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Correspondence

Detection of compound heterozygous variants in LPIN1 does not necessarily imply pathogenicity in a patient with rhabdomyolysis

[version 1; peer review: 4 approved]
PUBLISHED 13 Jan 2020
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Abstract

In a recent article by Yim et al., a 15-month-old male is described who experienced severe rhabdomyolysis with a creatine-kinase value (CKV) of 127494 U/l one day after intramuscular injection of an unidentified drug by the general practitioner. Rhabdomyolysis was not attributed to this injected drug but to compound heterozygous variants in LPIN1. The study has a number of shortcomings. Triggers of rhabdomyolysis should be unequivocally identified, a more extensive family history should be taken, and previous CKVs should be provided. Functional and biochemical tests should be carried out to confirm or exclude pathogenicity of the LPIN1 variants.

Keywords

LPIN1, rhabdomyolysis, myoglobinurea, renal insufficiency, genetics

Correspondence

In a recent article, Yim et al. reported a 15-month-old male who experienced severe rhabdomyolysis with a creatine-kinase value (CKV) of 127494 U/l one day after intramuscular injection of an unidentified drug by the general practitioner (GP)1. Rhabdomyolysis was not attributed to this injection but to compound heterozygous variants in LPIN11. Each of the parents carried one of these variants but was clinically unaffected1. This correspondence article provides reasonings as to why the detection of heterozygous variants in LPIN1 does not necessarily imply pathogenicity in this case.

Rhabdomyolysis may not only occur in mitochondrial disorders (beta-oxidation defects are mitochondrial disorders) and glycogenoses, but more frequently in response to drugs or toxins2. Thus, it is crucial to find out which drug the GP injected one day prior to admission, not only to identify the compound, but also to ensure that other patients were not exposed to any hazardous risks due to a possibly toxic drug.

Since the variant c.1949_1967dupGTGTCACCACGCAGTACCA was classified as likely pathogenic, the variant c.2410G>C as a variant of unknown significance, and since one parent each carried one of either variants, it is conceivable that the parent who carried the variant c.1949_1967dupGTGTCACCACGCAGTACCA also had experienced muscle manifestations previously. However, the family history is described as negative for rhabdomyolysis, malignant hyperthermia, or neuromuscular disorders making the pathogenicity of this variant quite unlikely. However, an extended family history should also be taken from the grandparents from the mother’s and father’s side to assess if they ever experienced any muscle symptoms.

Since LPIN1 variants have been previously reported in association with recurrent rhabdomyolysis3,4, it is quite likely that the index patient or one of the parents had elevated CKVs. Thus, the records of the index patient or the parent who carried the likely pathogenic LPIN1 variant should be checked to see if these individuals ever showed elevated CKVs. Of particular interest are CKVs after birth, exercise, infection, anaesthesia, or application of drugs. This is because CKV may particularly increase with these conditions. Since the younger sister of the index patient also carried the compound heterozygous LPIN1 variants, we should be informed about the course of the mother’s pregnancy with this younger child, about the sister’s CKVs at birth and later, and further follow-up, including genetic counselling.

In the case report1, the patient has a second episode of rhabdomyolysis at the age of six years. Current medication the index patient was taking at the time of this second episode should be examined, and also if the cause could have been triggered by exercise5. A male of 6 years of age most likely is lively and usually highly physically active.

Overall, this interesting case report has some limitations, which should be addressed before attributing rhabdomyolysis to the LPIN1 variants. Triggers of rhabdomyolysis should be unequivocally identified, a more extensive family history taken, and previous CKVs provided. Functional and biochemical tests should be carried out to confirm or exclude pathogenicity attributed to LPIN1 variants.

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No data is associated with this article.

Comments on this article Comments (1)

Version 1
VERSION 1 PUBLISHED 13 Jan 2020
  • Reader Comment 15 Jan 2020
    Felix Chi Kin Wong, Department of Chemical Pathology, Prince of Wales Hospital, Shatin, Hong Kong
    15 Jan 2020
    Reader Comment
    As one of the co-authors of the article by Yim et al (https://f1000research.com/articles/8-1566/v1), I would like to reply on behalf of my co-authors to the points raised by Drs Finisterer ... Continue reading
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Finsterer J and Aliyev R. Detection of compound heterozygous variants in LPIN1 does not necessarily imply pathogenicity in a patient with rhabdomyolysis [version 1; peer review: 4 approved]. F1000Research 2020, 9:15 (https://doi.org/10.12688/f1000research.21589.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Current Reviewer Status: ?
Key to Reviewer Statuses VIEW
ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
VERSION 1
PUBLISHED 13 Jan 2020
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Reviewer Report 28 Aug 2020
Chiara Pizzamiglio, MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, Queen Square, London, UK 
Approved
VIEWS 5
I have read with interest the correspondence from Josef Finsterer and Rahim Aliyev entitled “Detection of compound heterozygous variants in LPIN1 does not necessarily imply pathogenicity in a patient with rhabdomyolysis”.
 
I agree that in the article ... Continue reading
CITE
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HOW TO CITE THIS REPORT
Pizzamiglio C. Reviewer Report For: Detection of compound heterozygous variants in LPIN1 does not necessarily imply pathogenicity in a patient with rhabdomyolysis [version 1; peer review: 4 approved]. F1000Research 2020, 9:15 (https://doi.org/10.5256/f1000research.23792.r68521)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Reviewer Report 17 Aug 2020
Pushpa Raj Joshi, Department of Neurology, Martin-Luther-University Halle-Wittenberg, Halle, Germany 
Approved
VIEWS 8
The correspondence ‘Detection of compound heterozygous variants in LPIN1 does not necessarily imply pathogenicity in a patient with rhabdomyolysis’ by Josef Finsterer and Rahim Aliyev well argue against the conclusion of original submission ‘Case Report: The first probable Hong Kong ... Continue reading
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CITE
HOW TO CITE THIS REPORT
Joshi PR. Reviewer Report For: Detection of compound heterozygous variants in LPIN1 does not necessarily imply pathogenicity in a patient with rhabdomyolysis [version 1; peer review: 4 approved]. F1000Research 2020, 9:15 (https://doi.org/10.5256/f1000research.23792.r68527)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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8
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Reviewer Report 13 Aug 2020
Karolina M Stepien, Mark Holland Metabolic Unit, Adult Inherited Metabolic Diseases Department, Salford Royal NHS Foundation Trust, Salford, UK 
Approved
VIEWS 8
I note the comments from Finsterer and Aliyev.
I agree that it would be worth learning more about the first episode of rhabdomyolysis in this child who was confirmed to be compound heterozygous for two mutations causing LIPIN1. A ... Continue reading
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HOW TO CITE THIS REPORT
Stepien KM. Reviewer Report For: Detection of compound heterozygous variants in LPIN1 does not necessarily imply pathogenicity in a patient with rhabdomyolysis [version 1; peer review: 4 approved]. F1000Research 2020, 9:15 (https://doi.org/10.5256/f1000research.23792.r68525)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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13
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Reviewer Report 06 Aug 2020
Panupong Hansrivijit, Department of Internal Medicine, University of Pittsburgh Medical Center Pinnacle, Harrisburg, PA, USA 
Approved
VIEWS 13
Thank you for pointing out other etiologies that the original authors might have missed. However, I agree with the original authors' conclusion that rhabdomyolysis in this infant is related to spontaneous rhabdomyolysis from compound heterozygous variants of LPIN1 but the ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Hansrivijit P. Reviewer Report For: Detection of compound heterozygous variants in LPIN1 does not necessarily imply pathogenicity in a patient with rhabdomyolysis [version 1; peer review: 4 approved]. F1000Research 2020, 9:15 (https://doi.org/10.5256/f1000research.23792.r68520)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

Comments on this article Comments (1)

Version 1
VERSION 1 PUBLISHED 13 Jan 2020
  • Reader Comment 15 Jan 2020
    Felix Chi Kin Wong, Department of Chemical Pathology, Prince of Wales Hospital, Shatin, Hong Kong
    15 Jan 2020
    Reader Comment
    As one of the co-authors of the article by Yim et al (https://f1000research.com/articles/8-1566/v1), I would like to reply on behalf of my co-authors to the points raised by Drs Finisterer ... Continue reading
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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