Italian Case Report with a Double Mutation in PSEN1 (K311R and E318G)

Round 1

Reviewer 1 Report

The case report is well written, just few English minor errors have to be corrected. 

Anyway, it should be discussed the reason why, despite K311R mutation, the patient does not show any alteration in T-Tau CSF levels or maybe p-tau levels should be shown.

Finally, I suggest to add the following references:

• "Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021 Jun 18;13:695808";
• "Perrone F, Bjerke M, Hens E, Sieben A, Timmers M, De Roeck A, Vandenberghe R, Sleegers K, Martin JJ, De Deyn PP, Engelborghs S, van der Zee J, Van Broeckhoven C, Cacace R; BELNEU Consortium. Amyloid-β_1-43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations. Alzheimers Res Ther. 2020 Sep 11;12(1):108";
• Artuso V, Benussi L, Ghidoni R, Moradi-Bachiller S, Fusco F, Curtolo S, Roiter I, Forloni G, Albani D. Asymptomatic Carriers of Presenilin-1 E318G Variant Show no Cerebrospinal Fluid Biochemical Signs Suggestive of Alzheimer's disease in a Family with Late-onset Dementia. Curr Alzheimer Res. 2019;16(1):1-7

Author Response

Dear Reviewer, 
Thank you very much for your review and valuable suggestions. 

Despite the presence of the K311R variant, the patient does not show any alteration in T-Tau CSF levels, because there are still no significant correlations in this regard. The variant’s pathogenicity under examination is still of uncertain significance, therefore it will be advisable to wait for the patient's follow-up to re-evaluate the T-tau levels as the disease progresses.

Moreover, all the references suggested have been added and the English language has been improved.

Best regards

Reviewer 2 Report

 Reading and studying the manuscript by Bisceglia et al. it was very interesting. This paper is valuable due to its originality, the authors presenting a clinical case among the Italian population where they discovered the presence of two mutations (K311R and E318G) in PSEN1. The clinical case relates the medical history of a 67-year-old patient who in 2018 had with mild memory disorders. This aspect led the authors to genetically evaluate the patient for a possible diagnosis of Alzheimer's Dementia (AD).

The article is written in a concise and orderly manner, respecting the structure of the journal. Moreover, although the Conclusions section is not mandatory, the authors did offer us some relevant conclusions. I appreciate that the manuscript includes two figures that show genomic DNA sequencing result of double mutation in PSE N1 and example of the sequencing results after molecular cloning to determine cis-trans nature of the variants in PSEN1 gene.

The authors will certainly continue their research to provide the literature with new information on AD.

 

However, I have a few comments:

 

1. Numerous clinical cases have been reported in the literature in which either the K311R mutation or the E318G mutation occur at the PSEN1 level. Has the presence of both mutations in the same case been reported so far or is the case described in this manuscript the first with the two mutations?
2. The K311R mutation has also been described among other ethnic groups. Moreover, Sara Batelli (2008) describes two mutations (E318G and G394V) in an Italian patient. Can the Italian population be prone to double mutations in PSEN1?
3. The authors could further improve the bibliographic references by adding recent studies, thus strengthening the value of their work and interest in this topic.
4. The English language, although quite good, should be improved.
5. Figures 1 and 2 should be improved in terms of image quality, and the font size used should be increased for better readability.

 

Author Response

Dear Reviewer, 
Thank you very much for your review and valuable suggestions. 

To our knowledge, this is the first case of an Italian patient carrying both variants ever described in the Literature. Despite Sara Batelli (2008) described two mutations (E318G and G394V) in an Italian patient, the data available were insufficient to support the idea that the Italian population is subject to double mutations in PSEN1. It would be interesting to carry out a population study.

Moreover, recent references have been added, the English language has been improved, and image resolution has been improved.

Best regards

Reviewer 3 Report

Mutations in the PSEN1 gene are the most common cause of autosomal dominant Alzheimer’s disease, and are characterized by a high phenotype variability. PSEN1 mutations are characterized by an earlier age at onset, relatively rapid progression of the disease, and a considerable phenotypic variability.  AD genes show pleiotropy, with the same mutation resulting in different phenotypes with different severity. Knowledge about disease modifiers is limited. The discovery of each new  previously unknown genetic mutations becomes an event, and information about its penetrance is essential.

Paola Bisceglia and coauthors described the interesting case of a patient suffering from a mild form of cognitive decline, with absence of pathological findings in CSF and PET but carrying a double mutation in PSEN1 that is rarely diagnosed in patients with AD.  The authors correctly described the research methods, the clinical picture of the disease and discussed their results and the data available in the literature.

Author Response

Dear Reviewer, 
Thank you very much for your review and valuable suggestions. 

The English language has been improved. 

Best regards