Introduction
Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) is an
ultra-rare, progressive and fatal autosomal recessive disorder. It is a
multi-organ disease characterized by cachexia, gastrointestinal
dysmotility, ptosis, peripheral neuropathy, sensorineural deafness and
leukoencephalopathy with intact cognition in most studied patients.
MNGIE is caused by loss of thymidine phosphorylase (TP) activity due toTYMP mutations which lead to toxic increase in levels of
thymidine and deoxyuridine in plasma and tissues. The accumulation of
nucleosides results in unbalanced pools of intramitochondrial
deoxynucleotides causing point mutations and deletions, thus impairing
mitochondrial DNA (mtDNA) replication and leading to mtDNA depletion. As
a consequence, patients develop progressive mitochondrial respiratory
chain oxidative phosphorylation dysfunction resulting in a multisystem
mitochondrial disorder. The disease is progressive and death is
primarily due to severe malnutrition and gastrointestinal complications
such as perforations and peritonitis. Other infections originate
frequently from central venous catheters used in patients with MNGIE for
chronic total parenteral nutrition (TPN) as the main, sometimes even the
only source of nutritional intake. Most patients die between the 3rd and
4th decade.
Over the years, attempts to reduce toxic nucleoside accumulation by
hemodialysis failed because of rapid re-accumulation of thymidine.
Enzyme replacement therapy provided as erythrocyte-encapsulated TP
showed some efficacy in a very few patients but needs to be repeatedly
infused. A trial of repeated transfusions of platelets, which are rich
in TP, produced transient reduction of nucleoside levels. This
therapeutic modality could not constitute a long-term therapy but raised
the concept of performing HSCT as a continuous lifelong replacement
therapy of TP by the donor-derived cells which are rich in TP Since
nucleosides diffuse between extra-and intracellular compartments, TP
from normal donor cells has been shown to clear thymidine and
deoxyuridine from plasma and presumably also from tissues of patients
with MNGIE. We performed repeated platelet infusions in three patients,
which resulted in ~40% transient reduction of the
nucleoside levels and led us to perform the first HSCT in a patient with
MNGIE in 2005. Since 2005 to 2016 we have performed allogeneic HSCT in 6
patients with MNGIE disease from 3 consanguineous families. Here we
describe our single center experience with long-term follow up.