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)

The triple A syndrome is a complex and multisystemic autosomal recessive disease with the 3 main symptoms of adrenal insufficiency, alacrima, and achalasia accompanied by neurological impairment. Mutations in the AAAS gene on chromosome 12q13 are responsible for the disorder. AAAS encodes a protein named ALADIN, which belongs to the family of WD-repeat-containing proteins and has been shown to localize to nuclear pore complexes. The function of the protein is not clear. It is supposed that ALADIN plays an important role in RNA and (or) protein trafficking between the nucleus and cytoplasm. With transfection experiments, we analyzed the cellular localization of the wild-type and 17 natural mutant variants (9 missense, 5 nonsense, 3 frameshift mutations) of ALADIN. We show that most mutations cause mislocalization of the mutant ALADIN proteins in the cytoplasm. In contrast, some variants with mutations located at the N-terminus (Q15K, L25P) and 3 artificial C-terminus mutations (Q490X, R493X, and V497X) remain at the nuclear pore. Using a patient cell line, we show that the mutation 43C>A in exon 1 does not cause a missense mutation Q15K but, rather, results in aberrant splicing.
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PMID:Cellular localization of 17 natural mutant variants of ALADIN protein in triple A syndrome - shedding light on an unexpected splice mutation. 1660 5

We report on the first Chinese patient with triple-A syndrome, who presented at 22 months with status epilepticus secondary to hyponatraemia and hypoglycaemia. Subsequent endocrine investigations confirmed primary adrenal insufficiency and aldosterone deficiency. In the presence of achalasia and alacrima, this patient satisfies the diagnostic criteria of triple-A syndrome. Further molecular testing detected compound heterozygous mutations in the AAAS gene: a c.580C --> T transition in exon 7 and a c.771delG single nucleotide deletion in exon 8. Testing of parents and brother confirmed their heterozygous carrier status.
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PMID:Triple-A syndrome--the first Chinese patient with novel mutations in the AAAS gene. 1678 45

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

Allgrove syndrome (triple A syndrome) is a rare autosomal recessive disorder characterized by achalasia, alacrima, adrenal insufficiency, and--occasionally--autonomic instability. Disease causing mutations have been found in the AAAS gene on 12q13, but no strong phenotype-genotype correlation could be found. We present a 28 year-old woman with classical systemic features of triple A syndrome with prominent neurological dysfunctions/deficits, including distal muscular atrophy, progressive muscle weakness and wasting of both legs, sensibility dysfunction, hyperreflexia and autonomic dysfunction presented with excessive sweating. DNA sequencing of the AAAS gene revealed compound heterozygosity for previously reported mutations. A similar genotype was previously reported, but with a remarkably different phenotype.
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PMID:Heterogeneity of the triple A syndrome and assessment of a case. 1697 37

Triple A syndrome is an autosomal recessive disorder resulting from deleterious mutations in the AAAS gene located on chromosome 12q13. Typical clinical presentation of this syndrome includes adrenal insufficiency, achalasia, and alacrima. A 10-year-old female was diagnosed with Triple A syndrome at the age of 1 year. Initial analysis of the AAAS gene revealed apparently homozygosity for a novel 2bp deletion in exon 1. The father of the patient was heterozygous for this mutation but the mother and the maternal grandparents were apparently homozygous for the wild-type. Further studies demonstrated that the patient carried an intragenic 3.2kb deletion within both 5' and 3' breakpoints located within Alu-repeats. The deletion includes 5'-flanking region, exon 1, intron 1, exon 2, and part of intron 2 sequences of the AAAS gene. This Alu-mediated deletion was inherited from her mother and maternal grandmother. This is the first report that Alu-mediated rearrangement in conjunction with a novel two-bp deletion of the AAAS gene is a cause of Triple A syndrome. The results of our study lead to the hypothesis that an Alu-mediated mechanism may be responsible for large alterations in the AAAS gene. We also stress the importance of studying the family in genetic recessive diseases, such as Triple A syndrome, to avoid incorrect diagnosis and to provide accurate genetic counseling.
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PMID:An Alu-mediated rearrangement causing a 3.2kb deletion and a novel two base pair deletion in AAAS gene as the cause of triple A syndrome. 1791 Oct 39

The triple A syndrome is an autosomal recessive disorder characterized by adrenal insufficiency, alacrima, achalasia, and impairment of the central, peripheral, and autonomic nervous system functions. The disease is caused by mutations in the AAAS gene on chromosome 12q13 encoding the nuclear pore protein ALADIN. In the present study, we report three siblings with triple A syndrome caused by a compound heterozygous mutation consisting of a novel Val421 frameshift mutation in exon 14 and a previously described Ser236Pro (T>C transition) missense mutation in exon 8. The second mutation is one of the most frequent mutations in the AAAS gene, occurring in 17 independent patients from different countries. With haplotype analysis, we demonstrate a founder effect for at least 13 of the 17 patients. We conclude that, although very helpful in establishing the final diagnosis of triple A syndrome, DNA analysis is not useful for the prediction of the clinical expression and outcome of the disorder. Further investigations are necessary to evaluate the correlation between genotype and clinical phenotype in the triple A syndrome.
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PMID:Three siblings with triple A syndrome with a novel frameshift mutation in the AAAS gene and a review of 17 independent patients with the frequent p.Ser263Pro mutation. 1817 84

Allgrove syndrome is a rare autosomal recessive disorder characterised by childhood onset, alacrima, oesophageal achalasia, adrenocortical insufficiency, neurological and occasionally autonomic involvement. Although the disease has been associated with mutations in the ALADIN gene on chromosome 12q13, it is genetically heterogeneous. The case we report is interesting because of its onset in adulthood, long duration of disease and prominent neurological dysfunctions. After the onset of neurological abnormalities the diagnosis went unrecognised for years until the patient presented for evaluation of dysphagia. The presence of achalasia with dysphagia, adrenal insufficiency, reduced tear production, optic atrophy and peripheral motor-sensory neuropathy with axonal loss led us to clinically diagnose Allgrove syndrome even though a genetic study showed no mutations in the ALADIN gene exons. The case we report shares many clinical features with Allgrove syndrome and, even with the limitations of a single case, underlines the variability in this syndrome and the need for appropriate investigations along with a multidisciplinary approach.
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PMID:Case report of adult-onset Allgrove syndrome. 1817 81

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

We report a 22-year-old female who presented with distal muscular atrophy and weakness in all limbs for two years. Reflexes were symmetrically brisk and electrodiagnostic studies were consistent with upper and lower motor neuron involvement. A diagnosis of juvenile ALS was considered. However, surgery for achalasia in childhood and identification of alacrima and adrenal insufficiency suggested Triple A syndrome accompanied by neurological symptoms. Sequencing of the AAAS gene identified compound heterozygous mutations confirming the clinical diagnosis and demonstrating that Triple A syndrome can mimic juvenile ALS.
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PMID:Triple A syndrome mimicking ALS. 1861 37

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.
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PMID:Axonal neuropathy with unusual pattern of amyotrophy and alacrima associated with a novel AAAS mutation p.Leu430Phe. 1862 86


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