We read with interest the article by Capece et al. [1] who reported a pair of monozygotic male twins with a multisystem mitochondrial disorder (MID) due to the compound heterozygous paternal mutations p.Thr251Ile and p.Pro587Leu, which occured in cis, and the maternal variant p.Arg853Gly, which read in trans in POLG1. Phenotypically, the two patients (Patient‐1, Patient‐2) had psychomotor delay, mild mental retardation, congenital cataract, demyelinating polyneuropathy, gastrointestinal motility disorder (GID), cerebellar ataxia and myopathy and Patient‐1 had a fatal stroke‐like episode (SLE) at the age of 39 years [1]. The study is interesting, but several points require discussion.
The first point is that Patient‐1 was not subjected to autopsy [1]. Since the cause of the cerebral edema and resulting brain death remained unclear, it would have been crucial to search for the cause of the sudden headache, loss of consciousness, confusion, aphasia, myoclonus, and subsequent death within days of admission [1]. It should be noted whether the patient passed urine or stool during the attack, whether there was tongue bite, and whether cloni or myocloni were observed during the episode. We should also know whether an EEG was performed before death and whether paroxysmal activity was recorded?
The second point is that the results of the cerebral MRI modalities of Patient‐1 have been underreported [1]. If the edema were indeed classified as cytotoxic, one would expect that diffusion‐weighted imaging (DWI) would be hyperintense. Was the DWI hyperintensity focal or global? Was there any evidence of bleeding? Was the DWI/ADC lesion hyperintense on T2/FLAIR? Was magnetic resonance spectroscopy (MRS) performed to determine whether a lactate peak was present within the stroke‐like lesion (SLL)? An image of this MRI should have been presented. Were the findings interpreted as ischemic stroke, stroke‐like lesion (SLL), PRES, or ADEM? If the brain lesion was interpreted as SLL, it must be clarified whether the episode was triggered by a generalized seizure or not, as SLE are often triggered by seizures [2].
The third point is that no explanation was provided as to why the phenotype of the two monozygotic twins was different (table 1). Patient‐2 obviously never had a SLE. Were there any differences in medications or diet between the two? Did they have different jobs or did they live separately in different places and under different environmental conditions?
The fourth point is that we disagree with the assumption that the two cases expand the phenotypic spectrum of POLG1 mutations, as has been mentioned [1]. GID due to POLG1 mutations is a rare phenotypic manifestation of POLG1 variants but has been repeatedly reported [3, 4].
The fifth point is that patients were not tested for autonomic involvement [1]. Since the two patients had sensorimotor neuropathy and GID, it cannot be excluded that they had involvement of the autonomic fibers innervating the gastrointestinal tract. Once autonomic neuropathy has been ruled out, it should be clarified whether the GID is due to impairment of intestinal smooth muscle fibers or other causes.
The sixth point is that it has not been specified whether the muscular respiratory insufficiency is due to impairment of the nerves supplying the primary and secondary respiratory muscles or whether it is due to myopathy of these muscles.
Finally, it is incomprehensible why the index patient developed only thiamine deficiency without deficiencies in other essential nutritional components. If there is malnutrition due to impaired absorption, one would expect a deficiency of proteins, glucose, fats, other vitamins, trace elements and electrolytes. This discrepancy should be resolved.
Author Contributions
Josef Finsterer: conceptualization, methodology, writing – review and editing, writing – original draft.
Funding
The author has nothing to report.
Ethics Statement
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Consent
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Conflicts of Interest
The author declares no conflicts of interest.
Linked Articles
This article is linked to Capece papers. To view this article, visit https://doi.org/10.1111/ene.70658.
Acknowledgments
The author has nothing to report.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.