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• W2167804474 abstract "Triple A syndrome, alternatively referred to as Allgrove syndrome (MIM #231550), is a complex autosomal recessive disorder, characterized by a symptom cluster of alacrima, adrenocorticotropin hormone-resistant adrenal insufficiency, and achalasia.1Allgrove J. Clayden G.S. Grant D.B. et al.Familial glucocorticoid deficiency with achalasia of the cardia and deficient tear production.Lancet. 1978; 1: 1284-1286Abstract PubMed Scopus (382) Google Scholar Owing to marked clinical heterogeneity, some patients may suffer from progressive neurological impairment involving the central, peripheral, and the autonomous nervous systems (“4A syndrome”), while others may exhibit only 2 of these features (“2A phenotype”).2Prpic I. Huebner A. Persic M. et al.Triple A syndrome: genotype-phenotype assessment.Clin Genet. 2003; 63: 415-417Crossref PubMed Scopus (82) Google Scholar The disorder is related to mutations in the AAAS gene on chromosome 12q13, coding for ALADIN (“alacrima-achalasia-adrenal insufficiency neurologic disorder”), a unique 60-kDa WD repeat-containing component of the nuclear pore complex.3Tullio-Pelet A. Salomon R. Hadj-Rabia S. et al.Mutant WD-repeat protein in triple-A syndrome.Nat Genet. 2000; 26: 332-335Crossref PubMed Scopus (265) Google Scholar With a perspective of the localization and presumed cellular functions of ALADIN, aberrant nucleocytoplasmic shuttling and aberrant assembly of multimolecular complexes may be involved in the pathogenesis.4Cronshaw J.M. Matunis M.J. The nuclear pore complex protein ALADIN is mislocalized in triple A syndrome.Proc Natl Acad Sci U S A. 2003; 100: 5823-5827Crossref PubMed Scopus (151) Google Scholar Although the precise role of ALADIN in health and disease awaits refinement, it has been hypothesized that tissue-specific neurodegeneration by oxidative stress may be a central disease mechanism.5Storr H.L. Kind B. Parfitt D.A. et al.Deficiency of ferritin heavy-chain nuclear import in triple a syndrome implies nuclear oxidative damage as the primary disease mechanism.Mol Endocrinol. 2009; 23: 2086-2094Crossref PubMed Scopus (68) Google Scholar Of interest, genetic variation at the AAAS locus has not been associated with “idiopathic” achalasia.6Di Nardo G. Tullio-Pelet A. Annese V. et al.Idiopathic achalasia is not allelic to alacrima achalasia adrenal insufficiency syndrome at the ALADIN locus.Dig Liver Dis. 2005; 37: 312-315Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Here, we provide a detailed characterization of the pathological substrate of an individual with genetically confirmed triple A syndrome-associated achalasia. A 37-year-old patient was referred to our hospital due to progressive dysphagia and recurrent aspiration episodes. Medical history included manometry-confirmed achalasia with previous endoscopic pneumatic dilatation sessions. In addition, there was mild mental retardation, presumably by perinatal brain damage. Three years before, triple A syndrome was suspected owing to complete alacrima and features of autonomous neuropathy including neurogenic bladder dysfunction. Adrenal insufficiency was excluded repeatedly. On endoscopy, there was a marked dilation of the esophagus with abrogated motility and food retention. There was kinking in the esophagus, and the cardia could be passed easily. Barium esophagography demonstrated sigmoid-type megaesophagus, while cerebral magnetic resonance imaging was normal. Conventional surgery with an option to secondary esophagectomy in case of treatment failure was recommended, and the patient finally underwent an uncomplicated Heller cardiomyectomy procedure with a loose Nissen fundoplication. Given the clinical diagnosis of triple A syndrome, genetic studies of the AAAS gene were performed. The index patient (II:5) was determined positive for the compound heterozygous mutations p.Arg119* and p.Lys301Asn (Figure 1A). While the p.Arg119* presumably leads to a truncated mislocalized protein or, in the first place, to a nonsense-mediated RNA decay, we demonstrated with anti-ALADIN antibody staining that the novel p.Lys301Asn correctly localizes to the nuclear pore complex comparable with the p.Leu430Phe7Koehler K. Brockmann K. Krumbholz M. et al.Axonal neuropathy with unusual pattern of amyotrophy and alacrima associated with a novel AAAS mutation p.Leu430Phe.Eur J Hum Genet. 2008; 16: 1499-1506Crossref PubMed Scopus (20) Google Scholar (Figure 1B). These 2 are the only point mutations not leading to a mislocalization, but rather impairing ALADIN function at the nuclear pore complex. Routine histopathological analysis of the cardiomyectomy strip specimen delineated a normal smooth musculature without significant inflammatory infiltrates. Specialized immunofluorescence analysis was performed, including the neuronal markers PDG9.5 and neuronal nitrite oxide synthetase (nNOS), the smooth muscle markers α smooth muscle antigen (SMA) and histone deacetylase 8 (HDAC8) as well as the interstitial cells of Cajal (ICC)-related marker KIT and SK3 for labeling of ICC-related fibroblast-like cells (FLC) (Figure 2). There was an inconspicuous immunoreactivity within well-preserved muscle bundles for SMA and HDAC8. Likewise, KIT staining delineated a normal distribution of spindle-shaped ICC and KIT-negative FLCs within smooth muscle bundles. However, the distribution of the pan-neuronal marker PDG9.5 was very scarce in nerve bundles, while no myenteric neurons were identified. Even after antigen retrieval, nNOS staining failed to detect any specific labeling. Taken together, the dedicated pathological analyses of the neuromuscular interface support the notion of esophagus-specific neurodegeneration with a complete absence of inhibitory nitrergic neurons underlying this individual's achalasia, which adds to the very scarce literature on specialized pathological analysis of triple-A-related achalasia.8Khelif K. De Laet M.H. Chaouachi B. et al.Achalasia of the cardia in Allgrove's (triple A) syndrome: histopathologic study of 10 cases.Am J Surg Pathol. 2003; 27: 667-672Crossref PubMed Scopus (62) Google Scholar" @default.
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• W2167804474 date "2015-09-01" @default.
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• W2167804474 title "Organ-specific Neurodegeneration in Triple A syndrome-related Achalasia" @default.
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