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)

Achalasia of the cardia is an uncommon condition with an incidence of 0.1 cases per year per 100,000 population under 14 years. A review of experience at Booth Hall Children's Hospital over the past 10 years has revealed six cases of achalasia in children. This includes two cases of the rare syndrome of achalasia, alacrima and ACTH insensitivity (also known as Triple A syndrome) and its variants. There are 23 previously reported cases of Triple A syndrome and a further eight cases of its variants reported in the world literature. One-third of these cases (10 out of 31) have associated neurological abnormalities. The clinical and radiological features of achalasia are reviewed. The importance of barium studies in making the diagnosis is emphasized. However, early cases may show only spasm or incoordination, and manometry is required to confirm the diagnosis in these equivocal cases. In this series only three of the six barium studies were diagnostic and the remainder were diagnosed by manometry; all cases were subsequently confirmed by histology. Delay in diagnosis may result in severe lung damage due to repeated aspiration; this occurred in one of the six cases and was the cause of the child's death.
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PMID:Achalasia of the cardia in childhood and the syndrome of achalasia alacrima and ACTH insensitivity. 160 7

Allgrove syndrome (isolated glucocorticoid deficiency, achalasia and alacrima) was found in eight members of an inbred French Canadian/North American Indian pedigree. The high degree of consanguinity supports an autosomal recessive mode of inheritance for this disorder. Six patients presented with hypoglycaemia and other evidence of cortisol deficiency between 2.5 and 8 years of age; however, two others became cortisol deficient after initial testing showed normal cortisol responses to ACTH, evidence that the glucocorticoid insufficiency of this syndrome may not be congenital, but may develop as late as the third decade. No evidence of mineralocorticoid deficiency has been found during 65 patient-years of follow-up. Alacrima was the earliest and most consistent clinical sign of Allgrove syndrome. Other manifestations of peripheral or autonomic neuropathy were found in four patients. The patients showed similar facial features, and three had significant velo-pharyngeal incompetence. All showed oesophageal dysmotility even in the absence of symptomatic dysphagia. In-vitro studies of lymphocyte ACTH binding showed no differences from normal controls. If such lymphocyte binding, as has been suggested, reflects adrenal ACTH receptor activity, these data would suggest that the glucocorticoid deficiency of Allgrove syndrome is not the result of a defect in that receptor. However, the observation that ACTH does not elicit increased adenylate cyclase activity even in normal lymphocytes casts considerable doubt on the physiological significance of ACTH binding to lymphocytes. It seems likely, therefore, that true ACTH receptors are not expressed on peripheral lymphocytes, and any conclusions regarding a possible receptor defect in Allgrove syndrome must await studies of receptor expression on adrenal cell membranes.
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PMID:Allgrove syndrome: an autosomal recessive syndrome of ACTH insensitivity, achalasia and alacrima. 185 Jun 71

The Triple A syndrome is a rare condition comprising achalasia, alacrima and adrenocorticotrophic hormone (ACTH) insensitivity. A 12 year old Chinese girl with a variant of this syndrome (achalasia and alacrima), presenting with failure to thrive, is reported. Typical appearances of achalasia on barium swallow subsequently led to the correct diagnosis. The radiologist may be the first to recognize this syndrome and hence help anticipate its potentially life-threatening sequelae.
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PMID:Variant of the Triple A syndrome. 794 19

We analysed the charts of paediatric patients suffering from oesophageal disorders in 5 departments of paediatric surgery in Switzerland from 1972-1993 finding only 16 patients with proven achalasia (0.6%). The personal history showed a wide gap of several years from the first symptoms until diagnosis and treatment due to false interpretation of symptoms. Dilatations alone have never been definitely successful. In 16 patients, a Heller's procedure was done, 2 had an additional Thal, 12 a Nissen fundoplication, one a hiatoplasty and one no antireflux procedure. 3 patients needed further postoperative dilatations for several months up to 3 1/2 years. One patient suffering from an AAA syndrome (Achalasia/Alacrimia/ACTH deficiency) did not improve after Heller's procedure with Nissen fundoplication and dilatations. We finally had to resect the oesophagus and replace it by gastric transposition. Two children were lost for long-term follow-up. In 14 patients the follow-up is more than 10 years. 14 patients take normal food and are in the normal percentiles for length and height. Achalasia in childhood shows a wide spectrum of oesophageal dysmotility. In many cases, the propulsive force might be so weak that only a very lose antireflux procedure is tolerated. Occasionally, the whole oesophagus is without appropriate function and has finally to be resected as in our patient suffering from AAA syndrome. This child is now free of clinical pathological symptoms since several years.
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PMID:Achalasia in childhood and adolescence. 798 Nov 69

We describe two Hispanic adolescents with Allgrove syndrome (alacrima, achalasia, and sensorimotor polyneuropathy) in whom we documented cholinergic dysfunction by cardiovascular autonomic tests. Both patients had orthostatic hypotension and decreased heart rate variability.
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PMID:Allgrove syndrome: documenting cholinergic dysfunction by autonomic tests. 875 78

Allgrove syndrome (AS), also known as triple-A syndrome, is a rare cause of congenital adrenal insufficiency due to adrenocorticotropic hormone resistance. It is inherited in an autosomal recessive manner and is associated with achalasia, alacrima, and other neurological abnormalities, including autonomic, sensory, and upper- and lower-motor neuropathy, deafness, and mental retardation. Although the etiology of AS remains unknown, recently the disease was linked to a chromosome 12 locus (corresponding cytogenetic band 12q13) in consanguineous families of European ancestry. In the present study, we investigated four nonconsanguineous families with documented inheritance of AS for linkage with the reported 12q13 locus. Eighteen subjects were studied, of whom five were affected by AS. DNA was extracted from peripheral blood lymphocytes and amplified by standard methods with primers from polymorphic sequence tagged sites (STSs) located in the chromosome 12q13 region. Two-point logarithm-of-odds (LOD) score analysis revealed a maximum LOD score of 1.7 for STSs D12S361 and D12S368 without any recombinants [recombination distance (theta) = 0]. Multipoint linkage analysis defined an area of estimated genetic distance less than 0.5 cM (approximately 500,000 bp) between STSs D12S361 and D12S359 that is most likely to contain the AS gene(s). We conclude that, in Puerto Rican families, AS segregates with polymorphic markers that have been mapped to the chromosome 12q13 locus, revealing the absence of heterogeneity for this syndrome in a genetically distinct population. Candidate genes in the region include those that code for several of the keratin proteins, transcription factors, and others.
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PMID:Segregation of Allgrove (triple-A) syndrome in Puerto Rican kindreds with chromosome 12 (12q13) polymorphic markers. 928 47

We describe a previously unreported finding of periventricular heterotopias in a brain magnetic resonance imaging (MRI) study, in a girl with adrenocortical insufficiency, alacrima, achalasia, and neurologic deterioration (Allgrove syndrome). This finding could indicate that the underlying mechanism in this syndrome can be traced to the first half of fetal life and also might cause abnormal neuronal migration. This disorder recently has been linked to chromosome 12q13. There could be several explanations for the clinical heterogeneity in this syndrome: a contiguous gene syndrome involving multiple genes, including one whose deletion causes heterotopias, or a deficiency of a gene for a neurotrophic factor active during pre- and postnatal life and responsible for both migration and survival of neurons could be the cause. The identification of the responsible gene(s) will lead to further understanding of this multisystem disorder.
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PMID:Periventricular brain heterotopias in a child with adrenocortical insufficiency, achalasia, alacrima, and neurologic abnormalities (Allgrove syndrome). 1034 2

We report three brothers with Allgrove syndrome. All three had evidence of adrenal insufficiency and deficient tear production, though neither of them had achalasia, the third component of the disorder at the time of this report. Neurological abnormalities were present in the index case. The younger siblings were neurologically normal. The familial association of achalasia, alacrimia and adrenal insufficiency, rather than being fortuitous, is a distinct clinical entity.
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PMID:Familial glucocorticoid deficiency, alacrimia and achalasia--Allgrove syndrome. 1079 51

Triple A syndrome (Allgrove syndrome, MIM No. 231550) is a rare autosomal recessive disorder characterised by ACTH-resistant adrenal insufficiency, achalasia of the cardia, and alacrimia. The triple A gene has been previously mapped to chromosome 12q13 in a maximum interval of 6 cM between loci D12S1629 and D12S312. Using linkage analysis in 12 triple A families, mostly originating from North Africa, we confirm that the disease locus maps to the 12q13 region (Zmax = 10.89 at theta = 0 for D12S1604) and suggest that triple A is a genetically homogeneous disorder. Recombination events as well as homozygosity for polymorphic markers enabled us to reduce the genetic interval to a 3.9 cM region. Moreover, total linkage disequilibrium was found at the D12S1604 locus between a rare allele and the mutant chromosomes in North African patients. Analysis of markers at five contiguous loci showed that most of the triple A chromosomes are derived from a single founder chromosome. As all markers are located in a 0 cM genetic interval and only allele 5 at the D12S1604 locus was conserved in mutant chromosomes, we speculate that the triple A mutation is due to an ancient Arabian founder effect that occurred before migration to North Africa. Since we also found linkage disequilibrium at D12S1604 in two patients from Southern Europe (France and Spain), the founder effect might well extend to other Mediterranean countries. Taking advantage of a YAC contig encompassing the triple A minimal physical region, the triple A gene was mapped to a 1.7 Mb DNA fragment accessible to gene cloning.
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PMID:Linkage disequilibrium in inbred North African families allows fine genetic and physical mapping of triple A syndrome. 1095 24

Triple-A syndrome (MIM 231550; also known as Allgrove syndrome) is an autosomal recessive disorder characterized by adrenocorticotropin hormone (ACTH)-resistant adrenal insufficiency, achalasia of the oesophageal cardia and alacrima. Whereas several lines of evidence indicate that triple-A syndrome results from the abnormal development of the autonomic nervous system, late-onset progressive neurological symptoms (including cerebellar ataxia, peripheral neuropathy and mild dementia) suggest that the central nervous system may be involved in the disease as well. Using fine-mapping based on linkage disequilibrium in North African inbred families, we identified a short ancestral haplotype on chromosome 12q13 (<1 cM), sequenced a BAC contig encompassing the triple-A minimal region and identified a novel gene (AAAS) encoding a protein of 547 amino acids that is mutant in affected individuals. We found five homozygous truncating mutations in unrelated patients and ascribed the founder effect in North African families to a single splice-donor site mutation that occurred more than 2,400 years ago. The predicted product of AAAS, ALADIN (for alacrima-achalasia-adrenal insufficiency neurologic disorder), belongs to the WD-repeat family of regulatory proteins, indicating a new disease mechanism involved in triple-A syndrome. The expression of the gene in both neuroendocrine and cerebral structures points to a role in the normal development of the peripheral and central nervous systems.
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PMID:Mutant WD-repeat protein in triple-A syndrome. 1106 74


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