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Page 10 Bax. J Transl Genet Genom 2020;4:1-16 I http://dx.doi.org/10.20517/jtgg.2020.08

In the first proof of concept study, the administration of one dose of EE-TP (34 U/kg body weight) was
reported to decrease the urinary excretion of thymidine and 2’-deoxyuridine at three days post infusion to
6% and 13%, respectively, of the amounts excreted pre-therapy. Plasma concentrations of these metabolites
[48]
were shown to decrease in parallel . Escalation of the EE-TP dose in the treatment of four further
patients (from 3.7 to 108 U/kg body weight/4 weeks) was reported to reduce or eliminate plasma and urine
thymidine and 2’-deoxyuridine levels. Three months after initiating therapy, one patient gained 4 kg in
weight, coinciding with a decrease in nausea and vomiting, increased ability to walk longer distances and
an increase in the physical and mental components of the SF36 health and well-being survey. In another
patient, significant clinical improvements were reported in bilateral muscle power (wrist and first finger
abduction, knee flexion, ankle dorsiflexion and great toe extension), gait and balance, sensory ataxia and
fine finger function, after 23 months of monthly EE-TP administrations. Body weight increased from 57.4
to 63.2 kg, and a fall in plasma creatine kinase activity from 1200 U/L pre-therapy to levels within the
normal reference range was reported [77,84] . Patient reported outcomes included an ability to walk longer
distances, climb stairs without assistance, tie shoe laces, feel the sensation of sand and a return to weight
[84]
training and guitar playing .

No safety issues were reported other than mild reactions to EE-TP infusions in two patients. These were
recorded as being transient, occurring within the first 5-10 min of EE-TP infusion and could be managed
by pre-medication with antihistamine and corticosteroid anti-inflammatory drugs [77,84] . The development of
specific anti-thymidine phosphorylase antibodies were reported in only one patient [77,99] .

AHSCT
AHSCT is one of two therapeutic approaches under investigation which offers the potential of a permanent
normalisation of plasma metabolites and restoration of thymidine phosphorylase activity [82,83,94,100] . In 2015,
Halter et al. [100] conducted an international retrospective study of 24 patients with MNGIE who received
AHSCT from related or unrelated donors between 2005 and 2015. Of these 24 patients, 15 patients had
died, nine from transplant-related mortality and six from their disease. The remaining nine patients were
alive 283-2535 days post-transplant and showed that the plasma metabolite concentrations decreased to
nearly undetectable levels. Clinical improvements after AHSCT were reported in these cases and others
patients subsequently transplanted, including increased body weight and improvements in hearing,
swallowing, muscle strength, gastrointestinal manifestations and peripheral neuropathy [82,83,94,100-102] Despite
the potential of providing a cure, AHSCT is limited by the availability of a matched donor and the poor
clinical condition of patients. The procedure requires aggressive conditioning and immunosuppressive
chemotherapy, which is poorly tolerated by sick patients. The procedure carries a mortality risk of
63%, with survival being dependent on an human leukocyte antigen 10/10 match and the absence of
gastrointestinal and liver disease [46,83] . Gastrointestinal disease is a critical factor in the pathophysiology of
graft versus host disease and can lead to the activation of host antigen presenting cells and donor T-cells [103] .
Patients with MNGIE are likely to present a higher risk of developing gut graft versus host disease because
of the disease-related gastrointestinal damage. Disease-related hepatopathies, including hepatic steatosis,
hepatomegaly, increased transaminases, abnormal liver function, triglyceride hyperlipidaemia and
cirrhosis, have been reported in MNGIE and thus the presence of liver disease should be established prior
to transplantation [16,79] . The use of parental nutrition and the long-term effect this is likely to have on the
liver should also be considered. A published consensus proposal for standardising the AHSCT procedure in
patients with MNGIE recommends that patient recruitment should be restricted to those having an optimal
donor and without irreversible end stage MNGIE disease [46,100] . The potentially risky procedure presents a
dilemma for patients who are oligosymptomatic.

OLT
OLT is the second treatment approach offering the potential of a permanent normalisation or reduction
of plasma metabolites and restoration of thymidine phosphorylase activity [85,104] . The rationale is based on