Mitochondrial neurogastrointestinal encephalopathy: a clinicopathological mimic of Crohn’s disease

Abstract

BackgroundMitochondrial neurogastrointestinal encephalopathy (MNGIE), due to mutations in TYMP, often presents with gastrointestinal symptoms. Two sisters, initially managed for Crohn’s disease based upon clinical, imaging and pathological findings, were later found to have MNGIE. The cases provide novel clinicopathological insight, for two further reasons: both sisters remain ambulant and in employment in their late 20s and 30s; diagnosis in one sister was made after a suspected azathioprine-precipitated acute illness.Case presentationA 25-year-old female presented with diarrhoea, vomiting, abdominal pain, and bloating. Faecal calprotectin, colonic biopsies and magnetic resonance enterography were consistent with a diagnosis of Crohn’s disease. Azathioprine initiation preceded admission with a sore throat, headache, myalgia, and pyrexia. Withdrawal led to rapid clinical improvement. MRI brain revealed persistent, extensive white matter changes. Elevated plasma and urine thymidine and deoxyuridine, and genetic testing for TYMP variants, confirmed MNGIE. Testing of the patient’s sister, also diagnosed with Crohn’s disease, revealed identical variants. In this context, retrospective review of colonic biopsies identified histological findings suggestive of MNGIE.ConclusionsAzathioprine interference in nucleic acid metabolism may interact with the mitochondrial DNA depletion of MNGIE. Nucleotide supplementation, proposed for treatment by manipulating mitochondrial nucleoside pools, may require caution. The late onset and mild phenotype observed confirms presentation can occur later in life, and may reflect residual thymidine phosphorylase activity. Clinicians should consider measuring plasma thymidine levels in suspected Crohn’s disease to rule out MNGIE, particularly if white matter abnormalities are identified on neuroimaging.

Clinicopathology and Diagnosis Delay in a 40-Year-Old with Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)

“…Furthermore, the average age at death for MNGIE patients is 37 years usually secondary to their perilous nutritional status [10] with our patient being 40 years old at the time of diagnosis. This may be due to heterozygous TYMP variants manifesting at a later age and in milder forms secondary to residual TP activity [14]. This delay TP is a catabolic enzyme that plays an important role in pyrimide salvage and catalyzes phosphorolysis of the nucleosides thymidine or deoxyuridine to their respective bases thymine or uracil [2].…”

Advancement in the diagnosis of mitochondrial diseases

“…Some of the mutations that have been identified in KSS are the deletion of 3,236 bp of mitochondrial chromosome from 10,170 [35] , mtDNA duplication [36] , a mtDNA point mutation in the MTTL2 gene [37] , and a large mtDNA deletion [38] . Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease affects several parts of the body, mostly the digestive and nervous systems [39] . It is caused by a mutation in the thymidine phosphorylase gene (TYMP) that leads to decreased enzyme activity and increased thymidine levels [40] .…”

The Role of Mitochondrial Dysfunction in Vascular Disease, Tumorigenesis, and Diabetes

“…Mutations in mtDNA may result in oxidative chain defects and subsequent pathology development. Mitochondria-related nuclear mutations also contribute to pathological processes, such as coenzyme Q (CoQ) deficiency, glutaric acidemia type 2, mtDNA depletion syndrome, mitochondrial neuro-gastrointestinal encephalopathy (MNGIE) and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) (Patel et al, 2019;Yu et al, 2019).…”