Letter re: Aseptic pleocytosis can only be classified as a phenotypic manifestation of MNGIE after exclusion of all differential causes

We read with interest the article by Redha et al. about a cases series of five siblings of consanguineous parents with mitochondrial neuro-gastro-intestinal encephalopathy (MNGIE) due to the variant c.877T>C in TYMP1. ¹ The index case (35yo male) also suffered from aseptic meningitis and non-convulsive status epilepticus (NCSE). ¹ The five siblings benefited partially from mitochondrial cocktails and the index patient also benefited from intravenous immunoglobulins (IVIGs). ¹ The study is impressive, but some points require further discussion.

The first point is that the cause of aseptic pleocytosis has not been clarified. We should know whether all differential causes of aseptic pleocytosis have been completely ruled out. These include autoimmune encephalitis (AIE), systemic diseases with meningeal involvement such as sarcoidosis, Behçet’s disease, Sjögren’s syndrome, systemic lupus erythematosus and granulomatosis with polyangiitis, drug-induced aseptic meningitis due to non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics (sulfonamides, penicillins), intravenous immunoglobulins (IVIGs), and monoclonal antibodies), or neoplastic meningitis due to metastasis from solid neoplasms, or due to leukaemia or lymphoma. ² We should know whether all these differential diagnoses were ruled out in the index patient. Surprisingly, the virus panel did not include SARS-CoV-2 and JC virus.

The second point is that we disagree with the statement in the abstract that MNGIE is characterised by asymptomatic leukoencephalopathy. ¹ Of course, there are also patients with white matter lesions without CNS symptoms, but MNGIE due to TYMP1 variants is often associated with cognitive impairment or even dementia. ³ Memory impairment has been also reported in patients with MGNIE due to a variant in ECGF1. ⁴

The third point is that it is incomprehensible why siblings 2 and 3 were not tested for the causative TYMP1 variant but were nevertheless diagnosed with MNGIE. It is also incomprehensible why sibling 4 was tested for Charcot-Marie Tooth disease despite the genetically confirmed diagnosis of MNGIE in the index patient. We should know according to what criteria the index patient was provisionally diagnosed with MELAS. Did this patient meet the Hirano criteria, the Japanese criteria, or both for the diagnosis of MELAS?

The fourth point is that, with the exception of the index case, no long-term follow-up was reported. We should know the outcome of the four siblings, in especially what kind of treatment they received and how long they survived. It would also be interesting to know whether the parents of the five patients actually carried the causative TYMP1 variant.

The fifth point is the discrepancy between the statement in the abstract that all five siblings tested positive for the causative TYMP1 variant and the statement in the case description of the index patient that only three siblings tested positive for the causative TYMP variant. Do the authors mean that only those with a typical MNGIE phenotype also carried the mutation? In this case, we shuld know how typical MNGIE was defined and how many met this definition. These discrepancies should be clarified.

In summary, the interesting study has limitations that put the results and their interpretation into perspective. Removing these limitations could strengthen and support the study’s message. Before aseptic meningitis can be attributed to MNGIE, all possible differential causes of aseptic pleocytosis must be thoroughly ruled out.