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)

Human adrenal development is a complex and relatively poorly understood process. However, significant insight into some of the mechanisms regulating adrenal development and function is being obtained through the analysis of individuals and families with adrenal hypoplasia. Adrenal hypoplasia can occur: (1) secondary to defects in pituitary adrenocorticotropin (ACTH) synthesis, processing and release (secondary adrenal hypoplasia; e.g. HESX1, LHX4, SOX3, TPIT, pituitary POMC, PC1); (2) as part of several ACTH resistance syndromes (e.g. MC2R/ACTHR, MRAP, Alacrima, Achalasia, Addison disease), or as (3) a primary defect in the development of the adrenal gland itself (primary adrenal hypoplasia; e.g. DAX1/NR0B1 - dosage-sensitive sex reversal, adrenal hypoplasia congenita critical region on the X chromosome 1). Indeed, the X-linked form of primary adrenal hypoplasia due to deletions or mutations in the orphan nuclear receptor DAX1 occurs in around half of male infants presenting with a salt-losing adrenal crisis, where no obvious steroidogenic defect (e.g. 21-hydroxylase deficiency), metabolic abnormality (e.g. neonatal adrenoleukodystrophy) or physical cause (e.g. adrenal haemorrhage) is found. Establishing the underlying basis of adrenal failure can have important implications for investigating associated features, the likely long-term approach to treatment, and for counselling families about the risk of other children being affected.
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PMID:Disorders of adrenal development. 1849 31

The triple A syndrome is a rare autosomal recessive disease that is characterised by the triad of adrenocorticotropin (ACTH)-resistant adrenal insufficiency, achalasia and alacrima. In most patients, neurological and dermatological abnormalities are associated features. We report on the first Bosnian patient with triple A syndrome. Endocrine investigation confirmed primary adrenal insufficiency at the age of 5.8 years. Two months later, achalasia was diagnosed, and in the presence of alacrima, the patient satisfies the diagnostic criteria of triple A syndrome. In addition, a large number of associated neurological and dermatological features were present in this patient. Moreover, he has dysmorphic facial features, which have not been previously described in triple A syndrome. Triple A syndrome was confirmed by molecular analysis, revealing a nonsense mutation p.W84X in the AAAS gene. The parents are both heterozygous carriers of the mutation. The affected twin brother unfortunately died from hypoglycaemic shock, despite a normal cortisol rise in an ACTH stimulation test. Further, triple A syndrome patients carrying the identical homozygous p.W84X mutation have to be studied to assess a genotype-phenotype relationship for this mutation.
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PMID:Clinical and molecular genetic findings in a 6-year-old Bosnian boy with triple A syndrome. 1855 17

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

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.
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PMID:[Allgrove syndrome (triple A). Finding of a mutation not described in the AAAS gene]. 2282 7

Triple A (or Allgrove) syndrome is an autosomal recessive genetic disorder. Patients typically suffer from chronic adrenal insufficiency due to resistance to ACTH (Addison's disease), achalasia of the cardia, and defective tear formation (alacrima). The syndrome is caused by mutations in the AAAS gene which encodes the protein ALADIN, a constituent of eukaryotic nuclear pore complexes. The multi-systemic nature and variable manifestations of the triple A syndrome often confound its diagnosis and limit our understanding of its exact pathogenesis. We performed mutational screening of the AAAS gene in a Greek family of four individuals, including an affected propositus with typical symptoms of late-onset triple A syndrome. Our results are consistent with an autosomal recessive pattern of inheritance within the family, caused by a functional c.43C>A mutation in exon 1 of the AAAS gene. All members of the family were also homozygous for a silent c.855C>T nucleotide change within exon 9 of the AAAS gene, representing a common single nucleotide polymorphism. The compromising c.43C>A mutation is predicted to cause a p.Gln15Lys amino acid substitution in the ALADIN protein. However, it has been suggested that the functional impact of this mutation may be more severe, causing a shift in the reading frame of AAAS gene via formation of an aberrant premature donor splice site within exon 1. We propose that mutational analysis of the AAAS gene should be considered in adult patients with one or more clinical signs of the disease, as diagnosis of late-onset cases can be ambiguous.
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PMID:The genetic basis of triple A (Allgrove) syndrome in a Greek family. 2307 54

Triple A (Allgrove) syndrome was first described by Allgrove in 1978 in two pairs of siblings. Since then, about 100 cases have been reported, all of them displaying an autosomal recessive pattern of inheritance. Clinical picture is characterized by achalasia, alacrimia and ACTH-resistant adrenal failure. A progressive neurological syndrome including central, peripheral and autonomic nervous system impairment, and mild mental retardation is often associated. The triple A syndrome gene, designated AAAS, is localized on chromosome 12q13. It consists of 16 exons, encoding for a 546 aminoacid protein called ALADIN (Alacrimia-Achalasia-aDrenal Insufficiency Neurologic disorder).
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PMID:Triple A (Allgrove) syndrome: an unusual association with syringomyelia. 2380 Jan 7

BACKGROUND Allgrove syndrome, or triple "A" syndrome (3A syndrome), is a rare autosomal recessive syndrome with variable phenotype, and an estimated prevalence of 1 per 1,000,000 individuals. Patients usually display the triad of achalasia, alacrima, and adrenocorticotropin (ACTH) insensitive adrenal insufficiency, though the presentation is inconsistent. CASE REPORT Here, the authors report a case of Allgrove syndrome in a pediatric patient with delayed diagnosis in order to raise awareness of this potentially fatal disease as a differential diagnosis of alacrima. CONCLUSIONS The prevalence of Allgrove syndrome may be much higher as a result of underdiagnosis and missed diagnosis due to the variable presentation and sudden unexplained childhood death from adrenal crisis. The authors review the characteristic symptoms of Allgrove syndrome in relation to the case study in order to avoid missed or delayed diagnosis, potentially decreasing morbidity, and mortality in those affected by this disease.
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PMID:Alacrima as a Harbinger of Adrenal Insufficiency in a Child with Allgrove (AAA) Syndrome. 2769 38


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