Clinicopathological aspects of the neuropathy of neurogastrointestinal encephalomyopathy (MNGIE) in four patients including two with a Charcot–Marie–Tooth presentation

Abstract

We report on four patients with severe polyneuropathy associated with intestinal pseudoobstruction (MNGIE). Three patients presented characteristic supranuclear ophthalmoplegia, and hyperdense signals on T2 weighted cerebral MRI and dystrophic mitochondria in Schwann cells and in endothelial cells in nerve biopsy specimens. Two of these patients had a Charcot-Marie-Tooth (CMT) presentation. All three were heterozygous for a recessively transmitted double substitution in the TP gene: Glu286Lys/Glu289Ala, Asp156Gly/Leu177Pro and Glu289Ala/Gly387Asp. The fourth patient, who was the only patient of this series with an affected sib, had no oculomotor manifestations, nor T2 hyperdense signals on brain MRI, and no TP gene mutation and or morphological abnormalities of mitochondria on electron microscopic examination. He was the only patient of this series with an affected sib. The three patients with the full MNGIE syndrome died before the age of 30 years. Detailed results of nerve pathology show that severe axonal degeneration is associated with segmental abnormalities of the myelin sheath in this syndrome which appears genetically heterogeneous. Our findings suggest that only ophthalmoplegia and hyperdense signals on cerebral MRI are directly related to the mitochondriopathy.

Inherited mitochondrial neuropathies

“…In a study on four MNGIE patients two presented with a CMT-like phenotype [80]. Post-mortem studies of nerve specimens revealed severe axonal degeneration associated with segmental abnormalities of the myelin sheath [80]. In another study five MNGIE patients presented with demyelinating PNP [81].…”

“…Nerve conduction studies may reveal mixed axonal and demyelinating PNP. In a study on four MNGIE patients two presented with a CMT-like phenotype [80]. Post-mortem studies of nerve specimens revealed severe axonal degeneration associated with segmental abnormalities of the myelin sheath [80].…”

Astrocytic TYMP and VEGFA drive blood–brain barrier opening in inflammatory central nervous system lesions

“…Patients have a loss of function mutation in the intron 8 splice acceptor site leading to loss of exon 8 and lower levels of functional TYMP (Wong, 2012). In addition to mitochondrial deficits, attributed to accumulation of thymidine, patients exhibit T 2 hyperintense white matter lesions (Said et al, 2005). It is unclear whether these represent metabolic lesions, or more provocatively, inflammatory lesions secondary to dysregulated blood-brain barrier opening, although the mechanism by which loss of TYMP might lead to white matter lesion formation is unclear.…”

Late-onset MNGIE without peripheral neuropathy due to incomplete loss of thymidine phosphorylase activity

“…Contrary to patients reported so far, however, there was no evidence of PN, which is regarded as a cardinal feature of MNGIE [10] and, at times, mimics the neurophysiological and clinical presentation observed in CIDP or Charcot-Marie-Tooth disease [11,12]. Interestingly, rare cases with incomplete syndrome have been described, including one late-onset patient with normal NCS after 12 years of disease progression [5,13].…”