27.1 Clinical Features
and Laboratory Investigations Mitochondrial neurogastrointestinal encephalomy- opathy (MNGIE) is a multisystem mitochondrial dis- ease which has also been described under a number of other acronyms: myoneurogastrointestinal en- cephalopathy (also MNGIE); polyneuropathy, oph- thalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction (POLIP); oculogastrointestinal muscular dystrophy (OGIMD); mitochondrial en- cephalomyopathy with sensorimotor polyneur- opathy, ophthalmoplegia, and pseudo-obstruction (MEPOP); and chronic intestinal pseudo-obstruction (CIPO) with myopathy and ophthalmoplegia.
The disease has an autosomal recessive mode of inheritance. In the majority of the patients symptoms have their onset between the first and fifth decade, with a mean of 19 years and extremes of 5 months and 45 years. Initial symptoms are most frequently gas- trointestinal, ocular, or both. Gastrointestinal signs include dysphagia, borborygmi, abdominal pain, cramps, recurrent nausea, vomiting, diarrhea, malab- sorption, diverticulosis, and pseudo-obstruction. In most patients, delayed gastric emptying and dys- motility of small intestine, esophagus, and/or phar- ynx are found. The gastrointestinal dysmotility is caused by visceral myopathy and visceral neuropathy.
Some patients have liver problems, which may end in liver cirrhosis. Most often the liver problems are at- tributable to parenteral nutrition. Ocular signs in- clude chronic progressive external ophthalmoplegia, ptosis, and pigmentary retinopathy. Other common clinical features include thin body habitus, short stature, tinnitus, sensorineural hearing loss, sensori- motor peripheral neuropathy, and myopathy. Limb weakness is either distal, proximal, or diffuse.Areflex- ia may be present. There is rarely evidence of CNS in- volvement. Mental retardation is rare. The average life expectancy in MNGIE is 38 years, with a range of 26–58 years.
Laboratory investigations may reveal elevated blood lactate and pyruvate. CSF protein level is often raised. Nerve conduction velocity is moderately to markedly decreased and EMG reveals signs of dener- vation. These findings are consistent with a combina- tion of demyelination and axonal loss. In addition, some myopathic changes may be present in the EMG.
Some patients have an abnormal ECG with evidence of conduction disturbances. Laboratory studies show various mitochondrial abnormalities in skeletal mus- cle, including ragged red fibers with ultrastructurally abnormal mitochondria, muscle fibers with increased succinate dehydrogenase stain, cytochrome-c oxi- dase-negative fibers, and decreased activities of respi- ratory chain enzymes. In addition, multiple mito- chondrial DNA deletions or mitochondrial DNA de- pletion or both are found.
The diagnosis is confirmed by demonstrating elevated thymidine levels in plasma and deficient thymidine phosphorylase activity in leukocytes.
DNA-based confirmation of the diagnosis is also pos- sible.
27.2 Pathology
In MNGIE cerebral gray matter structures are intact.
Myelin pallor is found in the cerebral hemispheres, extending from the periventricular area into the arcu- ate fibers and into the internal capsule. The white matter is also pale in axonal preparations, but myelin pallor is relatively more marked. The corpus callosum is well myelinated. There are no signs of active myelin breakdown, no necrosis, and no significant astroglio- sis. Electron microscopy provides some evidence of loosening and thinning of myelin sheaths. Similar changes are present in the cerebellar white matter.
Myelin pallor is also seen in the central part of the pons. The optic nerves show myelin pallor, some vac- uolation, and some axonal loss. In the cranial nerves myelin pallor and endoneurial fibrosis are seen. In the spinal cord, tracts are either normal or also show some myelin pallor and vacuolation, in particular in- volving the dorsal columns. Within the spinal roots marked endoneurial fibrosis and myelin pallor are present, the changes being more severe in the dorsal than in the anterior roots. Within peripheral nerves variable combinations of scanty presence of myelin sheaths, abnormal internodal length, (rarely) onion bulbs, axonal loss, excessive endoneurial fibrosis, and perineural thickening are seen. Thus, the neuropathy displays mixed features of segmental demyelination and axonal degeneration. Visceral nerves show axon- al loss.
Mitochondrial Neurogastrointestinal Encephalomyopathy
Chapter 27
027_Valk_MitochondrialNeuro 08.04.2005 15:45 Uhr Seite 221
27.3 Pathogenetic Considerations
MNGIE is related to mutations in the thymidine phos- phorylase gene, TP, located on chromosome 22q13.32- qter. Thymidine phosphorylase catalyzes the re- versible phosphorolysis of the nucleoside thymidine to thymine and 2-deoxy D-ribose 1-phosphate. The en- zyme is likely to have an important role in nucleoside homeostasis by regulating the availability of thymi- dine for DNA synthesis. The forward reaction, conver- sion of thymidine to thymine, is favored under physi- ological conditions, and a defect in thymidine phos- phorylase leads to accumulation of thymidine. In nor- mal cells, thymidine is either degraded to thymine by thymidine phosphorylase or salvaged to deoxythymi- dine monophosphate by thymidine kinase and reuti- lized for DNA synthesis through nucleotide pools. Be- cause the thymidine salvage pathway is the only avail- able metabolic pathway for thymidine in MNGIE pa- tients, a large amount of thymidine should be salvaged to deoxythymidine monophosphate and subsequently converted to deoxythymidine triphosphate. The accu- mulation of thymidine is therefore likely to alter nu- cleoside and nucleotide pools. Mitochondria have sep- arate and independently regulated nucleotide pools and distinct thymidine kinase. Mitochondria depend more on the thymidine salvage pathway than on the de novo synthetic pathway. Mitochondrial DNA con- stantly replicates, even in quiescent cells. Therefore a constant supply of nucleotides is essential for the maintenance of the mitochondrial genome. Because of these unique properties of mitochondria, the imbal- ance in nucleotide pools probably affects mitochon- drial DNA more adversely than nuclear DNA, impair- ing mitochondrial DNA replication, repair, or both, and resulting in mitochondrial DNA depletion and multiple deletions.
Thymidine phosphorylase also has extracellular functions and is involved in angiogenesis and cell trophism. Thymidine phosphorylase is also called en- dothelial cell growth factor 1, because of its angio- genetic properties, and gliostatin, to denote its in- hibitory effects on glial cell proliferation. MNGIE pa- tients do not have vascular problems, suggesting that decreased thymidine phosphorylase activity does not interfere with normal angiogenesis.
The nature of the nervous system pathology in MNGIE is enigmatic. In both the CNS and PNS, myelin and axons are involved, but myelin more so than axons. It is remarkable that in PNS histopatho- logical abnormalities are associated with evident signs of dysfunction (peripheral polyneuropathy, vis- ceral neuropathy), whereas patients rarely have overt signs of CNS dysfunction. This and the nature of the histopathological findings constitute arguments for abnormal myelination (dysmyelination) rather than demyelination.
27.4 Therapy
No successful treatment is available. The use of coen- zyme Q, vitamin C, thiamin, riboflavin, and other vitamins does not halt progression of the disease.
Treatment in MNGIE is largely supportive. Manage- ment of the gastrointestinal and nutritional problems is important. Parenteral nutrition may be necessary.
Pharmacotherapy and celiac plexus neurolysis may achieve symptomatic pain relief in selected cases.
27.5 Magnetic Resonance Imaging
In MNGIE CT reveals diffuse hypodensity of cerebral and cerebellar white matter. MRI shows diffuse high signal intensity of cerebral and cerebellar white mat- ter on T2-weighted and FLAIR images, and usually but not invariably sparing of the U fibers and corpus callosum (Figs. 27.1 and 27.2). The thalami and basal ganglia may display patchy signal abnormalities (Fig. 27.1), but are spared in other patients (Fig. 27.2).
The internal capsule, external capsule, brain stem, and middle cerebellar peduncles may be involved as well. In some patients the white matter abnormalities on MRI are more limited in extent and involve the periventricular white matter most prominently.
Chapter 27 Mitochondrial Neurogastrointestinal Encephalomyopathy 222
Fig. 27.2. A 17-year-old patient with MNGIE. Note the diffuse- ly high signal intensity of the cerebral white matter on this T2- weighted MR image. The corpus callosum, internal capsule, and optic radiation are spared. From Simon et al. (1990), with permission
027_Valk_MitochondrialNeuro 08.04.2005 15:45 Uhr Seite 222
27.5 Magnetic Resonance Imaging 223
Fig. 27.1. The FLAIR images of a 47-year-old patient with MNGIE show diffuse signal abnormalities of the cerebral white matter with sparing of the corpus callosum.The basal ganglia,
thalami, and brain stem contain areas of abnormal signal. The cerebellar white matter is not affected. From Labauge et al.
(2002), with permission 027_Valk_MitochondrialNeuro 08.04.2005 15:45 Uhr Seite 223
