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Friedreich ataxia (FRDA) is a progressive neurodegenerative disease with developmental features caused by a genetic deficiency of frataxin, a small, nuclear-encoded mitochondrial protein. Frataxin deficiency leads to impairment of iron–sulphur cluster synthesis, and consequently, ATP production abnormalities. Based on the involvement of such processes in FRDA, initial pathophysiological hypotheses focused on reactive oxygen species (ROS) production as a key component of the mechanism. With further study, a variety of other events appear to be involved, including abnormalities of mitochondrially related metabolism and dysfunction in mitochondrial biogenesis. Consequently, present therapies focus not only on free radical damage, but also on control of metabolic abnormalities and correction of mitochondrial biogenesis. Understanding the multitude of abnormalities in FRDA thus offers possibilities for treatment of this disorder.

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Intramedullary screw fixation has been found to be a reliable treatment for certain fractures of the fifth metatarsal. Techniques for this treatment have been described relying largely on intraoperative fluoroscopy. Ten human cadaver specimens had their fifth metatarsals osteotomized and underwent retrograde intramedullary pin placement. Anatomic landmarks and the location of the sural nerve in relation to this starting point were measured. The trajectory of a pin reducing the osteotomy was analyzed. Using the resultant starting point and guide pin trajectory, intramedullary screw placement was performed reliably without the aid of fluoroscopy. This study demonstrates that intramedullary screw fixation of proximal fifth metatarsal fractures may be performed with the use of anatomic landmarks, which decreases the amount of intraoperative fluoroscopy needed.

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We compared inductively coupled plasma–mass spectrometry (ICP-MS) test results for the analysis of heavy metals (As, Ba, Cd, Hg, Pb, and Se) in pet foods and routine veterinary diagnostic specimens using intralaboratory and interlaboratory comparisons. Four laboratories, 1 principal laboratory and 3 collaborating laboratories, conducted instrument comparison (limit of detection [LOD], limit of quantification [LOQ], and linear dynamic range [LDR] on 24 data sets), in-house method comparison (accuracy and precision on 120 data sets), and interlaboratory comparison (reproducibility on 528 data sets using Horwitz equation analysis). Matrices tested included 2 types of pet food jerky treats (chicken and sweet potato), bovine blood, and bovine liver and kidney. The instrument comparison study confirmed that ICP-MS provided the sensitivity necessary for the analysis of all heavy metals tested at concentrations below the level of concern for routine diagnostic testing. The “in-house” method comparison samples, spiked at low (0.04 µg/g), medium (0.4 µg/g), and high (8.0 µg/g; note: the high validation level spike for mercury was 2 µg/g) concentration levels, indicated that ICP-MS can meet U.S. FDA acceptance criteria for both accuracy (90–105% recovery) and precision (< 6% coefficient of variation). The interlaboratory comparison studies showed that ICP-MS is a reproducible method for the analysis of heavy metals (HorRat value of 0.5–2.0) except for mercury in one laboratory, which used a different sample preparation method (open block rather than microwave digestion). Overall, our study showed that ICP-MS is a reproducible method for the analysis of heavy metals in spite of minor differences in methodology.

Friedreich ataxia is an autosomal recessive, neurodegenerative disease characterized by the deficiency of the iron‐sulfur cluster assembly protein frataxin. Loss of this protein impairs mitochondrial function. Mitochondria alter their morphology in response to various stresses; however, such alterations to morphology may be homeostatic or maladaptive depending upon the tissue and disease state. Numerous neurodegenerative diseases exhibit excessive mitochondrial fragmentation, and reversing this phenotype improves bioenergetics for diseases in which mitochondrial dysfunction is a secondary feature of the disease. This paper demonstrates that frataxin deficiency causes excessive mitochondrial fragmentation that is dependent upon Drp1 activity in Friedreich ataxia cellular models. Drp1 inhibition by the small peptide TAT‐P110 reverses mitochondrial fragmentation but also decreases ATP levels in frataxin‐knockdown fibroblasts and FRDA patient fibroblasts, suggesting that fragmentation may provide a homeostatic pathway for maintaining cellular ATP levels. The cardiolipin‐stabilizing compound SS‐31 similarly reverses fragmentation through a Drp1‐dependent mechanism, but it does not affect ATP levels. The combination of TAT‐P110 and SS‐31 does not affect FRDA patient fibroblasts differently from SS‐31 alone, suggesting that the two drugs act through the same pathway but differ in their ability to alter mitochondrial homeostasis. In approaching potential therapeutic strategies for FRDA, an important criterion for compounds that improve bioenergetics should be to do so without impairing the homeostatic response of mitochondrial fragmentation.

Friedreich ataxia is a slowly progressive neurodegenerative disorder leading to ataxia, dyscoordination, dysarthria and in many individuals vision and hearing loss. It is associated with cardiomyopathy, the leading cause of death in Friedreich ataxia (FRDA), diabetes and scoliosis. There are no approved therapies, but elucidation of the pathophysiology of FRDA suggest that agents that increase the activity of the transcription factor Nrf2 may provide a mechanism for ameliorating disease progression or severity. In this work, we review the evidence for use of omaveloxolone in FRDA from recent clinical trials. Though not at present approved for any indication, the present data suggest that this agent acting though increases in Nrf2 activity may provide a novel therapy for FRDA.