Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014848 (achalasia)
 2,804 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The past decade has seen major advances in the pharmacological understanding of the nervous system of the gastrointestinal tract, the enteric nervous system, and its importance for gut functions in several states of disease. Indeed, the enteric nervous system has become a promising target in the treatment of many gastrointestinal symptoms and disorders. Some of these new therapeutic concepts, such as botulinum toxin for achalasia and serotonergic drugs for functional bowel diseases, are already in clinical use. This paper is part 3 of three Minireviews in Pharmacology & Toxicology, and presents the neurogastrointestinal pharmacological therapeutic options in gastrointestinal pain, functional gastrointestinal disorders, inflammatory bowel diseases, cancer and related conditions with focus on future drug targets. The diagnosis of gastrointestinal neuropathy, the role of serotonin and related neuroendocrine transmitters, serotonergic drugs, and neurotrophic factors in neurogastrointestinal pharmacology will be addressed in this context.
 ...
PMID:The enteric nervous system III: a target for pharmacological treatment. 1282 68

Triple A or Allgrove syndrome is a rare autosomal recessive disease with alacrima, achalasia, and ACTH-resistant adrenal insufficiency. It is usually associated with neurological disorders. Recently, mutations in the AAAS, a candidate gene mapped to chromosome 12q13, were identified. We report a family with seven affected siblings. All of them have signs of alacrima, four were operated on for achalasia, five have neurological abnormalities including cranial nerve abnormalities, amyotrophic lateral sclerosis, pyramidal syndrome, distal motor neuropathy, and amyotrophy, and two have adrenal insufficiency. Triple A syndrome should be considered in any young patient with alacrima.
 ...
PMID:[Allgrove syndrome. Report on a family]. 1688 10

The triple A syndrome is caused by autosomal recessively inherited mutations in the AAAS gene and is characterized by achalasia, alacrima and adrenal insufficiency as well as progressive neurological impairment. We report on a 14-year-old girl with slowly progressive axonal motor neuropathy with conspicuous muscle wasting of hypothenars and calves as well as alacrima. The mutation analysis of the AAAS gene revealed a compound heterozygous mutation: a c.251G>A mutation in exon 2 that had been reported previously, and a novel c.1288C>T mutation in exon 14. At the transcriptional level, the c.251G>A transition results in an aberrant splicing and decay of this RNA strand so that the particular clinical picture results from the novel c.1288C>T, (p.Leu430Phe, L430F) mutation in a hemizygous form. With transfection experiments, we demonstrate that GFP-ALADIN(L430F) correctly localizes to nuclear pore complexes. Therefore, we conclude that this point mutation impairs ALADIN function at the nuclear pore.
 ...
PMID:Axonal neuropathy with unusual pattern of amyotrophy and alacrima associated with a novel AAAS mutation p.Leu430Phe. 1862 86

Allgrove syndrome (or triple A syndrome) is a rare autosomal recessive disorder characterized by alacrima, achalasia, ACTH-resistant adrenal insufficiency and autonomic/neurological abnormalities. It is caused by mutations in the AAAS gene, located on chromosome 12q13. We describe a 42-year-old patient who presented with neuropathy and was found to have alacrima, achalasia, mild autonomic dysfunction with significant central and peripheral nervous system involvement. She was later diagnosed with oligosymptomatic triple A syndrome. Sequencing of the AAAS gene identified two heterozygous mutations within exon 14 and its donor splice site (p.L430F-c.1288C>T and c.1331+1G>T), one of which is novel. Allgrove syndrome should be suspected in patients with neurological impairment associated with two or more of the main symptoms (alacrima, achalasia or adrenal insufficiency).
 ...
PMID:Triple A syndrome: a novel compound heterozygous mutation in the AAAS gene in an Italian patient without adrenal insufficiency. 2005 Dec 79

Nitric oxide (NO) is a functionally important neurotransmitter signaling molecule generated by mammalian and bacterial nitric oxide synthases (NOS), and by chemical conversion of dietary nitrite in the gastrointestinal (GI) tract. Neuronal NOS (nNOS) is the most abundant isoenzyme in the enteric nervous system, and targeted deletion in transgenic mice has clearly demonstrated its importance in normal gut function. Enteric neuropathy is also often associated with abnormal NO production, for example in achalasia and diabetic gastroparesis. Not surprisingly therefore, aberrant nNOS activity is widely implicated in enteric disease, and represents a potential molecular target for therapeutic intervention. One physiological signaling mechanism of NO bioactivity is through chemical reaction with the heme center of guanylyl cyclase, resulting in the conversion of cGMP from GTP. This second messenger nucleotide signal activates cGMP-dependent protein kinases, phosphodiesterases, and ion channels, and is implicated in the neuronal control of GI function. However, few studies in the GI tract have fully related NO bioactivity with specific molecular targets of NO-derived signals. In the central nervous system (CNS), it is now increasingly appreciated that NO bioactivity is often actively transduced via S-nitrosothiol (SNO) signals rather than via activation of guanylyl cyclase. Moreover, aberrant S-nitrosylation of specific molecular targets is implicated in CNS pathology. S-nitrosylation refers to the post-translational modification of a protein cysteine thiol by NO, forming an endogenous SNO. Because cysteine residues are often key regulators of protein function, S-nitrosylation represents a physiologically important signaling mechanism analogous to other post-translational modifications, such as O-phosphorylation. This article provides an overview of how neurotransmitter NO is produced by nNOS as this represents the most prominent and well defined source of SNO production in the enteric nervous system. Further, it provides a perspective of how S-nitrosylation signals derived from multiple diverse sources may potentially transduce NO bioactivity in the GI tract. Possible lessons that might be learnt from the CNS, such as SNO mediated auto-inhibition of nNOS activity and modulation of neuronal cell death, are also explored as these may have pathophysiological relevance in enteric neuropathy. Thus, S-nitrosylation may mediate previously underappreciated NO-derived signals in the enteric nervous system that regulate homeostatic gut functions and disease susceptibility.
 ...
PMID:S-nitrosothiol signals in the enteric nervous system: lessons learnt from big brother. 2144 85

"Triple A" syndrome is a rare, autosomal recessive condition whose main clinical features are alacrima, achalasia, and adrenal failure. Most patients also develop some neurologic abnormalities. We describe an 11-year-old boy with triple A syndrome who presented with progressive axonal motor neuropathy. Molecular analysis revealed compound heterozygous mutations in the AAAS gene, confirming the clinical diagnosis. The clinical presentation of patients with triple A syndrome is variable. Our patient manifested neurologic problems during early childhood, before other features of this condition were apparent. We highlight the neurologic presentation of this multisystem disorder. In the presence of complex axonal neuropathy, other features of this condition should be sought.
 ...
PMID:Neurologic presentation of triple A syndrome. 2200 Mar 20

The etiology of achalasia is believed to be the neuropathy associated with chronic inflammation of the nerve plexus, but the cause of plexus inflammation is unknown. The purpose of this study was to evaluate the pathophysiology of achalasia by examining the muscularis externa of the esophagus. We used the muscularis externa of the esophagus of 62 patients with achalasia (median 44 years, male : female 32:30) who underwent surgical treatment (achalasia group) and of 10 patients (median 65.5 years, male : female 9:1) who underwent esophagectomy for thoracic esophageal cancer (control group) to perform immunohistochemical staining with S-100, CD43, c-kit (CD117), n-NOS, vasoactive intestinal polypeptide (VIP), and ubiquitin. The cell counts that were positive for S-100, n-NOS, VIP, and ubiquitin were significantly lower in the achalasia group compared with the control group (P < 0.001, P= 0.001, P < 0.001, and P= 0.001, respectively). There were no statistically significant differences with respect to CD43 and c-kit staining (P= 0.586 and P= 0.209, respectively). In conclusion, the pathophysiology of achalasia is therefore considered to be an impaired production of NO and VIP, which both affect interstitial cell of Cajal and smooth muscles, and this impairment is therefore considered to play a role in the pathophysiology of achalasia.
 ...
PMID:Immunohistochemical study of the muscularis externa of the esophagus in achalasia patients. 2230 23

Allgrove syndrome (triple A) is a rare autosomal recessive disease. The classic triad includes, congenital adrenal insufficiency due to ACTH resistance, achalasia of the cardia and alacrimia. Neurological abnormalities are associated with autonomic neuropathy, sensory and motor defects, deafness, mental retardation, Parkinsonism and dementia. The gene responsible is the ADRACALIN or AAAS encoding a protein called ALADIN. We report a case of a 19 year-old male, assessed when he was 10 years old in our department due to suspected storage disease. Mild mental and language retardation, hypernasal voice, sensory-motor neuropathy with autonomic involvement and signs of spastic paraparesis, alacrimia. gastroesophageal reflux, and achalasia. Molecular studies showed to mutations, the undescribed p.Tyr 19 Cys, and IVS14 +1 G.
 ...
PMID:[Allgrove syndrome (triple A). Finding of a mutation not described in the AAAS gene]. 2282 7

Achalasia is a primary esophageal motility disorder. Unlike diffuse esophageal spasm, it has not previously been described in association with hereditary sensory and motor neuropathy (HSMN). An 18-year-old-male with HSMN with sensorineural deafness presented with a 2-day history of dysphagia to solids and liquids. Achalasia was diagnosed after extensive investigations, and his symptoms resolved with endoscopic and definitive surgical management. His monozygotic twin brother had also been diagnosed with HSMN and suffered from chronic dysphagia, which was also subsequently diagnosed with achalasia. This is the first case to illustrate an association between HSMN with sensorineural deafness and achalasia.
...
PMID:Novel association of achalasia with hereditary sensory and motor neuropathy with sensorineural deafness. 2389 Feb 50

Actually, achalasia can be defined as a primary esophageal motor disorder characterized by esophageal aperistalsis and abnormal post-deglutitive lower esophageal sphincter (LES) relaxation. Its incidence varies from 0.03 to 1.63 cases per 100,000 people per year and increases with age, while the prevalence is almost 10/100,000 with no difference between the sexes. Regarding etiology, the most frequent histologic alteration is represented by the loss of the myenteric nerve fibers regulating inhibitory nitrergic neurotransmission in the LES, with the presence of a lymphocytic infiltrate and collagen deposition. The cause of this loss remains unclear. Among the theories proposed, the infectious, hereditary and autoimmune etiologies have been widely investigated. The only infectious agent identified as a cause of achalasia is Trypanosoma Cruzi, responsible of Chagas' disease. Regarding hereditary component, in rare cases achalasia presents as part of a genetic syndrome such as Down syndrome, Allgrove syndrome and familial visceral neuropathy. Although, no disease-specific gene has been identified. The autoimmune hypothesis has focused on the association of specific HLA classes with achalasia. However, no consistent association has been observed across studies. Despite increasing understanding of the physiopathology of achalasia, its etiology remains largely unknown. The onset of the disease is characterized by chronic inflammation of the myenteric plexus of the esophagus secondary to an environmental insult. Probably, genetic factors are involved in the development of achalasia, although the precise molecular basis of the disease has not been identified.
 ...
PMID:Definition, incidence and etiology: what's new in the 21st century? 2414 Nov 99


<< Previous 1 2 3 Next >>