Early-Onset, Coexisting Autoimmunity and Decreased HLA-Mediated Susceptibility Are the Characteristics of Diabetes in Down Syndrome

Aitken, Rachel J; Mehers, Kay L.; Williams, A. J. K.; Brown, J. G. S.; Bingley, Polly J.; Holl, Reinhard W.; Rohrer, Tilman; Schober, Edith; Abdul-Rasoul, Majedah; Shield, Julian; Gillespie, Kathleen M.

doi:10.2337/dc12-1712

Cited by 42 publications

(49 citation statements)

References 37 publications

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“…A previous study showed that DS with diabetes had intermediate HLA association (7). The highest-risk HLA diplotype-DR3/DR4-was present in half as many DS diabetes cases compared with T1D (17% of DS diabetes, 38% of T1D, 3% of control subjects).…”

Section: Discussionmentioning

confidence: 90%

“…Large studies have shown childhood-onset autoimmune diabetes is four times more common in DS than in the general population and has an intermediate HLA association (6). There have been three reported cases of DS with diabetes diagnosed before 6 months (DS-PNDM) (7,8). However, it is not known whether DS was the cause of PNDM or a coincidental finding in these patients.…”

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confidence: 99%

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Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated

et al. 2019

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Identifying new causes of permanent neonatal diabetes (PNDM) (diagnosis <6 months) provides important insights into b-cell biology. Patients with Down syndrome (DS) resulting from trisomy 21 are four times more likely to have childhood diabetes with an intermediate HLA association. It is not known whether DS can cause PNDM. We found that trisomy 21 was seven times more likely in our PNDM cohort than in the population (13 of 1,522 = 85 of 10,000 observed vs. 12.6 of 10,000 expected) and none of the 13 DS-PNDM patients had a mutation in the known PNDM genes that explained 82.9% of non-DS PNDM. Islet autoantibodies were present in 4 of 9 DS-PNDM patients, but DS-PNDM was not associated with polygenic susceptibility to type 1 diabetes (T1D). We conclude that trisomy 21 is a cause of autoimmune PNDM that is not HLA associated. We propose that autoimmune diabetes in DS is heterogeneous and includes coincidental T1D that is HLA associated and diabetes caused by trisomy 21 that is not HLA associated.Permanent neonatal diabetes (PNDM) is diagnosed before the age of 6 months, and a genetic diagnosis is possible for .82% of cases (1). Twenty-four causative PNDM genes have been identified (1-4), and four of these cause monogenic autoimmune PNDM that results from destruction of the b-cells very early in life (FOXP3, IL2RA, LRBA, and STAT3). Identifying novel causes of autoimmune neonatal diabetes can provide key insights into the development of autoimmunity and can provide new targets for therapeutic intervention.Down syndrome (DS) is caused by trisomy of chromosome 21 and has an incidence of 1:700 to 1:1,100 live births (5). Large studies have shown childhood-onset autoimmune diabetes is four times more common in DS than in the general population and has an intermediate HLA association (6). There have been three reported cases of DS with diabetes diagnosed before 6 months (DS-PNDM) (7,8). However, it is not known whether DS was the cause of PNDM or a coincidental finding in these patients. The aim of our study was to use our large international cohort of PNDM patients to assess whether DS can aetiologically cause PNDM. We assessed clinical phenotype, islet autoantibodies, and polygenic risk of T1D in patients with monogenic PNDM and DS-PNDM. RESEARCH DESIGN AND METHODS Study PopulationWe defined PNDM as diabetes diagnosed before the age of 6 months, which is treated with continual insulin treatment. We studied 1,522 DNA samples from two international collections of PNDM patients, 1,360 recruited in Exeter and 162 recruited in Chicago. These either had a confirmed monogenic etiology (82.9% [n = 1,262]) or had been tested (and were negative) for all 24 known genes (17.1% [n = 260]). Clinical information was provided by the referring physician via a comprehensive referral form. This includes a section for the reporting of extra pancreatic clinical features. Genetic Testing Testing of the Known GenesAll individuals diagnosed in the first 6 months of life were tested for mutations either by rapid Sanger sequencing of

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Section: Discussionmentioning

confidence: 90%

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confidence: 99%

Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated

et al. 2019

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“…Although conditions such as autoimmune disease are common in people with DS, there is a lack of studies exploring the relationship of these conditions with thyroid disease. One study noted a prevalence of thyroid disease in 74% of a sample of 136 children with diabetes and DS (Aitken et al, ), but studies about the co‐occurrence of thyroid disease and other autoimmune conditions in adults are limited (Prasher, ).…”

Section: Resultsmentioning

confidence: 99%

Co‐occurring medical conditions in adults with Down syndrome: A systematic review toward the development of health care guidelines

Capone

Chicoine

Bulova

et al. 2017

American J of Med Genetics Pt A

131

136

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Adults with Down syndrome (DS) represent a unique population who are in need of clinical guidelines to address their medical care. The United States Preventive Service Task Force (USPSTF) has developed criteria for prioritizing conditions of public health importance with the potential for providing screening recommendations to improve clinical care. The quality of existing evidence needed to inform clinical guidelines has not been previously reviewed. Using the National Library of Medicine (NLM) database PubMed, we first identified 18 peer reviewed articles that addressed co-occurring medical conditions in adults with DS. Those conditions discussed in over half of the articles were prioritized for further review. Second, we performed detailed literature searches on these specific conditions. To inform the search strategy and review process a series of key questions were formulated a priori. The quality of available evidence was then graded and knowledge gaps were identified. The number of participating adults and the design of clinical studies varied by condition and were often inadequate for answering all of our key questions. We provide data on thyroid disease, cervical spine disease, hearing impairment, overweight-obesity, sleep apnea, congenital heart disease, and osteopenia-osteoporosis. Minimal evidence demonstrates massive gaps in our clinical knowledge that compromises clinical decision-making and management of these medically complex individuals. The development of evidence-based clinical guidance will require an expanded clinical knowledge-base in order to move forward.

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“…The presence of an extra copy of chromosome 21 in the DS genome puts DS individuals at high risk for developing certain comorbidities, such as AD, immune dysfunction, diabetes and leukemia (1,4,6,7,(84)(85)(86). Many of the DS comorbidities are associated with a dysfunctional PN (14-21) and aneuploidy has also been associated with proteotoxic stress and PN dysfunction (43)(44)(45)(46)(47)(48)(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

“…Down syndrome (DS) is a genetic condition originating from the presence of a third copy of chromosome 21 (Tri21) (1) and is the only known trisomy that does not result in early life lethality (2). DS is characterized by a variable phenotype with several comorbidities, including Alzheimer's disease (AD) (1), cognitive disabilities (3), diabetes (4), and leukemia (5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

Down syndrome fibroblasts exhibit diminished autophagic clearance and endosomal dysfunction after serum starvation

Aivazidis

Jain

Anderson

et al. 2018

Preprint

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Down syndrome (DS) is a genetic disorder caused by trisomy of chromosome 21 (Tri21). This unbalanced karyotype has the ability to produce proteotoxic stress and dysfunction of the proteostasis network (PN), which are mechanistically associated with several comorbidities found in the DS phenotype. Autophagy is the cellular process responsible for bulk protein degradation and its impairment could negatively impact protein quality control. Based on our previous observations of PN disruption in DS, we investigated possible dysfunction of the autophagic machinery in human DS fibroblasts. Both euploid (CTL) and DS fibroblasts induced autophagy successfully through serum starvation (SS), as evidenced by increased LC3-II abundance in CTL and DS. However, DS cells displayed evidence of autophagolysosome (AL) accumulation and impaired clearance of autophagosome cargo, e.g. accumulation of p62 and NBR1. Similar observations were also present in DS cells from multiple differentiation stages, implicating impeded autophagic degradation as a possible early pathologic mechanism in DS. Lysosomal pH and cathepsin B proteolytic activity were found to not differ in CTL and DS fibroblasts after SS, indicating that lysosomal dysfunction did not appear to contribute to unsuccessful autophagic clearance. Based on these results, we hypothesized that possible interference of the endosomal system with autophagy results in autophagosome fusion with endosomal vesicles and negatively impacts degradation. Consistent with this hypothesis, we observed increased abundance of the recycling endosome marker, Rab11, after SS in DS fibroblasts. Further, colocalization of autophagosome markers with resident proteins of early endosomes, late endosomes and recycling endosomes (Rab11) further support our hypothesis. In summary, our work is consistent with impairment of autophagic flux and general PN dysfunction as candidate mechanisms for pathology in DS.

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Early-Onset, Coexisting Autoimmunity and Decreased HLA-Mediated Susceptibility Are the Characteristics of Diabetes in Down Syndrome

Cited by 42 publications

References 37 publications

Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated

Trisomy 21 Is a Cause of Permanent Neonatal Diabetes That Is Autoimmune but Not HLA Associated

Co‐occurring medical conditions in adults with Down syndrome: A systematic review toward the development of health care guidelines

Down syndrome fibroblasts exhibit diminished autophagic clearance and endosomal dysfunction after serum starvation

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