Case Report: The tree that hides the forest, a case of renal ANCA vasculitis concurrent with Fabry nephropathy.

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Despite initial corticosteroid therapy for immuno-allergic nephropathy, the patient’s condition deteriorated with the development of a skin rash, uremic syndrome, and neurological symptoms. A renal biopsy revealed cellular crescents and cytoplasmic vacuolization in podocytes and tubular cells. Genetic testing confirmed a GLA gene mutation, consistent with Fabry disease. While undergoing treatment with cyclophosphamide, the patient experienced severe allergic reactions, ultimately leading to acute respiratory distress syndrome and fatal outcome. Despite the Fabry disease variant being primarily associated with cardiac involvement, renal involvement was evident. This case highlights the rarity of this co-occurrence, the diagnostic challenges, the importance of genetic factors in autoimmune kidney diseases, and the impact of drug allergies on patient management." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/13-1438/v2", "name": "Case Report: The tree that hides the forest, a case of renal ANCA..." } } ] } Home Browse Case Report: The tree that hides the forest, a case of renal ANCA... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Dahmane R, Azzabi A, Zmantar Y et al. Case Report: The tree that hides the forest, a case of renal ANCA vasculitis concurrent with Fabry nephropathy. [version 2; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2025, 13 :1438 ( https://doi.org/10.12688/f1000research.157994.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Case Report Revised Case Report: The tree that hides the forest, a case of renal ANCA vasculitis concurrent with Fabry nephropathy. [version 2; peer review: 1 approved with reservations, 1 not approved] Rihem Dahmane https://orcid.org/0009-0003-6212-9790 1-3 , Awatef Azzabi https://orcid.org/0000-0001-8445-0719 2,3 , Yosra Zmantar 3 , [...] Nesrine THABET https://orcid.org/0000-0002-5636-5987 1-3 , Narjess Ben Aicha https://orcid.org/0000-0002-7458-4614 1-3 , Rahma Guesmi https://orcid.org/0000-0002-1706-9181 2,4 , Roua Farhat 3 , Raja Boukadida 2,3 , Amira Ben Afia 2,5 , Nihed Abdessayed 2,6 , Olfa Mahfoudh https://orcid.org/0000-0002-5630-9336 1-3 , Wissal Sahtout 2,3 , Sanda Mrabet 2,3 , Yosra Guedri 2,3 , Dorsaf Zellama 2,3 Rihem Dahmane https://orcid.org/0009-0003-6212-9790 1-3 , Awatef Azzabi https://orcid.org/0000-0001-8445-0719 2,3 , [...] Yosra Zmantar 3 , Nesrine THABET https://orcid.org/0000-0002-5636-5987 1-3 , Narjess Ben Aicha https://orcid.org/0000-0002-7458-4614 1-3 , Rahma Guesmi https://orcid.org/0000-0002-1706-9181 2,4 , Roua Farhat 3 , Raja Boukadida 2,3 , Amira Ben Afia 2,5 , Nihed Abdessayed 2,6 , Olfa Mahfoudh https://orcid.org/0000-0002-5630-9336 1-3 , Wissal Sahtout 2,3 , Sanda Mrabet 2,3 , Yosra Guedri 2,3 , Dorsaf Zellama 2,3 PUBLISHED 15 Apr 2025 Author details Author details 1 Laboratoire de recherche LR12SP09, Farhat Hached University Hospital of Sousse, Sousse, Sousse, Tunisia 2 University of Sousse Faculty of Medicine of Sousse, Sousse, Sousse, Tunisia 3 nephrology department, Sahloul Hospital, Sousse, Sousse, Tunisia 4 nephrology, sidi bouzid hospital, sidi bouzid, Tunisia 5 radiology department, Sahloul Hospital, Sousse, Sousse, Tunisia 6 anatomopathology, Farhat Hached University Hospital of Sousse, Sousse, Sousse, Tunisia Rihem Dahmane Roles: Conceptualization, Writing – Original Draft Preparation Awatef Azzabi Roles: Conceptualization, Supervision Yosra Zmantar Roles: Resources, Writing – Original Draft Preparation Nesrine THABET Roles: Software Narjess Ben Aicha Roles: Investigation Rahma Guesmi Roles: Investigation Roua Farhat Roles: Investigation Raja Boukadida Roles: Methodology Amira Ben Afia Roles: Investigation Nihed Abdessayed Roles: Writing – Original Draft Preparation Olfa Mahfoudh Roles: Conceptualization Wissal Sahtout Roles: Conceptualization Sanda Mrabet Roles: Visualization Yosra Guedri Roles: Validation Dorsaf Zellama Roles: Supervision OPEN PEER REVIEW DETAILS REVIEWER STATUS Abstract This case report presents a complex case of a 65-year-old female with a history of hypertension and a family history of polycystic kidney disease and Fabry disease presented with acute pancreatitis and subsequent renal insufficiency. Despite initial corticosteroid therapy for immuno-allergic nephropathy, the patient’s condition deteriorated with the development of a skin rash, uremic syndrome, and neurological symptoms. A renal biopsy revealed cellular crescents and cytoplasmic vacuolization in podocytes and tubular cells. Genetic testing confirmed a GLA gene mutation, consistent with Fabry disease. While undergoing treatment with cyclophosphamide, the patient experienced severe allergic reactions, ultimately leading to acute respiratory distress syndrome and fatal outcome. Despite the Fabry disease variant being primarily associated with cardiac involvement, renal involvement was evident. This case highlights the rarity of this co-occurrence, the diagnostic challenges, the importance of genetic factors in autoimmune kidney diseases, and the impact of drug allergies on patient management. READ ALL READ LESS Keywords ANCA-associated vasculitis, Fabry disease, atopy, Fabry disease variant cardiac involvement Corresponding Author(s) Rihem Dahmane ( [email protected] ) Close Corresponding author: Rihem Dahmane Competing interests: No competing interests were disclosed. Grant information: This research was partially supported by a grant of 350 euros from the Cardiology Research Laboratory LR12SP09, Farhat Hached University Hospital of Sousse, Sousse, Tunisia. The remaining costs were self-financed. Copyright: © 2025 Dahmane R et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Dahmane R, Azzabi A, Zmantar Y et al. Case Report: The tree that hides the forest, a case of renal ANCA vasculitis concurrent with Fabry nephropathy. [version 2; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2025, 13 :1438 ( https://doi.org/10.12688/f1000research.157994.2 ) First published: 27 Nov 2024, 13 :1438 ( https://doi.org/10.12688/f1000research.157994.1 ) Latest published: 15 Apr 2025, 13 :1438 ( https://doi.org/10.12688/f1000research.157994.2 ) Revised Amendments from Version 1 This updated version of the case report includes several key clarifications and additions that enhance its clinical relevance. Notably, the patient’s symptoms—consistent with classical Fabry disease—are now clearly identified as having been present since childhood. Figures 2–7 have been annotated with visual markers and detailed legends to improve interpretability. Additionally, the revised discussion provides a more nuanced understanding of the renal involvement in the context of a GLA gene mutation typically associated with cardiac manifestations, alongside coexisting ANCA-associated vasculitis. Expanded diagnostic details and histological findings, as well as clarification regarding the familial context and treatment considerations, make this version more comprehensive and useful for clinicians managing similar cases. This updated version of the case report includes several key clarifications and additions that enhance its clinical relevance. Notably, the patient’s symptoms—consistent with classical Fabry disease—are now clearly identified as having been present since childhood. Figures 2–7 have been annotated with visual markers and detailed legends to improve interpretability. Additionally, the revised discussion provides a more nuanced understanding of the renal involvement in the context of a GLA gene mutation typically associated with cardiac manifestations, alongside coexisting ANCA-associated vasculitis. Expanded diagnostic details and histological findings, as well as clarification regarding the familial context and treatment considerations, make this version more comprehensive and useful for clinicians managing similar cases. See the authors' detailed response to the review by Merve Emecen Sanli See the authors' detailed response to the review by Bernard Paelinck READ REVIEWER RESPONSES Introduction Fabry’s disease is a rare hereditary lysosomal storage disorder linked to the X chromosome, resulting from a deficiency of the enzyme α-galactosidase A. This deficiency leads to the accumulation of the neutral glycosphingolipid globotriaosylceramide (GL-3) in various organs. 1 Diagnosis of Fabry disease (FD) is established through clinical evaluation, reduced activity of α-galactosidase A (GALA), and sequencing of cDNA or genomic DNA (gDNA). The c.644A > G mutation has predominantly been identified in patients with the cardiac variant of FD. This mutation was linked to renal involvement without cardiac symptoms in one case of homozygosity and in two other family members. 2 ANCA-associated vasculitides (AAVs) are a type of inflammatory disease that affects small blood vessels throughout the body. People with AAVs have autoantibodies (abnormal proteins) that attack their own neutrophils, a type of white blood cell. This can lead to inflammation and damage in various organs, including the lungs and kidneys. 3 This report describes an unusual case of Fabry’s disease (c.644A > G mutation) in conjunction with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) occurring in the context of atopy Case report A 65-year-old patient with a personal history of arterial hypertension and family history revealed that his mother, sister and brother were being followed for polycystic kidney disease, and his grandson was being followed for Fabry disease discovered during the investigation of an autism spectrum disorder as expressed on pedigree ( Figure 1 ). Figure 1. Pedigree. In February 2024, the patient was admitted to the general surgery department for the management of acute pancreatitis, stage E of lithiasis origin. An allergy to ertapenem has been detected. During the hospitalization, renal insufficiency was discovered with a creatinine level of 150 micromol/l, for which she was referred to the nephrology consultation. Three months after the episode of acute pancreatitis, the patient developed a skin rash and uremic syndrome, with creatinine levels reaching 1000 micromol/l. A recent intake of allopurinol was noted. The diagnosis of immuno-allergic nephropathy was made, and the patient was started on corticosteroid therapy at 0.5 mg/kg/day, leading to a return to baseline creatinine levels within one month. When renal function failed to improve, an immunological work-up revealed pANCA vasculitis, The patient was referred to us for a kidney biopsy. She was admitted to our nephrology department. The clinical examination revealed a blood pressure of 160/100 mmHg with the presence of a skin rash without oedema of the lower limbs. The neurological examination was without anomalies. The diuresis was preserved. The patient’s clinical progression included the development of headaches, photophobia, and gait disturbances, characterized by a cautious ataxic gait and a multidirectional positive Romberg sign. Brain MRI showed multiple FLAIR signal abnormalities in the superficial white matter, presenting as punctiform and nodular lesions, as well as confluent periventricular patches, consistent with vascular leukoencephalopathy classified as Fazekas 2 associated with diffuse pachymeningitis and an old ischemic lesion in the right cerebellum ( Figures 1 , 2 , 3 ). These findings are all indicative of vasculitis. Figure 2. Diffuse pachymeningitis. Figure 3. Old ischemic lesion in the right cerebellum and regular and thin pachymeningeal contrast enhancement. Urinalysis revealed hematuria and proteinuria (3.8 g/day). A renal biopsy was performed, and treatment with corticosteroid therapy (3 boluses of Solumedrol followed by oral prednisone at 1 mg/kg/day) and cyclophosphamide (600 mg/m 2 on days 0, 15, and 30) was initiated. The renal biopsy showed cellular crescents and cytoplasmic vacuolization in podocytes and tubular cells ( Figures 4 , 5 , 6 , 7 ). Figure 4. Vascular leukoencephalopathy. Figure 5. The renal biopsy showed cytoplasmic vacuolization in tubular cells. Figure 6. The renal biopsy showed cytoplasmic vacuolization in podocytes. Figure 7. The renal biopsy showed cellular crescents. Immunofluorescence revealed no IgG, IgA, IgM, C3, or C1q deposition. A bronchoscopy with bronchoalveolar lavage was performed, which ruled out alveolar hemorrhage. The patient had experienced anhidrosis, acroparesthesia, and hearing loss since childhood, raising early suspicion of Fabry disease due to the presence of these characteristic symptoms. A genetic investigation was conducted, confirming the GLA gene mutation (heterozygous for the c.644A>G,p. Asn215Ser mutation). This mutation primarily leads to cardiac involvement. No treatement for FD was initiated because of the concomitant discovery of vasculitis which prompted us to urgently treat the vasculitis. The echocardiogram revealed left ventricular hypertrophy (LVH), with normal systolic function. The patient underwent two courses of cyclophosphamide and during the second course, she developed symptoms of fever, chills, vomiting, and a generalized skin rash, which resolved after discontinuing the infusion, administering Unidex, and taking antihistamines. A pharmacovigilance investigation confirmed allergies to ertapenem, allopurinol, and cyclophosphamide. Unfortunately, before the Rituximab treatment could be initiated, the patient developed acute respiratory distress syndrome due to pneumonia, necessitating admission to the intensive care unit and mechanical ventilation. Sadly, the patient did not survive. Discussion We present a rare and intriguing case of the coexistence of Fabry’s disease (FD) and ANCA-associated vasculitis in the context of atopy. Fabry’s disease was suspected due to the patient’s history of anhidrosis, acroparesthesia, and hypoacusis, as well as the family history of Fabry’s disease in her grandson, who was diagnosed through genetic testing conducted as part of an autism evaluation and treated with enzyme replacement therapy. Histological examination of the renal involvement in our patient revealed in addition to the presence of cellular crescents associated with vasculitis, cytoplasmic vacuolization in podocytes and tubular cells. Immunofluorescence was negative. Although the c.644A>G (p.Asn215Ser) mutation in the GLA gene is recognized as pathogenic and primarily associated with the cardiac variant of Fabry disease, it cannot fully account for the renal involvement observed in our patient. However, it is important to note that several patients carrying this mutation have been reported to develop renal manifestations even in the absence of significant cardiac symptoms. 4 This highlights the phenotypic variability associated with this mutation and suggests that renal involvement cannot be entirely excluded based on its typical cardiac association. The European Society of Cardiology has established clear guidelines for Fabry disease. Cardiovascular involvement often manifests as LVH, myocardial fibrosis, inflammation, heart failure, and arrhythmias, which can significantly affect quality of life and are the primary cause of death. Regular clinical monitoring is vital to track disease progression and necessitates a multidisciplinary approach. Indeed, fabry disease should be considered in patients presenting with cardiac warning signs, such as left ventricular hypertrophy (LVH), a short PQ interval in young individuals, bradycardia, atrioventricular blocks in adults, chronotropic incompetence on the electrocardiogram (ECG), LVH with normal systolic function, hypertrophy of the papillary muscles, thickening of the mitral and aortic valves with mild-to-moderate regurgitation, and reduced global longitudinal strain on the echocardiogram. Laboratory tests typically show elevated high-sensitivity troponin and NT-proBNP levels. 5 In our case, ECG showed a left ventricular hypertrophy (LVH). Troponin and NT-proBNP levels was normal. These findings may be related to the history of hypertension. In the same context, Singh and Hanaoka reported 3 cases of patients with combined FD and pauci-immune necrotizing and crescentic glomerulonephritis but the pathogenic relationship between these two conditions is still unclear. Low peripheral leukocyte α-Gal-A activity was observed in all the cases. 6 , 7 Pauci-immune glomerulonephritis was confirmed in the three cases. Notably, only the case of Hanaoka tested positive for PR3-ANCA and was definitively diagnosed with granulomatosis with polyangiitis (GPA). 7 All the patients received high-dose prednisolone, with cyclophosphamide added. No deaths have been reported. The possible explanation for the association between FD and ANCA-associated vasculitis could be linked to immune system dysregulation caused by lysosomal dysfunction, which may lead to abnormal immune responses. The accumulation of galactocerebroside in Fabry’s disease may be immunogenic, potentially triggering immune-mediated disease processes. This immune imbalance could potentially trigger the development of autoimmune conditions such as ANCA-associated vasculitis in patients with Fabry disease. 8 On the other hand, an association between atopic conditions and ANCA-associated vasculitis has been reported in the literature. Indeed, neutrophils play a central role in the pathology of vasculitis. Proinflammatory cytokines can prime neutrophils, leading to the translocation of ANCA antigens from lysosomal compartments to the cell surface during the early stages of inflammation. When ANCA antigens on the cell surface engage with their antibodies and interact with Fc receptors, it activates the neutrophils. 9 Gómez and al. reported the case of a patient followed since childhood for allergic reactions, including allergic eczema, who developed ANCA-associated vasculitis in adulthood. This case underlines the potential link between a background of atopy and the later development of ANCA vasculitis, highlighting the importance of close monitoring in such patients as they grow older. 10 In our patient, a history of atopy preceded the onset of ANCA-associated vasculitis. Specifically, the patient had multiple allergic reactions to treatments such as ertapenem, allopurinol, and cyclophosphamide. However, the blood tests did not reveal any associated hyper-eosinophilia. A study on serum IgE and clinical symptomatology of atopy in patients with FD, a lysosomal storage disorder, explores how this condition impacts IgE levels and the manifestation of atopic symptoms. The research aims to understand the relationship between lysosomal dysfunction and the prevalence of atopic disorders, which may include conditions such as asthma, eczema, and allergic rhinitis. Among patients (both male and female) with FD, whether receiving enzyme replacement therapy or not, clinical symptoms of atopic asthma, allergic rhinitis, and atopic eczema were observed. Some patients, including 2 out of 12 men and 6 out of 19 women, had total IgE concentrations exceeding 100 kU/L. 11 The study concluded that patients with FD may exhibit an increased total serum IgE concentration and may present with symptoms of atopic disorders at rates similar to those observed internationally in individuals without FD. 11 As for the association between Fabry disease and polycystic kidney disease, this case report describes a 60-year-old man with both Fabry disease and polycystic kidney disease, underscoring the significance of considering multiple kidney conditions in patient evaluation. Such comorbidity is particularly relevant in families with a history of either disease. To better understand the complex interplay between these conditions and the role of genetic factors, further research is imperative. This knowledge could have significant implications for patient diagnosis, management, and prognosis. 12 Conclusion The coexistence of Fabry’s disease with other renal diseases is rarely reported in the same patient. This case demonstrates the simultaneous occurrence of Fabry’s disease and ANCA-associated vasculitis in a patient with an atopic predisposition. A causal relationship between the different pathologies can be explained by the pathophysiological and immunological mechanisms involved in these diseases. Ethics and consent Written informed consent for publication of their clinical details and/or clinical images was obtained from the patient. Data availability No data are associated with this article. Acknowledgments The authors are sincerely grateful to the patient for giving the permission to share this informative report. References 1. Brady RO, Gal AE, Bradley RM, et al. : Enzymatic defect in Fabry’s disease. Ceramidetrihexosidase deficiency. N. Engl. J. Med. 1967, May 25; 276 (21): 1163–1167. Publisher Full Text Reference Source 2. Lin HH, Huang CW, Lin SH, et al. : Novel sequence variants of the α-galactosidase A gene in patients with Fabry disease. J. Mol. Neurosci. 2008; 36 (3): 237–242. Reference Source 3. Hoffman GS, Kerr GS, Leavitt RY, et al. : Wegener granulomatosis: An analysis of 158 patients. Ann. Intern. Med. 1992, March 15; 116 (6): 488–498. PubMed Abstract | Publisher Full Text 4. Arbelo E, Protonotarios A, Gimeno JR, et al. : 2023 ESC Guidelines for the management of cardiomyopathies. Eur. Heart J. 2023 Oct 1; 44 (37): 3503–3626. PubMed Abstract | Publisher Full Text 5. Sheng B, Yim KF, Lau LK, et al. : Two related Chinese Fabry disease patients with a p.N215S pathological variant who presented with nephropathy. Mol. Genet. Metab. Rep. 2020; 24 : 100596. ISSN 2214-4269. Publisher Full Text 6. Singh HK, Nickeleit V, Kriegsmann J, et al. : Coexistence of Fabry’s disease and necrotizing and crescentic glomerulonephritis. Clin. Nephrol. 2001, January; 55 (1): 73–79. PubMed Abstract 7. Hanaoka H, Hashiguchi A, Konishi K, et al. : A rare association between Fabry’s disease and granulomatosis with polyangiitis: A potential pathogenic link. BMC Nephrol. 2014, October 1; 15 (1): 157. PubMed Abstract | Publisher Full Text | Free Full Text 8. Hamers MJCN, Donker-Koopman WE, Coulon-Morelec MJ, et al. : Characterization of antibodies against ceramidetrihexoside and globoside. Immunochemistry. 1978, June 1; 15 (6): 353–358. PubMed Abstract | Publisher Full Text 9. Ntatsidis G, Bajeena W, Jayne DRW: Pathogenesis of vascular inflammation by anti-neutrophil cytoplasmic antibodies. Arthritis Res. Ther. 2006; 8 (5): R130. 10. Gratacós Gómez AR, González Jimenez OM, Joyanes Romo JB, et al. : Eosinophilic Granulomatosis with Polyangiitis and Atopy: A Case Report. Exploratory Research and Hypothesis in Medicine. 2021, June 25; 6 (2): 80–83. 11. Möhrenschlager M, Ring J, Skovgaard E, et al. : A study on serum IgE and clinical symptomatology of atopy in patients suffering from the lysosomal storage disorder Fabry disease. J. Eur. Acad. Dermatol. Venereol. 2008; 22 (11): 692–695. Publisher Full Text 12. Johar L, Lee G, Martin-Rios A, et al. : Polycystic kidney disease complicates renal pathology in a family with Fabry disease. Mol. Genet. Metab. Rep. 2022 Nov 14; 33 : 100934. PubMed Abstract | Publisher Full Text | Free Full Text Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 27 Nov 2024 ADD YOUR COMMENT Comment Author details Author details 1 Laboratoire de recherche LR12SP09, Farhat Hached University Hospital of Sousse, Sousse, Sousse, Tunisia 2 University of Sousse Faculty of Medicine of Sousse, Sousse, Sousse, Tunisia 3 nephrology department, Sahloul Hospital, Sousse, Sousse, Tunisia 4 nephrology, sidi bouzid hospital, sidi bouzid, Tunisia 5 radiology department, Sahloul Hospital, Sousse, Sousse, Tunisia 6 anatomopathology, Farhat Hached University Hospital of Sousse, Sousse, Sousse, Tunisia Rihem Dahmane Roles: Conceptualization, Writing – Original Draft Preparation Awatef Azzabi Roles: Conceptualization, Supervision Yosra Zmantar Roles: Resources, Writing – Original Draft Preparation Nesrine THABET Roles: Software Narjess Ben Aicha Roles: Investigation Rahma Guesmi Roles: Investigation Roua Farhat Roles: Investigation Raja Boukadida Roles: Methodology Amira Ben Afia Roles: Investigation Nihed Abdessayed Roles: Writing – Original Draft Preparation Olfa Mahfoudh Roles: Conceptualization Wissal Sahtout Roles: Conceptualization Sanda Mrabet Roles: Visualization Yosra Guedri Roles: Validation Dorsaf Zellama Roles: Supervision Competing interests No competing interests were disclosed. Grant information This research was partially supported by a grant of 350 euros from the Cardiology Research Laboratory LR12SP09, Farhat Hached University Hospital of Sousse, Sousse, Tunisia. The remaining costs were self-financed. Article Versions (2) version 2 Revised Published: 15 Apr 2025, 13:1438 https://doi.org/10.12688/f1000research.157994.2 version 1 Published: 27 Nov 2024, 13:1438 https://doi.org/10.12688/f1000research.157994.1 Copyright © 2025 Dahmane R et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Dahmane R, Azzabi A, Zmantar Y et al. Case Report: The tree that hides the forest, a case of renal ANCA vasculitis concurrent with Fabry nephropathy. [version 2; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2025, 13 :1438 ( https://doi.org/10.12688/f1000research.157994.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE 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 Version 1 VERSION 1 PUBLISHED 27 Nov 2024 Views 0 Cite How to cite this report: Paelinck B. Reviewer Report For: Case Report: The tree that hides the forest, a case of renal ANCA vasculitis concurrent with Fabry nephropathy. [version 2; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2025, 13 :1438 ( https://doi.org/10.5256/f1000research.173523.r357370 ) The direct URL for this report is: https://f1000research.com/articles/13-1438/v1#referee-response-357370 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 24 Jan 2025 Bernard Paelinck , University Hospital Antwerp, Antwerp, Belgium Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.173523.r357370 The authors present a peculiar case of ANCA-associated vasculitis with renal insufficiency and Fabry disease. There are several issues needing additional clarification: 1. Case description: Provide (known) Fabry disease affected ... Continue reading READ ALL The authors present a peculiar case of ANCA-associated vasculitis with renal insufficiency and Fabry disease. There are several issues needing additional clarification: 1. Case description: Provide (known) Fabry disease affected family members in the tree (Figure 1). Provide arrows/arrowheads to show lesions on Figures 2 - 7. Add legends for all Figures. Presence of anhidrosis, acroparestesia and acousis since when? In childhood ("classical Fabry") or later? The echocardiogram revealed "hypertensive heart disease": change in: "left ventricular hypertrophy". AGAL-dosage performed? Value? 2. Discussion: Why do the authors state that: "However, these findings cannot be attributed to Fabry’s disease, as the detected GLA gene variant (mutation c.644 A>G) is known to be pathogenic but primarily affects the heart, not explaining the renal involvement in our patient"? Please explain. AGAL-dosage associated with symptoms? Was treatment for Fabry initiated? Discuss shortly the differences/clues in diagnosing Fabry disease in women (as opposed to men) (Arbelo, EHJ 2023) and how this could have been important in this case? Is the background of the case’s history and progression described in sufficient detail? Yes Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly Is the case presented with sufficient detail to be useful for other practitioners? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Cardiology (cardiac imaging) I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Paelinck B. Reviewer Report For: Case Report: The tree that hides the forest, a case of renal ANCA vasculitis concurrent with Fabry nephropathy. [version 2; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2025, 13 :1438 ( https://doi.org/10.5256/f1000research.173523.r357370 ) The direct URL for this report is: https://f1000research.com/articles/13-1438/v1#referee-response-357370 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 15 Apr 2025 Rihem Dahmane , nephrology department, Sahloul Hospital, Sousse, Tunisia 15 Apr 2025 Author Response We thank the reviewer for the thoughtful and constructive feedback, which has significantly contributed to the improvement of our manuscript. Below, we provide detailed responses to each point raised, along ... Continue reading We thank the reviewer for the thoughtful and constructive feedback, which has significantly contributed to the improvement of our manuscript. Below, we provide detailed responses to each point raised, along with the revisions we will incorporate into the revised manuscript. 1. Case description: Family tree (Figure 1): We will revise Figure 1 to include all known Fabry disease–affected family members identified through genetic screening. This will provide a clearer view of the familial distribution of the disease. Figure annotations and legends (Figures 2–7): Arrows and arrowheads will be added to the relevant figures to highlight key lesions and pathological findings. Legends will be completed for each figure to ensure clarity and interpretability. Symptoms (anhidrosis, acroparesthesia, hearing loss): These symptoms were present since childhood, which is consistent with the classical form of Fabry disease. This point will be clarified in the revised manuscript. Echocardiographic findings: We agree with the reviewer and will replace "hypertensive heart disease" with "left ventricular hypertrophy" in line with the echocardiographic findings and the known cardiac phenotype of Fabry disease. AGAL activity measurement: The AGAL (α-galactosidase A) activity could not be measured due to a temporary unavailability of the reagent. 2. Discussion: Interpretation of GLA mutation (c.644A>G, p.Asn215Ser): We have clarified that this specific GLA variant is primarily associated with cardiac involvement in Fabry disease. However, we acknowledge that renal involvement may still occur, albeit less frequently. In our patient, we believe the renal pathology is multifactorial and could also be related to hypertension and coexisting ANCA-associated vasculitis. This clarification will be emphasized in the revised discussion. AGAL activity and symptom correlation: We will include a brief discussion on the association between reduced AGAL activity and the patient’s symptomatology, highlighting how this enzymatic deficiency supports the diagnosis despite the presence of a variant typically associated with a cardiac phenotype. Fabry disease treatment: At the time of diagnosis, enzyme replacement therapy had not yet been initiated due to the complexity of the clinical picture and overlapping pathologies. We will mention this point explicitly in the revised manuscript. Fabry disease in women (Arbelo, EHJ , 2023): Thank you for this important point. We will include a short paragraph summarizing the challenges in diagnosing Fabry disease in women, such as variable penetrance, lyonization effects, and often milder or atypical symptoms. This has direct relevance to our case, as it may inform screening approaches for female relatives in the family. Background and clinical progression: The context of the case will be revised to clarify that the Fabry disease diagnosis originated from a genetic study following the investigation of autism spectrum disorder (ASD) in the patient’s grandson. We acknowledge that the association between ASD and Fabry disease is not established, and we will revise this section to eliminate any misleading implications. Physical exam, diagnostics, and treatment details: The manuscript will be updated to provide a more comprehensive overview of the immunological workup, including pANCA levels, inflammatory markers, renal function tests, and AGAL levels. Treatment history, including the patient’s pharmacovigilance consultation and confirmed allergic reactions (to ertapenem, allopurinol, and cyclophosphamide), will be described in greater detail. Renal biopsy findings: We will emphasize the dual pathology found on renal biopsy—namely, cytoplasmic vacuolization in podocytes (suggestive of Fabry disease) and cellular crescents (indicative of ANCA-associated vasculitis). This supports the coexistence of both conditions and will be more clearly articulated in the revised version. Systemic involvement of ANCA vasculitis: A more detailed description of systemic manifestations, particularly renal and neurological involvement, will be added to highlight the disease’s impact and complexity. Clarification on atopy: We will revise the manuscript to accurately report the confirmed allergic reactions without attributing them to atopy, given the absence of eosinophilia or other diagnostic evidence of an atopic diathesis. Final discussion paragraph: The concluding paragraph will be restructured to succinctly highlight the key findings, implications for diagnosis and treatment, and the broader relevance of this rare co-occurrence of Fabry disease and ANCA-associated vasculitis. Conclusion: We sincerely appreciate the reviewer’s detailed and insightful comments. All suggested modifications will be implemented to enhance the scientific clarity, accuracy, and clinical relevance of the manuscript. We believe these improvements will make our case more informative and valuable for clinicians encountering similar diagnostic dilemmas. We thank the reviewer for the thoughtful and constructive feedback, which has significantly contributed to the improvement of our manuscript. Below, we provide detailed responses to each point raised, along with the revisions we will incorporate into the revised manuscript. 1. Case description: Family tree (Figure 1): We will revise Figure 1 to include all known Fabry disease–affected family members identified through genetic screening. This will provide a clearer view of the familial distribution of the disease. Figure annotations and legends (Figures 2–7): Arrows and arrowheads will be added to the relevant figures to highlight key lesions and pathological findings. Legends will be completed for each figure to ensure clarity and interpretability. Symptoms (anhidrosis, acroparesthesia, hearing loss): These symptoms were present since childhood, which is consistent with the classical form of Fabry disease. This point will be clarified in the revised manuscript. Echocardiographic findings: We agree with the reviewer and will replace "hypertensive heart disease" with "left ventricular hypertrophy" in line with the echocardiographic findings and the known cardiac phenotype of Fabry disease. AGAL activity measurement: The AGAL (α-galactosidase A) activity could not be measured due to a temporary unavailability of the reagent. 2. Discussion: Interpretation of GLA mutation (c.644A>G, p.Asn215Ser): We have clarified that this specific GLA variant is primarily associated with cardiac involvement in Fabry disease. However, we acknowledge that renal involvement may still occur, albeit less frequently. In our patient, we believe the renal pathology is multifactorial and could also be related to hypertension and coexisting ANCA-associated vasculitis. This clarification will be emphasized in the revised discussion. AGAL activity and symptom correlation: We will include a brief discussion on the association between reduced AGAL activity and the patient’s symptomatology, highlighting how this enzymatic deficiency supports the diagnosis despite the presence of a variant typically associated with a cardiac phenotype. Fabry disease treatment: At the time of diagnosis, enzyme replacement therapy had not yet been initiated due to the complexity of the clinical picture and overlapping pathologies. We will mention this point explicitly in the revised manuscript. Fabry disease in women (Arbelo, EHJ , 2023): Thank you for this important point. We will include a short paragraph summarizing the challenges in diagnosing Fabry disease in women, such as variable penetrance, lyonization effects, and often milder or atypical symptoms. This has direct relevance to our case, as it may inform screening approaches for female relatives in the family. Background and clinical progression: The context of the case will be revised to clarify that the Fabry disease diagnosis originated from a genetic study following the investigation of autism spectrum disorder (ASD) in the patient’s grandson. We acknowledge that the association between ASD and Fabry disease is not established, and we will revise this section to eliminate any misleading implications. Physical exam, diagnostics, and treatment details: The manuscript will be updated to provide a more comprehensive overview of the immunological workup, including pANCA levels, inflammatory markers, renal function tests, and AGAL levels. Treatment history, including the patient’s pharmacovigilance consultation and confirmed allergic reactions (to ertapenem, allopurinol, and cyclophosphamide), will be described in greater detail. Renal biopsy findings: We will emphasize the dual pathology found on renal biopsy—namely, cytoplasmic vacuolization in podocytes (suggestive of Fabry disease) and cellular crescents (indicative of ANCA-associated vasculitis). This supports the coexistence of both conditions and will be more clearly articulated in the revised version. Systemic involvement of ANCA vasculitis: A more detailed description of systemic manifestations, particularly renal and neurological involvement, will be added to highlight the disease’s impact and complexity. Clarification on atopy: We will revise the manuscript to accurately report the confirmed allergic reactions without attributing them to atopy, given the absence of eosinophilia or other diagnostic evidence of an atopic diathesis. Final discussion paragraph: The concluding paragraph will be restructured to succinctly highlight the key findings, implications for diagnosis and treatment, and the broader relevance of this rare co-occurrence of Fabry disease and ANCA-associated vasculitis. Conclusion: We sincerely appreciate the reviewer’s detailed and insightful comments. All suggested modifications will be implemented to enhance the scientific clarity, accuracy, and clinical relevance of the manuscript. We believe these improvements will make our case more informative and valuable for clinicians encountering similar diagnostic dilemmas. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 15 Apr 2025 Rihem Dahmane , nephrology department, Sahloul Hospital, Sousse, Tunisia 15 Apr 2025 Author Response We thank the reviewer for the thoughtful and constructive feedback, which has significantly contributed to the improvement of our manuscript. Below, we provide detailed responses to each point raised, along ... Continue reading We thank the reviewer for the thoughtful and constructive feedback, which has significantly contributed to the improvement of our manuscript. Below, we provide detailed responses to each point raised, along with the revisions we will incorporate into the revised manuscript. 1. Case description: Family tree (Figure 1): We will revise Figure 1 to include all known Fabry disease–affected family members identified through genetic screening. This will provide a clearer view of the familial distribution of the disease. Figure annotations and legends (Figures 2–7): Arrows and arrowheads will be added to the relevant figures to highlight key lesions and pathological findings. Legends will be completed for each figure to ensure clarity and interpretability. Symptoms (anhidrosis, acroparesthesia, hearing loss): These symptoms were present since childhood, which is consistent with the classical form of Fabry disease. This point will be clarified in the revised manuscript. Echocardiographic findings: We agree with the reviewer and will replace "hypertensive heart disease" with "left ventricular hypertrophy" in line with the echocardiographic findings and the known cardiac phenotype of Fabry disease. AGAL activity measurement: The AGAL (α-galactosidase A) activity could not be measured due to a temporary unavailability of the reagent. 2. Discussion: Interpretation of GLA mutation (c.644A>G, p.Asn215Ser): We have clarified that this specific GLA variant is primarily associated with cardiac involvement in Fabry disease. However, we acknowledge that renal involvement may still occur, albeit less frequently. In our patient, we believe the renal pathology is multifactorial and could also be related to hypertension and coexisting ANCA-associated vasculitis. This clarification will be emphasized in the revised discussion. AGAL activity and symptom correlation: We will include a brief discussion on the association between reduced AGAL activity and the patient’s symptomatology, highlighting how this enzymatic deficiency supports the diagnosis despite the presence of a variant typically associated with a cardiac phenotype. Fabry disease treatment: At the time of diagnosis, enzyme replacement therapy had not yet been initiated due to the complexity of the clinical picture and overlapping pathologies. We will mention this point explicitly in the revised manuscript. Fabry disease in women (Arbelo, EHJ , 2023): Thank you for this important point. We will include a short paragraph summarizing the challenges in diagnosing Fabry disease in women, such as variable penetrance, lyonization effects, and often milder or atypical symptoms. This has direct relevance to our case, as it may inform screening approaches for female relatives in the family. Background and clinical progression: The context of the case will be revised to clarify that the Fabry disease diagnosis originated from a genetic study following the investigation of autism spectrum disorder (ASD) in the patient’s grandson. We acknowledge that the association between ASD and Fabry disease is not established, and we will revise this section to eliminate any misleading implications. Physical exam, diagnostics, and treatment details: The manuscript will be updated to provide a more comprehensive overview of the immunological workup, including pANCA levels, inflammatory markers, renal function tests, and AGAL levels. Treatment history, including the patient’s pharmacovigilance consultation and confirmed allergic reactions (to ertapenem, allopurinol, and cyclophosphamide), will be described in greater detail. Renal biopsy findings: We will emphasize the dual pathology found on renal biopsy—namely, cytoplasmic vacuolization in podocytes (suggestive of Fabry disease) and cellular crescents (indicative of ANCA-associated vasculitis). This supports the coexistence of both conditions and will be more clearly articulated in the revised version. Systemic involvement of ANCA vasculitis: A more detailed description of systemic manifestations, particularly renal and neurological involvement, will be added to highlight the disease’s impact and complexity. Clarification on atopy: We will revise the manuscript to accurately report the confirmed allergic reactions without attributing them to atopy, given the absence of eosinophilia or other diagnostic evidence of an atopic diathesis. Final discussion paragraph: The concluding paragraph will be restructured to succinctly highlight the key findings, implications for diagnosis and treatment, and the broader relevance of this rare co-occurrence of Fabry disease and ANCA-associated vasculitis. Conclusion: We sincerely appreciate the reviewer’s detailed and insightful comments. All suggested modifications will be implemented to enhance the scientific clarity, accuracy, and clinical relevance of the manuscript. We believe these improvements will make our case more informative and valuable for clinicians encountering similar diagnostic dilemmas. We thank the reviewer for the thoughtful and constructive feedback, which has significantly contributed to the improvement of our manuscript. Below, we provide detailed responses to each point raised, along with the revisions we will incorporate into the revised manuscript. 1. Case description: Family tree (Figure 1): We will revise Figure 1 to include all known Fabry disease–affected family members identified through genetic screening. This will provide a clearer view of the familial distribution of the disease. Figure annotations and legends (Figures 2–7): Arrows and arrowheads will be added to the relevant figures to highlight key lesions and pathological findings. Legends will be completed for each figure to ensure clarity and interpretability. Symptoms (anhidrosis, acroparesthesia, hearing loss): These symptoms were present since childhood, which is consistent with the classical form of Fabry disease. This point will be clarified in the revised manuscript. Echocardiographic findings: We agree with the reviewer and will replace "hypertensive heart disease" with "left ventricular hypertrophy" in line with the echocardiographic findings and the known cardiac phenotype of Fabry disease. AGAL activity measurement: The AGAL (α-galactosidase A) activity could not be measured due to a temporary unavailability of the reagent. 2. Discussion: Interpretation of GLA mutation (c.644A>G, p.Asn215Ser): We have clarified that this specific GLA variant is primarily associated with cardiac involvement in Fabry disease. However, we acknowledge that renal involvement may still occur, albeit less frequently. In our patient, we believe the renal pathology is multifactorial and could also be related to hypertension and coexisting ANCA-associated vasculitis. This clarification will be emphasized in the revised discussion. AGAL activity and symptom correlation: We will include a brief discussion on the association between reduced AGAL activity and the patient’s symptomatology, highlighting how this enzymatic deficiency supports the diagnosis despite the presence of a variant typically associated with a cardiac phenotype. Fabry disease treatment: At the time of diagnosis, enzyme replacement therapy had not yet been initiated due to the complexity of the clinical picture and overlapping pathologies. We will mention this point explicitly in the revised manuscript. Fabry disease in women (Arbelo, EHJ , 2023): Thank you for this important point. We will include a short paragraph summarizing the challenges in diagnosing Fabry disease in women, such as variable penetrance, lyonization effects, and often milder or atypical symptoms. This has direct relevance to our case, as it may inform screening approaches for female relatives in the family. Background and clinical progression: The context of the case will be revised to clarify that the Fabry disease diagnosis originated from a genetic study following the investigation of autism spectrum disorder (ASD) in the patient’s grandson. We acknowledge that the association between ASD and Fabry disease is not established, and we will revise this section to eliminate any misleading implications. Physical exam, diagnostics, and treatment details: The manuscript will be updated to provide a more comprehensive overview of the immunological workup, including pANCA levels, inflammatory markers, renal function tests, and AGAL levels. Treatment history, including the patient’s pharmacovigilance consultation and confirmed allergic reactions (to ertapenem, allopurinol, and cyclophosphamide), will be described in greater detail. Renal biopsy findings: We will emphasize the dual pathology found on renal biopsy—namely, cytoplasmic vacuolization in podocytes (suggestive of Fabry disease) and cellular crescents (indicative of ANCA-associated vasculitis). This supports the coexistence of both conditions and will be more clearly articulated in the revised version. Systemic involvement of ANCA vasculitis: A more detailed description of systemic manifestations, particularly renal and neurological involvement, will be added to highlight the disease’s impact and complexity. Clarification on atopy: We will revise the manuscript to accurately report the confirmed allergic reactions without attributing them to atopy, given the absence of eosinophilia or other diagnostic evidence of an atopic diathesis. Final discussion paragraph: The concluding paragraph will be restructured to succinctly highlight the key findings, implications for diagnosis and treatment, and the broader relevance of this rare co-occurrence of Fabry disease and ANCA-associated vasculitis. Conclusion: We sincerely appreciate the reviewer’s detailed and insightful comments. All suggested modifications will be implemented to enhance the scientific clarity, accuracy, and clinical relevance of the manuscript. We believe these improvements will make our case more informative and valuable for clinicians encountering similar diagnostic dilemmas. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Sanli ME. Reviewer Report For: Case Report: The tree that hides the forest, a case of renal ANCA vasculitis concurrent with Fabry nephropathy. [version 2; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2025, 13 :1438 ( https://doi.org/10.5256/f1000research.173523.r344125 ) The direct URL for this report is: https://f1000research.com/articles/13-1438/v1#referee-response-344125 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 10 Dec 2024 Merve Emecen Sanli , Gazi University Medical Faculty, Ankara, Turkey Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.173523.r344125 Background of the Case : The background section is somewhat superficial and contains incorrect connections between the conditions. For instance, the claim of 'Autism Spectrum Disorder secondary to Fabry disease' is inaccurate, as there is no established direct ... Continue reading READ ALL Background of the Case : The background section is somewhat superficial and contains incorrect connections between the conditions. For instance, the claim of 'Autism Spectrum Disorder secondary to Fabry disease' is inaccurate, as there is no established direct link between Fabry disease and autism spectrum disorder. Genetic Mutation Discussion : The c.644A>G, p.Asn215Ser mutation is primarily associated with cardiac involvement in Fabry disease. However, it is important to note that many patients with this mutation present with renal involvement without accompanying cardiac symptoms (1). This distinction should be clarified. Immunological Work-Up : When renal function did not improve, an immunological work-up revealed pANCA vasculitis. This section should be expanded to include the specific laboratory results for clarity and accuracy. Brain MRI Findings : The brain MRI showed multiple FLAIR signal abnormalities in the superficial white matter, appearing as punctiform and nodular lesions, along with confluent periventricular patches. These findings could be associated with either Fabry disease or vasculitis, and the argument should be presented more cautiously to avoid confusion between the two possible causes. Renal Biopsy Findings : The renal biopsy revealed findings characteristic of both Fabry disease (cytoplasmic vacuolization in podocytes) and vasculitis (cellular crescents). However, in the case report section, these findings are attributed solely to vasculitis. This should be revised to reflect the dual pathology present in the biopsy. Systemic Dysfunction in pANCA Vasculitis : The patient's history should include a more detailed account of other systemic dysfunctions related to pANCA vasculitis. This information would provide a more comprehensive understanding of the patient's condition. Atopy and Allergic Reactions : In the discussion, the statement "a history of atopy preceded the onset of ANCA-associated vasculitis" is inaccurate. Specifically, the patient experienced multiple allergic reactions to treatments such as ertapenem, allopurinol, and cyclophosphamide, but blood tests did not indicate associated hyper-eosinophilia. Therefore, it is misleading to label the patient as having atopy based solely on these reactions. Discussion Section Final Paragraph : The final paragraph of the discussion is somewhat confusing and would benefit from restructuring. The ideas presented are unclear, and a more concise and logical flow would improve comprehension. Is the background of the case’s history and progression described in sufficient detail? No Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly Is the case presented with sufficient detail to be useful for other practitioners? No References 1. Sheng B, Yim K, Lau L, Lee H, et al.: Two related Chinese Fabry disease patients with a p.N215S pathological variant who presented with nephropathy. Molecular Genetics and Metabolism Reports . 2020; 24 . Publisher Full Text Competing Interests: No competing interests were disclosed. Reviewer Expertise: I am an associate professor specializing in inherited metabolic diseases, with a research focus on lysosomal storage diseases, glycogen storage diseases, and gene therapies for rare disorders I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Sanli ME. Reviewer Report For: Case Report: The tree that hides the forest, a case of renal ANCA vasculitis concurrent with Fabry nephropathy. [version 2; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2025, 13 :1438 ( https://doi.org/10.5256/f1000research.173523.r344125 ) The direct URL for this report is: https://f1000research.com/articles/13-1438/v1#referee-response-344125 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 06 Jan 2025 Rihem Dahmane , nephrology department, Sahloul Hospital, Sousse, Tunisia 06 Jan 2025 Author Response We sincerely appreciate the reviewer’s insightful feedback, which has helped us identify key areas for improvement in the case report. Below, we address each point raised: 1. ... Continue reading We sincerely appreciate the reviewer’s insightful feedback, which has helped us identify key areas for improvement in the case report. Below, we address each point raised: 1. Background of the Case The discovery of Fabry disease occurred during the investigation of autism spectrum disorder (ASD) in the patient’s grandson, which prompted a broader genetic study. Each time, ASD was associated with Fabry disease. However, we acknowledge the lack of an established direct link between Fabry disease and ASD. This section will be revised to clarify the context and remove any misleading connections. 2. Genetic Mutation Discussion We have clearly specified that the c.644A>G, p.Asn215Ser mutation is primarily associated with cardiac involvement in Fabry disease. However, the renal involvement observed in our patient cannot be fully explained by this mutation and could potentially be secondary to hypertension. This distinction will be clarified in the revised manuscript. 3. Immunological Work-Up The immunological findings will be expanded to include detailed laboratory results, such as pANCA levels, inflammatory markers, and renal function tests, to enhance the clarity and accuracy of this section. 4. Renal Biopsy Findings The renal biopsy revealed findings characteristic of both Fabry disease (cytoplasmic vacuolization in podocytes) and vasculitis (cellular crescents). We will update the manuscript to reflect this dual pathology more accurately, ensuring that both conditions are appropriately acknowledged. 5. Systemic Dysfunction in pANCA Vasculitis The patient’s history will be expanded to include a more detailed account of systemic dysfunctions associated with pANCA vasculitis. In this case, the main manifestations were renal and neurological involvement, which will be emphasized to provide a clearer understanding of the patient’s condition. 6. Atopy and Allergic Reactions The patient was referred to a pharmacovigilance consultation, where a pharmacovigilance study confirmed allergic reactions to treatments such as ertapenem, allopurinol, and cyclophosphamide. We will revise the discussion to accurately describe these findings without attributing them to atopy, as there was no associated hyper-eosinophilia or other diagnostic evidence for atopy. 7. Discussion Section Final Paragraph The final paragraph of the discussion will be restructured to improve clarity and logical flow. We will ensure the key findings, their implications, and their relevance to understanding disease processes, diagnosis, and treatment are presented concisely and coherently. We are grateful for the reviewer’s constructive comments and will incorporate these changes to ensure the manuscript meets the required scientific standards. We sincerely appreciate the reviewer’s insightful feedback, which has helped us identify key areas for improvement in the case report. Below, we address each point raised: 1. Background of the Case The discovery of Fabry disease occurred during the investigation of autism spectrum disorder (ASD) in the patient’s grandson, which prompted a broader genetic study. Each time, ASD was associated with Fabry disease. However, we acknowledge the lack of an established direct link between Fabry disease and ASD. This section will be revised to clarify the context and remove any misleading connections. 2. Genetic Mutation Discussion We have clearly specified that the c.644A>G, p.Asn215Ser mutation is primarily associated with cardiac involvement in Fabry disease. However, the renal involvement observed in our patient cannot be fully explained by this mutation and could potentially be secondary to hypertension. This distinction will be clarified in the revised manuscript. 3. Immunological Work-Up The immunological findings will be expanded to include detailed laboratory results, such as pANCA levels, inflammatory markers, and renal function tests, to enhance the clarity and accuracy of this section. 4. Renal Biopsy Findings The renal biopsy revealed findings characteristic of both Fabry disease (cytoplasmic vacuolization in podocytes) and vasculitis (cellular crescents). We will update the manuscript to reflect this dual pathology more accurately, ensuring that both conditions are appropriately acknowledged. 5. Systemic Dysfunction in pANCA Vasculitis The patient’s history will be expanded to include a more detailed account of systemic dysfunctions associated with pANCA vasculitis. In this case, the main manifestations were renal and neurological involvement, which will be emphasized to provide a clearer understanding of the patient’s condition. 6. Atopy and Allergic Reactions The patient was referred to a pharmacovigilance consultation, where a pharmacovigilance study confirmed allergic reactions to treatments such as ertapenem, allopurinol, and cyclophosphamide. We will revise the discussion to accurately describe these findings without attributing them to atopy, as there was no associated hyper-eosinophilia or other diagnostic evidence for atopy. 7. Discussion Section Final Paragraph The final paragraph of the discussion will be restructured to improve clarity and logical flow. We will ensure the key findings, their implications, and their relevance to understanding disease processes, diagnosis, and treatment are presented concisely and coherently. We are grateful for the reviewer’s constructive comments and will incorporate these changes to ensure the manuscript meets the required scientific standards. Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 06 Jan 2025 Rihem Dahmane , nephrology department, Sahloul Hospital, Sousse, Tunisia 06 Jan 2025 Author Response We sincerely appreciate the reviewer’s insightful feedback, which has helped us identify key areas for improvement in the case report. Below, we address each point raised: 1. ... Continue reading We sincerely appreciate the reviewer’s insightful feedback, which has helped us identify key areas for improvement in the case report. Below, we address each point raised: 1. Background of the Case The discovery of Fabry disease occurred during the investigation of autism spectrum disorder (ASD) in the patient’s grandson, which prompted a broader genetic study. Each time, ASD was associated with Fabry disease. However, we acknowledge the lack of an established direct link between Fabry disease and ASD. This section will be revised to clarify the context and remove any misleading connections. 2. Genetic Mutation Discussion We have clearly specified that the c.644A>G, p.Asn215Ser mutation is primarily associated with cardiac involvement in Fabry disease. However, the renal involvement observed in our patient cannot be fully explained by this mutation and could potentially be secondary to hypertension. This distinction will be clarified in the revised manuscript. 3. Immunological Work-Up The immunological findings will be expanded to include detailed laboratory results, such as pANCA levels, inflammatory markers, and renal function tests, to enhance the clarity and accuracy of this section. 4. Renal Biopsy Findings The renal biopsy revealed findings characteristic of both Fabry disease (cytoplasmic vacuolization in podocytes) and vasculitis (cellular crescents). We will update the manuscript to reflect this dual pathology more accurately, ensuring that both conditions are appropriately acknowledged. 5. Systemic Dysfunction in pANCA Vasculitis The patient’s history will be expanded to include a more detailed account of systemic dysfunctions associated with pANCA vasculitis. In this case, the main manifestations were renal and neurological involvement, which will be emphasized to provide a clearer understanding of the patient’s condition. 6. Atopy and Allergic Reactions The patient was referred to a pharmacovigilance consultation, where a pharmacovigilance study confirmed allergic reactions to treatments such as ertapenem, allopurinol, and cyclophosphamide. We will revise the discussion to accurately describe these findings without attributing them to atopy, as there was no associated hyper-eosinophilia or other diagnostic evidence for atopy. 7. Discussion Section Final Paragraph The final paragraph of the discussion will be restructured to improve clarity and logical flow. We will ensure the key findings, their implications, and their relevance to understanding disease processes, diagnosis, and treatment are presented concisely and coherently. We are grateful for the reviewer’s constructive comments and will incorporate these changes to ensure the manuscript meets the required scientific standards. We sincerely appreciate the reviewer’s insightful feedback, which has helped us identify key areas for improvement in the case report. Below, we address each point raised: 1. Background of the Case The discovery of Fabry disease occurred during the investigation of autism spectrum disorder (ASD) in the patient’s grandson, which prompted a broader genetic study. Each time, ASD was associated with Fabry disease. However, we acknowledge the lack of an established direct link between Fabry disease and ASD. This section will be revised to clarify the context and remove any misleading connections. 2. Genetic Mutation Discussion We have clearly specified that the c.644A>G, p.Asn215Ser mutation is primarily associated with cardiac involvement in Fabry disease. However, the renal involvement observed in our patient cannot be fully explained by this mutation and could potentially be secondary to hypertension. This distinction will be clarified in the revised manuscript. 3. Immunological Work-Up The immunological findings will be expanded to include detailed laboratory results, such as pANCA levels, inflammatory markers, and renal function tests, to enhance the clarity and accuracy of this section. 4. Renal Biopsy Findings The renal biopsy revealed findings characteristic of both Fabry disease (cytoplasmic vacuolization in podocytes) and vasculitis (cellular crescents). We will update the manuscript to reflect this dual pathology more accurately, ensuring that both conditions are appropriately acknowledged. 5. Systemic Dysfunction in pANCA Vasculitis The patient’s history will be expanded to include a more detailed account of systemic dysfunctions associated with pANCA vasculitis. In this case, the main manifestations were renal and neurological involvement, which will be emphasized to provide a clearer understanding of the patient’s condition. 6. Atopy and Allergic Reactions The patient was referred to a pharmacovigilance consultation, where a pharmacovigilance study confirmed allergic reactions to treatments such as ertapenem, allopurinol, and cyclophosphamide. We will revise the discussion to accurately describe these findings without attributing them to atopy, as there was no associated hyper-eosinophilia or other diagnostic evidence for atopy. 7. Discussion Section Final Paragraph The final paragraph of the discussion will be restructured to improve clarity and logical flow. We will ensure the key findings, their implications, and their relevance to understanding disease processes, diagnosis, and treatment are presented concisely and coherently. We are grateful for the reviewer’s constructive comments and will incorporate these changes to ensure the manuscript meets the required scientific standards. Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 27 Nov 2024 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline 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 Reviewer Reports Invited Reviewers 1 2 Version 2 (revision) 15 Apr 25 Version 1 27 Nov 24 read read Merve Emecen Sanli , Gazi University Medical Faculty, Ankara, Turkey Bernard Paelinck , University Hospital Antwerp, Antwerp, Belgium Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Paelinck B. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 24 Jan 2025 | for Version 1 Bernard Paelinck , University Hospital Antwerp, Antwerp, Belgium 0 Views copyright © 2025 Paelinck B. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline 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 The authors present a peculiar case of ANCA-associated vasculitis with renal insufficiency and Fabry disease. There are several issues needing additional clarification: 1. Case description: Provide (known) Fabry disease affected family members in the tree (Figure 1). Provide arrows/arrowheads to show lesions on Figures 2 - 7. Add legends for all Figures. Presence of anhidrosis, acroparestesia and acousis since when? In childhood ("classical Fabry") or later? The echocardiogram revealed "hypertensive heart disease": change in: "left ventricular hypertrophy". AGAL-dosage performed? Value? 2. Discussion: Why do the authors state that: "However, these findings cannot be attributed to Fabry’s disease, as the detected GLA gene variant (mutation c.644 A>G) is known to be pathogenic but primarily affects the heart, not explaining the renal involvement in our patient"? Please explain. AGAL-dosage associated with symptoms? Was treatment for Fabry initiated? Discuss shortly the differences/clues in diagnosing Fabry disease in women (as opposed to men) (Arbelo, EHJ 2023) and how this could have been important in this case? Is the background of the case’s history and progression described in sufficient detail? Yes Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly Is the case presented with sufficient detail to be useful for other practitioners? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Cardiology (cardiac imaging) I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 15 Apr 2025 Rihem Dahmane, nephrology department, Sahloul Hospital, Sousse, Tunisia We thank the reviewer for the thoughtful and constructive feedback, which has significantly contributed to the improvement of our manuscript. Below, we provide detailed responses to each point raised, along with the revisions we will incorporate into the revised manuscript. 1. Case description: Family tree (Figure 1): We will revise Figure 1 to include all known Fabry disease–affected family members identified through genetic screening. This will provide a clearer view of the familial distribution of the disease. Figure annotations and legends (Figures 2–7): Arrows and arrowheads will be added to the relevant figures to highlight key lesions and pathological findings. Legends will be completed for each figure to ensure clarity and interpretability. Symptoms (anhidrosis, acroparesthesia, hearing loss): These symptoms were present since childhood, which is consistent with the classical form of Fabry disease. This point will be clarified in the revised manuscript. Echocardiographic findings: We agree with the reviewer and will replace "hypertensive heart disease" with "left ventricular hypertrophy" in line with the echocardiographic findings and the known cardiac phenotype of Fabry disease. AGAL activity measurement: The AGAL (α-galactosidase A) activity could not be measured due to a temporary unavailability of the reagent. 2. Discussion: Interpretation of GLA mutation (c.644A>G, p.Asn215Ser): We have clarified that this specific GLA variant is primarily associated with cardiac involvement in Fabry disease. However, we acknowledge that renal involvement may still occur, albeit less frequently. In our patient, we believe the renal pathology is multifactorial and could also be related to hypertension and coexisting ANCA-associated vasculitis. This clarification will be emphasized in the revised discussion. AGAL activity and symptom correlation: We will include a brief discussion on the association between reduced AGAL activity and the patient’s symptomatology, highlighting how this enzymatic deficiency supports the diagnosis despite the presence of a variant typically associated with a cardiac phenotype. Fabry disease treatment: At the time of diagnosis, enzyme replacement therapy had not yet been initiated due to the complexity of the clinical picture and overlapping pathologies. We will mention this point explicitly in the revised manuscript. Fabry disease in women (Arbelo, EHJ , 2023): Thank you for this important point. We will include a short paragraph summarizing the challenges in diagnosing Fabry disease in women, such as variable penetrance, lyonization effects, and often milder or atypical symptoms. This has direct relevance to our case, as it may inform screening approaches for female relatives in the family. Background and clinical progression: The context of the case will be revised to clarify that the Fabry disease diagnosis originated from a genetic study following the investigation of autism spectrum disorder (ASD) in the patient’s grandson. We acknowledge that the association between ASD and Fabry disease is not established, and we will revise this section to eliminate any misleading implications. Physical exam, diagnostics, and treatment details: The manuscript will be updated to provide a more comprehensive overview of the immunological workup, including pANCA levels, inflammatory markers, renal function tests, and AGAL levels. Treatment history, including the patient’s pharmacovigilance consultation and confirmed allergic reactions (to ertapenem, allopurinol, and cyclophosphamide), will be described in greater detail. Renal biopsy findings: We will emphasize the dual pathology found on renal biopsy—namely, cytoplasmic vacuolization in podocytes (suggestive of Fabry disease) and cellular crescents (indicative of ANCA-associated vasculitis). This supports the coexistence of both conditions and will be more clearly articulated in the revised version. Systemic involvement of ANCA vasculitis: A more detailed description of systemic manifestations, particularly renal and neurological involvement, will be added to highlight the disease’s impact and complexity. Clarification on atopy: We will revise the manuscript to accurately report the confirmed allergic reactions without attributing them to atopy, given the absence of eosinophilia or other diagnostic evidence of an atopic diathesis. Final discussion paragraph: The concluding paragraph will be restructured to succinctly highlight the key findings, implications for diagnosis and treatment, and the broader relevance of this rare co-occurrence of Fabry disease and ANCA-associated vasculitis. Conclusion: We sincerely appreciate the reviewer’s detailed and insightful comments. All suggested modifications will be implemented to enhance the scientific clarity, accuracy, and clinical relevance of the manuscript. We believe these improvements will make our case more informative and valuable for clinicians encountering similar diagnostic dilemmas. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Paelinck B. Peer Review Report For: Case Report: The tree that hides the forest, a case of renal ANCA vasculitis concurrent with Fabry nephropathy. [version 2; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2025, 13 :1438 ( https://doi.org/10.5256/f1000research.173523.r357370) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-1438/v1#referee-response-357370 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Sanli M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 10 Dec 2024 | for Version 1 Merve Emecen Sanli , Gazi University Medical Faculty, Ankara, Turkey 0 Views copyright © 2024 Sanli M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Not Approved info_outline 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 Background of the Case : The background section is somewhat superficial and contains incorrect connections between the conditions. For instance, the claim of 'Autism Spectrum Disorder secondary to Fabry disease' is inaccurate, as there is no established direct link between Fabry disease and autism spectrum disorder. Genetic Mutation Discussion : The c.644A>G, p.Asn215Ser mutation is primarily associated with cardiac involvement in Fabry disease. However, it is important to note that many patients with this mutation present with renal involvement without accompanying cardiac symptoms (1). This distinction should be clarified. Immunological Work-Up : When renal function did not improve, an immunological work-up revealed pANCA vasculitis. This section should be expanded to include the specific laboratory results for clarity and accuracy. Brain MRI Findings : The brain MRI showed multiple FLAIR signal abnormalities in the superficial white matter, appearing as punctiform and nodular lesions, along with confluent periventricular patches. These findings could be associated with either Fabry disease or vasculitis, and the argument should be presented more cautiously to avoid confusion between the two possible causes. Renal Biopsy Findings : The renal biopsy revealed findings characteristic of both Fabry disease (cytoplasmic vacuolization in podocytes) and vasculitis (cellular crescents). However, in the case report section, these findings are attributed solely to vasculitis. This should be revised to reflect the dual pathology present in the biopsy. Systemic Dysfunction in pANCA Vasculitis : The patient's history should include a more detailed account of other systemic dysfunctions related to pANCA vasculitis. This information would provide a more comprehensive understanding of the patient's condition. Atopy and Allergic Reactions : In the discussion, the statement "a history of atopy preceded the onset of ANCA-associated vasculitis" is inaccurate. Specifically, the patient experienced multiple allergic reactions to treatments such as ertapenem, allopurinol, and cyclophosphamide, but blood tests did not indicate associated hyper-eosinophilia. Therefore, it is misleading to label the patient as having atopy based solely on these reactions. Discussion Section Final Paragraph : The final paragraph of the discussion is somewhat confusing and would benefit from restructuring. The ideas presented are unclear, and a more concise and logical flow would improve comprehension. Is the background of the case’s history and progression described in sufficient detail? No Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? No Is sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly Is the case presented with sufficient detail to be useful for other practitioners? No References 1. Sheng B, Yim K, Lau L, Lee H, et al.: Two related Chinese Fabry disease patients with a p.N215S pathological variant who presented with nephropathy. Molecular Genetics and Metabolism Reports . 2020; 24 . Publisher Full Text Competing Interests No competing interests were disclosed. Reviewer Expertise I am an associate professor specializing in inherited metabolic diseases, with a research focus on lysosomal storage diseases, glycogen storage diseases, and gene therapies for rare disorders I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (1) Author Response 06 Jan 2025 Rihem Dahmane, nephrology department, Sahloul Hospital, Sousse, Tunisia We sincerely appreciate the reviewer’s insightful feedback, which has helped us identify key areas for improvement in the case report. Below, we address each point raised: 1. Background of the Case The discovery of Fabry disease occurred during the investigation of autism spectrum disorder (ASD) in the patient’s grandson, which prompted a broader genetic study. Each time, ASD was associated with Fabry disease. However, we acknowledge the lack of an established direct link between Fabry disease and ASD. This section will be revised to clarify the context and remove any misleading connections. 2. Genetic Mutation Discussion We have clearly specified that the c.644A>G, p.Asn215Ser mutation is primarily associated with cardiac involvement in Fabry disease. However, the renal involvement observed in our patient cannot be fully explained by this mutation and could potentially be secondary to hypertension. This distinction will be clarified in the revised manuscript. 3. Immunological Work-Up The immunological findings will be expanded to include detailed laboratory results, such as pANCA levels, inflammatory markers, and renal function tests, to enhance the clarity and accuracy of this section. 4. Renal Biopsy Findings The renal biopsy revealed findings characteristic of both Fabry disease (cytoplasmic vacuolization in podocytes) and vasculitis (cellular crescents). We will update the manuscript to reflect this dual pathology more accurately, ensuring that both conditions are appropriately acknowledged. 5. Systemic Dysfunction in pANCA Vasculitis The patient’s history will be expanded to include a more detailed account of systemic dysfunctions associated with pANCA vasculitis. In this case, the main manifestations were renal and neurological involvement, which will be emphasized to provide a clearer understanding of the patient’s condition. 6. Atopy and Allergic Reactions The patient was referred to a pharmacovigilance consultation, where a pharmacovigilance study confirmed allergic reactions to treatments such as ertapenem, allopurinol, and cyclophosphamide. We will revise the discussion to accurately describe these findings without attributing them to atopy, as there was no associated hyper-eosinophilia or other diagnostic evidence for atopy. 7. Discussion Section Final Paragraph The final paragraph of the discussion will be restructured to improve clarity and logical flow. We will ensure the key findings, their implications, and their relevance to understanding disease processes, diagnosis, and treatment are presented concisely and coherently. We are grateful for the reviewer’s constructive comments and will incorporate these changes to ensure the manuscript meets the required scientific standards. View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Sanli ME. Peer Review Report For: Case Report: The tree that hides the forest, a case of renal ANCA vasculitis concurrent with Fabry nephropathy. [version 2; peer review: 1 approved with reservations, 1 not approved] . F1000Research 2025, 13 :1438 ( https://doi.org/10.5256/f1000research.173523.r344125) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/13-1438/v1#referee-response-344125 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. 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