Aseptic Pleocytosis Can Only be Classified as a Phenotypic Manifestation of MNGIE After Exclusion of all Differential Causes

We appreciate the thoughtful commentary provided by Finsterer et al. and thank the authors for their careful review of our manuscript. We believe that such detailed discussions contribute to the advancement of the field and help refine the understanding of complex medical conditions like MNGIE.

Attributing Meningoencephalitis to MNGIE

We agree with the authors that attributing meningoencephalitis to MNGIE requires the exclusion of all other potential causes. As detailed in our manuscript, we conducted extensive evaluations to rule out autoimmune and paraneoplastic causes in the proband. Additionally, we performed a CT scan of the chest, abdomen, and pelvis to rule out any underlying malignancies.

It is well recognized that the choice of investigations should be guided by the specific clinical presentation of the patient. In this case, we also carried out an ANA panel, which did not reveal any significant abnormalities. The patient did not exhibit systemic symptoms suggestive of Sjögren’s syndrome, systemic lupus erythematosus, Behçet’s disease, or systemic vasculitis. Furthermore, the MRI findings were not consistent with CNS vasculitis and the presence of peripheral neuropathy that predated the CNS symptoms lead us to conclude that a brain biopsy was unnecessary.

Additionally, the patient was not on non-steroidal anti-inflammatory drugs, antibiotics (sulfonamides, penicillins), or intravenous immunoglobulins upon presentation. Thus, no further workup was deemed necessary.

Our evaluation showed no signs of leukemia based on the CBC, and the likelihood of CNS lymphoma was deemed low given the patient’s MRI results and the resolution of encephalopathy. At the time of assessment, the patient was not on non-steroidal anti-inflammatory drugs, antibiotics (including sulfonamides and penicillins), or intravenous immunoglobulins. The decision to administer IVIG was made empirically to address a potential case of immune-mediated limbic encephalitis.

While we recognize the significance of an extensive viral panel, the selection of viruses for testing was based on the clinical situation and panels available to us. and the most pertinent differential diagnoses at the time. Not that it’s a substitute to CNS testing, SARS-CoV-2 testing through nasal and pharyngeal swabs was being done routinely and was negative in this patient.

Association of Cognitive Impairment or Dementia with MNGIE

We respectfully disagree with the assertion that MNGIE is often associated with cognitive impairment or dementia. Upon reviewing the references provided by the authors, such associations were noted in only one case involving an ECGF1 mutation. ¹ In our systematic search across multiple databases, we did not find sufficient evidence to support this claim as a general feature of MNGIE.^2,3 Exceptions to the rule, observed in one isolated case, should not overshadow what is commonly reported in the literature. The majority of published studies, including our case series, describe the leukoencephalopathy associated with MNGIE as asymptomatic.

Genetic Testing and Diagnostic Processes

Contrary to the authors’ concerns, we explicitly stated in the manuscript that siblings 2 and 3 received a diagnosis of MNGIE following genetic testing (page 4). Furthermore, we clarified on pages 3 and 5 that Charcot-Marie-Tooth (CMT) disease workup was conducted for sibling 4 prior to the genetic diagnosis of MNGIE. At no point did we suggest that diagnoses were made without genetic confirmation or that CMT testing was performed after an MNGIE diagnosis.

The TYMP mutation was assessed in both parents and asymptomatic siblings, all of whom were found to be heterozygous for the mutation. This finding further underscores the pathogenicity of the genetic alteration.

We appreciate the authors’ focus on diagnostic approaches for MELAS. However, we would like to emphasize that the provisional MELAS diagnosis was based on a muscle biopsy and clinical features and was made over 20 years ago. The authors of this manuscript were not involved in this diagnosis, therefore we cannot clarify why diagnostic criteria for MELAS, such as Hirano or Japanese criteria or genetic testing was not employed for diagnosis.

Follow-up Reporting and Case Numbers

The case report was written shortly after the genetic diagnosis was made, and therefore only short-term follow-up data were available at the time of publication. The letter highlights an important limitation of our case series. Long-term follow-up was not possible at the time of publication, but we recognize its value in providing a more comprehensive understanding of disease progression and outcomes. Future studies, including follow-up data on these patients, could contribute significantly to the literature on MNGIE.

There seems to be a misunderstanding regarding the reported cases. As detailed in our manuscript, five siblings were described in total. Sibling 4 was the first to be diagnosed with MNGIE through genetic testing, albeit lost to follow-up initially. This led to the diagnosis of the proband and subsequently the three other symptomatic siblings (siblings 1, 2, and 3). We hope this clarification resolves any perceived discrepancy.

Conclusion

We sincerely thank Finsterer et al. for their insightful comments and for fostering a constructive dialogue on this topic. Addressing these points has allowed us to further clarify the findings in our manuscript and underscore the complexity of diagnosing and managing rare disorders like MNGIE. We hope this exchange contributes to a deeper understanding and continued exploration of this challenging condition.