Publications by authors named "Christiane S Hampe"

96 Publications

Mucopolysaccharidosis Type I: Current Treatments, Limitations, and Prospects for Improvement.

Biomolecules 2021 Jan 29;11(2). Epub 2021 Jan 29.

Immusoft Corp, Minneapolis, MN 55413, USA.

Mucopolysaccharidosis type I (MPS I) is a lysosomal disease, caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). IDUA catalyzes the degradation of the glycosaminoglycans dermatan and heparan sulfate (DS and HS, respectively). Lack of the enzyme leads to pathologic accumulation of undegraded HS and DS with subsequent disease manifestations in multiple organs. The disease can be divided into severe (Hurler syndrome) and attenuated (Hurler-Scheie, Scheie) forms. Currently approved treatments consist of enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). Patients with attenuated disease are often treated with ERT alone, while the recommended therapy for patients with Hurler syndrome consists of HSCT. While these treatments significantly improve disease manifestations and prolong life, a considerable burden of disease remains. Notably, treatment can partially prevent, but not significantly improve, clinical manifestations, necessitating early diagnosis of disease and commencement of treatment. This review discusses these standard therapies and their impact on common disease manifestations in patients with MPS I. Where relevant, results of animal models of MPS I will be included. Finally, we highlight alternative and emerging treatments for the most common disease manifestations.
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http://dx.doi.org/10.3390/biom11020189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911293PMC
January 2021

Interaction Between GAD65 Antibodies and Dietary Fish Intake or Plasma Phospholipid n-3 Polyunsaturated Fatty Acids on Incident Adult-Onset Diabetes: The EPIC-InterAct Study.

Diabetes Care 2021 Feb 10;44(2):416-424. Epub 2020 Dec 10.

Medical Research Council Epidemiology Unit, Institute of Metabolic Science, University of Cambridge School of Clinical Medicine, Cambridge, U.K.

Objective: Islet autoimmunity is associated with diabetes incidence. We investigated whether there was an interaction between dietary fish intake or plasma phospholipid n-3 polyunsaturated fatty acid (PUFA) concentration with the 65-kDa isoform of GAD (GAD65) antibody positivity on the risk of developing adult-onset diabetes.

Research Design And Methods: We used prospective data on 11,247 incident cases of adult-onset diabetes and 14,288 noncases from the EPIC-InterAct case-cohort study conducted in eight European countries. Baseline plasma samples were analyzed for GAD65 antibodies and phospholipid n-3 PUFAs. Adjusted hazard ratios (HRs) for incident diabetes in relation to GAD65 antibody status and tertiles of plasma phospholipid n-3 PUFA or fish intake were estimated using Prentice-weighted Cox regression. Additive (proportion attributable to interaction [AP]) and multiplicative interactions between GAD65 antibody positivity (≥65 units/mL) and low fish/n-3 PUFA were assessed.

Results: The hazard of diabetes in antibody-positive individuals with low intake of total and fatty fish, respectively, was significantly elevated (HR 2.52 [95% CI 1.76-3.63] and 2.48 [1.79-3.45]) compared with people who were GAD65 antibody negative and had high fish intake, with evidence of additive (AP 0.44 [95% CI 0.16-0.72] and 0.48 [0.24-0.72]) and multiplicative ( = 0.0465 and 0.0103) interactions. Individuals with high GAD65 antibody levels (≥167.5 units/mL) and low total plasma phospholipid n-3 PUFAs had a more than fourfold higher hazard of diabetes (HR 4.26 [2.70-6.72]) and an AP of 0.46 (0.12-0.80) compared with antibody-negative individuals with high n-3 PUFAs.

Conclusions: High fish intake or relative plasma phospholipid n-3 PUFA concentrations may partially counteract the increased diabetes risk conferred by GAD65 antibody positivity.
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http://dx.doi.org/10.2337/dc20-1463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818317PMC
February 2021

An Attenuation in the Incidence of Early Childhood Diabetes Correlates With Introduction of Rotavirus Vaccination in Israel.

J Infect Dis 2021 Apr;223(7):1305-1307

Endocrine Research, Schneider Children's Medical Center, Petah Tikva, Israel.

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http://dx.doi.org/10.1093/infdis/jiaa547DOI Listing
April 2021

Dysostosis Multiplex in Human Mucopolysaccharidosis Type 1 H and in Animal Models of the Disease.

Pediatr Endocrinol Rev 2020 Aug;17(4):317-326

Immusoft Corp, Minneapolis, MN 55413, USA, Department of Genetics, Cell Biology and Development and Center for Genome Engineering, University of Minnesota, Minneapolis, MN, USA.

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder, caused by deficiency of α-L-iduronidase, and consequent accumulation of dermatan and heparan sulfates. Severity of the disease ranges from mild (Scheie) to moderate (Hurler-Scheie) to severe (Hurler or MPS-IH). A prominent clinical manifestation of MPS-IH is dysostosis multiplex, a constellation of skeletal abnormalities. We performed a retrospective review comparing manifestations of dysostosis multiplex in patients presenting with MPSIH and relevant animal models. Dog, cat and mouse models of MPS-IH are extensively studied to better understand the pathology of the disease. While all animal models display certain characteristics of human MPSIH, species-specific manifestations must be considered when evaluating skeletal abnormalities. Moreover, some skeletal abnormalities emerge at species-specific developmental stages, e.g. thoracolumbar kyphosis is an early manifestation in humans, while it appears late in the mouse model. The choice of the appropriate diagnostic test is of importance to avoid misleading conclusions.
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http://dx.doi.org/10.17458/per.vol17.2020.hpl.dysostosismultiplexhumananimalDOI Listing
August 2020

For Debate: The Controversy whether Rotavirus Vaccination Attenuates the Incidence of Childhood Type 1 Diabetes.

Pediatr Endocrinol Rev 2020 08;17(4):284-286

Director, Endocrinology and Diabetes Research Unit, Schneider Children's Medical Center, 14 Kaplan Street, Petah Tikva 4920200, Israel, E-mail:

Recent epidemiological surveys performed in Australia, USA and Israel demonstrate that Rotavirus vaccination correlates with an attenuated prevalence and/or incidence of early childhood diabetes (T1D). Other studies failed to confirm the above.
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http://dx.doi.org/10.17458/per.vol17.2020.fd.lbh.rotavirustype1diabetesDOI Listing
August 2020

Mucopolysaccharidosis Type I: A Review of the Natural History and Molecular Pathology.

Cells 2020 08 5;9(8). Epub 2020 Aug 5.

Immusoft Corp, Minneapolis, MN 55413, USA.

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive inherited disease, caused by deficiency of the enzyme α-L-iduronidase, resulting in accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in organs and tissues. If untreated, patients with the severe phenotype die within the first decade of life. Early diagnosis is crucial to prevent the development of fatal disease manifestations, prominently cardiac and respiratory disease, as well as cognitive impairment. However, the initial symptoms are nonspecific and impede early diagnosis. This review discusses common phenotypic manifestations in the order in which they develop. Similarities and differences in the three animal models for MPS I are highlighted. Earliest symptoms, which present during the first 6 months of life, include hernias, coarse facial features, recurrent rhinitis and/or upper airway obstructions in the absence of infection, and thoracolumbar kyphosis. During the next 6 months, loss of hearing, corneal clouding, and further musculoskeletal dysplasias develop. Finally, late manifestations including lower airway obstructions and cognitive decline emerge. Cardiac symptoms are common in MPS I and can develop in infancy. The underlying pathogenesis is in the intra- and extracellular accumulation of partially degraded GAGs and infiltration of cells with enlarged lysosomes causing tissue expansion and bone deformities. These interfere with the proper arrangement of collagen fibrils, disrupt nerve fibers, and cause devastating secondary pathophysiological cascades including inflammation, oxidative stress, and other disruptions to intracellular and extracellular homeostasis. A greater understanding of the natural history of MPS I will allow early diagnosis and timely management of the disease facilitating better treatment outcomes.
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http://dx.doi.org/10.3390/cells9081838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463646PMC
August 2020

Geographic location determines beta-cell autoimmunity among adult Ghanaians: Findings from the RODAM study.

Immun Inflamm Dis 2020 09 7;8(3):299-309. Epub 2020 May 7.

Department of Public Health and Clinical Medicine, Section of Family Medicine, Umeå University, Umeå, Sweden.

Introduction: Beta-cell autoantibodies are established markers of autoimmunity, which we compared between Ghanaian adults with or without diabetes, living in rural and urban Ghana and in three European cities.

Methods: In the multicenter cross-sectional Research on Obesity and Diabetes among African Migrants (RODAM) study (N = 5898), we quantified autoantibodies against glutamic acid decarboxylase (GAD65Ab) by radioligand binding assay (RBA) and established cut-offs for positivity by displacement analysis. In a subsample, we performed RBA for zinc transporter-8 autoantibodies (ZnT8Ab). Associations of environmental, sociodemographic, and clinical factors with GAD65Ab were calculated.

Results: In this study population (age: 46.1 ± 11.9 years; female: 62%; Ghana-rural: 1111; Ghana-urban: 1455; Europe: 3332), 9.2% had diabetes with adult-onset. GAD65Ab concentrations were the highest in Ghana-rural (32.4; 10.8-71.3 U/mL), followed by Ghana-urban (26.0; 12.3-49.1 U/mL) and Europe (11.9; 3.0-22.8 U/mL) with no differences between European cities. These distributions were similar for ZnT8Ab. Current fever, history of fever, and higher concentrations of liver enzymes marginally explained site-specific GAD65Ab concentrations. GAD65Ab positivity was as frequent in diabetes as in nondiabetes (5.4% vs 6.1%; P = .25). This was also true for ZnT8Ab positivity.

Conclusion: Geographic location determines the occurrence of GAD65Ab and ZnT8Ab more than the diabetes status. Beta-cell autoimmunity may not be feasible to differentiate diabetes subgroups in this population.
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http://dx.doi.org/10.1002/iid3.306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416037PMC
September 2020

Placental Barrier and Autism Spectrum Disorders: The Roles of Prolactin and Dopamine in the Developing Fetal Brain-Part II.

Innov Clin Neurosci 2019 Nov;16(11-12):36-39

Dr. Yarlagadda is with the Department of Defense and the University of Virginia in Charlottesville, Virginia.

The inverse relationship between prolactin and dopamine is important in the context of treatment with antipsychotic medications in men and nonpregnant women with thought disorders. Likewise, increased levels of prolactin as confirmation of recent seizure and the reciprocal levels of prolactin and dopamine in both eclampsia (seizures) and pre-eclampsia might have significant potential effects on a growing fetus. In this article, we attempt to outline the influence of these associations on autism spectrum disorders (ASDs) in children born to mothers with established diagnoses of eclampsia and/or pre-eclampsia. Our previously published paper, "Placental Barrier and Autism Spectrum Disorders: The Role of Prolactin and Dopamine on the Developing Fetal Brain," summarized evidence for dysregulated dopamine and prolactin levels in the etiology of ASDs and suggested a possible method for assessing whether such aberrations increase the risk of ASDs. The present paper as Part 2 expands on the published data that support this theory and proposes a study design to corroborate this hypothesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006862PMC
November 2019

Serum C-peptide and osteocalcin levels in children with recently diagnosed diabetes.

Endocrinol Diabetes Metab 2020 Jan 29;3(1):e00104. Epub 2019 Nov 29.

Department of Surgery The Methodist Hospital Houston TX USA.

Background: We explored the association of C-peptide (marker of secreted insulin), proinsulin and proinsulin ⁄C-peptide ratio (PI/C) (markers of beta-cell endoplasmic reticulum [ER] stress) with undercarboxylated (uOC) and carboxylated osteocalcin (cOC) and their ratio (uOC/cOC) in children with recently diagnosed type 1 (T1D) or type 2 diabetes (T2D), and the correlation of these variables with partial remission (PR) in children with T1D.

Methods: Demographic and clinical data of children with new-onset diabetes (n = 68; median age = 12.2 years; 33.8% non-Hispanic White, 45.6% Hispanic/Latino, 16.2% African American and 4.4% other) were collected at diagnosis and during the first (V1), second (V2) and third clinical visits at 9.0, 32.0 and 175.7 weeks, respectively. Serum proinsulin, C-peptide, uOC and cOC values were measured 7.0 weeks after diagnosis. PR was defined as insulin dose-adjusted HbA1c (IDAA1c) ≤9.

Results: In children with new-onset T1D with DKA (33.3%) or T2D (29.4%), Spearman's correlation coefficient revealed a positive association between the C-peptide levels and both uOC and uOC/cOC ratio. In T1D (n = 48), both higher serum C-peptide levels and low PI:C ratio were associated with higher BMI percentile ( = 0.02,  = .001; = -0.01,  = .02, respectively) and older age at diagnosis ( = 0.13,  = .001; = -0.12,  = .001, respectively). Furthermore, in children with T1D, C-peptide levels at V1 correlated with IDAA1c ≤ 9 at V1 ( = .04).

Conclusion: C-peptide levels are associated with a higher uOC and uOC/cOC ratio in paediatric diabetes. In new-onset T1D children, older age and higher BMI were associated with lower beta-cell stress and higher preserved function, which was predictive of PR on follow-up.
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http://dx.doi.org/10.1002/edm2.104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947692PMC
January 2020

Autoimmunity plays a role in the onset of diabetes after 40 years of age.

Diabetologia 2020 02 11;63(2):266-277. Epub 2019 Nov 11.

MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge, UK.

Aims/hypothesis: Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort.

Methods: GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression.

Results: GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors.

Conclusions/interpretation: Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.
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http://dx.doi.org/10.1007/s00125-019-05016-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946728PMC
February 2020

Contribution of the Cerebellum to Predictive Motor Control and Its Evaluation in Ataxic Patients.

Front Hum Neurosci 2019 26;13:216. Epub 2019 Jun 26.

School of Medicine, University of Washington, Seattle, WA, United States.

Goal-directed movements are predictive and multimodal in nature, especially for moving targets. For instance, during a reaching movement for a moving target, humans need to predict both motion of the target and movement of the limb. Recent computational studies show that the cerebellum predicts current and future states of the body and its environment using internal forward models. Sensory feedback signals from the periphery have delays in reaching the central nervous system, ranging between tens to hundreds of milliseconds. It is well known in engineering that feedback control based on time-delayed inputs can result in oscillatory and often unstable movements. In contrast, the brain predicts a current state from a previous state using forward models. This predictive mechanism most likely underpins stable and dexterous control of reaching movements. Although the has long been suggested as loci of various forward models, few methods are available to evaluate accuracy of the forward models in patients with cerebellar ataxia. Recently, we developed a non-invasive method to analyze receipt of motor commands in terms of movement kinematics for the wrist joint ( ratio). In the present study, we have identified two components (F1 and F2) of the smooth pursuit movement. We found that the two components were in different control modes with different ratios. The major F1 component in a lower frequency range encodes both velocity and position of the moving target ( ratio) to synchronize movement of the wrist joint with motion of the target in a manner. The minor F2 component in a higher frequency range is biased to position control in order to generate intermittent small step-wise movements. In cerebellar patients, the F1 component shows a selective decrease in the ratio, which is correlated with decrease in accuracy of the pursuit movement. We conclude that the ratio of the F1 component provides a unique parameter to evaluate accuracy of the predictive control. We also discuss the pathophysiological and clinical implications for clinical ataxiology.
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http://dx.doi.org/10.3389/fnhum.2019.00216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6608258PMC
June 2019

Anti-GAD Antibodies and the Cerebellum: Where Do We Stand?

Cerebellum 2019 Apr;18(2):153-156

University of Washington, School of Medicine, Seattle, WA, 98109, USA.

Anti-GAD65 antibodies (anti-GAD65 Abs) are associated with cerebellar ataxia (CA). The significance of anti-GAD65 Abs has been a focus of debates. Since GAD65 is intracellularly located and associated with type 1 diabetes mellitus and different clinical neurological phenotypes such as CA, stiff-person syndrome, and epilepsy, some researchers have argued that anti-GAD65 Abs have no pathogenic roles. On the other hand, recent physiological studies in vitro and in vivo have elucidated that binding of GAD65 by anti-GAD65 Abs elicits loss of GAD65 functions pertaining GABA release with an epitope dependence, leading to the development of CA. Internalization of autoantibodies has been also clarified. These studies provide substantial evidence of the pathogenesis of anti-GAD65 Abs in CA. We also discuss methodological problems in the identification of anti-GAD65 Abs.
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http://dx.doi.org/10.1007/s12311-018-0986-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443918PMC
April 2019

Autoantibodies to the IA-2 Extracellular Domain Refine the Definition of "A+" Subtypes of Ketosis-Prone Diabetes.

Diabetes Care 2018 12 16;41(12):2637-2640. Epub 2018 Oct 16.

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX

Objective: Autoantibodies directed against tyrosine phosphatase IA-2 antibody (IA-2 Ab) are diagnostic for autoimmune type 1 diabetes. Conventional assays target the intracellular domain of IA-2. Among patients with ketosis-prone diabetes (KPD), characterized by presentation with diabetic ketoacidosis (DKA), >60% of adults lack three classic islet autoantibodies-IA-2, GAD65, and ZnT8 Abs-associated with type 1 diabetes. We aimed to determine whether apparently autoantibody-negative ("A-") KPD patients possess occult IA-2 Ab directed against full-length IA-2 (IA-2FL) or its extracellular domain (IA-2EC).

Research Design And Methods: We developed an assay that targets IA-2FL and IA-2EC and used it to analyze 288 subjects with A- KPD.

Results: Ten A- KPD patients were positive for IA-2EC Ab (3.5%), and three were also positive for IA-2FL Ab (1.0%), similar to frequencies in type 1 and type 2 diabetes.

Conclusions: Measurement of IA-2FL Ab and IA-2EC Ab improves the accuracy of the Aβ classification of KPD patients.
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http://dx.doi.org/10.2337/dc18-0613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245211PMC
December 2018

Immune-mediated Cerebellar Ataxias: Practical Guidelines and Therapeutic Challenges.

Curr Neuropharmacol 2019 ;17(1):33-58

University of Washington, School of Medicine, Seattle, WA 98109, United States.

Immune-mediated cerebellar ataxias (IMCAs), a clinical entity reported for the first time in the 1980s, include gluten ataxia (GA), paraneoplastic cerebellar degenerations (PCDs), antiglutamate decarboxylase 65 (GAD) antibody-associated cerebellar ataxia, post-infectious cerebellitis, and opsoclonus myoclonus syndrome (OMS). These IMCAs share common features with regard to therapeutic approaches. When certain factors trigger immune processes, elimination of the antigen( s) becomes a priority: e.g., gluten-free diet in GA and surgical excision of the primary tumor in PCDs. Furthermore, various immunotherapeutic modalities (e.g., steroids, immunoglobulins, plasmapheresis, immunosuppressants, rituximab) should be considered alone or in combination to prevent the progression of the IMCAs. There is no evidence of significant differences in terms of response and prognosis among the various types of immunotherapies. Treatment introduced at an early stage, when CAs or cerebellar atrophy is mild, is associated with better prognosis. Preservation of the "cerebellar reserve" is necessary for the improvement of CAs and resilience of the cerebellar networks. In this regard, we emphasize the therapeutic principle of "Time is Cerebellum" in IMCAs.
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http://dx.doi.org/10.2174/1570159X16666180917105033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341499PMC
April 2019

Endocrine disorders and the cerebellum: from neurodevelopmental injury to late-onset ataxia.

Handb Clin Neurol 2018 ;155:353-368

Department of Medicine, University of Washington, Seattle, United States.

Hormonal disorders are a source of cerebellar ataxia in both children and adults. Normal development of the cerebellum is critically dependent on thyroid hormone, which crosses both the blood-brain barrier and the blood-cerebrospinal fluid barrier thanks to specific transporters, including monocarboxylate transporter 8 and the organic anion-transporting polypeptide 1C1. In particular, growth and dendritic arborization of Purkinje neurons, synaptogenesis, and myelination are dependent on thyroid hormone. Disturbances of thyroid hormone may also impact on cerebellar ataxias of other origin, decompensating or aggravating the pre-existing ataxia manifesting with motor ataxia, oculomotor ataxia, and/or Schmahmann syndrome. Parathyroid disorders are associated with a genuine cerebellar syndrome, but symptoms may be subtle. The main conditions combining diabetes and cerebellar ataxia are Friedreich ataxia, ataxia associated with anti-GAD antibodies, autoimmune polyglandular syndromes, aceruloplasminemia, and cerebellar ataxia associated with hypogonadism (especially Holmes ataxia/Boucher-Neuhäuser syndrome). The general workup of cerebellar disorders should include the evaluation of hormonal status, including thyroid-stimulating hormone and free thyroxine levels, and hormonal replacement should be considered depending on the laboratory results. Cerebellar deficits may be reversible in some cases.
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http://dx.doi.org/10.1016/B978-0-444-64189-2.00023-8DOI Listing
October 2018

GAD65 autoantibody characteristics in patients with co-occurring type 1 diabetes and epilepsy may help identify underlying epilepsy etiologies.

Orphanet J Rare Dis 2018 04 10;13(1):55. Epub 2018 Apr 10.

Department of Medicine, School of Medicine, University of Washington, 850 Republican, Seattle, WA, 98109, USA.

Background: Autoantibodies against the smaller isoform of glutamate decarboxylase (GAD65Ab) reflect autoimmune etiologies in Type 1 diabetes (T1D) and several neurological disorders, including Stiff Person Syndrome (SPS). GAD65Ab are also reported in cases of epilepsy, indicating an autoimmune component. GAD65Ab in patients with co-occurring T1D, epilepsy or SPS may be part of either autoimmune pathogenesis. To dissect the etiologies associated with GAD65Ab, we analyzed GAD65Ab titer, epitope specificity and enzyme inhibition in GAD65Ab-positive patients diagnosed with epilepsy (n = 28), patients with epilepsy and T1D (n = 10), patients with SPS (n = 20), and patients with T1D (n = 42).

Results: GAD65Ab epitope pattern in epilepsy differed from T1D and SPS patients. Four of 10 patients with co-occurring T1D and epilepsy showed GAD65Ab profiles similar to T1D patients, while lacking GAD65Ab characteristics found in GAD65Ab-positive epilepsy patients. One of these patients responded well to anti-epileptic drugs (AEDs), while another patient did not require medication for seizure control. The third patient was refractory due to a diagnosis of meningioma. The response of the remaining patient to AEDs was unknown. GAD65Ab in the remaining six patients with T1D and epilepsy showed profiles similar to those in epilepsy patients.

Conclusions: Different autoimmune responses associated with T1D, epilepsy and SPS are reflected by disease-specific GAD65Ab patterns. Moreover, the epileptic etiology in patients diagnosed with both T1D and epilepsy may present two different etiologies regarding their epileptic condition. In one group T1D co-occurs with non-autoimmune epilepsy. In the other group GAD65Ab are part of an autoimmune epileptic condition.
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http://dx.doi.org/10.1186/s13023-018-0787-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892043PMC
April 2018

Arginine Metabolism Is Altered in Adults with A-β + Ketosis-Prone Diabetes.

J Nutr 2018 02;148(2):185-193

Diabetes Research Center, Division of Diabetes, Endocrinology and Metabolism.

Background: A-β + ketosis-prone diabetes (KPD) is a subset of type 2 diabetes in which patients have severe but reversible β cell dysfunction of unknown etiology. Plasma metabolomic analysis indicates that abnormal arginine metabolism may be involved.

Objective: The objective of this study was to determine the relation between gut microbiome and arginine metabolism and the relation between arginine availability and β cell function in KPD patients compared with control participants.

Methods: Kinetics of arginine and related metabolites were measured with stable isotope tracers, and insulin secretory responses to arginine and glucose were determined under euglycemic and hyperglycemic conditions in 6 KPD patients and 6 age-, gender-, and body mass index-matched control participants. Glucose potentiation of arginine-induced insulin secretion was performed in a different set of 6 KPD and 3 control participants.

Results: Arginine availability was higher in KPD patients during euglycemia [53.5 ± 4.3 (mean ± SEM) compared with 40.3 ± 2.4 μmol · kg lean body mass (LBM)-1 · h-1, P = 0.03] but declined more in response to hyperglycemia (Δ 10.15 ± 2.6 compared with Δ 3.20 ± 1.3 μmol · kg LBM-1 · h-1, P = 0.041). During hyperglycemia, ornithine flux was not different between groups but after an arginine bolus, plasma ornithine AUC trended higher in KPD patients (3360 ± 294 compared with 2584 ± 259 min · μmol · L-1, P = 0.08). In both euglycemia and hyperglycemia, the first-phase insulin responses to glucose stimulation were lower in KPD patients (euglycemic insulin AUC 282 ± 108 compared with 926 ± 257 min · μU · mL-1, P = 0.02; hyperglycemic insulin AUC 358 ± 79 compared with 866 ± 292 min · μU · mL-1, P = 0.05), but exogenous arginine restored first-phase insulin secretion in KPD patients to the level of control participants.

Conclusion: Compared with control participants, KPD patients have increased arginine availability in the euglycemic state, indicating a higher requirement. This is compromised during hyperglycemia, with an inadequate supply of arginine to sustain metabolic functions such as insulin secretion. Exogenous arginine administration restores a normal insulin secretory response.
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http://dx.doi.org/10.1093/jn/nxx032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6251649PMC
February 2018

Time Is Cerebellum.

Cerebellum 2018 Aug;17(4):387-391

School of Medicine, University of Washington, Seattle, WA, 98109, USA.

The cerebellum characteristically has the capacity to compensate for and restore lost functions. These compensatory/restorative properties are explained by an abundant synaptic plasticity and the convergence of multimodal central and peripheral signals. In addition, extra-cerebellar structures contribute also to the recovery after a cerebellar injury. Clinically, some patients show remarkable improvement of severe ataxic symptoms associated with trauma, stroke, metabolism, or immune-mediated cerebellar ataxia (IMCA, e.g., multiple sclerosis, paraneoplastic cerebellar degeneration, gluten ataxia, anti-GAD65 antibody-associated cerebellar ataxia). However, extension of a cerebellar lesion can impact upon the fourth ventricle or the brainstem, either by direct or indirect mechanisms, leading to serious complications. Moreover, cerebellar reserve itself is affected by advanced cell loss and, at some point of disease progression, deficits become irreversible. Such phase transition from a treatable/restorable state (the reserve is still sufficient) to an untreatable state (the reserve is severely affected) is a loss of therapeutic opportunity, highlighting the need for early treatment during the restorable stage. Based on the motto of "Time is Brain," a warning that stresses the importance of early therapeutic intervention in ischemic diseases, we propose "Time is Cerebellum" as a principle in the management of patients with cerebellar diseases, especially immune ataxias whose complexity often delay the therapeutic intervention. Indeed, this concept should not be restricted to ischemic cerebellar diseases. We argue that every effort should be made to reduce the diagnostic delay and to initiate early therapy to avoid the risk of transition from a treatable state to an irreversible condition and an associated accumulation of disability. The myriad of disorders affecting the cerebellum is a challenging factor that may contribute to irreversible disability if the window of therapeutic opportunity is missed.
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http://dx.doi.org/10.1007/s12311-018-0925-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028834PMC
August 2018

Assessment of disturbed glucose metabolism and surrogate measures of insulin sensitivity in obese children and adolescents.

Nutr Diabetes 2017 Dec 14;7(12):301. Epub 2017 Dec 14.

Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA, 98109, USA.

Background: With the rising prevalence of obesity and type 2 diabetes (T2D) in obese children, it is becoming imperative to detect disturbed glucose metabolism as early as possible in order to prevent T2D development.

Subjects/methods: Cross-sectional study of 92 obese children (median age 11.7 years, 51% female) and 7 lean children (median age 11.4 years, 57% female) who underwent an oral glucose tolerance test (OGTT) in a tertiary pediatric care center. Glucose tolerance was assessed and different indices for β-cell function, insulin sensitivity and insulin secretion were calculated.

Results: Nineteen obese children were identified with prediabetes (PD, 12 impaired glucose tolerance, 4 increased fasting glucose and 3 combined). Compared with the 73 obese children with normal glucose tolerance (nGT), subjects with PD had higher insulin resistance, but lower insulin sensitivity and β-cell function, although their glycated hemoglobin (HbA) levels were comparable. The Whole Body Insulin Sensitivity Index (WBISI) and β-cell function by Insulin Secretion-Sensitivity Index-2 (ISSI-2) strongly correlated with the OGTT glucose area under the curve 0-120 min (r = 0.392, p < 0.0002; r = 0.547, p < 0.0001, respectively). When testing the relation between early insulin response during OGTT by insulinogenic index and insulin sensitivity assessed by WBISI, a hyperbolic relationship between insulin secretion and insulin sensitivity was found. The calculated disposition index was lower in subjects with PD vs. nGT (median 459 vs. 792, p = 0.004). We identified the OGTT 30-min/120-min insulin ratio as a simple marker, which is significantly lower in obese children with vs. without PD (median 0.87 vs. 1.29, p = 0.021) and which has a better sensitivity and specificity for detecting PD than HbA among obese children.

Conclusions: Children with identified PD had changes of several markers for β-cell function, insulin sensitivity and resistance before changes in HbA occurred. The lower disposition index indicates that these children have already inadequate β-cell compensation for the degree of insulin resistance.
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http://dx.doi.org/10.1038/s41387-017-0004-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865547PMC
December 2017

Elevated unmethylated and methylated insulin DNA are unique markers of A+β+ ketosis prone diabetes.

J Diabetes Complications 2018 02 31;32(2):193-195. Epub 2017 Oct 31.

Department of Medicine, Section of Diabetes and Endocrinology, Baylor College of Medicine, Houston, TX, USA. Electronic address:

A+β+ ketosis prone diabetes (KPD) is associated with slowly progressive autoimmune beta cell destruction. Plasma unmethylated and methylated insulin DNA (biomarkers of ongoing beta cell damage and systemic inflammation, respectively) were elevated in A+β+ KPD compared to all other KPD subgroups.
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http://dx.doi.org/10.1016/j.jdiacomp.2017.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170161PMC
February 2018

Effect of dietary palmitic and stearic acids on sucrose motivation and hypothalamic and striatal cell signals in the rat.

Am J Physiol Regul Integr Comp Physiol 2018 02 1;314(2):R191-R200. Epub 2017 Nov 1.

Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine , Seattle, Washington.

We have reported that motivation for sucrose is increased in rats fed a moderate (31%) mixed-fat diet for 4-6 wk. In this study, rats were fed diets containing 32% stearic (STEAR) or palmitic (PALM) acid, and behavior, metabolic profile, and cell signals were compared with those of rats fed a matched low-fat diet (LF; 11% fat) diet. Rats fed STEAR or PALM increased sucrose motivation relative to LF rats (one-way ANOVA for lever presses; P = 0.03). Diet did not change fasting glucose, insulin, total cholesterol, triglycerides, intravenous glucose tolerance test glucose profile, percent body fat, or total kilocalories, although kilocalories as fat were increased (ANOVA, P < 0.05). Cell signals were assessed in rats ranked from high to low sucrose motivation. Diet did not alter Thr and Ser phosphorylation of Akt in the medial hypothalamus (HYP) and striatum (STR). However, Ser phosphorylation of GSK3Β was decreased in HYP and STR from both high- and low-performer tertiles of STEAR and PALM rats (ANOVA within each brain region, P < 0.05). Two histone 3 (H3) modifications were also assessed. Although there was no effect of diet on the transcription-repressive H3 modification, H3K27me3, the transcription-permissive H3 modification, H3K4me3, was significantly decreased in the HYP of high performers fed PALM or STEAR (ANOVA, P = 0.013). There was no effect of diet on H3K4me3 levels in HYP of low performers, or in STR. Our findings suggest signal-specific and brain region-specific effects of PALM or STEAR diets and may link downstream signaling effects of GSK3Β activity and H3 modifications with enhanced motivational behavior.
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http://dx.doi.org/10.1152/ajpregu.00340.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867676PMC
February 2018

Probiotic strains and mechanistic insights for the treatment of type 2 diabetes.

Endocrine 2017 Nov 19;58(2):207-227. Epub 2017 Oct 19.

Center for Integrative Brain Research, Seattle Children's Hospital & Research Institute, Seattle, WA, 98101, USA.

Introduction: The intestinal microbial composition appears to differ between healthy controls and individuals with Type 2 diabetes (T2D). This observation has led to the hypothesis that perturbations of the intestinal microbiota may contribute to the development of T2D. Manipulations of the intestinal microbiota may therefore provide a novel approach in the prevention and treatment of T2D. Indeed, fecal transplants have shown promising results in both animal models for obesity and T2D and in human clinical trials. To avoid possible complications associated with fecal transplants, probiotics are considered as a viable alternative therapy. An important, however often underappreciated, characteristic of probiotics is that individual strains may have different, even opposing, effects on the host. This strain specificity exists also within the same species. A comprehensive understanding of the underlying mechanisms at the strain level is therefore crucial for the selection of suitable probiotic strains.

Purpose: The aim of this review is to discuss the mechanisms employed by specific probiotic strains of the Lactobacillus and the Bifidobacterium genuses, which showed efficacy in the treatment of obesity and T2D. Some probiotic strains employ recurring beneficial effects, including the production of anti-microbial lactic acid, while other strains display highly unique features, such as hydrolysis of tannins.

Conclusion: A major obstacle in the evaluation of probiotic strains lays in the great number of strains, differences in detection methodology and measured outcome parameters. The understanding of further research should be directed towards the development of standardized evaluation methods to facilitate the comparison of different studies.
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http://dx.doi.org/10.1007/s12020-017-1433-zDOI Listing
November 2017

Immune-mediated cerebellar ataxias: from bench to bedside.

Cerebellum Ataxias 2017 21;4:16. Epub 2017 Sep 21.

University of Washington, School of Medicine, Seattle, WA 98109 USA.

The cerebellum is a vulnerable target of autoimmunity in the CNS. The category of immune-mediated cerebellar ataxias (IMCAs) was recently established, and includes in particular paraneoplastic cerebellar degenerations (PCDs), gluten ataxia (GA) and anti-GAD65 antibody (Ab) associated-CA, all characterized by the presence of autoantibodies. The significance of onconeuronal autoantibodies remains uncertain in some cases. The pathogenic role of anti-GAD65Ab has been established both in vitro and in vivo, but a consensus has not been reached yet. Recent studies of anti-GAD65 Ab-associated CA have clarified that (1) autoantibodies are generally polyclonal and elicit pathogenic effects related to epitope specificity, and (2) the clinical course can be divided into two phases: a phase of functional disorder followed by cell death. These features provide the rationale for prompt diagnosis and therapeutic strategies. The concept "Time is brain" has been completely underestimated in the field of immune ataxias. We now put forward the concept "Time is cerebellum" to underline the importance of very early therapeutic strategies in order to prevent or stop the loss of neurons and synapses. The diagnosis of IMCAs should depend not only on Ab testing, but rather on a rapid and comprehensive assessment of the clinical/immune profile. Treatment should be applied during the period of preserved cerebellar reserve, and should encompass early removal of the conditions (such as remote primary tumors) or diseases that trigger the autoimmunity, followed by the combinations of various immunotherapies.
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http://dx.doi.org/10.1186/s40673-017-0073-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5609024PMC
September 2017

Associations between Liver Enzyme Levels and Parameters of the Metabolic Syndrome in Obese Children.

Horm Res Paediatr 2017 12;88(3-4):265-273. Epub 2017 Sep 12.

Center for Integrative Brain Research, Seattle Children's Hospital and Research Institute, Seattle, Washington, USA.

Background: Obesity is strongly associated with insulin resistance, hypertension, dyslipidemia, and therefore risk for metabolic syndrome (MetS), which is an increasing problem in youth. The potential role of elevated liver enzyme levels in this context needs to be further investigated.

Methods: This paper provides a post hoc analysis of a cross-sectional study of 77 obese nondiabetic children (51% female; median age 11.7 years; BMI >97th percentile) enrolled at the University of Bonn, Bonn, Germany. Anthropometric parameters, lipid profiles, glycemic control, and liver enzyme levels were evaluated. Glucose and insulin levels were determined during an oral glucose tolerance test (OGTT). Gender- and age-specific cutoff values were used to assess MetS.

Results: A high prevalence of hypertension (51%), dyslipidemia (52%), elevated liver enzyme levels (51%), and hyperglycemia (24%) was found. There was considerable overlap between the presence of different MetS risk factors in individuals, and 40% of the participants had ≥3 of a maximum of 5 MetS risk factors. Elevated liver enzyme levels were significantly associated with reduced insulin sensitivity, as the OGTT-insulin response was significantly higher in participants with elevated transaminases (p = 0.01). This association was independent of hyperglycemia and dyslipidemia (p = 0.03).

Conclusions: We conclude that liver enzyme levels are related to insulin sensitivity in obese children and could therefore be an indirect indicator for MetS. Testing for disturbed glucose metabolism should be considered for obese children with elevated liver enzymes.
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http://dx.doi.org/10.1159/000479868DOI Listing
June 2018

Pathogenic Roles of Glutamic Acid Decarboxylase 65 Autoantibodies in Cerebellar Ataxias.

J Immunol Res 2017 12;2017:2913297. Epub 2017 Mar 12.

School of Medicine, University of Washington, Seattle, WA 98109, USA.

Reports suggesting a pathogenic role of autoantibodies directed against glutamic acid decarboxylase 65 (GAD65Abs) in cerebellar ataxias (CAs) are reviewed, and debatable issues such as internalization of antibodies by neurons and roles of epitopes are discussed. GAD65 is one of two enzymes that catalyze the conversion of glutamate to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). A pathogenic role of GAD65Ab in CAs is suggested by in vivo and in vitro studies. (1) Intracerebellar administration of cerebrospinal fluid (CSF) immunoglobulins (IgGs) obtained from GAD65Ab-positive CA patients impairs cerebellar modulation of motor control in rats. (2) CSF IgGs act on terminals of GABAergic neurons and decrease the release of GABA in cerebellar slices from rats and mice. (3) Absorption of GAD65Ab by recombinant GAD65 diminishes the above effects, and monoclonal human GAD65Ab (b78) mimic the effects of CSF IgGs in vivo and in vitro. Studies using GAD65-KO mice confirm that the target molecule is GAD65. (4) Notably, the effects of GAD65Ab depend on the epitope specificity of the monoclonal GAD65Ab. Taken together, these results indicate that epitope-specific GAD65Ab-induced impairment of GABA release is involved in the pathogenesis of GAD65Ab-positive CA and support the early detection of GAD65Ab-associated CA to initiate immunotherapy before irreversible neuronal death in the cerebellum.
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http://dx.doi.org/10.1155/2017/2913297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5366212PMC
May 2017

A method for high-throughput functional imaging of single cells within heterogeneous cell preparations.

Sci Rep 2016 12 16;6:39319. Epub 2016 Dec 16.

UW Diabetes Institute, Department of Medicine, University of Washington, Seattle, WA, 98195, USA.

Functional characterization of individual cells within heterogeneous tissue preparations is challenging. Here, we report the development of a versatile imaging method that assesses single cell responses of various endpoints in real time, while identifying the individual cell types. Endpoints that can be measured include (but are not limited to) ionic flux (calcium, sodium, potassium and hydrogen), metabolic responsiveness (NAD(P)H, mitochondrial membrane potential), and signal transduction (HO and cAMP). Subsequent to fluorescent imaging, identification of cell types using immunohistochemistry allows for mapping of cell type to their respective functional real time responses. To validate the utility of this method, NAD(P)H responses to glucose of islet alpha versus beta cells generated from dispersed pancreatic islets, followed by the construction of frequency distributions characterizing the variability in the magnitude of each individual cell responses were compared. As expected, no overlap between the glucose response frequency distributions for beta cells versus alpha cells was observed, thereby establishing both the high degree of fidelity and low rate of both false-negatives and false-positives in this approach. This novel method has the ability not only to resolve single cell level functional differences between cell types, but also to characterize functional heterogeneity within a given cell type.
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http://dx.doi.org/10.1038/srep39319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5159830PMC
December 2016

Epilepsy and behavioral changes, type 1 diabetes mellitus and a high titer of glutamic acid decarboxylase antibodies.

Pediatr Diabetes 2016 12 29;17(8):617-622. Epub 2015 Dec 29.

Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA, USA.

Autoantibodies to the 65 kDa isoform of glutamate acid decarboxylase (GAD65Ab) are associated with a range of clinical disorders, including type 1 diabetes (T1D) and stiff-person syndrome (SPS). In this article we describe a young girl who was diagnosed with T1D at the end of her first year of life and developed drug-resistant epilepsy 18 months later, followed by behavioral disturbances. She was admitted to our center at the age of 5 yr, at which time high GAD65Ab titers were detected in the patient's serum and cerebrospinal fluid (CSF). The titer remained elevated during 19 months of follow-up. Furthermore, GAD65Ab in both serum and CSF showed epitope binding characteristics similar to those observed for GAD65Ab in SPS patients, and GAD65Ab in the serum reduced GAD65 enzyme activity. Our results suggest an association between high GAD65Ab titers and epilepsy in children with T1D. Careful titration and characterization of GAD65Ab regarding inhibition of enzyme activity and epitope specificity may be helpful in identifying T1D patients at risk for neurological complications.
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http://dx.doi.org/10.1111/pedi.12346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927419PMC
December 2016

Neuronal central nervous system syndromes probably mediated by autoantibodies.

Eur J Neurosci 2016 06 28;43(12):1535-52. Epub 2016 Mar 28.

Institut NeuroMyoGène, INSERM U1217/UMR CNRS 5310, Lyon, France.

In the last few years, a rapidly growing number of autoantibodies targeting neuronal cell-surface antigens have been identified in patients presenting with neurological symptoms. Targeted antigens include ionotropic receptors such as N-methyl-d-aspartate receptor or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, metabotropic receptors such as mGluR1 and mGluR5, and other synaptic proteins, some of them belonging to the voltage-gated potassium channel complex. Importantly, the cell-surface location of these antigens makes them vulnerable to direct antibody-mediated modulation. Some of these autoantibodies, generally targeting ionotropic channels or their partner proteins, define clinical syndromes resembling models of pharmacological or genetic disruption of the corresponding antigen, suggesting a direct pathogenic role of the associated autoantibodies. Moreover, the associated neurological symptoms are usually immunotherapy-responsive, further arguing for a pathogenic effect of the antibodies. Some studies have shown that some patients' antibodies may have structural and functional in vitro effects on the targeted antigens. Definite proof of the pathogenicity of these autoantibodies has been obtained for just a few through passive transfer experiments in animal models. In this review we present existing and converging evidence suggesting a pathogenic role of some autoantibodies directed against neuronal cell-surface antigens observed in patients with central nervous system disorders. We describe the main clinical symptoms characterizing the patients and discuss conflicting arguments regarding the pathogenicity of these antibodies.
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http://dx.doi.org/10.1111/ejn.13212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914447PMC
June 2016

Placental Barrier and Autism Spectrum Disorders: The Role of Prolactin and Dopamine on the Developing Fetal Brain.

Innov Clin Neurosci 2015 Sep-Oct;12(9-10):14-7

Dr. Yarlagadda is Chief of Psychiatry, Behavioral Health Services, McDonald Army Health Center, Fort Eustis, Virginia; Dr. Acharya is Professor of Obstetrics and Gynecology, UiT-The Arctic University of Norway, Consultant Obstetrician and Gynecologist, University Hospital of North Norway, Tromsø, Norway, and Visiting Professor of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden; Dr. Kasaraneni is with Norton Healthcare, Louisville, Kentucky; Dr. Hampe is Associate Professor of Medicine, Department of Medicine, University of Washington, Seattle, Washington; and Dr. Clayton is Professor and Chair, Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, Virginia.

Dopamine and prolactin exhibit opposite effects on lactation. However, a possible role for increased prolactin/dopamine ratio in postpartum mood and thought disorders and as a prognostic indicator of the mother's future mental health has not been well investigated. Postpartum depression is a serious condition with potentially devastating outcomes for both the mother and the infant. Early detection and treatment of this condition can have impressive results. Treatment options include antidepressant medications for mood disorders and use of antipsychotics and electroconvulsive therapy to address postpartum psychosis. Although there are obvious benefits of such treatments on the welfare of the mother and her child, broader implications of these treatments on lactation and child growth and development are not known. This review article explores a possible link between in-utero exposure to a high maternal prolactin/dopamine ratio and subsequent development of autism spectrum disorders. We hypothesize that a comprehensive, biologically oriented approach to the use of psychotropics in the regulation of neurotransmission during pre- and postpartum periods may result in better outcomes in this population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655894PMC
December 2015