Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): Position paper on diagnosis, prognosis, and treatment by the MNGIE International Network

Abstract

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by TYMP mutations and thymidine phosphorylase (TP) deficiency. Thymidine and deoxyuridine accumulate impairing the mitochondrial DNA maintenance and integrity. Clinically, patients show severe and progressive gastrointestinal and neurological manifestations. The onset typically occurs in the second decade of life and mean age at death is 37 years. Signs and symptoms of MNGIE are heterogeneous and confirmatory diagnostic tests are not routinely performed by most laboratories, accounting for common misdiagnosis. Factors predictive of progression and appropriate tests for monitoring are still undefined. Several treatment options showed promising results in restoring the biochemical imbalance of MNGIE. The lack of controlled studies with appropriate follow-up accounts for the limited evidence informing diagnostic and therapeutic choices. The International Consensus Conference (ICC) on MNGIE, held in Bologna, Italy, on 30 March to 31 March 2019, aimed at an evidence-based consensus on diagnosis, prognosis, and treatment of MNGIE among experts, patients, caregivers and other stakeholders involved in caring the condition. The conference was conducted according to the National Institute of Health Consensus Conference methodology. A consensus development panel formulated a set of statements and proposed a research agenda. Specifically, the ICC produced recommendations on: (a) diagnostic pathway; (b) prognosis and the main predictors of disease progression; (c) efficacy and safety of treatments; and (f) research priorities on diagnosis, prognosis, and treatment. The Bologna ICC on diagnosis, management and treatment of MNGIE provided evidence-based guidance for clinicians incorporating patients’ values and preferences.

1 |. INTRODUCTION

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disease caused by mutations in the thymidine phosphorylase gene (TYMP).¹ TYMP encodes for thymidine phosphorylase (TP), which catabolizes thymidine (dThd) and deoxyuridine (dUrd) into their respective bases. TYMP mutations markedly reduce/abolish TP activity leading to accumulation of dThd and dUrd and mitochondrial DNA (mtDNA) defects.

MNGIE is an ultra-rare condition, characterized by severe gastrointestinal (GI) and neurological symptoms that is often misdiagnosed.² Although the disease is progressive and fatal, natural history is still uncharacterized.^3–5 Various experimental therapeutic approaches aimed to the temporary enzyme replacement, for example, erythrocyte encapsulated TP (EE-TP) infusions,¹ or permanent restoration of TP activity through hematopoietic stem cell transplantation (HSCT)⁶ and orthotopic liver transplantation (OLT).⁷ Since the severity of GI symptoms influences treatment success, timing of HSCT and OLT is crucial.^6,7 Possible future options include gene therapy, which has shown preclinical efficacy.^8–14

An International Consensus Conference (ICC) was held to produce an unbiased, evidence-based assessment on MNGIE, leading to a consensus and guidance on the following areas: (a) diagnostic pathway; (b) prognosis and main predictors of disease progression; (c) efficacy and safety of treatments.

2 |. METHOD

2.1 |. Panel/experts selection

The Bologna MNGIE ICC was organized and promoted by the Azienda Ospedaliero-Universitaria di Bologna, Policlinico S.Orsola-Malpighi, and the IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy, according to the NIH Consensus Development Program methodology¹⁵ and the Methodological Handbook of the Italian National Guideline System.¹⁶ The members of the technical committee (TC) and scientific committee (SC), the expert workgroups (EWGs), and the consensus development panel (CDP) were invited based on their expertise in the field, ensuring the participation of all the clinical and nonclinical stakeholders (including patients) and a broad involvement of healthcare professionals from all the clinical aspects of MNGIE. Researchers were identified based on a review of the main authors in the field. The official language of the conference was English supported by a professional translator. A declaration of interest form was signed by every participant. Of the 36 stakeholders invited to the ICC, four declined and five accepted but did not participate. One member attended via teleconference.

2.2 |. The assignment, scoping, and assessment stages

The assignment, scoping, and assessment stages occurred between January 2018 and March 2019. The ICC took place in Bologna on 30 and 31 March. During assignment, the SC appointed a TC, a CDP, and three EWGs (Appendix 1, see section Other Material). The SC identified three MNGIE topics (diagnosis, prognosis, and treatment) and questions to be addressed by the EWGs (scoping). Assessment of the evidence was carried out by the TC through a systematic literature search with evidence mapping¹⁷ according to the PRISMA guidelines¹⁸ (Appendix 2, see section Other Material). Studies of any design, in English language, published in full on peer-reviewed journals, reporting original data on diagnosis, prognosis, and/or treatment of MNGIE on humans were searched on MEDLINE and the Cochrane Central Register of Controlled Trials in January 2018 and 2019 and finally updated in May 2020. Retrieved studies were selected independently by LV, EB and RD. Disagreement was resolved by discussion. Each study was graded according to four classes of methodological quality (from class I, highest quality to class IV, lowest quality) according to the Classification of Evidence Schemes of the Clinical Practice Guideline Process Manual of the American Academy of Neurology¹⁹ (Appendix 3, see section Other Material) and appraised by the EWGs to draft answers to the questions posed by the SC. During the ICC the scientific evidence and the answers to the questions were presented by the EWGs. The final statements by the CDP were presented at the end of day 2 to the audience including stakeholders and general public.

3 |. RESULTS

The literature search retrieved 1305 citations after duplicate removal; 1146 were excluded because the covered topic was not of interest for our review (Appendix 2, see section Other Material). Of the 159 full text articles selected, 81 were excluded mostly because they were animal studies or studies describing genetic mutations causing the clinical manifestations of MNGIE. The 78 selected articles were submitted to the three EWGs. Since 36 of them were out of scope regarding the specific topics, 42 were used for the statements (four of them were assigned to two topics each). The CDP issued the following Position Statements on diagnosis, prognosis and treatment of MNGIE. In Appendix 4 (see section Other Material), a summary of the scientific evidence and rationale for the statements is presented.

3.1 |. Position statements on the diagnosis of MNGIE

The following statements are based on seven class III level studies (case series with controls),^20–26 seven class IV level studies (two case series and five case reports)^3,4,27–31 and expert opinion. Results are summarized in the diagnostic algorithm (Figure 1).

FIGURE 1.

Diagnostic algorithm in mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

3.1.1 |. Clinical elements that can indicate MNGIE

MNGIE can be suspected when one or more of the following clinical cardinal elements are present:

• Symptoms and signs of otherwise unexplained GI dysmotility

• Thin constitution/cachexia, even with normal food behavior and nutritional intake

• Neurological features such as ptosis and symptoms suggesting peripheral neuropathy

• A progressive course of the above with frequent misdiagnosis

The features of the full-blown MNGIE typically are:

• Symptoms onset: childhood, adolescence/young adulthood (typical), adulthood (late onset, >40 years)

• GI symptoms/signs: sub-occlusive episodes, nausea, vomiting, early satiety, borborygmi, severe abdominal pain, abdominal distension, dysphagia, constipation and diarrhea, acute peritonitis due to small bowel perforation

• Unexplained weight loss, thinness, cachexia, even with normal food behavior and nutritional intake

• Radiological GI signs: small bowel diverticulosis, GI dilation (eg, gastric or intestinal dilation)

• Neurological symptoms/signs: chronic progressive external ophthalmoplegia (CPEO), ptosis, peripheral neuropathy, hearing loss

• Neuroradiological signs: leukoencephalopathy without other neuroradiological abnormalities

• Metabolic alterations: liver steatosis evolving in cirrhosis, pancreatitis, early onset diabetes mellitus, increased triglyceride levels, elevated plasma lactate

MNGIE is most frequently misdiagnosed as:

• Anorexia nervosa

• GI diseases: Crohn’s disease, coeliac disease, esophagitis and/or gastritis, irritable bowel syndrome, superior mesenteric artery syndrome, Whipple’s disease, chronic intestinal pseudo-obstruction

• Neurological diseases: chronic inflammatory demyelinating polyneuropathy, Charcot-Marie-Tooth disease, other mitochondrial diseases such as CPEO, Kearns-Sayre syndrome

3.1.2 |. Recommended diagnostic tests

Cardinal diagnostic tests:

• Swallowing test, gastric emptying and GI manometry (when possible): altered GI motility and transit

• Brain MRI: leukoencephalopathy without any other neuroradiological abnormalities (almost universally present) (Table 1 and Figure 2)

• Nerve conduction studies: peripheral neuropathy, predominantly demyelinating

TABLE 1.

Recommended brain MRI protocol

MRI technical requirements

Brain MRI should be performed using a magnetic field of at least 1.5 T with a slice thickness = 3–5 mm for 2D acquisition or ≤ 3 mm for 3D reconstruction

MRI protocol

Axial 2D T2 FLAIR/T2-weighted Sagittal 2D T2-FLAIR/T2-weighted 3D T2-FLAIR/T2-weighted in alternative to axial and sagittal T2-FLAIR/T2-weighted Axial DWI Axial T2a or SWI Axial 2D or 3D Tl-weighted before and after contrasta Single voxel proton MRS sequence in white matter with signal intensity changesb Description of leucoencephalopathy (Figure 2)

White matter hyperintensity in T2-weighted imaging, usually bilateral, patchy and/or diffuse, periventricular and/or subcortical. It may be cloud-like in the early stage of the disease.

White matter hyperintensity generally spares U fibers, does not have mass effect or contrast enhancement and must be mostly symmetrical. Its reversibility after therapy is still under debate.

The involvement of corpus callosum, white matter capsules, basal ganglia, thalami, midbrain, pons, and cerebellar white matter in general has been observed in patients with long standing condition.

Abbreviations: DWI, diffusion-weighted imaging; FLAIR, fluid-attenuated inversion recovery; MRS, magnetic resonance spectroscopy; SWI, susceptibility-weighted imaging.

^aMNGIE patients show no post-contrast enhancement in contrast with some white matter disorders.

^bMNGIE patients show normal metabolite ratios: this is not the case for most brain white matter disorders.³²

FIGURE 2.

Brain MRI examination from a 27-year-old severely affected mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) male patient. A, Axial T2-FLAIR shows bilateral and symmetrical diffuse cerebral white matter hyperintensity, with relative sparing of subcortical U fibers and patchy bilateral hyperintesities in the basal ganglia, thalami and corpus callosum. B, Hyperintensities are also seen bilaterally in the pons and cerebellar white matter. (Courtesy of Prof Raffaele Lodi and Dr. Laura Ludovica Gramegna, IRCCS Istituto delle Scienze Neurologiche di Bologna)

Ancillary tests:

• Muscle biopsy: ragged-red and COX deficient fibers, deficiencies of respiratory chain enzyme activities, ultra-structurally abnormal mitochondria, and mtDNA depletion, multiple deletions, and somatic point mutations

• Mucosal GI histology of small bowel (to exclude other conditions), and gut full thickness biopsy (when possible)

3.1.3 |. Recommended metabolic and genetic tests

Mandatory tests to confirm MNGIE diagnosis:

• TYMP sequencing: homozygous or compound heterozygous allelic pathogenic variants, no further testing.

• If one variant of uncertain significance or a wild-type sequence is identified, the following biochemical assessments should be performed:

  • TP activity: severely reduced or virtually absent in the buffy coat (below 8% of the mean of reference TP values; laboratory cutoffs may differ depending on sample processing and biochemical assay). If TP activity is only partially reduced, then it is mandatory to measure plasma dThd and dUrd levels. The diagnosis is excluded if TP activity is normal.
  • dThd and dUrd levels: increased in plasma (assessment of urine is unreliable)

3.2 |. Position statements on the prognosis of MNGIE

The following statements are based on one class II level study (retrospective cohort),⁴ two class III level study (retrospective cohorts),^3,5 four class IV level studies (four case reports)^29,33–35 and expert opinion.

3.2.1 |. The natural history of MNGIE

• Mean age at onset: 17.9 years (5 months to 43 years).

• GI symptoms (57% at onset; 100% at diagnosis); onset/diagnosis: diarrhea, abdominal pain, borborygmi, vomiting, pseudo-obstruction (32%−65%), weight loss/cachexia (100%); evolution: diverticulosis/diverticulitis (67%), hepatopathy (22%).

• Neurological symptoms/signs (43% at onset; 100% at diagnosis); onset/diagnosis/evolution: ocular signs (ptosis, ophthalmoparesis) (74%−100%), polyneuropathy (92%−100%), hearing loss (39%−45%), leucoencephalopathy (±100%); cognitive impairment (20%).

• Symptoms are cumulative and progressive.

• Mean age at death is reported to range between 35 and 37 years; survival 100% before 19 years and <5% after 50 years.

• Death is mainly due to GI and liver complications (intestinal perforation, intestinal bleeding, liver failure, aspiration pneumonia, complications due to small intestinal bacterial overgrowth [SIBO] or infection related to central venous catheter for parenteral nutrition) and cachexia.

Overall survival is the only outcome reported in the literature. Weight loss is an important feature of MNGIE, but data on its prognostic role are lacking.

3.2.2 |. Phenotypes of MNGIE

MNGIE has two different presentations distinguished by age of onset: “Early Onset” (or “Classic”) and “Late Onset” (Table 2). Severity can vary among family members. Available data do not allow a differentiation of clinical phenotypes based on symptoms at onset (GI or neurological). Neurological manifestations may be subtle and insidious leading to late recognition by both patients and physicians. When GI symptoms are the first manifestation, the diagnosis and consequently the appropriate treatment may be significantly delayed because of misdiagnosis.

TABLE 2.

Features of “Classic” and “Late Onset” phenotype of MNGIE

Classic phenotype (n = 161)a	Late Onset phenotype (n = 8)a
Age of onset <40 years old	Age of onset ≥40 years old
Leukocyte TP enzymatic activity: 0%10%	Leukocyte TP enzymatic activity: 10%−30%
Plasma levels: dThd > 4 and/or dUrd > 5 μmol/L	Plasma levels: dThd 0.05–4 and/or dUrd 0.05–5 μmol/L
GI symptoms 100%	GI symptoms 100%
Leukoencephalopathy 100%	Leukoencephalopathy 100%
Polyneuropathy 92%−100%	Polyneuropathy 60%
Ocular signs 74%−100%	Ocular signs 100%
Hearing loss 39%−45%	Hearing loss 75%

Abbreviations: ICC, International Consensus Conference; MNGIE, mitochondrial neurogastrointestinal encephalomyopathy.

^aNumber of cases described at the time of the ICC.

In clinical practice, the presence and/or severity of GI involvement are considered a negative prognostic factor, for both morbidity and mortality. Apparently, there is no correlation between genotype, phenotype and outcome. Residual TP activity of 10% to 15% has been associated with moderate increases of nucleosides and “Late Onset” MNGIE compared to the “Classic” form.

3.2.3 |. Impact of different phenotypes on the natural history of MNGIE and outcomes

Whether “Classic” (“Early Onset”) and “Late Onset” phenotypes have different disease progression remains unsettled. All patients with Late Onset phenotype reported in the literature were alive at follow-up ranging between 8 and 24 years. In the “Classic” phenotype, age of onset is not related to life expectancy. At present, overall survival after onset is the only available outcome reported in the literature.

3.2.4 |. Events indicating disease progression

The following events can be considered as important milestones related to progression: GI sub-occlusive episode, decompressive percutaneous endoscopic gastrostomy (PEG), aspiration pneumonia, abdominal surgical procedures, septic episode due to SIBO, need for enteral tube feeding or PEG, onset of intestinal failure (and subsequent need of parenteral nutrition), liver cirrhosis, loss of unaided walking ability. Recommended assessments to monitor MNGIE progression are listed in Table 3.

TABLE 3.

Recommended assessments to monitor MNGIE progression

Clinical/instrumental assessments of disease course	Parameters	Frequency of assessment (months)
GI symptoms severity	Abdominal pain (assessed with VAS), diarrhea, vomiting, oral intake (assessed with diary)	3
Metabolic assessment	FGF21a, GDF15a, blood lactate	6
Body weight and body composition trajectory	BMI, prealbumin, albumin, CRP, BIA (bioimpedentiometry)	3
Polyneuropathy	Electroneurography	12
Hepatic function and imaging	LFTs, PT, INR, liver function impairment (assessed with Child-Pugh score)	3
	ultrasound, elastography	6
Quality of life (QoL)	SF36	6
Fatigue	FSS or FIS	6
Functional status	Karnofsky/Lansky Performance Status Scale	6
Leukoencephalopathy	Brain MRI (no contrast agent required)	24

Abbreviations: BIA, bioelectrical impedance analysis; BMI, body mass index; CRP, C-reactive protein; FGF, fibroblast growth factor 21; FSS, fatigue severity scale; FIS, fatigue impact scale; GDF, growth differentiation factor 15; GI, gastrointestinal; INR, international normalized ratio; LFTs, liver function tests; MNGIE, mitochondrial neurogastrointestinal encephalomyopathy; MRI, magnetic resonance imaging; PT, prothrombin time; SF, short form 36; VAS, visual analogue scale.

^aFGF21 and GDF15 are ancillary biomarkers of mitochondrial myopathy due to mtDNA maintenance defects recently established for their usefulness in documenting natural history of progression or improvements (after therapy) marking skeletal muscle in mitochondrial myopathies (³⁶).

3.3 |. Position statements on the treatment of MNGIE

The following statements are based on 25 class IV level studies (one retrospective cohort, one case series, 24 case reports)^{6,7,13,14,37–58} and expert opinion.

3.3.1 |. Treatments effective in temporarily restoring the biochemical imbalance

“Short term” is defined as a period of time required to stabilize a patient waiting for permanent treatment or as compassionate use.

Overall, hemodialysis (HD), continuous ambulatory peritoneal dialysis (CAPD), EE-TP, and platelet infusion have been effective in achieving temporary improvement of the biochemical imbalance in several MNGIE patients. However, there are practical limitations, safety issues and unclear clinical effects associated with these approaches.

Specifically:

• EE-TP seems to be effective on a monthly-based administration in terms of biochemical and clinical improvement (four patients out of five); mild immunological reaction against bacterial TP mainly with repeated infusions may occur (two out of five patients). EE-TP is currently under clinical evaluation.

• CAPD seems to be well tolerated with anecdotal biochemical efficacy; peritoneal sclerosis due to repeated procedures may be a safety concern.

• HD has very short-term biochemical effects as nucleosides return to high levels a few hours after the procedure. Disadvantages include the need of venous access, an intensive procedure schedule (3–4 sessions per week) and the possible occurrence of hypotension, fluid overload or infections.

• Platelet infusion has been reported to achieve some biochemical improvement. Safety issues include allergic and immunological reactions.

We suggest consideration of EE-TP or CAPD in patients waiting for a permanent treatment option, or for compassionate use.

3.3.2 |. Effective treatments that permanently restore the biochemical imbalance

Permanent treatment options are aimed at restoring TP resulting in the long-term clearance of dUrd and dThd. The improved biochemical profile is expected to be associated with clinical stabilization (ie, halting tissue damage progression) or improvement.

• HSCT is effective in permanently restoring the biochemical imbalance. It requires chemotherapy and immunosuppressive therapy and is associated with a high risk for complications and mortality related to therapy, including graft vs host disease.

• OLT is effective for permanent restoration of the biochemical imbalance and it does not require preoperative conditioning. Patients with severe malnutrition or previous episodes of small bowel perforation, sub-occlusion or sepsis related to SIBO could be at high risk of peri- and post-operative complications and should not be considered for OLT; metabolic complications such as chronic kidney insufficiency, diabetes or cardiovascular disease related to long-life immunosuppressive therapy may be long-term issues.

3.3.3 |. Treatments that improve the patient’s health in terms of quality of life and functional status

Any temporary or permanent treatment should be considered as soon as diagnosis is confirmed. EE-TP and CAPD are effective with some temporary improvement of QoL and minimal complications. HSCT is effective in the long term for improving QoL and functional status, although limited by high post-treatment mortality rate (63%) in severely symptomatic adult patients. OLT is effective in the long term for improving QoL and functional status, although limited evidence is available.

3.3.4 |. Appropriateness of treatments that temporarily or permanently restore the biochemical imbalance

Temporary treatments should be considered at any age based on clinical condition, before permanent treatments, for example, while waiting/on list for either HSCT or OLT. Once the diagnosis is confirmed, permanent treatments are recommended as early as possible for both HSCT and OLT according to eligibility criteria (eg, severity). Ideal candidates should be those at an early stage of MNGIE. In patients who are oligosymptomatic, either HSCT or OLT can be considered. HSCT should be considered in pediatric patients and young adults with normal liver function, mild or no GI manifestations (eg, absence of intestinal pseudo-obstruction, peritonitis, pancreatitis) and in case of matched donors with normal genotype. A busulphan-based myeloablative regimen as a preparation to HSCT is recommended. OLT would be the preferred permanent treatment option for patients with progressive liver involvement (ie, fibrosis and/or abnormal liver function). Transplant from a living donor can be considered only if the donor’s TYMP genotype is normal. In fully informed patients who are severely affected by MNGIE and unlikely to survive permanent correction procedures, temporary metabolite restorative treatments (EE-TP and CAPD) should be offered and discussed.

3.3.5 |. Assessments predicting the effect of treatment

The following assessments may be predictive of effects of treatment:

• Serial plasma levels of dThd and dUrd

• Serial TP activity measurement in buffy coat (only for HSCT)

The clinical outcome after treatment depends upon the patient’s disease status prior to treatment. Assessments evaluating the disease status at the time of diagnosis may indicate whether a proposed treatment is likely to be effective. The extent of hepatic, GI involvement, and cachexia are key indicators of survival; therefore, assessments evaluating these aspects may be predictive of treatment outcome. Several clinical outcome assessments may be used to monitor the effect of treatment. Some of these assessments were discussed in the “Prognosis” section.

4 |. DISCUSSION

This is the first consensus statement on MNGIE, prompted by the severity of a condition that, although very rare, affects mainly young adults causing substantial reduction of life expectancy and QoL. Several potentially useful treatments can be offered to patients, and more may be soon available. It is important to coordinate the work of clinicians and researchers in order to generate new useful evidence and provide patients with reliable and consistent information about their condition.

4.1 |. Main findings

The ICC developed over 2 days. During the first day, one representative of each of the three EWG presented (in a meeting open to the general audience) the results of a systematic search of the literature relative to the topic. Each representative summarized the scientific evidence and proposed conclusions. Presentations were followed by discussion, moderated by the chair of the CDP and by a methodologist, during which disagreements were resolved and tentative recommendations were drafted. No disagreement required formal voting. Multi-stakeholder involvement in the public discussion was ensured by involving patients’ advocacy organizations.

4.2 |. Strengths and limitations

MNGIE is genetically determined and gene therapies are still at a preclinical stage. Nevertheless, promising treatments that could potentially modify the course of the condition are emerging. The efficacy of available treatments is still not completely defined and probably influenced by the stage of the disease. Due to the rarity of the condition, the evidence on MNGIE is limited to few case reports and small case series. The ICC aimed at reaching for the first time an evidence-based consensus involving researchers, patients and their families and healthcare providers on the clinical and instrumental hallmarks of MNGIE, its expected course and the main criteria guiding the choice of the most appropriate treatment in individual patients. Research priorities were also identified (Appendix 5, see section Other Material).

Our process had several limitations. First, since the available evidence is scanty and of low quality, the provided guidance is mainly based on the opinion of experienced clinicians and researchers, and therefore subject to bias. Adopting a rigorous and explicit methodology and warranting the possibility of discussion in every stage of the process through public presentations compensated this limitation. In order to avoid a prevailing view by medical experts, we ensured a formal participation of a leading patient advocacy association among the stakeholders in the CDP that formulated the guidance and prompted questions and comments by patients and their families in the audience during discussion. Personal interests that could bias the point of view of individuals were declared by each participant. Second, there was a partial overlapping in the composition of the EWGs and the SC, since some of the members of the formers were also part of the latter. This could have been a potential source of bias that we mitigated by creating groups as large as possible, facilitating a plurality of views within different areas. Due to the rarity of MNGIE and its recent discovery, the number of knowledgeable researchers and clinicians was low. Although the conference was international and almost all invited persons accepted the invitation, the total number of participants did not allow a complete separation of roles.

SYNOPSIS.

This is the first International Consensus Conference (ICC) aimed at an evidence-based consensus on diagnosis, prognosis and treatment among experts, patients, caregivers, and other stakeholders involved in MNGIE. The ICC provided recommendations on diagnostic pathway, prognosis and the main predictors of disease progression, efficacy and safety of treatments, and, finally, identified priorities on cogent research topics on MNGIE.

Abbreviations:

CAPD

continuous ambulatory peritoneal dialysis

CDP

consensus development panel

CPEO

chronic progressive external ophthalmoplegia

dThd

thymidine

dUrd

deoxyuridine

EE-TP

erythrocyte encapsulated TP

EWGs

expert workgroups

GI

gastrointestinal

HD

hemodialysis

HSCT

hematopoietic stem cell transplantation

ICC

International Consensus Conference

MNGIE

mitochondrial neurogastrointestinal encephalomyopathy

mtDNA

mitochondrial DNA

OLT

orthotopic liver transplantation

PEG

percutaneous endoscopic gastrostomy

QoL

quality of life

SC

scientific committee

SIBO

small intestinal bacterial overgrowth

TC

technical committee

TP

thymidine phosphorylase