Clinical spectrum of early onset “Mediterranean” (homozygous p.P131L mutation) mitochondrial neurogastrointestinal encephalomyopathy

Abstract

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive mitochondrial disorder characterized by cumulative and progressive gastrointestinal and neurological findings. This retrospective observational study, aimed to explore the time of presentation, diagnosis and clinical follow‐up of 13 patients with a confirmed MNGIE disease of Mediterranean origin. The mean age of symptom onset was 7 years (6 months−21 years) and the average diagnosis age was 15.4 years ±8.4. Four of 13 patients (30%) died before 30 years at the mean age of 19.7 years ±6.8. Cachexia and gastrointestinal symptoms were observed in all patients (100%). The mean body mass index standard deviation score at diagnosis was 4.8 ± 2.8. At least three subocclusive episodes were presented in patients who died in last year of their life. The main neurological symptom found in most patients was peripheral neuropathy (92%). Ten patients (77%) had leukoencephalopathy and the remaining three patients without were under 10 years of age. The new homozygous “Mediterranean” TYMP mutation, p.P131L (c.392 C > T) was associated with an early presentation and poor prognosis in nine patients (69%) from five separates families. Based on the observations from this Mediterranean MNGIE cohort, we propose that the unexplained abdominal pain combined with cachexia is an indicator of MNGIE. High‐platelet counts and nerve conduction studies may be supportive laboratory findings and the frequent subocclusive episodes could be a negative prognostic factor for mortality. Finally, the homozygous p.P131L (c.392 C > T) mutation could be associated with rapid progressive disease with poor prognosis.

Hematopoietic stem cell transplantation with reduced toxicity conditioning regimen in mitochondrial neurogastrointestinal encephalopathy syndrome

“…Three patients of these patients had a homozygous p.P131L (c.392C>T) TYMP mutation, and one patient had a homozygous p.G72E (c.215G>A) mutation. We concluded that the “Mediterranean”/homozygous p.P131L (c.392C>T) mutation is associated with a rapidly progressive clinical course and poor prognosis 12 . The mean age at diagnosis of our patients was 16.4 years and all patients had persistent GI manifestations and neurological deficit findings at the time of diagnosis.…”

“…In the study published by Kalkan Uçar et al. in 2022, patients diagnosed with MNGIE at Ege University Faculty of Medicine, Department of Pediatrics, Department of Pediatric Metabolism and Nutrition were evaluated 12 . In this patient group, we performed AHSCT on four patients.…”

Ocular manifestations of mitochondrial neurogastrointestinal encephalomyopathy: A case report and literature review

“…Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive multisystem disorder characterized by severe gastrointestinal and neurological symptoms (Kalkan Uçar et al, 2022; Pacitti et al, 2018). Gastrointestinal dysmotility, cachexia, peripheral neuropathy, diffuse leukoencephalopathy, external ophthalmoplegia, and ptosis are the main manifestations (Hirano et al, 2021).…”

“…Gastrointestinal dysmotility, cachexia, peripheral neuropathy, diffuse leukoencephalopathy, external ophthalmoplegia, and ptosis are the main manifestations (Hirano et al, 2021). TYMP gene is identified as the pathogenic gene (Kalkan Uçar et al, 2022). It encodes thymidine phosphorylase that catalyzes the reversible phosphorylation of thymidine and deoxyuridine to thymine, uracil, and 2-deoxyribose 1-phosphate (Valentino et al, 2007).…”

“…Besides progressive external ophthalmoplegia and ptosis, some patients are also troubled by blurry vision (Durrani et al, 2019;Tawk et al, 2020;Wang et al, 2017). Pigmentary retinopathy and optic atrophy (Kalkan Uçar et al, 2022;Martí et al, 2005) have been reported. However, we first describe the severe inner retina impairment in MNGIE with electrophysiological examinations and optical coherence tomography (OCT).…”