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PubMed2003

The hypoparathyroidism of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protective effect of male sex.

In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, hypoparathyroidism (HP) is the most common endocrine component. It occurs in most (but not all) patients. Determinants of its occurrence are unknown, and there is no proof for its autoimmune nature. Recently, the Ca(2+)-sensing receptor (CaSR) was reported to be an autoantigen in HP. With our group of 90 patients, we aimed at identifying the determinants and pathomechanism of HP. For the determinants, we evaluated gender and the HLA class II. For the pathomechanism, we searched for parathyroid autoantibodies, including antibodies against CaSR and PTH. Also, we studied whether AIRE is expressed in the human parathyroid, because its absence could be a pathogenetic factor. We found a clear gender linkage with lower and later incidence in males. Of the 14 patients who had escaped HP, 13 were males. This was associated with adrenal failure, which was the first or only endocrinopathy in 47% of males vs. 7% of females. In contrast, we found no linkage to the HLA class II. By immunofluorescence, 19% of the patients had antibodies to parathyroid epithelia. By immunoblotting, these recognized several parathyroid proteins. No antibodies were observed against the CaSR or PTH. By RT-PCR, AIRE mRNA was not found in the parathyroid.

Adolescent↗
PubMed2005

Autoimmune regulator-1 messenger ribonucleic acid analysis in a novel intronic mutation and two additional novel AIRE gene mutations in a cohort of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients.

CONTEXT: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disease associated with mutations in the AIRE gene. OBJECTIVE: Our objective was to investigate clinical and mutational characteristics of 12 Slovenian patients from 10 families with APECED. METHODS: Direct sequencing, restriction fragment length polymorphism, and amplification refractory mutation system analyses were used to identify AIRE gene mutations. Autoimmune regulator (AIRE)-1 mRNA analysis was used to confirm pathogenicity of the intronic mutation. RESULTS: The prevalence of APECED in Slovenian population was estimated to be 1 in 43,000, which is significantly higher compared with the neighboring populations. Three novel mutations were identified among six different mutations detected in the AIRE gene. The first novel mutation was an intronic mutation (653-7_-5delCTC) affecting proper splicing by using a nearby new acceptor splice site as demonstrated by AIRE-1 mRNA analyses. The second and third novel mutations were frame-shift mutations located in exon 5 (540delG) and exon 9 (1064-1068dupCCCGG), both leading to premature truncation of the AIRE protein. The Finnish R257X mutation was the most frequent AIRE gene mutation in Slovenian patients with APECED (16 of 24 alleles). CONCLUSIONS: Three novel AIRE gene mutations were identified. For the first time, a novel intronic mutation was investigated on the mRNA level in APECED. This could be particularly important for APECED patients where no or only heterozygous mutation on the genomic DNA level is detected.

Adolescent↗
PubMed2005

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome with renal failure: impact of posttransplant immunosuppression on disease activity.

CONTEXT: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder caused by mutations in the gene AIRE (autoimmune regulator). APECED affects mainly endocrine organs resulting in hypoparathyroidism, adrenocortical failure, diabetes mellitus, hypogonadism, and hypothyroidism. Nonendocrine organ manifestations are autoimmune hepatitis, vitiligo, pernicious anemia, exocrine pancreatic insufficiency, and alopecia. APECED's first manifestation generally is mucocutaneous candidiasis presumably related to T cell dysfunction. PATIENT: A 5-yr-old Iranian girl presented first with pernicious anemia, exocrine pancreatic insufficiency, and nail candidiasis. She had renal dysfunction due to chronic interstitial nephritis (CIN), which progressed to end-stage renal failure. She was transplanted 1 yr later. Common causes of CIN were excluded. APECED was suspected first because she developed progressively hypoparathyroidism, adrenocortical failure, glucose intolerance, and hypothyroidism. RESULTS: Genetic analysis revealed a large homozygous deletion (g.424_2157del1734), spanning exons 2-4, in the AIRE gene. The predicted protein, if it is produced, has only 44 amino acids (exon 1) in common with the wild-type protein. Immunosuppression after the first renal transplant included prednisone, azathioprine, and cyclosporine A. Multiple acute rejection episodes occurred. Chronic rejection resulted in lost graft and she was retransplanted 2 yr later. Surprisingly, all APECED-related symptoms including candidiasis and autoantibody levels decreased, presumably due to the reinforced immunosuppression (tacrolimus, mycophenolate mofetil, prednisone). CONCLUSIONS: This is the first report of an APECED patient with CIN resulting in end-stage renal failure. Clinical and biological improvement was observed under posttransplant multidrug immunosuppression including tacrolimus and mycophenolate mofetil.

Anti-Inflammatory Agents↗
PubMed1997

Coexpression of stromelysin-3 and insulin-like growth factor II in tumors of ectodermal, mesodermal, and endodermal origin: indicator of a fetal cell phenotype.

Stromelysin-3 (ST-3) is thought to play an important role in invasion and tumor progression. We have analyzed ST-3 expression in fibroblasts with defined topographical relations to breast cancers. We demonstrate that these fibroblasts exhibit the same distinctive pattern of messenger ribonucleic acid (mRNA) expression that we have previously shown for insulin-like growth factor II (IGF-II). Tumor-derived fibroblasts and skin fibroblasts produce abundant ST-3 mRNA. Fibroblasts from normal breast stroma distant from the malignant tumor in the same patient express considerably less ST-3 mRNA. When we analyzed ST-3 and IGF-II gene expression in sarcomas, we found a similar pattern of coexpression. Immunohistochemical analysis of IGF-II and ST-3 protein expression in sarcomas and breast tumors confirmed the mRNA data. ST-3 mRNA expression was also seen in most colon cancer cell lines, again matching reports of IGF-II gene expression. As the two proteins are known to play an important role during fetal growth and development, their coexpression in fibroblasts from malignant tumors of ectodermal (breast cancer) and mesodermal (sarcoma) origin and in epithelial cells of endodermal origin (colon cancer) implies a more primitive cellular phenotype. The regained ability to express such developmentally regulated proteins might, therefore, be a more general marker indicating a fetal-type phenotype of cells in a malignant tumor.

Breast Neoplasms↗
PubMed1999

Severe autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy in an adolescent girl with a novel AIRE mutation: response to immunosuppressive therapy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disorder for which the gene (AIRE) has recently been identified on chromosome 21q22.3. We present the mutational analyses of a French-Canadian family with APECED, in which there are two affected siblings, as well as the response to cyclosporine A(CyA) therapy in the index patient, the eldest sibling. Haplotype analysis suggested compound heterozygozity at the AIRE locus. Direct sequencing of exon 8 revealed a previously described mutation, a 13-bp deletion (1085-1097) of maternal origin, found in the index patient, her affected sister, and her unaffected sister. A novel missense mutation characterized by a T-->G transversion at nucleotide position 398, resulting in a leu-->arg amino acid substitution (L93R), was found in exon 2. The mutation was present in the father, the brother, the index patient, and the affected sister. The presence of the mutation in the propositus was verified by cloning of PCR products from genomic DNA. The mutation destroys a PstI restriction enzyme site, as confirmed in the aforementioned patients. Screening of 50 French-Canadian controls with PstI digestion did not show destruction of the restriction-enzyme site. The index patient's phenotype was severe, manifested by classic features of the illness (adrenal insufficiency, hypoparathyroidism, candidiasis, and keratoconjunctivitis with alopecia universalis), as well as by severe exocrine pancreatic insufficiency, diabetes mellitus, hepatic inflammation, growth hormone (GH) deficiency due to lymphocytic hypophysitis, and primary ovarian failure. Oral CyA (5 mg/kg/day) was initiated at 13 yr of age. After 8 months of therapy, stimulated pancreatic lipase increased 24-fold with normalization of stool fat (from 31.5 g/day to 2.5 g/day, normal(N) < 5). There was complete resolution of her photophobia, and considerable hair regrowth was diffusely apparent. Minimal side effects were noted. Our experience supports the use of oral CyA for the treatment of severe APECED-associated exocrine pancreatic failure and keratoconjunctivitis.

Adolescent↗
PubMed2000

ss-cell autoantibodies, human leukocyte antigen II alleles, and type 1 diabetes in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is caused by lack of functional products of the autoimmune regulator gene located on chromosome 21q22.3. The patients are at high risk of developing insulin-dependent (type 1) diabetes, but the positive predictive value of GAD65 or islet cell antibodies for type 1 diabetes is only 27%. Autoantibodies against the IA-2 tyrosine phosphatase-like protein (IA-2 ab) or insulin (IAA) have been suggested to be better markers for active ss-cell destruction. We studied these antibodies in sera from 60 Finnish patients with APECED, 12 of whom subsequently developed type 1 diabetes. Four (36%) of the 11 patients for whom we had prediabetic samples had IA-2 ab, and 4 (36%) had IAA. None of the 48 nondiabetics had IAA, and only 2 (4%) had IA-2 ab. Both had the antibodies for years without diabetes. Thus, IA-2 ab or IAA have a low sensitivity (36%), but high specificity (96% or 100%), with a positive predictive value of 67% for type 1 diabetes in patients with APECED. Data for human leukocyte antigen haplotypes were available for 59 of the patients, including 11 diabetics, and for 8 additional nondiabetic Finnish patients. No association between type 1 diabetes and high risk genotypes was seen. None of the 11 patients with type 1 diabetes, but 15 of the 56 (27%; P: < 0.05) nondiabetic patients and 24 of 93 (26%; P: < 0.05) of the control subjects had the DQB1*0602 allele, which is considered protective for type 1 diabetes. This is remarkable, as previously no positive or negative associations have been reported for any disease components of APECED with human leukocyte II antigens.

Adolescent↗
PubMed2000

Novel mutations of the autoimmune regulator gene in two siblings with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is the first multiple autoimmune disease that has been shown to be caused by mutations of a single gene named autoimmune regulator (AIRE). Fourteen different mutations of the AIRE gene have been identified in 61 patients from 55 families with APECED. However, there has been no report documenting AIRE gene mutations in the Asian population. We report on 2 siblings with variable manifestations of APECED who were born to a Japanese mother and a Korean father. The 11yr-old girl had intractable thrush and ungual candidiasis, hypoparathyroidism, and occipital alopecia. The 9-yr-old boy had mild ungual candidiasis alone. Direct sequencing revealed novel frameshift mutations of the AIRE gene: an insertion of a cytosine at nucleotide 29635 at the exon 10 (29635insC), which should lead to a premature termination at the codon 371, producing a truncated protein missing the second plant homeodomain-type zinc finger motif and the third LXXLL motif, and a deletion of a guanine at nucleotide 33031 at the exon 13 (33031delG), which should result in a premature termination at the codon 520, yielding a truncated protein missing the third LXXLL motif. The mother was heterozygous for 29635insC, and the father was heterozygous for 33031delG. The frameshift mutations were undetected in 40 alleles of 20 Japanese control subjects. The results imply that the C-terminus of AIRE protein including the third LXXLL motif plays a critical role in the development of APECED, and that the phenotypic spectrum can vary between siblings with the same mutations.

Child↗
PubMed1998

Common mutations in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients of different origins.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; OMIM *240300, also called APS 1,) is a rare autosomal recessive disorder that is more frequent in certain isolated populations. It is generally characterized by two of the three major clinical symptoms that may be present, Addison's disease and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. Patients may also have a number of other clinical symptoms including chronic gastritis, gonadal failure, and rarely, autoimmune thyroid disease and insulin-dependent diabetes mellitus. We and others have recently identified the gene for APECED, which we termed AIRE (for autoimmune regulator). AIRE is expressed in thymus, lymph nodes, and fetal liver and encodes a protein containing motifs suggestive of a transcriptional regulator, including two zinc finger motifs (PHD finger), a proline-rich region, and three LXXLL motifs. Six mutations, in cluding R257X, the predominant Finnish APECED allele, have been defined. R257X was also observed in non-Finnish APECED patients occurring on different chromosomal haplotypes suggesting different mutational origins. Here we present mutation analyses in an extended series of patients, mainly of Northern Italian origin. We have detected 12 polymorphisms, including one amino acid substitution, and two additional mutations, R203X and X546C, in addition to the previously described mutations, R257X, 1096-1097insCCTG, and a 13-bp deletion (1094-1106del). R257X was also the common mutation in the Northern Italian patients (10 of 18 alleles), and 1094-1106del accounted for 5 of 18 Northern Italian alleles. Both R257X and 1094-1106del were both observed in patients of four different geo-ethnic origins, and both were associated with multiple different haplotypes using closely flanking polymorphic markers showing likely multiple mutation events (six and four, respectively). The identification of common AIRE mutations in different APECED patient groups will facilitate its genetic diagnosis. In addition, the polymorphisms presented provide the tools for investigation of the involvement of AIRE in other autoimmune diseases, particularly those affecting the endocrine system.

Female↗
PubMed2006

Requirement for Map2k1 (Mek1) in extra-embryonic ectoderm during placentogenesis.

Map2k1(-/-) embryos die at mid-gestation from abnormal development and hypovascularization of the placenta. We now show that this phenotype is associated with a decreased labyrinth cell proliferation and an augmented cell apoptosis. Although the activation of MAP2K1 and MAP2K2 is widespread in the labyrinthine region, MAPK1 and MAPK3 activation is restricted to the cells lining the maternal sinuses, suggesting an important role for the ERK/MAPK cascade in these cells. In Map2k1(-/-) placenta, ERK/MAPK cascade activation is perturbed. Abnormal localization of the syncytiotrophoblasts is also observed in Map2k1(-/-) placenta, even though this cell lineage is specified at the correct time during placentogenesis. The placental phenotype can be rescued in tetraploid experiments. In addition, Map2k1-specific deletion in the embryo leads to normal embryo development and to the birth of viable Map2k1(-/-) mice. Altogether, these data enlighten the essential role of Map2k1 in extra-embryonic ectoderm during placentogenesis. In the embryo, the Map2k1 gene function appears dispensable.

Alleles↗
PubMed1988

Origin of the dorsal surface of the neural tube by progressive delamination of epidermal ectoderm and neuroepithelium: implications for neurulation and neural tube defects.

Knowledge of the morphogenetic events involved in the development of the dorsal portion of the neural tube is important for understanding neural tube closure, neural crest cell formation and emigration, and the origin of neural tube defects. Here, I characterize the progressive development of the tips of the neural folds during fold elevation in the trunk of mouse and chick embryos and the events leading to formation of the dorsal portion of the neural tube as the epidermal ectoderm (EE) and neuroepithelium (NE) separate from each other. The nature and timing of appearance of collagen IV, laminin and fibronectin were analysed by immunofluorescent and immunogold labelling, and ruthenium red and tannic acid were used to enhance staining for proteoglycans and glycosaminoglycans. As the neural folds elevate, the NE and EE delaminate progressively beginning at the basal surface of the lateral extremes of the neural plate. Nevertheless, the two epithelia remain connected across the zone of delamination by their previously existing basal laminae. In each fold, proteoglycan granules appear at the interface between the NE and EE before delamination begins, and then an (interepithelial) space begins to open and propagate dorsally. Other extracellular matrix (ECM) molecules appear within the space a short distance behind its tip and basal lamina deposition begins shortly thereafter. As fusion occurs, the interepithelial spaces of the two folds coalesce and the final separation of the EE from the NE is accomplished. These observations suggest that the previously recognized delay in deposition of ECM and basal lamina on the dorsal portion of the neural tube and on the overlying EE is a direct consequence of the delamination of the two epithelia and the establishment of two new basal surfaces. The observation that the surface of the dorsal third of the neural tube forms by delamination rather than by juxtaposition of previously existing basal surfaces of the two epithelial is discussed in terms of possible implications for models of neurulation and the origin of neural tube defects.

Animals↗
PubMed1998

Effects of Shh and Noggin on neural crest formation demonstrate that BMP is required in the neural tube but not ectoderm.

To define the timing of neural crest formation, we challenged the fate of presumptive neural crest cells by grafting notochords, Sonic Hedgehog- (Shh) or Noggin-secreting cells at different stages of neurulation in chick embryos. Notochords or Shh-secreting cells are able to prevent neural crest formation at open neural plate levels, as assayed by DiI-labeling and expression of the transcription factor, Slug, suggesting that neural crest cells are not committed to their fate at this time. In contrast, the BMP signaling antagonist, Noggin, does not repress neural crest formation at the open neural plate stage, but does so if injected into the lumen of the closing neural tube. The period of Noggin sensitivity corresponds to the time when BMPs are expressed in the dorsal neural tube but are down-regulated in the non-neural ectoderm. To confirm the timing of neural crest formation, Shh or Noggin were added to neural folds at defined times in culture. Shh inhibits neural crest production at early stages (0-5 hours in culture), whereas Noggin exerts an effect on neural crest production only later (5-10 hours in culture). Our results suggest three phases of neurulation that relate to neural crest formation: (1) an initial BMP-independent phase that can be prevented by Shh-mediated signals from the notochord; (2) an intermediate BMP-dependent phase around the time of neural tube closure, when BMP-4 is expressed in the dorsal neural tube; and (3) a later pre-migratory phase which is refractory to exogenous Shh and Noggin.

Animals↗
PubMed2004

Induction of tooth and eye by transplantation of activin A-treated, undifferentiated presumptive ectodermal Xenopus cells into the abdomen.

Activin A can induce the Xenopus presumptive ectoderm (animal cap) to form different types of mesoderm and endoderm at different concentrations and the animal cap treated with activin can function as an organizer during early development. The dissociated Xenopus animal cap cells treated with activin form an aggregate and it develops into various tissues in vitro. In this study, to induce jaw cartilage from undifferentiated cells effectively, we developed a culture method to manipulate body patterning in vitro, using activin A and dissociated animal cap cells. An aggregate consisting only of activin A-treated dissociated cells developed into endodermal tissues. However, when activin A-treated cells were mixed with untreated cells at a ratio of 1:5, the aggregate developed cartilage with the maxillofacial regional marker genes, goosecoid, Xenopus Distal-less 4 and X-Hoxa2. When this aggregate was transplanted into the abdominal region of host embryos, maxillofacial structures containing cartilage and eye developed. We raised these embryos to adulthood and found that tooth germ had developed in the transplanted tissue. Here, we show the induction of jaw cartilage, tooth germ and eye structures from animal caps using activin A in the aggregation culture method. This differentiation system will help to promote a better understanding of the regulating mechanisms of body patterning and tooth induction in vertebrates.

Abdomen↗
PubMed2002

A novel missense mutation of AIRE gene in a patient with autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED), accompanied with progressive muscular atrophy: case report and review of the literature in Japan.

Autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED) also known as autoimmune polyglandular syndrome type I, is a rare autosomal recessive disorder that results in several autoimmune diseases due to mutations in the AIRE (autoimmune regulator) gene. A 39-year-old female patient developed chronic mucocutaneous candidiasis at 3 yrs, idiopathic hypoparathyroidism at 11 yrs, chronic hepatitis at 23 yrs, Addison's disease and diabetes mellitus type I at 27 yrs. In addition, the patient developed progressive muscular atrophy of unknown etiology at the beginning of the third decade, and is bedridden at the present time. Her grandparents, parents, brother and daughter did not develop any features of APECED, but her father died of hepatoma. Direct sequencing of the AIRE gene revealed a novel missense mutation at exon 1 (R15C), which was identified to be of maternal origin. The other mutation was not found despite repeated sequencing of the whole coding regions. The R15C mutation was not detected in patients with idiopathic hypoparathyroidism (N= 10), idiopathic Addison's disease (N = 3), and normal subjects (N = 55). Although we could not analyze the father's gene, these results suggest that the patient is probably a compound heterozygote of the AIRE gene, in which the other abnormal allele could not be identified by the present analytical method. These data are compatible with the recent review that only one defective allele was detectable in some patients with clinically evident APECED. We found only six Japanese patients compatible with diagnosis of APECED, indicating that this autoimmune disease is extremely rare in our country.

Adult↗
PubMedDate not supplied

Immunological findings in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and their family members: are heterozygotes subclinically affected?

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED; APS-1) is an autosomal recessive autoimmune disease, caused by mutations in the AIRE (autoimmune regulator) gene. Due to the proposed role of AIRE in central immune tolerance, the immune investigation of four females diagnosed with APECED, their siblings, parents and 14 age-matched controls was performed. The parameters analyzed included immunoglobulins, autoantibodies, cellular immunity and production of cytokines IFNgamma, IL-4 and IL-10, reflecting Th1xTh2 balance. Low IFNgamma levels (455 +/- 191 pg/ml) were detected in all affected girls compared to controls (910 +/- 406 pg/ml). Two girls with homozygous R257X mutations showed similarly marked elevation of IgM and increase of CD3+CD4+ lymphocytes. Positive autoantibodies against smooth muscle were found in one affected girl; another girl and her mother had antibodies against gastric parietal cells. Interestingly, all fathers had dramatically elevated levels of IgA and activated T lymphocytes. High frequency of abnormal immune results among parents is a novel finding which might suggest a subclinical immune deficit in heterozygotes with AIRE mutations.

Adolescent↗
PubMed2000

Organ-specific and non-organ-specific autoantibodies in children and young adults with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

OBJECTIVE: The aim of the study was to assess the complex of autoantibodies which can be detected in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a rare autosomal recessive disease in which the extent of autoimmunity is still unknown. DESIGN: Antibodies (A) to parathyroid glands, adrenal cortex (AC-A), ovary and testis (steroid cell antibodies, SC-A), pancreatic islet cells (IC-A), gastric parietal cells, and non-organ-specific antigens were investigated in 11 APECED patients living in the Salento region of southern Italy. Further measurements included antibodies to cytochrome P450 (CYP) enzymes: cholesterol side-chain cleavage enzyme (CYP11A), 21-hydroxylase (CYP21) and 17alpha-hydroxylase (CYP17); and to glutamic acid decarboxylase 65-kDa isoform (GAD65), tyrosine phosphatase-like protein IA2, thyroglobulin (TG), thyroperoxidase (TPO), thyrotropin receptor, liver CYP enzymes and intrinsic factor. METHODS: Antibodies to organs and subcellular fractions were detected by immunofluorescence. Radiobinding, immunoradiometric, and immunoblotting assays were used for the other measurements. RESULTS: AC-A and SC-A were positive in all sera; among antibodies to adrenal CYP enzymes, only CYP21-A were present in all the patients with Addison's disease of short-medium duration (<15 years). Of three patients with Addison's disease of long duration (>15 years), two tested positive for antibodies to all three CYP enzymes, and the other for only CYP11A-A. In all sera CYP11A-A and/or CYP17-A were found. Two patients tested positive for both IC-A and GAD65-A, one for both IC-A and IA2-A, and one for GAD65-A; the fasting C-peptide assay showed no statistical difference between these four subjects and the others. All four hypothyroid patients were positive for TPO-A, while two of them were positive and two were negative for TG-A; two euthyroid subjects had positivity for TG-A. Liver-kidney microsomal antibodies reacting against the CYP2A6 were detected in two patients with autoimmune hepatitis. All but one sera contained anti-nuclear antibodies at a titre ranging between 1:20 and 1:80; however, only two patients had a connective tissue disease (Sjögren's syndrome). CONCLUSIONS: Several autoantibodies may be detected in any APECED patient. Our data confirm that CYP21-A and TPO-A are major autoantibodies involved in APECED-associated Addison's disease and hypothyroidism respectively, while CYP11A-A and CYP17-A correlate with positivity for SC-A. Markers of islet cell autoimmunity are frequent, but prevalence and modalities of progression to overt beta-cell failure have to be clarified. Low-titre non-organ-specific autoantibodies are a feature of autoimmunity in APECED, but their role has yet to be fully explained.

Adolescent↗
PubMed2001

Identification of a novel mutation in the autoimmune regulator (AIRE-1) gene in a French family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is clinically characterized by the presence of two of the three major clinical symptoms: Addison's disease and/or hypoparathyroidism and/or chronic mucocutaneous candidiasis. Because of its autosomal recessive inheritance, this rare disorder constitutes an interesting model for understanding the molecular background of autoimmunity. Recently, mutations in the autoimmune regulator (AIRE-1) gene have been identified in APECED patients. Here we report, in a large French APECED family, the identification of a novel AIRE-1 missense mutation (Pro326Leu) in association with the Arg257Stop mutation which is detected in more than 80% of mutant Finnish AIRE-1 alleles. This Pro326Leu substitution occurs in the first plant homeodomain (PHD)-type zinc-finger domain of the protein which has been identified in a number of nuclear proteins involved in chromatin-mediated transcriptional regulation, such as ATRX, TIF1, KRIP-1 and Mi-2 autoantigen. This mutation highlights the key role of this amino acid in the structure of the PHD domain and confirms that exon 8 constitutes a mutational hotspot.

Adult↗
PubMed2005

Characterization of the humoral immune response to glutamic acid decarboxylase in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and/or type 1 diabetes.

OBJECTIVE: A humoral autoimmune response to glutamic acid decarboxylase (GAD65) is common both in patients with type 1 diabetes and in those with the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome, while overt type 1 diabetes is relatively rarely diagnosed in APECED patients. The aim of this study was to assess whether this difference in the incidence of type 1 diabetes is associated with variability in the humoral immune response to GAD65, one of the major autoantigens in type 1 diabetes. METHODS: Epitope- and isotype-specific GAD65 autoantibodies were analysed in 20 patients with APECED and 20 patients with newly diagnosed type 1 diabetes alone by radiobinding assays. RESULTS: GAD65 autoantibodies targeted the middle and carboxy-terminal regions of GAD65 and occasionally the amino-terminal region in the APECED patients and comprised mainly the IgG1 subclass and less frequently the IgG2 and IgG4 subclasses. The profile of epitope- and isotype-specific GAD65 autoantibodies was similar in type 1 diabetes and APECED, except that IgG2 subclass antibodies were observed more often and at higher levels in the patients with type 1 diabetes alone (P < 0.05). None of the measured parameters separated APECED patients with type 1 diabetes from those without type 1 diabetes. CONCLUSION: APECED-associated humoral autoimmunity to GAD65 does not differ markedly from that observed in type 1 diabetes; only IgG2-GAD65 antibodies may be more closely associated with the latter entity.

Adult↗
PubMed1989

Periodic hypersomnia, congenital ectodermal disorders and multiple exostosis.

A case of periodic hypersomnia in an 11-year-old female with the unique features of mental deficiency, incontinentia pigmenti, acanthosis nigricans and hereditary multiple exostosis (diaphysial aclasis) is reported. The clinical, polysomnographic and Multiple Sleep Latency test features of this case with a follow up of seven years are consistent with a diagnosis of periodic (intermittent) excessive somnolence. The unique presentation, however, does differ from Kleine-Levin syndrome and suggests a relationship between the predominantly ectodermal, congenital disorders and the sleep-wake pattern dysfunction.

Child↗