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

mesenteric artery syndrome [15,16,30-33] . The speed at which the neuropathic symptoms develop has resulted
in misdiagnoses of chronic inflammatory demyelinating polyneuropathy or Charcot-Marie-Tooth disease
in some patients [34-36] . The disorder has also been misdiagnosed as other mitochondrial DNA depletion
syndromes such as POLG or RRM2B mutations or other mitochondrial diseases, including Kearns-Sayre
syndrome and chronic progressive external ophthalmoplegia [16,37,38] . Many patients undergo invasive
diagnostic procedures, for example exploratory surgery, and sometimes repeatedly, due to episodes of
pseudo-obstruction, or unnecessary therapies, for example intravenous immunoglobulin [39-41] . As with
many other rare diseases, diagnostic delays are not uncommon for patients with MNGIE, with reported
delays of between 5 and 10 years [26,27] . Due to the progressive nature of the disease, a late diagnosis is often
associated with a poor response to therapy and subsequent poor prognosis [42,43] .

Diagnostic methods
Clinical investigations
Patients typically undergo referral to a number of clinical specialties before obtaining a correct diagnosis
through biochemical testing and TYMP sequencing. Clinical signs which raise a suspicion of MNGIE are
gastrointestinal dysmotility, cachexia, peripheral neuropathy, ptosis and external ophthalmoplegia [2,3,16] . To
understand the basis of the of the presenting symptoms, patients invariably undergo a number of different
diagnostic procedures.

To evaluate the gastrointestinal symptoms, a range of diagnostic modalities are used and include abdominal
ultrasound, abdominal imaging (X-ray and computed tomography), upper gastrointestinal tract contrast
radiography, esophagogastroduodenoscopy, sigmoidoscopy, colonoscopy, liquid phase scintigraphy,
antroduodenal manometry, biopsy and histopathological examination [44-46] . These assessments often reveal
hepatomegaly, hepatosteatosis, dilatation and thickening of the stomach and small intestine, jejunum
diverticulosis, reduced gastroduodenal motility and transit, decreased lower oesophageal sphincter
pressure, a low amplitude of oesophageal contractions, gastroparesis, reflux oesophagitis, panagastritis,
non-specific chronic inflammation in the small intestine and foamy cells in the intestinal wall [21,23,30,47-55] .

Diagnostic techniques used to evaluate the neuromuscular and neurological symptoms include
electromyography to assess the presence, duration and severity of myopathy; nerve conduction
velocity to assess the extent of the peripheral nervous system involvement; and brain MRI to confirm
leukoencephalopathy. The peripheral neuropathy symptoms manifest as paraesthesia with a stocking-
glove distribution and profound limb weakness and muscle atrophy, prominently affecting the lower
[16]
extremities . Unilateral or bilateral foot drop, as well as clawed hands, may occur. Diagnostic assessments
show decreased motor and sensory nerve conduction velocities and prolonged F-wave, indicating severe
[2]
demyelinating and axonal sensorimotor polyneuropathy . The segmental demyelination is thought
[56]
to be a result of an uneven distribution of mtDNA abnormalities along the nerve Asymptomatic
leukoencephalopathy is a hallmark of MNGIE and its presence in combination with the gastrointestinal and
[16]
neurological symptoms significantly narrows the diagnosis to MNGIE . In the majority of patients, the
leukoencephalopathy is initially patchy but becomes progressively more diffuse, appearing as hypointense
on T1- and hyperintense on T2-weighted images and in fluid-attenuated inversion recovery and fast spin
echo T2 sequences [16,43,57,58] .

Ophthalmological assessments, including visual evoked potential and neuro-ophthalmologic evaluations,
have revealed prolonged P100 latency and retinitis, respectively [29,49] . Audiology investigations have
confirmed unilateral or bilateral sensorineural hearing impairment in some patients [29,43,59,60] .

Occasional cardiac complications have been diagnosed in some patients, including abnormal ECG, with
individuals displaying left ventricular hypertrophy and bundle branch block, a prolonged QT interval,