral Neuropathic Pain (DPNP)

Diabetes is a chronic disease caused either by the lack of production of insulin (patients with type 1 diabetes) or or the inability of the body to effectively use the insulin it produces (patients with type 2 diabetes).

About 40% to 50% of patients with diabetes experience diabetic peripheral neuropathy, and about half of them also experience nerve pain. DPNP is a disabling disease and can have negative effects on quality of life.

There are about four million patients with moderate to severe DPNP in the United States, and about two million adult patients diagnosed with DPNP seek treatment annually. Approximately half of patients with DPNP do not achieve adequate reduction in pain with approved medications, and approved therapies have significant tolerability issues such as somnolence and dizziness.

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dpnp

References

  1. Lodi, R., Tonon, C., Calabrese, V., and Schapira, A. H. (2006) Friedreich's ataxia: from disease mechanisms to therapeutic interventions. Antioxid Redox Signal 8, 438-443
  2. Lodi, R., Cooper, J. M., Bradley, J. L., Manners, D., Styles, P., Taylor, D. J., and Schapira, A. H. (1999) Deficit of in vivo mitochondrial ATP production in patients with Friedreich ataxia. Proc Natl Acad Sci U S A 96, 11492-11495
  3. Vorgerd, M., Schöls, L., Hardt, C., Ristow, M., Epplen, J. T., and Zange, J. (2000) Mitochondrial impairment of human muscle in Friedreich ataxia in vivo. Neuromuscul Disord 10, 430-435
  4. Ghanekar, S. D., Miller, W. W., Meyer, C. J., Fenelon, K. J., Lacdao, A., and Zesiewicz, T. A. (2019) Orphan Drugs In Development For The Treatment Of Friedreich's Ataxia: Focus On Omaveloxolone. Degener Neurol Neuromuscul Dis 9, 103-107
  5. Paupe, V., Dassa, E. P., Goncalves, S., Auchère, F., Lönn, M., Holmgren, A., and Rustin, P. (2009) Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia. PloS one 4, e4253-e4253
  6. Petrillo, S., Piermarini, E., Pastore, A., Vasco, G., Schirinzi, T., Carrozzo, R., Bertini, E., and Piemonte, F. (2017) Nrf2-Inducers Counteract Neurodegeneration in Frataxin-Silenced Motor Neurons: Disclosing New Therapeutic Targets for Friedreich's Ataxia. Int J Mol Sci 18, 2173
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