Metabolic Brain Disease

, Volume 34, Issue 1, pp 1–2 | Cite as

Silencing of FOXRED1 in C57b1/6 mice does not generate an appropriate animal model of Leigh syndrome

  • Josef FinstererEmail author


With interest we read the article by Salama et al. who pretended to have developed a mouse model of Leigh syndrome by blocking the FOXRED1 gene with small interfering RNAs (siRNA) using C57b1/6 mice (Salama et al. 2018). Neuropathological studies showed degeneration of the corpus striatum, similar to Leigh syndrome, why these animals were regarded as a putative animal model for Leigh syndrome (Salama et al. 2018). We have the following comments and concerns.

Pathognomonic for Leigh syndrome are bilaterally symmetric lesion of the basal ganglia, midbrain, brainstem, or cerebellum, which are usually hyperintens on T2-weighted images (Finsterer 2008). Thus, it would be interesting to know if C57b1/6 mice underwent imaging studies of the brain and if these typical subcortical lesions were also seen in the investigated animals.

Leigh syndrome in humans is frequently associated with epilepsy (Monden et al. 2013), which is often intractable or responds only to a ketogenic diet (Laugel et al. 2007). Thus, we should be informed how many of the 20 animals undergoing FOXRED1 silencing developed clinical seizures during the further course or had electrical seizures or epilepsy-typical potentials on EEG. Epilepsy in Leigh syndrome significantly determines the outcome of these patients, why it is crucial that an animal model of Leigh syndrome phenotypically manifests with epilepsy.

Since some of the patients with Leigh syndrome may develop stroke-like episodes (SLEs) (Morin et al. 1999), a typical manifestation of MELAS syndrome, we should be informed if neuropathological investigations of the 20 animals showed features of a stroke-like lesion in any of them. The stroke-like lesion is the morphological equivalent of a SLE on imaging, characterised by a vasogenic edema not confined to vascular territory. Stroke-like lesions typically show dynamic increases and regressions over time.

Occasionally, extra-cerebral manifestations can be found in human Leigh syndrome (Finsterer 2008). These include polyneuropathy, myopathy, diabetes, short stature, cardiomyopathy, anemia, renal insufficiency, diarrhoea, or hypertrichosis (Finsterer 2008). Thus, we should know if any of the 20 animals undergoing FOXRED1 silencing developed any of these extra-cerebral manifestations. Particularly affected organs in Leigh syndrome are the heart, the muscle the peripheral nerves, and the endocrine organs, why we should be informed if there were any indications for cardiomyopathy, arrhythmias, endocrine abnormalities, myopathy or neuropathy.

In summary, we do not agree with the conclusions that the data provided justify to regard C57b1/6 mice undergoing FOXRED1 silencing as an animal model of Leigh syndrome. The value of an animal model is high if genotypic and phenotypic characteristics of the animal and human are closely similar.


Author contribution

JF: design, literature search, discussion, first draft.

Compliance with ethical standards

Conflict of interest

There are no conflict of interest.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Krankenanstalt Rudolfstiftung, Messerli InstituteVeterinary University of ViennaViennaAustria

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