Mitochondrial neurogastrointestinal encephalopathy (MNGIE)
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare, progressive genetic disorder primarily affecting multiple systems in the body, especially the gastrointestinal and neurological systems. It is caused by mutations in the thymidine phosphorylase (TP) gene or DNA polymerase gamma, inherited in an autosomal recessive manner. MNGIE can manifest in individuals from early infancy to adulthood, with symptoms typically including severe gastrointestinal dysfunction, drooping eyelids (ptosis), and peripheral neuropathy. These symptoms often lead to significant weight loss and cachexia, ultimately impacting life expectancy. Diagnosis is confirmed through a combination of clinical evaluation and laboratory tests, including low levels of TP and mitochondrial dysfunction indicators. While treatments such as platelet infusions and stem cell transplants have shown some promise, challenges remain due to the complexity of the disease and limitations in available therapies. For families with a history of MNGIE, genetic counseling and prenatal diagnosis are recommended to manage the risk of passing on this condition.
Mitochondrial neurogastrointestinal encephalopathy (MNGIE)
ALSO KNOWN AS: Polyneuropathy ophthalmoplegia leukoencephalopathy and intestinal pseudoobstruction (POLIP) syndrome; Familial visceral myopathy Type 2; myoneurogastrointestinal encephalopathy syndrome; oculogastrointestinal muscular dystrophy (OGIMD); mitochondrial encephalomyopathy with sensorimotor polyneuropathy, ophthalmoplegia, and pseudo-obstruction (MEPOP)
DEFINITION MNGIE is a chronic and progressive mitochondrial disease which affects multiple systems in the body. The prevalence rate is unknown. Currently, about seventy cases have been reported. It is an autosomal recessive genetic disorder caused by mutations in the gene encoding thymidine phosphorylase or DNA polymerase gamma.
Risk Factors
The age at onset ranges from five months to forty-three years, and the age at death ranges from twenty-six to fifty-eight years. MNGIE affects both genders equally and is not restricted to a particular ethnic population. Consanguinity is common among parents of affected children. The clinical and molecular features are attributed to the mutations in the TP or DNA polymerase gamma genes, inherited as an autosomal recessive trait. At least forty-nine mutations have been reported in the TP gene. Fewer mutations have been found in the polymerase gene. Therefore, there is predominance of the genetic factor in the pathogenesis of MNGIE. Variations in clinical features in the same family among siblings have been attributed to environmental and other genetic factors. Some sporadic cases have also been documented.
Etiology and Genetics
MNGIE is a rare autosomal recessive multisystemic disease associated with mutations in the mitochondrial DNA. The ages of onset and death vary considerably among the patients. The earliest manifestations are gastrointestinal (GI) symptoms, followed by ptosis and opthalmoparesis. GI symptoms are most prominent, leading to weight loss and cachexia and finally to death. A majority of patients exhibit mitochondrial dysfunction, such as respiratory chain enzyme deficiencies, point mutations, deletion and depletion of mitochondrial DNA.
Mutations in the gene encoding the enzyme thymidine phosphorylase (TP) on chromosome 22q13.32-qter were found to be the cause of the disease. TP catalyzes the conversion of the nucleosides, doexythymidine and deoxyuridine to the corresponding bases thymine and uracil. Low TP activity caused by mutations leads to the accumulation of toxic levels of the nucleosides, which affects several tissues including skeletal muscle. Excess nucleosides cause imbalance, leading to defects in mitochondrial DNA replication, resulting in depletion. Therefore, reducing the toxic levels of nucleosides provides a practical therapeutic strategy in MNGIE patients.
Symptoms
The age of onset of MNGIE is usually between the second and fifth decades of life. In some patients, the age of onset is later, at the fourth decade. These patients survive longer despite exhibiting characteristic clinical features. Gastrointestinal dysfunction with failure to move food along the digestive tract is the major clinical feature leading to cachexia (loss of weight and muscle mass). Other clinical symptoms include droopy eyelids or ptosis, progressive external ophthalmoplegia (loss of function of eye muscles), peripheral neuropathy with tingling and numbness in the hands and feet, deterioration of brain white matter called leukoencephalopathy, and mitochondrial dysfunction. Patients usually die of gastrointestinal problems and their poor nutritional status. The clinical symptoms are homogenous with minor variations and easily recognized, but MNGIE can be misdiagnosed in the early stages.
Screening and Diagnosis
Diagnosis of MNGIE is based on a combination of clinical and laboratory tests. Presence of ptosis, gastrointestinal dysfunction, peripheral neuropathy, mitochondrial defects and low thymidine phosphorylase levels confirm the diagnosis. TP levels are less than 10 percent of normal in the patients, and half of normal in carriers of the disease. Only mutations that result in total or almost total loss of TP activity are pathogenic. Biochemical assay of the enzyme in the buffy coat of blood from patients establishes the diagnosis in most cases. Examination of muscle biopsy reveals respiratory chain deficiency in addition to site-specific point mutations, depletion, and deletions of mitochondrial DNA.
Treatment and Therapy
Low TP levels cause multisystemic accumulation of toxic levels of deoxythymidine or deoxyuridine detectable in plasma and urine. Therefore, therapy is aimed at reduction of circulating nucleosides. Since TP activity is highest in platelets and lymphocytes, infusion of platelets was attempted to correct the defect. However, platelet infusion is only transiently effective in reducing the nucleoside levels and partially increasing the TP levels. Allogenic stem cell transplantation has been successful in providing a permanent cure for some patients, but the risks involved in the procedure and the difficulty of finding matched donors make this treatment impractical or impossible for many patients. Enzyme replacement, which has shown promising results in some early tests, has been proposed as an alternate treatment for these patients.
Prevention and Outcomes
The parents of an affected child are asymptomatic obligate carriers and have one mutant allele. They should be tested before contemplating having children. Prenatal diagnosis is also suggested for subsequent pregnancies for parents with an affected child. The mostly homogenous clinical symptoms in combination with the diagnostic laboratory tests can be used to successfully diagnose MNGIE. However, in the early stages prompt medical referral to specialists is necessary to prevent possible misdiagnosis. Furthermore, treatment to reduce nucleoside levels should be initiated early to prevent mitochondrial dysfunction, which is not reversible.
Bibliography
Bax, Bridget E., et al. “Clinical and Biochemical Improvements in a Patient with MNGIE Following Enzyme Replacement.” Neurology 81.14 (2013): 1269–271. Print.
Hirano, Michio, Caterina Garone, and Catarina M. Quinzii. “CoQ10 Deficiencies and MNGIE: Two Treatable Mitochondrial Disorders.” Biochimica et Biophysica Acta 1820.5 (2012): 625–31. Print.
Hirano, Michio, Yutaka Nishigaki, and Ramon Martí. “Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): A Disease of Two Genomes.” The Neurologist 10.1 (2004): 8–17.
Lara, M. C., et al. “Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): Biochemical Features and Therapeutic Approaches.” Bioscience Reports 27 (2007): 151–63.
Martí, Ramon, Yutaka Nishigaki, Maya R. Vilá, and Michio Hirano. “Alteration of Nucleotide Metabolism: A New Mechanism for Mitochondrial Disorders.” Clinical Chemistry and Laboratory Medicine 41 (2003): 845–51.
McKusick, Victor A., et al. “Mitochondrial DNA Depletion Syndrome 1 (MNGIE Type); MTDPS1.” Online Mendelian Inheritance in Man. Johns Hopkins U, 18 Feb. 2013. Web. 1 Aug. 2014.
Soufi, Ghazaleh Jamalipour, et al. "Mitochondrial Neurogastrointestinal Encephalopathy: A Case Report." Egyptian Journal of Radiology and Nuclear Medicine, vol. 55. no. 137, 9 July 2024, doi.org/10.1186/s43055-024-01310-2. Accessed 9 Sept. 2024.