Mitochondrial Neurogastrointestinal Encephalomyopathy: Into the Fourth Decade, What We Have Learned So Far

Abstract

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an ultra-rare metabolic autosomal recessive disease, caused by mutations in the nuclear gene TYMP which encodes the enzyme thymidine phosphorylase. The resulting enzyme deficiency leads to a systemic accumulation of the deoxyribonucleosides thymidine and deoxyuridine, and ultimately mitochondrial failure due to a progressive acquisition of secondary mitochondrial DNA (mtDNA) mutations and mtDNA depletion. Clinically, MNGIE is characterized by gastrointestinal and neurological manifestations, including cachexia, gastrointestinal dysmotility, peripheral neuropathy, leukoencephalopathy, ophthalmoplegia and ptosis. The disease is progressively degenerative and leads to death at an average age of 37.6 years. As with the vast majority of rare diseases, patients with MNGIE face a number of unmet needs related to diagnostic delays, a lack of approved therapies, and non-specific clinical management. We provide here a comprehensive collation of the available knowledge of MNGIE since the disease was first described 42 years ago. This review includes symptomatology, diagnostic procedures and hurdles, in vitro and in vivo disease models that have enhanced our understanding of the disease pathology, and finally experimental therapeutic approaches under development. The ultimate aim of this review is to increase clinical awareness of MNGIE, thereby reducing diagnostic delay and improving patient access to putative treatments under investigation.

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

“…Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an extremely rare and fatal metabolic disorder with an autosomal recessive mode of inheritance. MNGIE is caused by mutations at the level of a nuclear gene involved in the pyrimidine deoxyribonucleosides metabolism, thus indirectly affecting the replication and the expression of genes in the mitochondria [1][2][3]. The prevalence of MNGIE worldwide is estimated to be <10 in a million [4] with around 200 patients with MNGIE identified in the world [5].…”

“…The prevalence of MNGIE worldwide is estimated to be <10 in a million [4] with around 200 patients with MNGIE identified in the world [5]. MNGIE is a progressive and degenerative disorder in which several organ systems are involved, and it is associated with high morbidity [3]. Although the clinical picture is usually complex, the main symptoms are gastrointestinal (GI) dysmotility, peripheral neuropathy, progressive external ophthalmoplegia, cachexia, diffuse leukoencephalopathy seen on magnetic resonance imaging (MRI) of the brain, and evidence of dysfunctionality of the mitochondria [6].…”

“…As such, MNGIE can be described as a result of an intergenomic communication defect in which mutations in a nuclear gene affect the expression of mitochondrial genes [7]. Other diagnostic methods for MNGIE include clinical examination, TP activity, MRI, electrodiagnostic procedures, and biochemical findings [3]. There are no specific modes of therapies for MNGIE; rather, patients are managed symptomatically while considering each patient as an individual [3].…”

“…Other diagnostic methods for MNGIE include clinical examination, TP activity, MRI, electrodiagnostic procedures, and biochemical findings [3]. There are no specific modes of therapies for MNGIE; rather, patients are managed symptomatically while considering each patient as an individual [3]. Laforce et al [10] reported that the average age of death for patients with MNGIE is 37 years.…”

Quantification of Plasma and Urine Thymidine and 2’-Deoxyuridine by LC-MS/MS for the Pharmacodynamic Evaluation of Erythrocyte Encapsulated Thymidine Phosphorylase in Patients with Mitochondrial Neurogastrointestinal Encephalomyopathy

“…Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a fatal autosomal recessive disorder caused by mutations in TYMP, the gene that encodes for thymidine phosphorylase (EC 2.4.2.4). The resulting enzyme deficiency leads to elevated concentrations of the deoxyribonucleosides, thymidine and 2'-deoxyuridine in cellular and extra-cellular compartments, which then generate imbalances within the mitochondrial deoxyribonucleotide pools, causing mitochondrial DNA (mtDNA) mutations and depletion, and ultimately mitochondrial dysfunction [1]. Currently there are no licensed therapies available for patients with MNGIE, although a number of experimental therapeutic approaches have been investigated.…”