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

Allgrove syndrome or triple-A syndrome is an autosomal recessive disorder characterized by adrenal insufficiency, achalasia and alacrima. Affected patients may also present with a constellation of central and peripheral nervous system manifestations. The gene for Allgrove syndrome (ALADIN) is located on chromosome 12q13. Here we report a 23-year-old man with alacrimia, achalasia, optic atrophy and progressive amyotrophic lateral sclerosis-like presentations. Sequencing of ALADIN gene showed a novel 6-bp sequence variant that the patient was homozygous and his father was heterozygous for the defect. A probable mechanism of action of this newly diagnosed missense mutation would be to cause abnormal splicing of the ALADIN gene.
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PMID:A novel DNA sequence variation in the first genetically confirmed allgrove syndrome in iran. 1907 97

The nuclear pore complex (NPC) consists of approximately 30 different proteins and provides the only sites for macromolecular transport between cytoplasm and nucleus. ALADIN was discovered as a new member of the NPC. Mutations in ALADIN are known to cause triple A syndrome, a rare autosomal recessive disorder characterized by adrenal insufficiency, alacrima, and achalasia. The function and exact location of the nucleoporin ALADIN within the NPC multiprotein complex is still unclear. Using a siRNA-based approach we downregulated the three known membrane integrated nucleoporins NDC1, GP210, and POM121 in stably expressing GFP-ALADIN HeLa cells. We identified NDC1 but not GP210 and POM121 as the main anchor of ALADIN within the NPC. Solely the depletion of NDC1 caused mislocalization of ALADIN. Vice versa, the depletion of ALADIN led also to disappearance of NDC1 at the NPC. However, the downregulation of two further membrane-integral nucleoporins GP210 and POM121 had no effect on ALADIN localization. Furthermore, we could show a direct association of NDC1 and ALADIN in NPCs by fluorescence resonance energy transfer (FRET) measurements. Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated. The loss of integration of ALADIN in the NPC is a main pathogenetic aspect for the development of the triple A syndrome and suggests that the interaction between ALADIN and NDC1 may be involved in the pathogenesis of the disease.
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PMID:The nuclear pore complex protein ALADIN is anchored via NDC1 but not via POM121 and GP210 in the nuclear envelope. 1978 45

Triple A syndrome is a rare autosomal recessive disorder characterized by ACTH-resistant adrenal failure, alacrima, achalasia, and progressive neurological manifestations. The majority of cases are associated with mutations in the AAAS gene, which encodes a novel, 60-kDa WD-repeat nuclear pore protein, alacrima-achalasia-adrenal insufficiency neurological disorder (ALADIN) of unknown function. Our aim was to elucidate the functional role of ALADIN by determining its interacting protein partners using the bacterial two-hybrid (B2-H) technique. Nonidentical cDNA fragments were identified from both a HeLa S-3 cell and human cerebellar cDNA library that encoded the full-length ferritin heavy chain protein (FTH1). This interaction was confirmed by both co-immunoprecipitation and fluorescence lifetime imaging microscopy-fluorescence resonance energy transfer studies. Immunoblotting showed that fibroblasts from triple A patients (with known AAAS mutations) lack nuclear FTH1, suggesting that the nuclear translocation of FTH1 is defective. Cells transfected with FTH1 and visualized by confocal microscopy had very little nuclear FTH1, but when cotransfected with AAAS, FTH1 is readily visible in the nuclei. Therefore, FTH1 nuclear translocation is enhanced when ALADIN is coexpressed in these cells. In addition to its well known iron storage role, FTH1 has been shown to protect the nucleus from oxidative damage. Apoptosis of neuronal cells induced by hydrogen peroxide was significantly reduced by transfection of AAAS or by FTH1 or maximally by both genes together. Taken together, this work offers a plausible mechanism for the progressive clinical features of triple A syndrome.
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PMID:Deficiency of ferritin heavy-chain nuclear import in triple a syndrome implies nuclear oxidative damage as the primary disease mechanism. 1985 93

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).
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PMID:Triple A syndrome: a novel compound heterozygous mutation in the AAAS gene in an Italian patient without adrenal insufficiency. 2005 Dec 79

Adrenocorticotrophin resistance syndromes comprise familial glucocorticoid deficiency (FGD) and triple A syndrome, which are rare autosomal recessive diseases with distinct clinical features and molecular etiologies. Mutations of melanocortin-2 receptor (MC2R) have been described in segregation with FGD in 25% of patients. More recently melanocortin-2 receptor accessory protein (MRAP), a small single-transmembrane domain protein, was described as an essential protein for the traffic of MC2R and its expression on the plasma membrane. About 20% of FGD patients carry homozygous mutations of MRAP. The ALADIN protein (for alacrima/achalasia/adrenal insufficiency/neurologic disorder) was identified as the molecular basis of triple A syndrome. The elucidation of the genetic basis of the ACTH resistance syndrome has contributed to the better understanding of MC2R function. However, in some patients the molecular etiology is not yet known and awaits further genetic studies.
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PMID:The molecular basis of adrenocorticotrophin resistance syndrome. 2037 27

Triple A syndrome is an autosomal recessive disorder characterized by alacrima, achalasia, ACTH-resistant adrenal insufficiency, autonomic dysfunction, and neurodegeneration. Mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN have been reported in these patients. Over the period 1977-2008 we evaluated ten subjects with the clinical diagnosis of triple A syndrome. Molecular analysis was performed in seven patients and revealed that all except one are compound heterozygotes for two mutations in the AAAS gene. Two novel mutations were detected: c.123+2T>C resulted in splice defect while c.1261_1262insG mutation resulted in a truncated protein (p.V421fs), which most probably is not functional. Genotype-phenotype correlation could not be established. In all our patients, except one sibling of previously diagnosed brother and sister, genetic analysis was performed when at least two symptoms were present, usually alacrima and achalasia. Based on our experience, we recommend that in case of the presence of alacrima and at least one more symptom of triple A syndrome, adrenal function testing and molecular analysis should be performed. In all children with mutation in AAAS gene, regular follow up of adrenal function is necessary to avoid adrenal crisis and start substitution therapy as soon as adrenal insufficiency is noted.
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PMID:Triple A syndrome: 32 years experience of a single centre (1977-2008). 2049 90

Triple A syndrome is caused by mutations in the gene encoding ALADIN, leading to achalasia, alacrima and addisonism. Neurologic manifestations of the disease include motor neuron disease-like presentations, motor-sensory or autonomic neuropathy, optic atrophy, cerebellar ataxia, Parkinsonism, and mild dementia. We report a 60-year-old Japanese man with triple A syndrome. He was born to non-consanguineous parents. He underwent a surgical operation for achalasia at age 40, and thereafter, he developed a slowly progressive gait disturbance. Neurological examinations at age 60 revealed limb muscle wasting and weakness with pyramidal tract signs, distal-dominant sensory disturbance, optic atrophy, and autonomic dysfunction. Alacrima was detected using Schirmer test. All of these features were consistent with typical triple A syndrome. He lacked adrenal insufficiency that is frequently observed in patients with the classic phenotype of triple A syndrome. His sural nerve biopsy showed a moderate loss of myelinated fibers and hypomyelination. He was homozygous for a missense mutation, p.R155H, in the disease-causing gene, AAAS. Seven patients with genetically-confirmed, adult or late-onset triple A syndrome, including ours, have been reported to date. All the patients showed upper and lower motor neuron signs (100%), while sensory disturbance (29%) and autonomic dysfunction (57%) were less frequent. Careful assessment for alacrima followed by molecular genetic analysis of AAAS should be considered in patients who show a combined phenotype of motor neuron disease and sensory/autonomic disturbance, even in elderly patients.
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PMID:Adult or late-onset triple A syndrome: case report and literature review. 2067 35

Triple-A syndrome is characterized by triad of adrenocorticotrophic hormone (ACTH)-resistant adrenal insufficiency, alacrimia and achalasia cardia. It is a rare disease and inherited by autosomal recessive pattern. Allgrove syndrome is characterized by mutation(s) in AAAS gene, located on chromosome 12q13, that codes for ALADIN protein. Most mutations produce a truncated protein, although missense and point-mutations have also been reported. Some patients with Triple-A syndrome may not have mutations in AAAS gene; in those there is no specific genotype-phenotype correlation. Although alacrimia is not the usual presenting manifestation, probably it is the earliest and most consistent feature. Achalasia cardia and adrenal insufficiency are the early and usual presenting manifestations. Neurological features appear at later age and autonomic manifestations are the most common neurological disorder. Polyneuropathy, amyotrophy, optic atrophy are the other common neurological problems. Alacrimia is diagnosed by Schirmer's test while ahalasia cardia and adrenal insufficiency are best diagnosed by esophageal monometry and ACTH stimulated cortisol levels respectively. Alacrimia is treated with artificial tears while achalasia cardia with either pneumatic dilatation or Heller's myotomy. Adrenal insufficiency is treated with glucocorticoid and if necessary mineralocorticoid replacement.
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PMID:Triple-A syndrome. 2068 90

Triple-A or Allgrove syndrome is a rare multisystem disease classically associated with esophageal achalasia, adrenal insufficiency and alacrima. Here, we describe the poorly understood neurological characteristics often associated with this condition, through the clinical and electrophysiological analysis of eight patients. All patients were genetically confirmed and had a mutation in the ALADIN gene. They all displayed a classical picture of Triple-A syndrome: all suffered from achalasia and alacrima and half of them from adrenal insufficiency. However, all harbored a neurological picture characterized by a recognizable pattern of peripheral neuropathy. Other neurological features included cognitive deficits, pyramidal syndrome, cerebellar dysfunction, dysautonomia, neuro-ophthalmological signs and bulbar and facial symptoms. This neurological picture was prominent in all patients and misled the initial diagnosis in six of them, which had a late onset. We then review the previous neurological reports of this disease, to improve the understanding of this rare condition. Diagnosis of late-onset Triple-A syndrome is difficult when the clinical picture is mainly neurological and when endocrine or gastrointestinal signs are minor. The characteristics of the peripheral neuropathy, among other neurological signs, can be of help.
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PMID:Neurological features in adult Triple-A (Allgrove) syndrome. 2165 42

Triple A syndrome is a rare disease of autosomal recessive inheritance. It was first described in 1978. The typical triad includes adrenocorticotrophic-hormone-resistant glucocorticoid insufficiency, reduced or absent tearing (alacrima) and achalasia. But clinical symptoms can be extremely heterogeneous and of variable clinically expression. This report describes a 7-year-old boy with a 1 year history of fatigue and muscle weakness. Physical examination showed skin and mucosal hyperpigmentation, and hormonal analysis revealed isolated glucocorticoid function. Medical history was marked by megaoesophagus and achalasia. The absence of tears when crying had been noted since birth. In the presence of the classical triad, triple A syndrome was diagnosed. Clinical diagnosis was confirmed by molecular analysis of the AAAS gene on chromosome 12q13. The novel compound heterozygous mutation c.1304delA and c.1292-1294delTTCinsA was found.
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PMID:Triple A syndrome: two novel mutations in the AAAS gene. 2168 24


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