NeurometPlus

Incidence

MNGIE is transmitted as an autosomal recessive trait.

Clinical Characteristics

Myoneurogastrointestinal encephalopathy, or mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE), is a multisystem disorder clinically characterized by onset between the second and fifth decades of life, ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility (often pseudoobstruction), diffuse leukoencephalopathy, thin body habitus, peripheral neuropathy, and myopathy. MNGIE (Mitochondrial NeuroGastroIntestinal Encephalomyopathy) syndrome usually appears between the ages of 10 and 40 and is characterized by the association of the following symptoms: chronic progressive ophthalmoplegia, peripheral neuropathy, cerebral white matter disorders, and gastrointestinal disorders (recurring episodes of diarrhea and/or vomiting caused by abnormal intestinal motility). Patients are usually very thin and small in stature. The morphological study of their muscle usually reveals a small proportion of 'ragged-red' muscle fibers, i.e. demonstrating a proliferation of mitochondria. Biochemical analysis of the respiratory chain in the muscles of these patients often discloses partial deficiencies in one or more respiratory complexes. Southern blotting of muscular DNA shows multiple forms of deleted mitochondrial DNA, but these are only a small fraction of the total mitochondrial DNA. There may also be a partial depletion of mitochondrial DNA that may coexist with multiple deletions. Other symptoms may be associated, but their presence is not required to diagnose the syndrome. They include hearing loss, pigmentary retinopathy, cerebellar disorders, etc. MNGIE is transmitted as an autosomal recessive trait. The causative gene maps to 22q13.32-qter and codes for the thymidine phosphorylase. The syndrome can now be diagnosed either by dosage of thymidine phosphorylase activity in leukocytes or by gene analysis. Physiopathological mechanisms by which deficient thymidine phosphorylase activity leads to MNGIE symptoms remain unclear. Therapies lowering plasma thymidine might be beneficial, however an effective treatment has not yet been developed. In 16 of 22 patients reviewed by Hirano in 1994, symptoms began before age 20. In 20 of 24 patients, the initial symptoms were gastrointestinal, ocular, or both. The neurologic manifestations were predominantly outside the central nervous system, although many patients showed signs of leukoencephalopathy on brain MRI scans. As reviewed by Hirano et al. (1998), laboratory studies of MNGIE patients demonstrated defects in oxidative phosphorylation, including lactic acidosis, ragged-red fibers in skeletal muscle biopsies, ultrastructurally abnormal mitochondria, and decreased activities of the mitochondrial electron-transport enzymes. He studied 4 ethnically distinct MNGIE families. Probands from each family were shown by Southern blot analysis to have multiple mtDNA deletions in skeletal muscle. MNGIE without Leukoencephalopathy may be observed. Vissing et al. (2002) reported 2 sisters who presented at age 15 years with unsteady gait and gastrointestinal malabsorption. Other features included neurogenic changes on EMG, peripheral neuropathy, ophthalmoplegia, and diffuse muscle weakness. The disorder was indistinguishable from MNGIE, except for absence of leukoencephalopathy on MRI and mildly reduced thymidine phosphorylase activity (42% of control).

Precipitants

None

Provocation Tests

None

Diagnostic Procedures

The syndrome can now be diagnosed either by dosage of thymidine phosphorylase activity in leukocytes or by gene analysis. Southern blot analysis usually have multiple mtDNA deletions in skeletal muscle.