MNGIE Natural History Study

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE, ORPHA#298; OMIM#603041) is an autosomal recessive disease caused by loss-of-function mutations in TYMP, the gene encoding the enzyme thymidine phosphorylase (TP).

Epidemiology and disease course:

MNGIE is an ultra-rare disease with limited available epidemiological studies. Most of the knowledge about disease course of MNGIE derives from single centre experiences, case reports, and two retrospective observational cohort studies published so far. MNGIE is a chronic debilitating and ultimately fatal condition, with average age of diagnosis around 18 years. Depending on the studied cohort, the majority of patients are thought not to survive beyond 40 years.

The earliest and most debilitating signs of MNGIE are gastrointestinal (GI), with a wide range of symptoms reported (including abdominal pain and cramps, nausea or vomiting, diarrhoea or constipation, pseudo-obstruction and gastroparesis, dysphagia, malabsorption and cachexia). GI symptoms occur in almost all reported patients. Other typical symptoms are primary mitochondrial myopathy with weakness of the eye muscles (chronic progressive external ophthalmoplegia and ptosis) in almost all patients, and peripheral neuropathy also found in most patients. All patients have leukoencephalopathy on brain magnetic resonance imaging (MRI), but this is thought to remain asymptomatic.

A wide range of other clinical features have been reported in retrospective cohort studies, and through many additional case reports in the literature. However, a comprehensive review of clinical and laboratory data from all reported and unpublished patients is lacking, and many aspects of the disease remain poorly understood.

Study rationale:

Innovative treatment strategies are emerging for MNGIE, including with ATMPs that are currently undergoing regulatory approval for clinical studies. An up-to-date and comprehensive retrospective natural history study is important to better characterize the typical presentation, clinical phenotype and progression of MNGIE, and to inform patient management, clinical trial design and the choice of clinical and biochemical outcome measures in the future.

For this, natural history data based on standardised clinical data collection are required, with quantitative measures, and taking into account the various treatment modalities currently on offer. This study is set up to include as many as possible of the published and unpublished cases of MNGIE patients worldwide, providing a deep characterization of the clinical features of this syndrome, identifying biochemical, molecular genetics, and histological/ histochemical parameters for early diagnosis and prognosis, and better understanding of therapeutic outcomes. This will also provide further knowledge about the epidemiology and establish a large database about clinicians currently involved in care for MNGIE patients, who can be approached to offer their patients the possibility to be contacted about novel and emerging interventional trials.

Research objective:

The overall aim of this study is to conduct a retrospective natural history study of patients who received a molecular or biochemical diagnosis of MNGIE worldwide, in order to comprehensively describe the presentation and clinical progression of MNGIE, define genetic and clinical subgroups, and make an inventory of treatment strategies currently being offered and their impact on disease progression. The study will capture standardised, anonymous clinical data from clinicians involved in care for MNGIE patients.

Specific Study Objectives:

• Characterize the clinical phenotype, symptom onset and progression of patients affected by genetically or biochemically confirmed MNGIE.
• Evaluate clinical symptoms and biomarkers most predictive of disease progression, and amenable to develop as outcome measures for future clinical trials.
• Identify common or different patterns of disease manifestation and progression in MNGIE patients to establish genotype-phenotype correlation-based subgroups.
• Inform treatment in MNGIE based on the outcomes from the therapeutic options available so far.
• Identify unmet needs to prioritize future research.
• Establish a database of clinicians currently involved in care for MNGIE patients

Study outcomes:

This study will lead to a detailed understanding of the symptoms and clinical manifestations present in patients with MNGIE, their onset and progression, and their response to available treatments. Study results will be detailed in a clinical study report, published as an open-access paper in a peer-reviewed journal, and presented at scientific and disease-focused conferences.

Inclusion criteria

All patients with a laboratory-confirmed TP deficiency:

• any age or stage of disease; living or deceased
• both previously published and unpublished patients
• symptomatic and asymptomatic patients
• TP deficiency defined by a and/or b and/or c:

• Homozygous or compound heterozygous pathogenic or likely pathogenic mutations in the TYMP gene; and/or
• Decreased TP enzyme activity <20% of normal; and/or
• Increased plasma dThd> 1 µmol/L, or increased plasma dUrd > 5 µmol/L.

Exclusion criteria

• There are no formal exclusion criteria for this retrospective observational study.