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At a glance

POLIP is an acronym that stands for Polyneuropathy, Ophthalmoplegia, Leukoencephalopathy, chronic Intestinal Pseudoobstruction Syndrome and consider a mitochondrial myopathy characterized by a tetrad of progressive sensorimotor peripheral nerve disease. Other clinical features include myopathy, diffuse leukoencephalopathy, and ptosis.

Synonyms

MyoNeuroGastroIntestinal Encephalopathy Syndrome; MNGIE Syndrome.

Incidence

Very rare; estimated to be at 0.15 to 1 per 1 million.

Genetic inheritance

Autosomal recessive.

Pathophysiology

Caused by mutations in the nuclear gene TYMP (previously known as ECGF1). TYMP codes for thymidine phosphorylase and is located on chromosome 22q13.33 Thymidine phosphorylase enzyme deficiency results in systemic accumulation of deoxyribonucleosides thymidine (dThd) and deoxyuridine (dUrd). The accumulation of nucleosides also causes imbalances in mitochondrial DNA (mtDNA) deoxyribonucleoside triphosphates (dNTPs), which may play a direct or indirect role in the mtDNA depletion/deletion abnormalities.

Diagnosis

Detailed patient history, thorough clinical examination, imaging (MRI and CT), genomic DNA screening for mutations in TYMP gene and biochemical analysis contribute to the diagnosis of this syndrome. MRI and CT scans are consistent with leukodystrophy involving the cerebral and cerebellar white matter. Histology shows widespread endoneurial fibrosis and demyelination in the peripheral nervous system. Muscle biopsy with histologic features of mitochondrial myopathy (ragged red fibers, muscle fibers with increased succinate dehydrogenase stain or ultrastructurally abnormal mitochondria). Biochemical examination of the liver and muscle tissues reveals defect of cytochrome c oxidase (complex IV of the respiratory chain). Nerve conduction and electromyographic (EMG) studies are compatible with a sensorimotor neuropathy; quantitative EMG may show a myogenic process. Southern blot analysis reveals multiple deletions of mtDNA.

Clinical aspects

Symptoms begin before age of 10 years. The first signs are gastrointestinal symptoms (recurrent nausea, vomiting, or diarrhea with intestinal dysmotility) in the majority of cases, or an ophthalmoparesis in some cases. The neurologic manifestations are predominantly outside the central nervous system (CNS); gastrointestinal (GI) dysmotility is a result of severe visceral neuropathy. Gastrostomy or jejunostomy tube feeding may fail because of dysmotility. Malabsorption with intermittent diarrhea and chronic malnutrition ensues. Parenteral alimentation is often necessary. Lactic acidosis after moderate glucose loads may occur. Prokinetic agents, including erythromycin and cisapride, are unsuccessful in improving intestinal motility. Visual disturbances may manifest as blepharoptosis and ophthalmoparesis. Proximal muscle weakness and mild ataxia are common. Neurosensory hearing loss, proximal myopathy with marked muscle atrophy, polyneuropathy, and encephalopathy (with hypodense areas in the white matter on MRI examination) are present. In addition, there also may be an autonomic neuropathy. Electrocardiography may show cardiac conduction abnormalities. Respiratory function may be severely affected. The prognosis is poor because of a severe weight loss bordering on cachexia, with a mean survival age of 28.5 years. The prognosis seems to be worsened by a young age of ...

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