Response to “Autosomal Recessive Alport Syndrome Should Be Diagnosed in an m.3243A＞G Carrier Only If a Pathogenic COL4A3 Variant Has Been Detected”

The Authors Reply We sincerely appreciate the constructive comments provided by the author regarding our case report of a 29-year-old woman with Alport syndrome and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode syndrome (MELAS) (1,2). We are grateful for the opportunity to clarify several aspects of our report.

First, concerning the diagnosis of MELAS, we acknowledge that the patient does not currently fulfill the established diagnostic criteria (3,4). Nevertheless, given the presence of the m.3243A＞G variant with a heteroplasmy level of 26% and the patient's features, including short stature, hearing loss, diabetes, high serum lactate, proteinuria, and granular swollen cells in tubular epithelial cells, we considered MELAS a strong differential diagnosis. We fully agree that the diagnosis should be approached with caution, especially in the absence of definitive findings (e.g. seizures). As the clinical manifestations of MELAS can be heterogeneous and progressive, we plan to carefully monitor the patient for the potential emergence of additional characteristic features, including seizures, cognitive decline, and other signs indicative of multisystem involvement.

Second, regarding the pathogenicity of the COL4A3 c.2955_2957del variant, we recognized that this variant has not yet been definitively classified as pathogenic. We described it as a variant of interest based on its location within a gene implicated in Alport syndrome and in consideration of the patient's renal biopsy findings, including a thin basement membrane, which may be consistent with mutations in genes encoding type IV collagen. Although we acknowledge that a confirmed pathogenic variant or classic histopathological features are generally required for a definitive diagnosis of Alport syndrome, our case underscores the diagnostic challenges when the presentation is atypical or incomplete. Further functional analyses of the identified variants are warranted to clarify their pathogenicity.

Third, regarding the family history, we agree that information concerning the mode of inheritance is critical, particularly in cases involving both mitochondrial and autosomal variants. Unfortunately, parental genetic testing was not performed at the time of our report, limiting our ability to confirm segregation of both mtDNA and COL4A3 variants. We concur that such information is highly informative and recommend including familial genetic analyses when feasible in future cases.

Fourth, we appreciate the comment that emphasizes the importance of systematic screening for multisystem involvement, including cardiac and neurological assessments. Although the patient underwent basic neurological and renal evaluations, we agree that a more comprehensive and prospective approach is essential for suspected mitochondrial disorders. Additional examinations will be planned during the follow-up.

In conclusion, we thank the author for their thoughtful critique, which has provided an opportunity to address the limitations of our case and elaborate on our clinical reasoning. We hope that this exchange will contribute to ongoing discussion and promote a better understanding of complex cases involving both nuclear and mitochondrial genetic variants.

The authors state that they have no Conflict of Interest (COI).