Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1762617 (weakness)
 37,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We present the current knowledge on the genetic and phenotypic aspects of mitochondrial DNA depletion syndromes. The human mitochondrial DNA encodes 13 of the 82 structural proteins of the mitochondrial electron transport chain. The replication and maintenance of the mtDNA require a large number of nuclear encoded enzymes and balanced nucleotide pools. Mitochondrial nucleotide synthesis is of major importance because of the constant need for nucleotides for mtDNA maintenance even in quiescent cells. As de novo enzymes are not present in the mitochondria, synthesis is accomplished via the salvage pathway. Defective mtDNA synthesis and maintenance manifest by multiple deletions or by depletion of the mitochondrial genome. Patients with multiple deletions typically present with progressive external ophthalmoplegia, ptosis and, exercise intolerance after the first decade of life. mtDNA depletion is usually an infantile disease characterized by severe muscle weakness, hepatic failure, or renal tubulopathy with fatal outcome. Linkage analysis in families with multiple mtDNA deletions reveal mutations in proteins that participate in mtDNA replication, the mitochondrial DNA polymerase gene, and the Twinkle gene, a putative mitochondrial helicase and in factors which play a role in mitochondrial nucleotide metabolism, the adenine nucleotide translocator, and the thymidine phosphorylase gene. We have recently identified mutations in an additional two essential proteins in the nucleotide salvage pathway, the mitochondrial deoxyribonucleoside kinases. The phenotype was distinctive for each gene, with hepatic failure and encephalopathy associated with mutations in the deoxyguanosine kinase gene and isolated devastating myopathy as the sole manifestation of thymidine kinase 2 deficiency. The tissue selectivity of these disorders and especially the exclusive muscle involvement in thymidine kinase 2 mutations is puzzling. The normal sequence of the remaining mtDNA copies in spite of a serious mitochondrial nucleotide imbalance is also unexpected. We propose several tissue-specific protective mechanisms and a time window, likely encompassing fetal life and even early infancy, during which nuclear nucleotide synthesis provides mitochondrial needs in all organs. We also speculate on future genes to be discovered in other phenotypes of mtDNA depletion.
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PMID:Depletion of the other genome-mitochondrial DNA depletion syndromes in humans. 1211 Sep 44

Clinical, biochemical, and genetic features of a Spanish family with mitochondrial neurogastrointestinal encephalomyopathy are reported. The proband presented with severe gastrointestinal dysmotility and the affected sister had extraocular muscle weakness. In both affected individuals, biochemical defects of thymidine phosphorylase and a pathogenic G-to-A transition mutation at nucleotide 435 in the thymidine phosphorylase gene were identified. The first thymidine phosphorylase mutation identified in Spain showed phenotypic variability at onset.
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PMID:Phenotypic variability in a Spanish family with MNGIE. 1217 87

Patients diagnosed with abdominal pain related to mitochondrial neurogastrointestinal encephalopathy (MNGIE) may benefit from splanchnic nerve blockade. MNGIE, varying in age of onset and rate of progression, is caused by loss of function mutation in thymidine phosphorylase gene. Gastrointestinal dysmotility, pseudo-obstruction and demyelinating sensorimotor peripheral neuropathy (stocking-glove sensory loss, absent tendon reflexes, distal limb weakness, and wasting) are the most prominent manifestations. Patients usually die in early adulthood (mean 37.6 years; range 26-58 years). We report a case of an 18-year-old patient with MNGIE. Our patient's abdominal pain was relieved after splanchnic nerve blockade.
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PMID:Abdominal pain related to mitochondrial neurogastrointestinal encephalomyopathy syndrome may benefit from splanchnic nerve blockade. 1697 39

The mitochondrial neurogastrointestinal encephalomyopathy syndrome (MNGIE) is a rare and life-threatening, autosomal recessive, multisystem disorder, caused by the mutations in the thymidine phosphorylase gene. Herein, we report a case of a 21 year-old male with a long history of intestinal pseudo-obstruction who was diagnosed with MNGIE syndrome after an extensive examination. In this case, our objective was to bring the gastroenterologist's attention to this difficult to diagnose syndrome in the coexistence of intestinal pseudo-obstruction and neurologic manifestations. The patient was a member of a consanguineous family of six children, in whom two sisters had died due to this disorder and one sister was affected and is still alive. The patient presented with cachexia, abdominal pain, diarrhea and muscle weakness, and was previously considered to have gluten sensitive enteropathy and treated with dietary solutions.
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PMID:Chronic intestinal pseudo-obstruction and neurological manifestations in early adulthood: considering MNGIE syndrome in differential diagnosis. 2059 55

We reviewed retrospectively 12 muscle biopsies of patients who were clinically diagnosed with a primary muscle diseases from the clinical data base of Thammasat University Hospital from January 2005 to January 2007. Most patients were male and had median age of 30.5 years (range 14 to 56). The most common clinical presentation was proximal muscle weakness. Nine of eleven patients had elevated CK concentrations ranging from 338 to 1023 IU/L. Clinicopathological correlation revealed specific diagnoses in nine patients. Suspected cases of mitochondrial neurogastrointestinal encephalopathy (MNGIE), myofibrillar myopathy (MFM) and distal myopathy with rimmed vacuoles (DMRV) were confirmed by molecular genetic studies examining thymidine phosphorylase, GNE, ZASP myotilin, desmin, abeta-crystalline and filamin C genes. Specific histopathological findings on muscle biopsy help to select cases for advance molecular testing.
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PMID:Primary muscle diseases in Thammasat University Hospital: muscle biopsy study of 12 cases. 2129 20

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndromes is a rarely seen multisystem disorder with autosomal recessive inheritance due to thymidine phosphorylase gene mutation. It is characterized by progressive external ophthalmoplegia and/or pitosis, progressive gastrointestinal dismotility and abdominal pain, postprandial emesis, cachexia, demyelinating peripheral neuropathy, symmetrical and distal weakness especially in lower extremities and diffuse leucoencephalopathy in cranial magnetic resonance. Endocarditis is the infectious and inflammatory disease of the endothelial surface of the heart. MNGIE syndrome is a condition in which immune system is suppressed and infection risk increased. Herein we summarized a previously not reported endocarditis case in a patient with MNGIE syndrome who was under follow up for three years. In MNGIE syndrome of acute dyspnea, infective endocarditis should be kept in mind and prompt evaluation for surgical treatment should be done.
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PMID:Endocarditis in Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE) Syndrome: The First in the Literature. 2547 31

Mitochondrial neurogastrointestinal encephalopathy (MNGIE), usually an autosomal-recessive inherited condition, causes gastrointestinal dysmotility, ophthalmoplegia, ptosis, leukoencephalopathy and neuropathy. The chromosome 22 disorder, due to mutations in the nuclear gene TYMP encoding thymidine phosphorylase (TP), leads to the accumulation of thymidine and deoxyuridine, with mitochondrial dysfunction.This report describes a patient with an MNGIE-like syndrome with a heterozygous TYMP mutation who showed marked, but transient improvement postallogeneic haematopoietic stem cell transplantation (HSCT).The patient, showing ptosis and ophthalmoplegia, was initially managed for myasthenia gravis. She developed gastrointestinal symptoms, dysarthria, dysphagia and weakness, and MNGIE was considered due to its low TP levels and improvement after platelet transfusions. She underwent HSCT, with dramatic improvement, but regressed 18 months later despite normal TP levels, platelet counts and full chimerism.MNGIE may encompass a spectrum of disorders. TP deficiency alone is unlikely to explain all clinical signs, and other factors, including the possible development of anti-TP antibodies, which may play a role in the pathophysiology.
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PMID:Transient clinical improvement of a mitochondrial neurogastrointestinal encephalomyopathy-like syndrome after allogeneic haematopoietic stem cell transplantation. 2876 76

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive and fatal multisystem metabolic disorder. It presents with wide-ranging gastrointestinal and neurologic symptoms. It is caused by a mutation in the TYMP gene which impairs thymidine phosphorylase (TP) activity, therefore leading to the accumulation of thymidine and deoxyuridine in plasma and tissues. Thus, MNGIE can be diagnosed by findings of high levels of thymidine and deoxyuridine. Herein, we present the case of a 40-year-old male who presented with diarrhea, vomiting, and abdominal pain, severe weight loss, neurologic deficits, and distal motor weakness progressing over a period of 13 years. The combination of this broad clinical picture along with results of magnetic resonance imaging, electromyography, colonic biopsies, genetic testing, and elevated plasma and tissue thymidine and deoxyuridine levels confirmed the diagnosis of MNGIE. TYMP gene mutation impairs TP function. TP mutations in the nuclear DNA lead to mitochondrial DNA deletions causing mitochondrial failure and ultimately cell death. Treatment modalities are targeting the restoration of TP activity or aiming to decrease the high levels of thymidine and pyrimide. However, diagnosing this disease is still a challenge and often overdue. This patient's 13-year delay in diagnosis shows the importance of a complete neurological exam and muscle strength testing in patients with gastrointestinal symptoms. The diagnosis of MNGIE requires interdepartmental collaborative work for diagnosis delay prevention and for optimal patient care.
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PMID:Clinicopathology and Diagnosis Delay in a 40-Year-Old with Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE). 3235 81