Abstract
Friedreich’s ataxia (FA) is an autosomal recessive neurodegenerative disorder, which results primarily from reduced expression of the mitochondrial protein frataxin. FA has an estimated prevalence of one in 50,000 in the population, making it the most common hereditary ataxia. Paradoxically, mortality arises most frequently from cardiomyopathy and cardiac failure rather than from neurological effects. Decreased high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-l) levels in the general population are associated with an increased risk of mortality from cardiomyopathy and heart failure. However, the pathophysiology of heart disease in FA is non-vascular and there are conflicting data on HDL-cholesterol in FA. Two studies have shown a decrease in HDL-cholesterol compared with controls and two have shown there was no difference between FA and controls. One also showed that there was no difference in serum Apo-A-I levels in FA when compared with controls. Using a highly specific stable isotope dilution mass spectrometry-based assay, we demonstrated a 21.6% decrease in serum ApoA-I in FA patients (134.8 mg/dL, n = 95) compared with non-affected controls (172.1 mg/dL, n = 95). This is similar to the difference in serum ApoA-I levels between non-smokers and tobacco smokers. Knockdown of frataxin by > 70% in human hepatoma HepG2 cells caused a 20% reduction in secreted ApoA-I. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor caused a 200% increase in HMG-CoA in the control HepG2 cells with a similar increase in the frataxin knockdown HepG2 cells, back to levels found in the control cells. There was a concomitant 20% increase in secreted ApoA-I to levels found in the control cells that were treated with simvastatin. This study provides compelling evidence that ApoA-I levels are reduced in FA patients compared with controls and suggest that statin treatment would normalize the ApoA-I levels.
Highlights
Friedreich’s ataxia (FA) is an autosomal recessive neurodegenerative disorder, which results primarily from reduced expression of the mitochondrial protein frataxin [1,2,3]
Re-analysis of the serum samples from these FA patients one-year after the initial analysis revealed almost identical values (S2 Table) showing that samples do not deteriorate on storage and showed that the assay is very robust
ApoA-I levels increased with age, serum ApoA-I levels among cases were not correlated with GAA1 length (Fig 3)
Summary
Friedreich’s ataxia (FA) is an autosomal recessive neurodegenerative disorder, which results primarily from reduced expression of the mitochondrial protein frataxin [1,2,3]. The exact mechanism of frataxin action has not been completely defined, the protein is involved in the assembly of iron-sulfur clusters, which are important for optimal mitochondrial function [4]. Progressive ataxia is a characteristic feature of FA [5], a significant number of patients experience hypertrophic cardiomyopathy that eventually progresses to heart failure. Heart failure due to cardiomyopathy rather than neurodegeneration, is the primary cause of death in FA [6,7,8,9]. The heart typically maintains adequate systolic function [10] in FA patients who develop a severe hypertrophic cardiomyopathy until shortly before death [11]. Fibrosis and iron overload represent early manifestations of cardiomyopathy in FA prior to left ventricular hypertrophy [6]. It was suggested that these effects could be due to subclinical myocardial disease in FA caused by mitochondrial cardiomyopathy with metabolic syndrome [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
