Introduction
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare autosomal recessive condition that affects the body's digestive and nervous systems. The condition is characterized by progressive gastrointestinal disorders and demyelinating peripheral neuropathy. Basically, genetic etiology makes aberrant changes to the mitochondria, which is the organelle of power. A malfunctioning powerhouse leads to systemic failure in various body parts.
Who Is Susceptible to MNGIE Disease?
MNGIE is an extremely rare disorder seen in fewer than 200 individuals across recorded medical literature. The European incidence has been estimated at less than one in a million, with 1 to 9 reports per 1,000,000 individuals worldwide. It has also been mentioned in the literature that the condition often goes unrecognized or misdiagnosed; hence the true prevalence might be even higher. The condition has not shown any gender predilection. The patients pass through a normal gestation period with the earliest onset as soon as five months, but usually between the first and fifth decade with a mean age of 18. The ethnic predisposition is yet to be determined as the condition has been seen to be widely distributed among Hispanics, Americans, Western Europeans, Jamaicans, Ashkenazi Jewish, Middle Eastern, and Canadians.
What Causes MNGIE Disease?
MNGIE disease is caused due to mutations in the TYMP gene, also known as the ECGF1 gene, which is located near the telomere (end part) of the long arm (q arm) of chromosome 22 (22q13.32-qter). The TYMP gene encodes the information for the enzyme thymidine phosphorylase. Thymidine belongs to the nucleoside class of molecules and is chemically modified to form the building block of the DNA. This chemical modification is mediated by the TYMP- encoded enzyme, thymidine phosphorylase, by breaking down thymidine into smaller molecules that helps regulate the level of nucleosides in the cells.
What Is the Pathophysiology of MNGIE Disease?
TYMP gene mutations reduce or eliminate the activity of the enzyme thymidine phosphorylase, which leads to the accumulation of high amounts of thymidine. This aberrant accumulation leads to damage to mitochondrial DNA or mtDNA. The mitochondria, also regarded as the cell powerhouse, contain a small amount of DNA and require nucleosides, including thymidine, to repair or replicate mtDNA as per need. Deficient enzymatic activity or loss of therewith and its following buildup disrupts the mitochondria's normal DNA maintenance and repair cycle. Due to the lack of splicing of mutant strands of mtDNA, the mutations accumulate over the mtDNA leading to its instability. Additionally, the normal mtDNA might carry less genetic material than the wild type. These accumulations of several abnormalities impair normal mitochondria function.
What Is the Histopathology of MNGIE Disease?
Renal biopsy studies under a microscope reveal cytoplasmic inclusions, which are representative of aberrant mitochondria, in the submucosal ganglion cells. The duodenum sample reveals focal muscle atrophy and focal loss of Auerbach's plexus with fibrosis. Intestinal and stomach lining samples show mtDNA depletion, mitochondrial proliferation, and smooth cell atrophy. Loss of intestinal cells with Cajal is also seen in the small bowel sample. Skeletal muscle biopsy also reveals ragged red fibers, which is characteristic of abnormal mitochondrial proliferation.
What Are the Signs and Symptoms of MNGIE Disease?
The signs and symptoms of MNGIE disease are:
Prior to Onset:
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Fatigability.
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Mild gastrointestinal symptoms.
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Thin body habitus.
Gastrointestinal Symptoms:
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Progressive GI dysmotility.
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Enteric myopathy.
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Gastric hypomotility.
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Small bowel hypomotility.
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Early satiety.
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Nausea.
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Dysphagia.
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Gastroesophageal reflux.
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Postprandial emesis.
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Abdominal pain.
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Abdominal distention.
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Diarrhea.
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Weight loss.
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Cachexia.
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Reduced muscle mass.
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Active hepatic cirrhosis.
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Macrovesicular steatosis.
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Diverticula (or diverticulitis).
Ophthalmologic Symptoms:
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Ptosis.
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Ophthalmoplegia (extraocular muscle weakness).
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Ophthalmoparesis.
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Diplopia.
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Eye movement defects.
Neurological Symptoms:
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Peripheral neuropathy.
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Axonal neuropathy.
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Paraesthesia.
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Weakness.
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Tingling sensation.
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Numbness.
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Pain.
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Unilateral or bilateral foot drop.
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Clawed hands.
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Sensorineural hearing loss.
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Seizures.
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Migraines.
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Anxiety.
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Ataxia.
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Trigeminal neuralgia.
Other Symptoms:
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Spasticity.
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Intellectual disability.
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Cognitive dysfunction.
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Memory loss.
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Depression.
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Dementia.
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Anemia.
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Peritonitis.
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Hypergonadotropic hypogonadism.
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Hypogonadotropic hypogonadism.
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Myopathy.
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Red ragged fibers.
How to Diagnose MNGIE Disease?
The presence of clinical features along with a similar familial history is suggestive of MNGIE disease, which can be further confirmed by neuroimaging and other studies. The initial diagnosis is made by the primary clinician based on the presenting features, following which specialist consultation along with examinations is warranted.
Neuroimaging studies reveal abnormal brain white matter on MRI (magnetic resonance imaging), relative sparing of the corpus callosum, and MRA (magnetic resonance spectroscopy) may show an increase in lactate within the white matter.
The absolute diagnosis is established by genetic studies and laboratory findings correlating with the histological evidence. Genetic studies, using single, multigene, or comprehensive genetic panels, are aimed to point out the genetic component of the condition.
Laboratory studies show diminished buffy coat thymidine phosphorylase enzyme activities and decreased plasma concentration of thymidine and deoxyuridine.
How to Treat MGNIE Disease?
The primary management of MNGIE disease is to provide supportive therapy for swallowing difficulties, and airway management. Domperidone is prescribed against nausea and vomiting and, antibiotics for bacterial overgrowth. To manage neuropathic symptoms, Amitriptyline, Nortriptyline, and Gabapentin are prescribed.
Measures must be taken to prevent aspiration pneumonia and ruptured diverticula. Certain drugs that interfere with mitochondrial function and liver-metabolized drugs must be avoided. Gastrointestinal evaluation must be done using abdominal films, abdominal CT (computed tomography of the abdomen), upper GI contrast radiography, esophagogastroduodenoscopy, sigmoidoscopy, liquid phase scintigraphy, and gastroduodenal manometry. Nutritional support has to be provided, and a cardiac plexus block with bupivacaine can be administered to manage visceral pain.
What Is the Prognosis of MNGIE Disease?
MNGIE is a relentlessly progressive degenerative disorder with a poor prognosis with a mean mortality age of 37.6 years between the age of 26 to 58 years. The most common causes of death include malnutrition, metabolic acidosis, aspiration pneumonia, intestinal perforation, peritonitis, and bacterial growth complications.
What Is the Differential Diagnosis of MNGIE Disease?
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Anorexia nervosa.
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Intestinal pseudo-obstruction.
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Inflammatory bowel disease.
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Celiac disease.
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Irritable bowel disease.
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Superior mesenteric artery syndrome.
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Oxidative phosphorylation diseases.
What Are the Complications of MNGIE Disease?
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Aspiration pneumonia.
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Ruptured diverticula.
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Fatal peritonitis.
Conclusions
MNGIE is a potentially life-threatening condition with no definite treatment. Several management protocols have been implemented with fairly good success. Supplementation has not yet proven effective. Modern treatment options like allogeneic stem cell transplantation, polymeric enzyme-loaded nanoparticles, and platelet transfusion have been attempted but with limited success. Hemodialysis shows a very short-term decrease (three hours) in clinical feature presentation. Hence has not been indicated.
