Neuropathy due to impaired axonal transport of non-fragmented mitochondria in MYH14 mutation carriers
Bibliographic record
Abstract
With interest we read the article by Almutawa et al. about a family with neuropathy, hypoacusis, and foot deformity, being attributed to the heterozygous variant R941L in MYH14 [[1]Almutawa W. Smith C. Sabouny R. Smit R.B. Zhao T. Wong R. Lee-Glover L. Desrochers-Goyette J. Ilamathi H.S. Suchowersky O. Germain M. Mains P.E. Parboosingh J.S. Pfeffer G. Innes A.M. Shutt T.E. Care4Rare Canada ConsortiumThe R941L mutation in MYH14 disrupts mitochondrial fission and associates with peripheral neuropathy.EBioMedicine. 2019; 45: 379-392https://doi.org/10.1016/j.ebiom.2019.06.018Summary Full Text Full Text PDF Scopus (16) Google Scholar]. Neuropathy was attributed to impaired fission of mitochondria resulting in oversized organelles inappropriate for retrograde axonal transportation [1Almutawa W. Smith C. Sabouny R. Smit R.B. Zhao T. Wong R. Lee-Glover L. Desrochers-Goyette J. Ilamathi H.S. Suchowersky O. Germain M. Mains P.E. Parboosingh J.S. Pfeffer G. Innes A.M. Shutt T.E. Care4Rare Canada ConsortiumThe R941L mutation in MYH14 disrupts mitochondrial fission and associates with peripheral neuropathy.EBioMedicine. 2019; 45: 379-392https://doi.org/10.1016/j.ebiom.2019.06.018Summary Full Text Full Text PDF Scopus (16) Google Scholar, 2Ueda E. Ishihara N. Mitochondrial hyperfusion causes neuropathy in a fly model of cmt2a.EMBO Rep. 2018; 19 (pii: e46502)https://doi.org/10.15252/embr.201846502Crossref Scopus (4) Google Scholar]. We have the following concerns. A main shortcoming of the study is that no nerve biopsies were carried out. Assuming that neuropathy was due to impaired fission and thus reduced axonal transport of mitochondria [[1]Almutawa W. Smith C. Sabouny R. Smit R.B. Zhao T. Wong R. Lee-Glover L. Desrochers-Goyette J. Ilamathi H.S. Suchowersky O. Germain M. Mains P.E. Parboosingh J.S. Pfeffer G. Innes A.M. Shutt T.E. Care4Rare Canada ConsortiumThe R941L mutation in MYH14 disrupts mitochondrial fission and associates with peripheral neuropathy.EBioMedicine. 2019; 45: 379-392https://doi.org/10.1016/j.ebiom.2019.06.018Summary Full Text Full Text PDF Scopus (16) Google Scholar], it is conceivable that nerve biopsy may show paucity of mitochondria within motor and sensory axons and in nerve terminals. Concerning mitochondrial functions, it is desirable to confirm normal function of the respiratory chain by appropriate biochemical investigations [[3]Amiott E.A. Lott P. Soto J. Kang P.B. McCaffery J.M. DiMauro S. Abel E.D. Flanigan K.M. Lawson V.H. Shaw J.M. Mitochondrial fusion and function in charcot-marie-tooth type 2A patient fibroblasts with mitofusin 2 mutations.Exp Neurol. 2008; 211: 115-127Crossref PubMed Scopus (72) Google Scholar]. A further shortcoming is that neuropathy was classified as axonal [[1]Almutawa W. Smith C. Sabouny R. Smit R.B. Zhao T. Wong R. Lee-Glover L. Desrochers-Goyette J. Ilamathi H.S. Suchowersky O. Germain M. Mains P.E. Parboosingh J.S. Pfeffer G. Innes A.M. Shutt T.E. Care4Rare Canada ConsortiumThe R941L mutation in MYH14 disrupts mitochondrial fission and associates with peripheral neuropathy.EBioMedicine. 2019; 45: 379-392https://doi.org/10.1016/j.ebiom.2019.06.018Summary Full Text Full Text PDF Scopus (16) Google Scholar] although there was only borderline CMAP reduction, thus not fulfilling the criteria for axonal degeneration [[4]Yadegari S. Nafissi S. Kazemi N. Comparison of electrophysiological findings in axonal and demyelinating guillain-barre syndrome.Iran J Neurol. 2014; 13: 138-143Google Scholar]. Additionally, we should know which nerves were involved, if involvement was symmetric/asymmetric, if there was upper/lower limb predominance, and if there was distal, proximal, or diffuse distribution of the lesions. We also should know if motor and sensory nerves were equally affected and if there was involvement of the autonomic fibres. Missing is an explanation of hypoacusis. We should know if it was due to sensory or neuronal involvement, which could be best achieved by application of acoustically-evoked potentials [[5]Abou-Elew M.H. Hosni N.A. Obaid E.A. Ewida A.H. The N3 potential and the efferent cochlear pathway in profound sensorineural hearing loss.J Laryngol Otol. 2017; 131: 334-340Google Scholar]. We should know why among the cranial nerves only the acoustic nerve was affected and why this cranial nerve was affected long before the onset of peripheral neuropathy. No funding was received Author contribution: JF: design, literature search, discussion, first draft, critical comments Informed consent: was obtained The study was approved by the institutional review board None. The R941L mutation in MYH14 disrupts mitochondrial fission and associates with peripheral neuropathyAs impairments in mitochondrial fission cause peripheral neuropathy, this insight into the function of NMIIC likely explains the peripheral neuropathy phenotype associated with the R941L mutation. Full-Text PDF Open Access
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".