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Page 6 Bax. J Transl Genet Genom 2020;4:1-16 I http://dx.doi.org/10.20517/jtgg.2020.08

structurally abnormal mitochondria, mtDNA deletions, depletions or point mutations and decreased single
or multiple electron transport chain enzyme activities [9,45,70,71] . The absence of mitochondrial abnormalities
in skeletal muscle should not be used to preclude a diagnosis of MNGIE as there are reports of patients
diagnosed with MNGIE without muscle mitochondrial pathologies [59,72] .

TREATMENT OPTIONS FOR PATIENTS WITH MNGIE
Symptomatic therapies
Currently, there are no specific treatments for patients with MNGIE, whose efficacy has been confirmed in
regulatory approved clinical trials. Treatment requires a coordinated approach among multiple specialists,
including gastroenterologists, neurologists, pain management teams, nutritionists and physiotherapists,
audiologists and ophthalmologists to manage the specific complications this multisystem disease presents.

The gastrointestinal symptoms vary from patient to patient and may include dysmotility, abdominal
pain, diarrhoea, nausea, vomiting, premature satiety, borborygmic and dysphagia. Symptoms are treated
with bowel motility stimulant drugs, analgesics, anti-emetics, dietary modification and antibiotics, the
latter for intestinal bacterial overgrowth, a complication of dysmotility [45,50] . For patients suffering from
epigastric pain, splanchnic nerve blockade or coeliac plexus blockade with bupivacaine can be employed
to reduce pain [68,73,74] . Post-prandial emesis and nausea may be controlled through the administration
of metoclopramide, domperidone, amitriptyline or bisacodyl [41,74] Gastro-oesophageal reflux related to
[41]
gastroparesis can be controlled by prokinetic agents . Diverticula, secondary to the severe gut dysmotility,
[75]
may lead to complications of gut perforation and require emergency abdominal surgery . Malnutrition
is a critical issue for the majority of patients and, although enteral or parenteral nutritional support is
often administered, this has not been shown to alter the disease trajectory [76-78] . Nasogastric nutrition is
poorly tolerated by some patients due to the gastrointestinal dysmotility and long-term total parenteral
nutrition use has been reported to be associated with hepatic steatosis and elevated transaminases [16,47,79] .
The administration of total parenteral nutrition should be carefully considered, as the lipid components are
[77]
metabolised by the mitochondrion, the site of the primary pathology in MNGIE . Portal hypertension,
complicated by ascites and oesophageal varices, may also develop and these are treated as in other
[48]
conditions .
The neurological symptoms also vary from case to case, and may include paraesthesia, numbness, pain in
the limbs, symmetric and distal muscle weakness, hearing loss and ocular symptoms. Neuropathic pain is
treated with centrally acting agents such as amitriptyline, gabapentin and pregabalin [41,79] . Physiotherapy
[80]
and occupational therapy may be required, according to the needs of the patient . Ocular symptoms
may be treated with corrective lenses and surgery for strabismus or ptosis. Cochlear implants or auditory
aids may assist patients with sensorineural hearing loss [60,81] . For patients with psychiatric symptoms,
antidepressants and antipsychotics may provide benefit.

Medications that interfere with mitochondrial function should be avoided, for example, valproate,
phenytoin, chloramphenicol, linezolid, aminoglycosides, volatile anaesthetics and tetracycline. Hepatically
metabolised drugs should be administered with care or contraindicated depending on the patient’s liver
[46]
function . Genetic counselling should be offered to individuals diagnosed with MNGIE and their families.
Investigational causative therapies
MNGIE is relentlessly progressive and degenerative, with an almost universally fatal outcome and
there is thus a critical requirement to develop treatments that will provide benefit. Early therapeutic
intervention to normalise the metabolic derangement is essential to prevent non-reversible organ damage.
Fortunately, the past two decades has seen some exciting advancements in the development of a number of