SCN8A Encephalopathy: Case Report and Literature Review
Round 1
Reviewer 1 Report
The case report is interesting but the authors should specifically emphasize on the x-factor of this article. The scientific methodology and data presentation need improvement in the sense that it should be more readily understandable to the readers. A separate conclusion and future perspective should be added.
Author Response
Reviewer A:
Many thanks for your very insightful comments. We have tried our best to correct our manuscript in a point-by-point manner according to your comments. Our responses to your individual comments are included below.
Q: The case report is interesting but the authors should specifically emphasize on the x-factor of this article. The scientific methodology and data presentation need improvement in the sense that it should be more readily understandable to the readers. R: We have revised the paper according to your suggestions. Please see the new version of the manuscript.
Q: A separate conclusion and future perspective should be added.
R: We have revised the paper according to your suggestion. Please see lines 224-234 in the new version of the manuscript.
Reviewer 2 Report
The authors present a case report of a patient presenting with DEE and a SCN8A variant, responsive to Oxcarbazepine.
There are various typos/corrections of terms required:
Voltage sense should be sensor
observed mutated point- ?point mutation
myoclonic shoulders? Myoclonic seizures of the shoulders
How was the variant identified- exome or panel? In silico scores and determination of pathogenicity should be included
It is surprising this patient did not respond to phenytoin. Was the patient loaded with phenytoin prior to commencing maintenance? What were the phenytoin levels- were they therapeutic?
The levetiracetam dose is quite low? The usual maintenance dose would be 40mg/kg/day before considering it ineffective? Is this meant to be twice daily? The same applies to the valproate dose
In the summary of previously reported cases it is unclear whether + for Phenytoin mean tried or was effective?
“gene screens” is not a recognised term
“Only 6 (16.67%) of the patients 115 ultimately became seizure-free”- it should be emphasised that these are from case reports or series, not longitudinal studies, therefore it is not possible to draw conclusions about natural history
In the discussion, the authors should include a discussion of new methods to understand both pathogenicity of sodium channel variants and of whether variants are GOF or LOF (e.g. https://stm.sciencemag.org/content/12/556/eaay6848.abstract) as this is one of the difficulties facing clinicians when patients have novel mutations.
Author Response
Reviewer B:
Many thanks for your very insightful comments. We have tried our best to correct our manuscript in a point-by-point manner according to your comments. Our responses to your individual comments are included below.
Q: Voltage sense should be sensor
R: We have corrected that phrasing according to your suggestion. Please see line 49 in the new version of the manuscript.
Q: observed mutated point- ?point mutation
R: We have corrected that phrasing according to your suggestion. Please see line 58 in the new version of the manuscript.
Q: myoclonic shoulders? Myoclonic seizures of the shoulders
R: We have corrected that phrasing according to your suggestion. Please see line 68 in the new version of the manuscript.
Q: How was the variant identified- exome or panel? In silico scores and determination of pathogenicity should be included.
R: The variant was identified with whole-exome sequencing. Please see line 80 in the new version of the manuscript.
Based on the patient's clinical manifestations, the function of the point mutation should be gain-of-function. However, the in silico scores of the mutation points are far beyond our ability to determine that conclusively. What we could do was to check the PubMed (https://pubmed.ncbi.nlm.nih.gov/), National Center for Biotechnology Information (https://www.ncbi.nlm.nih.gov/), Ensembl (https://asia.ensembl.org/index.html), and UCSC (https://genome.ucsc.edu/) genome browsers to search for any new data regarding the point mutations discussed in our paper, and we have made some minor changes to our Table 1.
Q: It is surprising this patient did not respond to phenytoin. Was the patient loaded with phenytoin prior to commencing maintenance? What were the phenytoin levels- were they therapeutic?
R: Please see the following original text from a study by Braakman et al. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862112/): "When a seizure occurred, administration of oral phenytoin at home or, if oral phenytoin treatment failed, intravenous administration at the emergency department, both in a dosage of 10 mg/kg, prevented clustering of seizures and status epilepticus." This means that the phenytoin provided a rapid anti-seizure effect to their patient with SCN8A mutation. In our case, we did use the loading dose (20 mg/kg) when our patient was initially sent to the emergency department. The following 3 days of continued use of phenytoin did not, however, stop her seizures. We did not check the TDM of phenytoin because of the nonlinear kinetics of phenytoin, especially in children (https://n.neurology.org/content/32/1/42). We have also added text indicating the loading dose in lines 72-73 of the revised manuscript.
Q: The levetiracetam dose is quite low? The usual maintenance dose would be 40mg/kg/day before considering it ineffective? Is this meant to be twice daily? The same applies to the valproate dose
R:
Regarding levetiracetam, please see the website https://www.rxlist.com/keppra-drug.htm#indications, which includes the following text:
“Pediatric Patients 6 To <16 Years Of Age
Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). Increase the daily dose every 2 weeks by increments of 20 mg/kg (10 mg/kg twice daily) to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.”
Regarding valproate, please see the website https://www.uptodate.com/contents/valproate-drug-information, which includes the following text:
“Generalized nonmotor (absence) seizures, focal onset seizures with or without impaired consciousness or awareness (simple and complex): Children and Adolescents: Initial: 15 mg/kg/day in 1 to 3 divided doses; increase by 5 to 10 mg/kg/day at weekly intervals until seizures are controlled or side effects preclude further increases; daily doses >250 mg should be given in divided doses; maintenance: 30 to 60 mg/kg/day in 2 to 3 divided doses; Depakote and Depakote Sprinkle can be given twice daily …
Parenteral: Children and Adolescents: Limited data available in some cases depending on seizure types and age (Piña-Garza 2013): IV: Total daily IV dose is equivalent to the total daily oral dose; however, IV dose should be divided with a frequency of every 6 hours; if IV form is administered 2 to 3 times/day, close monitoring of trough concentrations is recommended; switch patients to oral product as soon as clinically possible as IV use >14 days has not been studied.”
Q: In the summary of previously reported cases it is unclear whether + for Phenytoin mean tried or was effective?
R: We are sorry to have caused any confusion. The + means "expose". We have changed Table 1 accordingly.
Q: “gene screens” is not a recognised term
R: We have revised the term in light of your comment. Please see line 93 in the new version of the manuscript.
Q: “Only 6 (16.67%) of the patients 115 ultimately became seizure-free”- it should be emphasised that these are from case reports or series, not longitudinal studies, therefore it is not possible to draw conclusions about natural history
R: We completely agree with your comment and have revised the text accordingly. Please see lines 117-118 in the new version of the manuscript.
Q: In the discussion, the authors should include a discussion of new methods to understand both pathogenicity of sodium channel variants and of whether variants are GOF or LOF (e.g. https://stm.sciencemag.org/content/12/556/eaay6848.abstract) as this is one of the difficulties facing clinicians when patients have novel mutations.
R: Thank you for the suggestion. Please see lines 192-207 of the revised manuscript.
Author Response File: 
Author Response.pdf
