BACKGROUND: Mitochondrial neurogastrointestinal encephalopathy is a rare multisystem autosomal recessive disease caused by mutations in the TYMP gene, that encodes for thymidine phosphorylase. Mitochondrial neurogastrointestinal encephalopathy is a progressive degenerative disease characterized by a distinctive tetrad of gastrointestinal dysmotility, peripheral neuropathy, ophthalmoplegia with ptosis, and asymptomatic leukoencephalopathy. It provides a diagnostic dilemma to physicians in regions like Pakistan because of a lack of genetic study availability and associated financial constraints of the population. However, with careful examination and a few basic investigations, mitochondrial neurogastrointestinal encephalopathy can be diagnosed by ruling out most of the close differentials.
METHODS: We report the case of a 23-year-old Asian female whose chief complaints were epigastric pain, bilious emesis, weight loss for 3 months, and bilateral lower limb weakness for 20 days. All clinical signs and symptoms along with relevant investigations including nerve conduction studies, electromyography, and magnetic resonance imaging of the brain were highly suggestive of mitochondrial neurogastrointestinal encephalopathy syndrome. Because of financial constraints, genetic studies could not be performed. The patient was managed with a multidisciplinary approach involving gastroenterology, physiotherapy, and nutrition departments. Currently, therapeutic options for the disease include allogeneic hematopoietic stem cell transplant and carrier erythrocyte entrapped thymidine phosphorylase; however, these could not be provided to the patient owing to certain limitations.
CONCLUSIONS: As misdiagnosis and delayed diagnosis are quite common in this disease, the prime objective of this case report is to increase the basic understanding of this disease, especially its signs and symptoms, and address the limitations regarding the diagnostic investigations and management of patients with mitochondrial neurogastrointestinal encephalopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a multi-system disorder caused by several homozygous or compound heterozygous mutations, mostly in the nuclear gene of TYMP. Our current knowledge on the underlying pathology of the disease is derived through the study of about 200 cases of different ethnicities. Clinical presentations include severe cachexia, weakness, ptosis, diplopia, abdominal cramps or digestive tract disorders, hearing impairment, and paresthesia.Herein, we aim to present five novel mutations of the nuclear gene of TYMP in six Iranian patients diagnosed with MNGIE. In our population, age at the time of diagnosis was 18 to 49 years, while the onset of the symptoms varied from 13 to 20 years. We detected two pathogenic non-frameshift nonsense premature stop codon mutations (c.1013C > A, and c.130C > T), one variant of uncertain significance (VUS) non-frameshift missense mutation (c.345G > T), one likely pathogenic frameshift insertion (c.801_802insCGCG), and one likely benign homozygous non-frameshift deletion (c.1176_1187del) from two siblings. Our findings also confirm the autosomal recessive inheritance pattern of MNGIE in the Iranian population. The lack of knowledge in the area of nuclear gene-modifier genes shadows the genotype-phenotype relationships of MNGIE.

Diseases due to mutations of polymerase γ (POLG) usually present with progressive external ophthalmoplegia. However, a few studies have been reported on POLG1 mutations with the mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)-like phenotype. All cases with POLG1 mutations mimicking MNGIE have never shown leukoencephalopathy on brain magnetic resonance imaging (MRI) or demyelinating polyneuropathy. We present a 26-year-old male with gait disturbance, recurrent bowel obstruction, peripheral neuropathy, ophthalmoplegia or ptosis, which represented MNGIE phenotype. Though he displayed demyelinating peripheral neuropathy or leukoencephalopathy on brain MRI, genetic analysis revealed heterozygous mutation in POLG1 gene. We report for the first time two newly characteristics in our patient with heterozygous POLG1 mutations with the MNGIE-like phenotype: leukoencephalopathy and demyelinating polyneuropathy.

Celiac disease (CD) is a chronic disease involving a number of systems in addition to gastrointestinal tract. Although not clear, it has been supposed that the neurological symptoms of CD develop due to immune-mediated mechanisms. In this paper, we present a rare case diagnosed with CD at 12 years of age, and presented with a clinical picture resembling mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). She had onset of her neurological symptoms at the age of 6 years, they progressed despite various therapies, and she became wheelchair-bound.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder. The mutation in the ECGF1 gene causes severe deficiency of thymidine phosphorylase (TP), which in turn increases thymidine and deoxyuridine in the blood, serum, and tissue. The toxic levels of these products cause malfunction of the mitochondrial respiratory chain and mitochondrial DNA. Commonly, patients become symptomatic between 15 and 20 years of age (range 5 months to 35 years). The most commonly affected systems are gastrointestinal, followed by ocular, and nervous system. The disease is often fatal; high mortality rate is reported between 20 and 40 years of age. Treatment modalities that can increase thymidine phosphorylase activity and decrease thymidine and deoxy-uridine have shown symptomatic improvements in patients with MNGIE. Platelet transfusion, hemodialysis, peritoneal dialysis or allogeneic hematopoietic stem cell transplantation (HSCT) have been tried. The survival and long-term benefits of these measures are still not clear. Engrafted patients after stem cell transplantation have showed improvements in serum thymidine and deoxyuridine. We are reporting a case of MNGIE from Saudi Arabia, who underwent allogeneic hematopoietic stem cell transplantation. No MNGIE case has been previously reported from Saudi Arabia or the Gulf Arab countries. From the available literature, so far only 11 patients with MNGIE have undergone stem cell transplantation.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is caused by deficiency in thymidine phosphorylase (TP), that regulates thymidine (dThd) and deoxyuridine (dUrd). Toxic levels of dThd and dUrd can lead to mitochondrial dysfunction by impairing mitochondrial DNA replication, causing GI and neurologic deterioration. We studied the impact of bone marrow transplant (BMT) and platelets, as a source of TP on the clinical outcome of MNGIE. We report a case of MNGIE, who presented with severe vomiting. Over time, he was non-ambulatory and his GI symptoms got progressively worse with severe dysphagia, abdominal pain episodes, persistent vomiting and diarrhea. Being unfit for intense conditioning regimen, he received a mini BMT, with mild conditioning regimen. Bone marrow was obtained from his HLA fully matched brother. One month after transplantation, donor chimerism in peripheral blood was 33%. Excellent clinical responses were achieved 3 months after transplantation and circulating donor cell chimerism decreased to 24% with a significant increase in platelet TP activity. Ten months post transplant the patient\'s symptoms recurred and fresh single donor platelets were infused, with a significant increase in platelet TP activity. Mini BMT and platelet transfusion can transiently increase circulating TP activity and might prevent progress of this fatal disease.