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)

Familial isolated glucocorticoid deficiency is a form of potentially lethal hereditary unresponsiveness to ACTH that manifests as primary adrenal insufficiency, usually without mineralocorticoid deficiency. Affected children commonly present with hyperpigmentation, recurrent hypoglycemia, chronic asthenia and failure to thrive within the first 2 years of life. Typically, they have deficient production of cortisol and adrenal androgens in the presence of markedly elevated ACTH levels, while renin and aldosterone levels are usually normal and responsive to activation of the renin-angiotensin axis. Clinical awareness of these syndromes is of considerable prognostic and therapeutic importance. The etiological involvement of the ACTH receptor gene in isolated glucocorticoid deficiency has been recently established in many, but not all, affected families. Several naturally occurring mutations of the ACTH receptor gene have been identified to date and have helped illuminate the mechanisms of ligand binding and signal transduction by this receptor. Discovery of the molecular defect(s) responsible for isolated glucocorticoid deficiency in cases with a normal ACTH receptor gene coding region and for the triple A syndrome (adrenal insufficiency, alacrima, achalasia) will hopefully provide further insight into the mechanisms of adrenocortical function and will increase the prospect of new therapeutic approaches.
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PMID:Isolated glucocorticoid deficiency and ACTH receptor mutations. 1071 60

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

ACTH resistance syndromes consist of a group of rare disorders with three various molecular etiologies. However, all these diseases share the feature of severe glucocorticoid adrenal insufficiency. The simplest disorder is the isolated familial glucocorticoid deficiency (FGD) which could be divided in two different types. In FGD type 1, ACTH receptor mutations have been described and are responsible for the loss of function of the receptor, leading to the ACTH unresponsiveness. Patients with FGD type 2 show the same phenotype as in the previous syndrome but no mutation of the ACTH receptor has been reported in these cases. It has been proposed that morbidity of one or several other gene(s) could be responsible for this syndrome although there is no information about their chromosomal localization. The third molecular form of the disease corresponds to the Triple A syndrome for the triad of association "ACTH resistance, Achalasia, Alacrima", thus reflecting a large spectrum of additional symptoms. It has recently been reported that the morbid gene in this last syndrome maps to chromosome 12q13. The aim of this review is to examine the clinical aspect as well as the current knowledge of the molecular and genetic aspects of the different forms of the disease.
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PMID:[ACTH resistance syndromes]. 1108 94

ACTH insensitivity results from a group of rare autosomal recessive genetic defects. Familial glucocorticoid deficiency is one of these syndromes in which about half of all cases have inactivating mutations of the ACTH receptor. The remaining patients with this syndrome have defects in one or more other as yet unidentified genes that are unlinked to the ACTH receptor. The triple A syndrome is a distinct clinical syndrome which includes alacrima (absence of tears), achalasia and various neurological defects in addition to ACTH insensitivity. In all cases the defect lies in a gene located on chromosome 12.
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PMID:The molecular pathogenesis of ACTH insensitivity syndromes. 1135 96

Familial glucocorticoid deficiency due to corticotropin (ACTH) resistance consists of two distinct genetic syndromes that are both inherited as autosomal recessive traits: isolated ACTH resistance (iACTHR), which may be caused by inactivating mutations of the ACTH receptor (the MC2R gene) or mutations in an as yet unknown gene(s), and Allgrove syndrome (AS). The latter is also known as triple-A syndrome (MIM 231550). In three large cohorts of AS kindreds, the disease has been mapped to chromosome 12; most recently, mutations in the AAAS gene on 12q13 were found in these AS families. AAAS codes for the WD-repeat containing ALADIN (for alacrima-achalasia-adrenal insufficiency-neurologic disorder) protein. We investigated families with iACTHR (n = 4) and AS (n = 6) and a Bedouin family with ACTHR and a known defect of the TSH receptor. Four AS families were of mixed extraction from Puerto Rico (PR); most of the remaining six families were Caucasian families from North America (NA). Sequencing analysis found no MC2R genetic defects in any of the kindreds. No iACTHR kindreds, but all of AS families, had AAAS mutations. The previously reported IVS14+1G-->A splice donor mutation was found in all PR families, apparently due to a founder effect; one NA kindred was heterozygous for this mutation. In the latter family, long-range PCR failed to identify a deletion or other rearrangements of the AAAS gene. No other heterozygote or transmitting parent had any phenotype that could be considered part of AS. The IVS14+1G-->A mutation results in a premature termination of the predicted protein; although it was present in all PR families (in the homozygote state in three of them), there was substantial clinical variation between them. One PR family also carried a novel splice donor mutation of the AAAS gene in exon 11, IVS11+1G-->A; the proband was a compound heterozygote. A novel point mutation, 43C-->A(Gln15Lys), in exon 1 of the AAAS gene was identified in the homozygote state in a Canadian AS kindred with a milder AS phenotype. The predicted amino acid substitution in this family is located in a sequence that may participate in the preservation of stability of ALADIN beta-strands, whereas the splicing mutation in exon 11 may interfere with the formation of WD repeats in this molecule. We conclude that 1) AAAS does not appear to be frequently mutated in families with iACTHR; 2) AAAS is mutated in AS families from PR (that had previously been mapped to 12q13) and NA; and, 3) there is significant clinical variability between patients with the same AAAS defect.
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PMID:Spectrum of mutations of the AAAS gene in Allgrove syndrome: lack of mutations in six kindreds with isolated resistance to corticotropin. 1170 18

Allgrove's or "4 A" syndrome is a rare autosomal recessive condition with alacrima, achalasia, autonomic disturbance, and ACTH insensitivity among other features. Recent studies have identified mutations in the AAAS, a candidate gene on chromosome 12q13 in such patients. Manifestations in adult patients are rarely reported. The syndrome usually presents during the first decade of life with dysphagia or severe (occasionally fatal) hypoglycaemic or hypotensive attacks, related to adrenocortical insufficiency. Onset of adrenal insufficiency or other features may be delayed to adulthood. In contrast with paediatric patients, adult patients with Allgrove's syndrome may present with multisystem neurological disease; the childhood history of achalasia or alacrima may be overlooked. The authors describe two families with two affected siblings and a further unrelated patient with typical clinical features of Allgrove's syndrome, who exhibit signs of multisystem neurological disease including hyperreflexia, muscle wasting, dysarthria, ataxia, optic atrophy, and intellectual impairment. None of the cases have developed adrenal insufficiency but all have progressive neurological disability. Autonomic dysfunction was a significant cause of morbidity in two cases. The three index cases represent the longest described follow up of Allgrove's syndrome into adulthood. It is speculated that they represent a subgroup of patients who follow an often undiagnosed chronic neurological course. Recognition of the syndrome presenting in adult life permits treatment of unrecognised autonomic dysfunction, adrenal insufficiency and dysphagia, and appropriate genetic advice.
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PMID:Allgrove or 4 "A" syndrome: an autosomal recessive syndrome causing multisystem neurological disease. 1270 Mar 13

Allgrove syndrome is a genetic disorder inherited in an autosomal recessive pattern and characterized by a triad of adrenal insufficiency, achalasia, and alacrima. The gene affected by the mutation in patients with Allgrove syndrome is termed either AAAS or ALADIN (alacrima/achalasia/adrenal insufficiency/neurologic disorder). Adrenal insufficiency in patients with this disorder may develop as late as the third decade of life. We describe a 24-year-old female with Allgrove syndrome, in whom initial testing with 250 microg corticotropin (ACTH) stimulation test performed on 3 occasions produced normal serum cortisol values and results of the 1-microg ACTH stimulation tests performed on 6 occasions were conflicting. Insulin-induced hypoglycemia produced a nadir serum glucose value of 36 mg/dL without adequate serum cortisol stimulation, confirming presence of adrenal insufficiency. Gene sequencing identified 2 mutations in the triple A gene: an IVSC14 + 1 G to A mutation, which has been previously reported, and a novel R155P exon 6 mutation. We conclude that a novel R155P mutation in the ALADIN gene is associated with Allgrove syndrome and that insulin-induced hypoglycemia, rather than ACTH stimulation tests, should be used for accurate diagnosis of adrenal insufficiency in this disorder.
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PMID:The diagnosis of adrenal insufficiency in a patient with Allgrove syndrome and a novel mutation in the ALADIN gene. 1569 Mar 14

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.
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PMID:[Allgrove syndrome. Report on a family]. 1688 10

The triple A or Allgrove's syndrome is an autosomal recessive disorder characterized by the triad of achalasia cardia, alacrima and ACTH resistant adrenocortical insufficiency. Mutations of the Achalasia-Addisonianism-Alacrima-Syndrome (AAAS) gene on chromosome 12q13 are associated with this syndrome. We report an Indian family where two siblings were homozygous for a known mutation of the AAAS gene and presented with the classical triad of symptoms. The mother and the brother were heterozygous and asymptomatic. The affected siblings had iron deficiency anemia and the younger sister had pes cavus and palmoplantar keratosis. Neurological symptoms were absent in both affected children. Recognition of this syndrome can lead to early treatment of adrenal insufficency and genetic counselling.
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PMID:Mutations of the AAAS gene in an Indian family with Allgrove's syndrome. 1693 55

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder, in 40% of patients caused by mutation in the ACTH receptor gene. In the remaining affected persons most probably mutation refers to regulatory region of ACTH receptor or other factors responsible for differentiation of the adrenal cortex. FGD is characterized by elevated ACTH and low serum morning cortisol level that does not respond to exogenous ACTH stimulation. Mineralocorticoid function remains unaffected. Clinical symptoms of FGD are due to glucocorticoid deficiency and are manifested in infancy or early childhood. Typically they include skin hyperpigmentation, failure to thrive, hypoglycaemia, which in some children may be lethal. Allgrove's syndrome, is considered to be a separate condition, characterized by glucocorticoid deficiency along with alacrimia, achalasia and neurological deficits. Treatment of FGD includes substitution of glucocorticoids with dose adjustment depending on the clinical state. Such treatment usually prevents from hypoglycaemia and provides normal growth and development of the patient.
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PMID:[Familial glucocorticoid deficiency]. 1788 Aug 14


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