A group of mitochondrial disorders are characterized by mutations in the nuclear genome affecting expression and replication of the genes on the mitochondrial genetic material. Progressive external ophthalmoplegia (PEO) was the first disease identified in this group caused by defects in the intergenomic communication . MNGIE, a rare progressive multisystem autosomal recessive disorder caused by a mutation in TYMP gene is also a member of this group of disorders.
TYMP gene which encodes the cytosolic enzyme named thymidine phosphorylase, TP, is located at chromosome 22q13.33. This protein catalyzes phosphorylation of mitochondrial dThd and dUrd to thymine and uridine, respectively (Figure 4). TP plays an important role in the metabolic pathways of various cells including those in the brain, muscle, RBCs, WBCs, and bone marrow, relying on the salvage pathway for recovering nucleosides [15, 16]. MNGIE usually presents with symptoms of gastrointestinal dysfunction, such as gastrointestinal motility disorders, gastro-esophageal reflux, dysphagia, abdominal pain and distention, and diarrhea leading to severe weight loss and cachexia . At this stage of the disease, most of the patients are misdiagnosed as malabsorption syndrome, inflammatory bowel disease (IBD), anorexia nervosa, or intestinal pseudo-obstruction, often leading to unnecessary medical interventions and delay in diagnosis of up to 10 years [6, 18-20]. Ptosis, ophthalmoparesis, hearing loss, and sensory-motor neuropathy constitute the most common neurologic features of patients with MNGIE . Due to the high metabolic activity of extraocular muscles, deterioration in their function resulting in ophthalmoplegia or ophthalmoparesis occurs early in the course of the disease that parallels the disease progression . Neuroimaging studies such as brain MRI and magnetic resonance spectroscopy (MRS) might yield a clue about the diagnosis of MNGIE, with the absence of leukoencephalopathy ruling out MNGIE in most cases. Unlike the patient reported here, who had involvement of splenium of the corpus callosum, it is relatively spared in most individuals [8, 10, 22]. Our patient was found to have leukoencephalopathy, with diffuse T2 hyperintensity in both cerebral hemispheres white matter on brain MRI, though, she had normal cognitive function. This, in turn, is likely to be due to the impaired blood-brain barrier function in these patients leading to edema in lieu of demyelination .
Other disorders with phenotypes similar to MNGIE, caused by mutations in RRM2B and POLG genes have been reported [24, 25]. Therefore, it is prudent to test the individuals suspected of having MNGIE for these genes as well. In our patient whole exome sequencing was done and no mutations in these genes were detected.
To the best of our knowledge, around 80 pathogenic mutations in the TYMP gene have so far been reported. Attempts to draw a genotype-phenotype correlation in this disorder have mostly been discouraging, except for c. 622G>A variant (p.Val208Met), producing less severe TP dysfunction, leading to a late-onset disease [26-28].
Current treatment modalities for MNGIE mainly focus on restoration of the activity of TP and lowering the circulatory levels of the nucleoside substrates. Hematopoietic stem cell transplantation (HSCT) has so far been used to restore TP enzyme activity in patients with MNGIE. A retrospective analysis of 24 patients who underwent HSCT for the treatment of MNGIE revealed a survival rate of 37.5% after a median follow-up of almost four years. Most of the deaths were attributed to the transplantation with MNGIE complications leading to death in a quarter of the patients . It was found that younger patients without gastrointestinal dysmotility and liver disease receiving HSCT from an HLA-matched donor would benefit mostly from this type of treatment, highlighting the importance of diagnosis in the momentous days early in the course of the illness, when HSCT would change the course of the disease . Hemodialysis and peritoneal dialysis have also been proposed as treatment modalities in these patients intending to remove the nucleosides from the peripheral circulation. A prospective study evaluating a 29-year-old patient with MNGIE who underwent extensive hemodialysis for one year also revealed that it has only a transient effect on the serum and urine levels of nucleosides with no long-term effects; there were no changes in the level of the toxic metabolites in the CSF in both short-term (within 24 hours) and long-term (at months 6 and 12) . Our patient in this report underwent hemodialysis with only mild improvements in the gastrointestinal symptoms. These findings cast doubt on the efficacy of dialysis in the treatment of MNGIE. Other therapeutic modalities including platelet infusion, which was also performed in our patient, and orthotopic liver transplantation have also been reported for the treatment of this disease in the literature [4, 31].
The mutation found initially by WES and subsequently confirmed using Sanger sequencing is predicted to disrupt the proper function of TYMP protein since different reports have identified frameshift mutations before and after this region resulting in the impaired TYMP [32-34].
Our patient had many of the clinical, laboratory, and imaging features seen in MNGIE. The detected novel nonsense mutation in the TYMP gene would be of importance for genetic counseling and subsequent early diagnosis and initiation of proper therapy. On account of the wide clinical spectrum of signs and symptoms presented by patients with MNGIE, molecular diagnostic methods would be of paramount importance.