Clinical Description
MNGIE disease is characterized by the following major manifestations: gastrointestinal dysmotility, cachexia, progressive external ophthalmoplegia with or without ptosis, peripheral neuropathy, and leukoencephalopathy.
Gestation and delivery are normal. The earliest reported age of onset is five months; onset is usually between the first and fifth decades. In about 60% of individuals, symptoms begin before age 20 years (mean age at onset: 18 years) [Garone et al 2011].
Prior to the onset of symptoms, many individuals with MNGIE disease are healthy, but usually have a long history of subtle fatigability, mild gastrointestinal symptoms, or thin body habitus.
The order in which manifestations appear is unpredictable; however, in a review of 102 patients, the first symptoms were gastrointestinal (~57%), ptosis/ophthalmoplegia (~19%), peripheral neuropathy (~14%), and myopathy (~5%) [Garone et al 2011].
Late-onset MNGIE disease occurs in individuals harboring pathogenic TYMP variants that produce less severe thymidine phosphorylase dysfunction [Martí et al 2005].
Gastrointestinal dysmotility and cachexia. Progressive GI dysmotility, caused primarily by enteric myopathy, occurs in virtually all individuals with MNGIE disease at some point during the course of the illness [Giordano et al 2008]. Symptoms usually progress slowly over several decades and can affect any part of the GI tract. Gastric and small bowel hypomotility are the most common. Symptoms include early satiety, nausea, dysphagia, gastroesophageal reflux, postprandial emesis, episodic abdominal pain, episodic abdominal distention, and diarrhea.
Weight loss and cachexia coincide with the onset of GI symptoms. The average weight loss is about 15 kg [Nishino et al 2000]. Affected individuals invariably have a thin body habitus and reduced muscle mass. Despite severe GI dysfunction, serum concentrations of micronutrients, vitamins E and B12, and folate are typically normal.
Histologic findings. Rectal biopsy can show eosinophilic cytoplasmic inclusions, representing abnormal mitochondria, in the submucosal ganglion cells [Perez-Atayde et al 1998].
Duodenal pathology can demonstrate focal muscle atrophy or absence with increased nerve numbers, serosal granulomas, and focal loss of Auerbach's plexus with fibrosis [Teitelbaum et al 2002].
Mitochondrial DNA depletion, mitochondrial proliferation, and smooth cell atrophy are observed in the external layer of the muscularis propria in the stomach and in the small intestine [Giordano et al 2006, Giordano et al 2008].
Loss of the pacemaker cells that stimulate gut contraction (interstitial cells of Cajal) is also noted in the small bowel [Zimmer et al 2009].
Eye findings. Ptosis and ophthalmoplegia (weakness of the extraocular muscles) or ophthalmoparesis (lack of function of the extraocular muscles) are common findings. Because of the absence of symptoms like diplopia, individuals with MNGIE disease are often unaware of the eye movement defect. Instead, the abnormalities are usually first noted by a health care provider.
Sensorimotor neuropathy. All individuals with MNGIE disease have peripheral neuropathy. The neuropathy is demyelinating in all cases and about half also have axonal neuropathy. In some, the first symptoms are paresthesias and weakness. Paresthesias occur in a stocking-glove distribution and may be described as tingling, numbness, or even pain. The weakness is usually symmetric and distal. Lower extremities are more prominently affected than upper extremities. Unilateral or bilateral foot drop, as well as clawed hands, may occur. The severity of the neuropathic symptoms often fluctuates during the early stages of the disease.
The segmental demyelination is hypothesized to be caused by the uneven distribution of mtDNA abnormalities (depletion, single-nucleotide variants, deletions, duplications) along the nerve. Areas with the highest concentration of these pathogenic variants may be predisposed to demyelination.
Electrodiagnostic features can include decreased motor and sensory nerve conduction velocities, prolonged F-wave latency, and partial conduction block. Myopathic changes are common.
Histologically, demyelination and remyelination (onion bulb formation) are observed. Loss of large myelinated fibers is common.
Leukoencephalopathy. The leukoencephalopathy is usually asymptomatic. Spasticity is not present. Although intellectual disability is described in some individuals, dementia can be a rare late feature of the disease [Carod-Artal et al 2007].
Other highly variable clinical manifestations
Active hepatic cirrhosis with increased liver enzymes and macrovesicular steatosis
Anemia
Early-onset sensorineural hearing loss involving either the cochlea or eighth cranial nerve.
Diverticula, which may become infected (diverticulitis) or perforate, causing peritonitis, which may be fatal.
Prognosis. MNGIE disease is a progressive, degenerative disease with a poor prognosis. In the study of Garone et al [2011], the mean age of death was 35 years (range 15-54 years).
Other laboratory findings
Significantly increased CSF protein (typically 60 - >100 mg/dL; normal: 15 - 45 mg/dL)
Lactic acidemia (increased serum concentration of lactate without a change in the pH) and hyperalaninemia are common. Lactic acidosis (increased serum lactate concentration associated with a decrease in blood pH) is unusual, but is more likely to occur in the presence of renal or hepatic impairment.
Evidence of mitochondrial dysfunction manifest by any of the following:
Histologic abnormalities of a mitochondrial myopathy including ragged-red fibers (Gomori trichrome) and defects in single or multiple OXPHOS enzyme complexes. The most common defect is in cytochrome c oxidase (complex IV).
Acquired mitochondrial DNA (mtDNA) deletions/duplications detected in any tissue by
Southern blot analysis and long-range
PCRMitochondrial DNA depletion detected by quantitation of mtDNA relative to nuclear DNA
Site-specific mtDNA single-nucleotide variants detected in blood and tissues