Mitochondrial neurogastrointestinal encephalomyopathy

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a very rare inherited condition characterized by progressive gastrointestinal and neurological dysfunction.

Terminology

Mitochondrial neurogastrointestinal encephalomyopathy has been known as a number of different names previously, including ^1,9:

• myoneurogastrointestinal encephalopathy

• polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction

• oculogastrointestinal muscular dystrophy

• mitochondrial encephalomyopathy with sensorimotor polyneuropathy, ophthalmoplegia, and pseudo-obstruction

• chronic intestinal pseudo-obstruction with myopathy and ophthalmoplegia

• thymidine phosphorylase deficiency

• congenital oculoskeletal myopathy

'Mitochondrial neurogastrointestinal encephalomyopathy' is the preferred terminology with international consensus ².

Epidemiology

Mitochondrial neurogastrointestinal encephalomyopathy is considered extremely rare ^2,9, with an estimated prevalence of 1-9/1,000,000 ⁹. The condition has been described to affect patients from a wide range of ethnicities, without any particular predisposition ⁹.

Clinical presentation

The mean age of onset is approximately 18 years ². However, mitochondrial neurogastrointestinal encephalomyopathy can present in a wide range of age groups, from infancy to middle-age ². Onset before 40 years of age is known as the ‘classic’ phenotype, whilst onset at 40 years or older is known as the ‘late onset’ phenotype ².

Clinical features are diverse, progressive, and include ^1-3,9:

• gastrointestinal: altered bowel habit due to gastrointestinal dysmotility, abdominal cramps/pain, abdominal distension, nausea and vomiting, gastro-esophageal reflux disease, malabsorption, borborygmi, dysphagia

  • complications: weight loss and cachexia, colonic pseudo-obstruction and megacolon, diverticulosis and diverticulitis, intestinal perforation causing peritonitis, small intestinal bacterial overgrowth

  • overall, gastrointestinal features are thought to be the most debilitating features of this condition

• neurological: sensorimotor peripheral neuropathy (mostly demyelinating), sensorineural hearing loss (more common in the late onset phenotype), myopathy

  • notably, stroke, seizures, cognitive impairment and dementia are usually not clinical features

• ocular: chronic progressive external ophthalmoplegia, bilateral ptosis

• other:

  • hepatic steatosis, which can lead to cirrhosis and complications thereof (e.g. esophageal varices)

  • diabetes mellitus

  • pancreatitis

  • hypertriglyceridemia

  • short stature

Pathology

Genetics

Mitochondrial neurogastrointestinal encephalomyopathy is caused by mutation to nuclear DNA, with a mutation in the TYMP gene on chromosome 22q13.32 ^2,4,9. This is inherited in an autosomal recessive pattern ^2,9.

The TYMP gene normally encodes for the enzyme thymidine phosphorylase, which has a role in breaking down the pyrimidines thymidine and deoxyuridine ^2,9. Thymidine phosphorylase is highly expressed in certain hematopoietic cells (e.g. platelets and lymphocytes) and in the liver ^5,9.

Due to a mutation in the TYMP gene, there is reduced or absent thymidine phosphorylase activity, which leads to accumulation of thymidine and deoxyuridine, which is thought to alter normal mitochondrial deoxynucleotide pools, thus being deleterious to mitochondrial DNA ^2,9.

This results in the constellation of vast clinical features encompassing mitochondrial neurogastrointestinal encephalomyopathy. Between patients with the same mutation (e.g. patients from the same affected family), there may be differences in their clinical phenotype, possibly due to mitochondrial DNA heteroplasmy ⁹.

Markers

• serum thymidine phosphorylase activity: decreased ^2,9

  • classic phenotype: 0-10% activity ²

  • late onset phenotype: 10-30% activity ²

• serum thymidine levels: increased ^2,9

• serum deoxyuridine levels: increased ^2,9

Microscopic appearance

Skeletal muscle biopsy demonstrates classic features of mitochondrial myopathy, such as presence of ragged red and cytochrome c oxidase (COX)-deficient fibers, and ultrastructurally abnormal mitochondria ^1,2. In peripheral nerves, there is evidence of demyelination and ultrastructurally abnormal mitochondria ⁹. In the brain, there is no evidence of demyelination, but features of vasogenic edema ⁹.

Radiographic features

Gastrointestinal system

Various imaging modalities may demonstrate features of complications of the condition, such as ²:

• colonic pseudo-obstruction and megacolon

• diverticulosis and diverticulitis

• gastroparesis

• hepatic steatosis and cirrhosis

• pancreatitis

Central nervous system

MRI brain is nearly always abnormal ^2,9. There is evidence of a leukoencephalopathy, including T2 and FLAIR white matter hyperintensities in the centrum semiovale which are bilateral, either diffuse or patchy, and spare subcortical U-fibers ^2,6,7,9. In longstanding disease, there may be more extensive involvement of structures such as the corpus callosum, basal ganglia, thalamus, and those in the posterior fossa ². There is typically no enhancement with administration of gadolinium ^2,6,7.

Treatment and prognosis

Management options can be broadly classified into treatments which temporarily restore the biochemical balance, and treatments which permanently restore the biochemical balance, and symptomatic treatments.

• treatments which temporarily restore the biochemical balance ^2,5,9:

  • autologous erythrocyte encapsulated thymidine phosphorylase: enzyme replacement

  • dialysis: either continuous ambulatory peritoneal dialysis or intermittent hemodialysis

  • platelet transfusion: enzyme replacement

• treatments which permanently restore the biochemical balance ^2,5,8,9:

  • allogeneic hematopoietic stem cell transplant

  • orthotopic liver transplant: ensuring the donor has a normal TYMP genotype

• symptomatic treatments: nutritional management, analgesia, antiemetics, etc. ^2,9

Prognosis is poor, with a mean age of death of approximately 37 years ^2,9.

History and etymology

The condition was first described by K Okamura and colleagues in 1976 ^9,10.

Differential diagnosis

• MNGIE-like disorders: e.g. due to mutations of RRM2B, POLG, etc. ^7,9

• other causes of leukoencephalopathy or leukodystrophy