Letter to the Editor: Gastrointestinal Pseudo-Obstruction Is Not an Uncommon Phenotypic Manifestation of POLG1 Variants-Authors' Reply.

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Learn more: PMC Disclaimer | PMC Copyright Notice letter Eur J Neurol . 2026 Jun 1;33(6):e70658. doi: 10.1111/ene.70658 Letter to the Editor: Gastrointestinal Pseudo‐Obstruction Is Not an Uncommon Phenotypic Manifestation of POLG1 Variants—Authors' Reply Giuliana Capece 1, 2 , Renzo Manara 3 , Leonardo Salviati 4 , Carlo Viscomi 5 , Luca Bello 2 , Elena Pegoraro 2, ✉ Author information Article notes Copyright and License information 1 PhD Program in Translation Specialistic Medicine “G.B. Morgagni”, Curriculum “Clinical and Translational Neurosciences”, University of Padova, Padova, Italy 2 Neuromuscular Unit, Department of Neurosciences DNS, University of Padova, Padova, Italy 3 Neuroradiology, Department of Neurosciences DNS, University‐Hospital of Padova, Padova, Italy 4 Department of Women's and Children's Health, University of Padova, Padova, Italy 5 Department of Biomedical Sciences, University of Padova, Padova, Italy * Correspondence: Elena Pegoraro ( elena.pegoraro@unipd.it ) ✉ Corresponding author. Revised 2026 May 7; Received 2026 May 7; Accepted 2026 May 22; Collection date 2026 Jun. © 2026 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMC Copyright notice PMCID: PMC13239112  PMID: 42223185 See " Gastrointestinal Pseudo‐Obstruction Is Not an Uncommon Phenotypic Manifestation of POLG1 Variants ", e70655. We thank Prof. Josef Finsterer for his comments on our article [ 1 ] and appreciate the opportunity to address the points raised. The patient's transient loss of consciousness was witnessed by his relatives; urinary and fecal incontinence, tongue biting, or clonic movements were not observed by them neither by first responders and helicopter paramedics. However, on recovery of consciousness, the patient showed transient aphasia and confusion. After admission in the Emergency Department, myoclonic jerks and rapid deterioration into coma were reported. The following day, brain death was declared. According to Italian law [ 2 ], brain death requires two EEG recordings (30 min each) within a 6‐h interval demonstrating absent cerebral activity. In our patient, both recordings excluded status epilepticus and other paroxysmal abnormalities. We agree that an autopsy would have clarified the cause of death; no autopsy was performed in keeping with the wishes of patient's family. We also wish to emphasize that the twin brother, now 44 years old, has never experienced any seizures. Brain MRI (Figure S1 ) showed widespread hyperintensity on DWI (panel a–c) and FLAIR (panel d–f). The lesions didn't follow a vascular territory and were not consistent with PRES or ADEM. No evidence of bleeding was detected. To note, the images in Supporting Information (Figure S1 ) show a diffuse DWI hyperintensity involving the whole white matter of all the cerebral lobes. In addition, the scanner normalizes the signal intensity of the images; therefore, the cortex appears relatively DWI‐hypointense in spite of its severe involvement. For this reason, we had added in the text ADC values, which are more objective and clearly indicative of a severe global involvement of the cortex. The acute episode (loss of consciousness, then transient aphasia and confusion) was preceded by headache and may be consistent with a focal seizure. Both headache and focal seizures are well‐recognized presentations of stroke‐like episodes (SLEs) [ 3 ]. The subsequent myoclonic jerks and neurological deterioration may reflect either a severe SLE or a metabolic decompensation due to mitochondrial dysfunction. A lactate peak on magnetic resonance spectroscopy would have supported the identification of the stroke‐like lesion [ 3 ], but it could not be performed in the emergency setting. Both patients exhibited overlapping phenotypes with no relevant differences in major comorbidities and treatments. As they lived in the same household, differential environmental exposures are unlikely. Well‐preserved skeletal muscle tissue for biochemical and molecular analyses was available only for patient #1 (Table S1 ). Moreover, it is important to note that, among other factors, epigenetics—even when influenced by minor environmental differences—may contribute to the development of distinct biological profiles in monozygotic twins. Although severe gastrointestinal involvement in POLG ‐related disorders has been reported [ 4 ], our patients exhibited a diffuse leukoencephalopathy sparing the U‐fibers and corpus callosum, as described in TYMP ‐related MNGIE. To the best of our knowledge, this is the first report of a POLG ‐related MNGIE phenotype closely resembling the CNS involvement of the TYMP ‐related form, thereby expanding the phenotypic spectrum of POLG ‐related disorders. We also emphasize that in our manuscript we focused more on the encephalopathy than on the GID. The NGS panel covered all OMIM genes associated with autonomic neuropathy, all of which were negative; PRDM12 was not included, but is associated with a distinct clinical phenotype. As no autopsy was carried out, in keeping with the wishes of the patient's family, we were unable to assess the involvement of intestinal smooth muscle, and both patients refused rectal biopsy to study myenteric plexus. Respiratory assessment showed reduced inspiratory and expiratory muscle strength. Since peripheral neuropathies rarely involve the respiratory muscles [ 5 ], the respiratory insufficiency is best attributed to primary muscle weakness in our case. As gastrointestinal involvement may lead to malabsorption, both patients received regular vitamin and protein supplementation. However, patients with mitochondrial disorders may be particularly vulnerable to thiamine deficiency [ 6 ]. Since thiamine is involved in carbohydrate metabolism and energy production as the precursor of thiamine pyrophosphate [ 6 ], mitochondrial dysfunction may reduce tolerance to thiamine deficiency. Consequently, higher thiamine requirements may be necessary to compensate for impaired cellular energy production [ 6 ]. Author Contributions Carlo Viscomi: writing – original draft, writing – review and editing. Leonardo Salviati: writing – original draft, writing – review and editing. Renzo Manara: writing – original draft, writing – review and editing. Giuliana Capece: writing – original draft, writing – review and editing. Elena Pegoraro: writing – original draft, writing – review and editing. Luca Bello: writing – original draft, writing – review and editing. Conflicts of Interest The authors declare no conflicts of interest. Linked Articles This article is linked to Finsterer papers. To view this article, visit https://doi.org/10.1111/ene.70655 . Supporting information Figure S1: Massive stroke‐like episode. Axial diffusion weighted imaging (DWI) sequences (a–c) and FLAIR sequences (d–f) show diffuse cytotoxic and vasogenic edema with obliteration of sulcal spaces and compression of the ventricles. Table S1: Biochemical and molecular analysis of the patient's skeletal muscle. (A) Spectrophotometric analysis of the respiratory chain. (B) Analysis of mtDNA content by real‐time PCR. ENE-33-e70658-s001.docx (311.8KB, docx) Data Availability Statement Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. References 1. Capece G., Caumo L., Volta S., et al., “Wernicke Encephalopathy Complicating a Distinctive POLG Phenotype With MNGIE‐Like Features,” European Journal of Neurology 33, no. 3 (2026): e70554, 10.1111/ene.70554. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 2. Decreto 11 Aprile 2008 , Aggiornamento Del Decreto 22 Agosto 1994 n. 582 1994. Regolamento Recante Le Modalità per l'accertamento e La Certificazione Della Morte (Gazzetta Ufficiale, 1994). [ Google Scholar ] 3. Khasminsky V., Auriel E., Luckman J., et al., “Clinicoradiologic Criteria for the Diagnosis of Stroke‐Like Episodes in MELAS,” Neurology Genetics 9, no. 4 (2023): e200082, 10.1212/NXG.0000000000200082. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ] 4. Finn L. S., Goldstein A., and Hedrick H. L., “Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) Phenotype Associated With Unique Compound Heterozygous POLG Variants: Case Presentation and Review of the Literature,” Pediatric and Developmental Pathology 28, no. 4 (2025): 288–299, 10.1177/10935266251321317. [ DOI ] [ PubMed ] [ Google Scholar ] 5. Burakgazi A. Z. and Höke A., “Respiratory Muscle Weakness in Peripheral Neuropathies,” Journal of the Peripheral Nervous System 15, no. 4 (2010): 307–313, 10.1111/j.1529-8027.2010.00293.x. [ DOI ] [ PubMed ] [ Google Scholar ] 6. Lee Y. C., Wei Y. H., Lirng J. F., et al., “Wernicke's Encephalopathy in a Patient With Multiple Symmetrical Lipomatosis and the A8344G Mutation of Mitochondrial DNA,” European Neurology 47, no. 2 (2002): 126–128, 10.1159/000047967. [ DOI ] [ PubMed ] [ Google Scholar ] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article. Supplementary Materials Figure S1: Massive stroke‐like episode. Axial diffusion weighted imaging (DWI) sequences (a–c) and FLAIR sequences (d–f) show diffuse cytotoxic and vasogenic edema with obliteration of sulcal spaces and compression of the ventricles. Table S1: Biochemical and molecular analysis of the patient's skeletal muscle. (A) Spectrophotometric analysis of the respiratory chain. (B) Analysis of mtDNA content by real‐time PCR. ENE-33-e70658-s001.docx (311.8KB, docx) Data Availability Statement Data sharing not applicable to this article as no datasets were generated or analyzed during the current study. Articles from European Journal of Neurology are provided here courtesy of John Wiley & Sons Ltd on behalf of European Academy of Neurology (EAN) ACTIONS View on publisher site PDF (218.6 KB) Cite Collections Permalink RESOURCES Similar articles Cited by other articles Links to NCBI Databases Follow NCBI NCBI on X (formerly known as Twitter) NCBI on Facebook NCBI on LinkedIn NCBI on GitHub NCBI RSS feed Connect with NLM NLM on X (formerly known as Twitter) NLM on Facebook NLM on YouTube National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894 Web Policies FOIA HHS Vulnerability Disclosure Help Accessibility Careers NLM NIH HHS USA.gov Back to Top

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