Friedreich's Ataxia related Diabetes: Epidemiology and management practices.

AIMS: Friedreich's Ataxia (FRDA) is a progressive neuromuscular disorder typically caused by GAA triplet repeat expansions in both frataxin gene alleles. FRDA can be complicated by diabetes mellitus (DM). The objective of this study was to describe the prevalence of, risk factors for, and management practices of FRDA-related DM. METHODS: FACOMS, a prospective, multi-site natural history study, includes 1,104 individuals. Extracted data included the presence of DM and other co-morbidities, genetic diagnosis, and markers of disease severity. We performed detailed medical record review and a survey for the subset of individuals with FRDA-related DM followed at one FACOMS site, Children's Hospital of Philadelphia. RESULTS: FRDA-related DM was reported by 8.7% of individuals. Age, severe disease, and FRDA cardiac complications were positively associated with DM risk. FRDA-related DM was generally well-controlled, as reflected by HbA1c, though diabetic ketoacidosis did occur. Insulin is the mainstay of treatment (64-74% overall); in adults, metformin use was common and newer glucose-lowering agents were used rarely. CONCLUSIONS: Clinical factors identify individuals at increased risk for FRDA-related DM. Future studies should test strategies for FRDA-related DM screening and management, in particular the potential role for novel glucose-lowering therapies in preventing or delaying FRDA-related cardiac disease.

Plasma circulating cell-free mitochondrial DNA in the assessment of Friedreich's ataxia.

Friedreich's ataxia (FRDA) is one of the most devastating childhood onset neurodegenerative disease affecting multiple organs in the course of progression. FRDA is associated with mitochondrial dysfunction due to deficit in a nuclear encoded mitochondrial protein, frataxin. Identification of disease-specific biomarker for monitoring the severity remains to be a challenging topic. This study was aimed to identify whether circulating cell-free nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in blood plasma can be a potential biomarker for FRDA. Clinical information was assessed using International Cooperative Ataxia Rating Scale and the disease was confirmed using Long-range PCR for GAA repeat expansion within the gene encoding frataxin. The frataxin expression was measured using Western blot. Plasma nDNA and mtDNA levels were quantified by Multiplex real-time PCR. The major observation is that the levels of nDNA found to be increased, whereas mtDNA levels were reduced significantly in the plasma of FRDA patients (n=21) as compared to healthy controls (n=21). Further, plasma mtDNA levels showed high sensitivity (90%) and specificity (76%) in distinguishing from healthy controls with optimal cutoff indicated at 4.1×10(5)GE/mL. Interestingly, a small group of follow-up patients (n=9) on intervention with, a nutrient supplement, omega-3 fatty acid (a known enhancer of mitochondrial metabolism) displayed a significant improvement in the levels of plasma mtDNA, supporting our hypothesis that plasma mtDNA can be a potential monitoring or prognosis biomarker for FRDA.

Detection of interruptions in the GAA trinucleotide repeat expansion in the FXN gene of Friedreich ataxia.

Friedreich ataxia is a neurodegenerative disorder caused by the expansion of a GAA trinucleotide repeat sequence within the first intron of the FXN gene. Interruptions in the GAA repeat may serve to alleviate the inhibitory effects of the GAA expansion on FXN gene expression and to decrease pathogenicity. We have developed a simple and rapid PCR- and restriction enzyme-based assay to assess the purity of GAA repeat sequences.