We read with interest the article by Gschwind et al. on a mid-forty male with developmental delay, spastic paraplegia, and cerebellar ataxia who developed post-infectious lactic acidosis from which he eventually succumbed.[1] Post-mortem work-up revealed necrotising leuko-encephalo-myopathy due to the novel homozygous variant c.365C>T in NDUFV1.[1] The study is appealing but raises concerns that should be discussed.

A limitation of the study is that a SARS-CoV-2 infection was not ruled out as the cause of gastro-enteritis leading to the initial admission. 

Because the events apparently took place after the start of the SARS-CoV-2 pandemic, it cannot be ruled out that the patient deteriorated because of an undiagnosed COVID-19 infection. Arguments for a SARS-CoV-2 infection are that the patient was institutionalised and manifested with gastro-enteritis. Institutionalised patients are at an increased risk of contracting and dying from a SARS-CoV-2 infection.[2] It is also known that SARS-CoV-2 infections can manifest itself not only in the lungs but also in extra-pulmonary sites, including the gastro-intestinal tract.[3] In patients with manifestations of COVID-19 with extra-pulmonary onset, the causative agent can be difficult to confirm. We should be told whether the patient was SARS-CoV-2 vaccinated at the time of the first deterioration. 

A further limitation of the study is that no electroencephalography (EEG) had been recorded to rule out non-convulsive status epilepticus (NCSE).[1] During the second episode the patient developed coma, which requires work-up by an EEG if the cause remains undetermined. Elevated cerebral lactate could be also due to non-convulsive seizure activity. A negative history for epilepsy does not rule out newly developing seizures.

There is a discrepancy between the diagnosis cerebellar ataxia and the obviously unaffected cerebellum. There was neither atrophy nor any parenchymal lesion on MRI. We should know whether cerebellar ataxia was attributed to lesions within the cerebellar peduncles seen on autopsy. In view of the conspicuous spinal lesion, it should also be discussed whether the ataxia was not more spinal than cerebellar.

There is a discrepancy between the statements “there were no dysmorphic features” and “the only medical contact was the orthopedic surgeon for bilateral pes equinovarus treatment”.[1] Pes equinovarus should be regarded as a dysmorphic feature.

Missing is the family history and genetic investigations of the mtDNA to assess the effect of the NDUFV1 variant on mtDNA. 

Overall, the interesting study has some limitations that call the results and their interpretation into question.

Funding: no funding was received

Author contribution: JF: design, literature search, discussion, first draft, critical comments, final approval. 

Disclosures: the author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Compliance with Ethics Guidelines: This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

1. Gschwind, Markus, et al. "Early‐onset leukoencephalomyelopathy due to a biallelic NDUFV1 variant in a mid‐forties patient." Annals of Clinical and Translational Neurology 9.6 (2022): 888-892. https://doi.org/10.1002/acn3.51556 . 

2. Arlotto, Sylvie, et al. "Who were hospitalized deceased patients from COVID-19 during the first year of pandemic? Retrospective analysis of 1104 deceased patients in South of France." Journal of Epidemiology and Global Health 12.2 (2022): 196-205.

3. Finsterer, Josef, et al. "Extrapulmonary onset manifestations of COVID-19." Clinics 76 (2021): e2900.; https://doi.org/10.6061/clinics/2021/e2900