Adult-onset Type Research Articles

Improving clinical utility of GAD65 autoantibodies by electrochemiluminescence assay and clinical phenotype when identifying autoimmune adult-onset diabetes

Aims/hypothesisIt is important to differentiate the two major phenotypes of adult-onset diabetes, autoimmune type 1 diabetes and non-autoimmune type 2 diabetes, especially as type 1 diabetes presents in adulthood. Serum GAD65 autoantibodies (GADA) are the most sensitive biomarker for adult-onset autoimmune type 1 diabetes, but the clinical value of GADA by current standard radiobinding assays (RBA) remains questionable. The present study focused on the clinical utility of GADA differentiated by a new electrochemiluminescence (ECL) assay in patients with adult-onset diabetes.MethodsTwo cohorts were analysed including 771 diabetic participants, 30–70 years old, from the Action LADA study (n = 6156), and 2063 diabetic participants, 20–45 years old, from the Diabetes in Young Adults (DiYA) study. Clinical characteristics of participants, including requirement of early insulin treatment, BMI and development of multiple islet autoantibodies, were analysed according to the status of RBA-GADA and ECL-GADA, respectively, and compared between these two assays.ResultsGADA was the most prevalent and predominant autoantibody, >90% in both cohorts. GADA positivity by either RBA or ECL assay significantly discriminated clinical type 1 from type 2 diabetes. However, in both cohorts, participants with ECL-GADA positivity were more likely to require early insulin treatment, have multiple islet autoantibodies, and be less overweight (for all p < 0.0001). However, clinical phenotype, age at diagnosis and BMI independently improved positive predictive value (PPV) for the requirement of insulin treatment, even augmenting ECL-GADA. Participants with GADA detectable by RBA, but not confirmed by ECL, had a phenotype more similar to type 2 diabetes. These RBA-GADA positive individuals had lower affinity GADA compared with participants in which GADA was confirmed by ECL assay.Conclusions/interpretationDetection of GADA by ECL assay, given technical advantages over RBA-GADA, identified adult-onset diabetes patients at higher risk of requiring early insulin treatment, as did clinical phenotype, together allowing for more accurate clinical diagnosis and management.Graphical abstract

Cognitive Deficits, Apathy, and Hypersomnolence Represent the Core Brain Symptoms of Adult-Onset Myotonic Dystrophy Type 1.

Myotonic dystrophy type 1 is the most common form of muscular dystrophy in adults, and is primarily characterized by muscle weakness and myotonia, yet some of the most disabling symptoms of the disease are cognitive and behavioral. Here we evaluated several of these non-motor symptoms from a cross-sectional time-point in one of the largest longitudinal studies to date, including full-scale intelligence quotient, depression, anxiety, apathy, sleep, and cerebral white matter fractional anisotropy in a group of 39 adult-onset myotonic dystrophy type 1 participants (27 female) compared to 79 unaffected control participants (46 female). We show that intelligence quotient was significantly associated with depression (P < 0.0001) and anxiety (P = 0.018), but not apathy (P < 0.058) or hypersomnolence (P = 0.266) in the DM1 group. When controlling for intelligence quotient, cerebral white matter fractional anisotropy was significantly associated with apathy (P = 0.042) and hypersomnolence (P = 0.034), but not depression (P = 0.679) or anxiety (P = 0.731) in the myotonic dystrophy type 1 group. Finally, we found that disease duration was significantly associated with apathy (P < 0.0001), hypersomnolence (P < 0.001), IQ (P = 0.038), and cerebral white matter fractional anisotropy (P < 0.001), but not depression (P = 0.271) or anxiety (P = 0.508). Our results support the hypothesis that cognitive deficits, hypersomnolence, and apathy, are due to the underlying neuropathology of myotonic dystrophy type 1, as measured by cerebral white matter fractional anisotropy and disease duration. Whereas elevated symptoms of depression and anxiety in myotonic dystrophy type 1 are secondary to the physical symptoms and the emotional stress of coping with a chronic and debilitating disease. Results from this work contribute to a better understanding of disease neuropathology and represent important therapeutic targets for clinical trials.

Assessment of self-reported and objective daytime sleepiness in adult-onset myotonic dystrophy type 1.

Excessive daytime sleepiness (EDS) in myotonic dystrophy type 1 is mostly of central origin but it may coexist with sleep-related breathing disorders. However, there is no consensus on the sleep protocols to be used, assessments vary, and only a minority of patients are regularly tested or are on treatment for EDS. Our study presents data on self-reported and objective EDS in adult-onset myotonic dystrophy type 1. Sixty-three patients with adult-onset DM1 were subjected to EDS-sleep assessments (polysomnography, Multiple Sleep Latency Test, Epworth Sleepiness Scale). Correlation coefficients were computed to assess the relationship between sleep and sleepiness test results, fatigue, and quality of life. 33% and 48% of patients had EDS based, respectively, on the Epworth Sleepiness Scale and the Multiple Sleep Latency Test, with a low concordance between these tests (k = 0.19). Thirteen patients (20%) displayed 2 or more sleep-onset rapid eye movement periods on Multiple Sleep Latency Test. Patients having EDS by Multiple Sleep Latency Test had a shorter disease duration (P < .05), higher total sleep time and sleep efficiency and lower wake after sleep onset on polysomnography. Patients with self-reported EDS reported significantly higher fatigue score compared with patients without EDS (P < .05). No other difference was found in demographic, clinical, and respiratory features. EDS test results are contradictory, making treatment options difficult. Combining quantitative tests and self-reported scales may facilitate physicians in planning EDS care with patients and families. Sansone VA, Proserpio P, Mauro L, etal. Assessment of self-reported and objective daytime sleepiness in adult-onset myotonic dystrophy type 1. J Clin Sleep Med. 2021;17(12):2383-2391.

244-OR: Toward Improved Identification of Adult-Onset Type 1 Diabetes (T1D): Clinical Characteristics Associated with T1D Polygenic Risk Scores in the Million Veteran Program (MVP)

Adult onset T1D is often misdiagnosed as T2D, leading to poor metabolic control and increased risk of microvascular complications and cardiovascular morbidity and mortality. We examined characteristics associated with a T1D genetic risk score in Veterans, a population where new diagnoses are generally presumed to be T2D, since persons with typical juvenile-onset T1D are excluded from military service. A 30 SNP T1D genetic risk score (GRS), previously validated with the Wellcome Trust Case Control Consortium (WTCCC), was applied to 111,663 Veterans with diabetes in the MVP. Patients were stratified by T1D GRS centile groups (≤5th, &amp;gt;5th-≤36th, &amp;gt;36th-≤50th, and &amp;gt;50th) which corresponded to T1D specificity in the WTCCC of 29%, 53%, 90%, and 95%, respectively. Typical T1D clinical characteristics were significantly more common (p&amp;lt;0.001) across increasing GRS centile groups: diabetic ketoacidosis 1.07%, 1.34%, 1.95%, 3.55%; hypoglycemia prompting an emergency department visit 3.95%, 3.84%, 4.45%, 5.45%; random plasma glucose &amp;lt;50 mg/dl at a primary care visit 8.05%, 7.99%, 9.01%, 12.43%; years to starting outpatient insulin Rx 4.40, 4.31, 3.97, 3.38; any use of a T1D ICD code 16.56%, 17.76%, 20.90%, 27.62%; low C-peptide if tested 2.91%, 9.75%, 18.96%, 32.55%; and GAD antibody (+) if tested 8.80%, 23.39%, 32.73%, 45.00%. Among the 5% tested, years to starting insulin fell significantly (p&amp;lt;0.001) in lowest to highest centile groups, from 2.59 to 1.28 yr for GAD(-), and from 1.77 vs. 0.90 yr for GAD(+). Conclusions: The 10% of US Veterans with diabetes in MVP in the two highest T1D GRS centile groups have characteristics suggestive of T1D, although only 5% were tested for GAD antibodies, and most had no use of T1D diagnosis codes. Since adult-onset T1D may be misdiagnosed as T2D in settings where T2D is more common, genetic analyses and/or clinical characteristics may warrant definitive testing and appropriate management. Disclosure P. K. Yang: None. M. K. Rhee: None. C. Mercado: None. R. A. Oram: Consultant; Self; Janssen Research &amp; Development, LLC. M. Vujkovic: None. P. Reaven: Research Support; Self; AstraZeneca, Dexcom, Inc. K. Cho: None. L. S. Phillips: Other Relationship; Self; Diasyst Inc., Research Support; Self; AbbVie Inc., Eli Lilly and Company, GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Kowa Pharmaceuticals America, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Pharma Ltd., Pfizer Inc., Sanofi-Aventis. A. Leong: None. S. Jackson: None. B. R. Charest: None. M. N. Weedon: None. Y. J. Cheng: None. Y. V. Sun: None. S. Raghavan: None. E. M. Litkowski: None. B. T. Legvold: None. Funding U.S. Department of Veterans Affairs (CSP2008, I01CX001899, I01CX001737); National Institutes of Health (R18DK066204, R21AI156161, U01DK091958, U01DK098246, UL1TR002378)

Predictive factors associated with diabetic kidney disease in adult-onset Type 1 Diabetes

Predictive factors associated with diabetic kidney disease in adult-onset Type 1 Diabetes

Association of Childhood Fat Mass and Weight With Adult-Onset Type 2 Diabetes in Denmark

Childhood obesity, defined by cutoffs based on the weight-based marker of body mass index, is associated with adult type 2 diabetes (T2D) risk. Whether childhood fat mass (FM) is the driver of these associations is currently unknown. To quantify and compare height-independent associations between childhood FM and weight with adult T2D risk in a historic Danish cohort. This population-based retrospective cohort study included schoolchildren from The Copenhagen School Health Records Register born between January 1930 and December 1985 with follow-up to adulthood through December 31, 2015. Analyses were based on 269 913 schoolchildren aged 10 years with 21 896 established adult T2D cases and 261 192 children aged 13 years with 21 530 established adult T2D cases for whom childhood height and weight measurements, as well as predicted FM, were available. Statistical analyses were performed between April 2019 to August 2020. Childhood FM and weight at ages 10 and 13 years. Diagnoses of T2D were established by linkage to national disease registers for adults aged at least 30 years. Sex-specific Cox regression quantified associations, adjusted for childhood height, which were evaluated within 5 birth-cohort groups. Group-specific results were pooled using random-effects meta-analyses accounting for heterogeneity across group-specific associations. This cohort study analyzed data from 269 913 children aged 10 years (135 940 boys [50.4%]) with 21 896 established adult T2D cases and 261 192 children aged 13 years (131 025 boys [50.2%]) with 21 530 established adult T2D cases. After adjusting for childhood height, increases in FM and weight (per kilogram) among boys aged 10 years were associated with elevated T2D risks at age 50 years of 12% (hazard ratio [HR], 1.12; 95% CI, 1.10-1.14) and 7% (HR, 1.07; 95% CI, 1.05-1.09), respectively, and among girls aged 10 years of 15% (HR, 1.15; 95% CI, 1.13-1.17) and 10% (HR, 1.10; 95% CI, 1.08-1.11), respectively. Among children aged 13 years, increases in FM and weight (per kilogram) were associated with increased T2D risks at age 50 years of 10% (HR, 1.10; 95% CI, 1.09-1.10) and 6% (HR, 1.06; 95% CI, 1.05-1.07) for boys, respectively, and of 10% (HR, 1.10; 95% CI, 1.10-1.11) and 7% (HR, 1.07; 95% CI, 1.06-1.08), respectively, for girls. This cohort study found that a 1-kg increase in childhood FM was more strongly associated with increased adult T2D risk than a 1-kg increase in weight, independent of childhood height. Information on FM, rather than weight-based measures, focuses on a modifiable component of weight that may be associated with adult T2D risk. These findings support the assessment of childhood FM in adiposity surveillance initiatives in an effort to reduce long-term T2D risk.

Hypoglycemic attacks and growth failure are the most common manifestations of citrin deficiency after 1 year of age.

Citrin deficiency develops in different symptomatic periods from the neonatal period to adulthood. Some infantile patients are diagnosed by newborn mass screening or symptoms of neonatal intrahepatic cholestasis caused by citrin deficiency, some patients in childhood may develop hepatopathy or dyslipidemia as failure to thrive and dyslipidemia caused by citrin deficiency, and some adults are diagnosed after developing adult-onset type 2 citrullinemia (CTLN2) with hyperammonemia or encephalopathy. A diagnosis is needed before the development of severe phenotypic CTLN2 but is often difficult to obtain because newborn mass screening cannot detect all patients with citrin deficiency, and undiagnosed patients often appear healthy in childhood. There are only a few reports that have described patients in childhood. To explore the clinical features of undiagnosed patients with citrin deficiency in childhood, we studied 20 patients who were diagnosed after the first year of life. Of these patients, 45% experienced hypoglycemic attacks in childhood. The acetoacetic acid level during hypoglycemic attacks was lower than expected. Growth failure at diagnosis (45%) was also noted. From the patients' history, fat- and protein-rich food preferences (80%), a low birth weight (70%), and prolonged jaundice or infantile hepatopathy (40%) were identified. To diagnose citrin deficiency in childhood, we should ask about food preferences and a history of infantile hepatopathy for all children with severe hypoglycemia or growth failure and consider the genetic test for citrin deficiency if the patient has characteristic food preferences or a history of infantile hepatopathy.

The dystonia gene THAP1 controls DNA double-strand break repair choice

The Shieldin complex shields double-strand DNA breaks (DSBs) from nucleolytic resection. Curiously, the penultimate Shieldin component, SHLD1, is one of the least abundant mammalian proteins. Here, we report that the transcription factors THAP1, YY1, and HCF1 bind directly to the SHLD1 promoter, where they cooperatively maintain the low basal expression of SHLD1, thereby ensuring a proper balance between end protection and resection during DSB repair. The loss of THAP1-dependent SHLD1 expression confers cross-resistance to poly (ADP-ribose) polymerase (PARP) inhibitor and cisplatin in BRCA1-deficient cells and shorter progression-free survival in ovarian cancer patients. Moreover, the embryonic lethality and PARPi sensitivity of BRCA1-deficient mice is rescued by ablation of SHLD1. Our study uncovers a transcriptional network that directly controls DSB repair choice and suggests a potential link between DNA damage and pathogenic THAP1 mutations, found in patients with the neurodevelopmental movement disorder adult-onset torsion dystonia type 6.

Neurocognitive Features of Motor Premanifest Individuals With Myotonic Dystrophy Type 1.

ObjectiveThe goal of the study was to identify brain and functional features associated with premanifest phases of adult-onset myotonic dystrophy type 1 (i.e., PreDM1).MethodsThis cross-sectional study included 68 healthy adults (mean age = 43.4 years, SD = 12.9), 13 individuals with PreDM1 (mean age: 47.4 years, SD = 16.3), and 37 individuals with manifest DM1 (mean age = 45.2 years, SD = 9.3). The primary outcome measures included fractional anisotropy (FA), motor measures (Muscle Impairment Rating Scale, Grooved Pegboard, Finger-Tapping Test, and grip force), general cognitive abilities (Wechsler Adult Intelligence Scales), sleep quality (Scales for Outcomes in Parkinson's Disease–Sleep), and apathy (Apathy Evaluation Scale).ResultsIndividuals with PreDM1 exhibited an intermediate level of white matter FA abnormality, where whole-brain FA was lower relative to healthy controls (difference of the estimated marginal mean [EMMdifference] = 0.02, 95% confidence interval (CI) 0.01–0.03, p < 0.001), but the PreDM1 group had significantly higher FA than did individuals with manifest DM1 (EMMdifference = 0.02, 95% CI 0.009–0.03, p < 0.001). Individuals with PreDM1 exhibited reduced performance on the finger-tapping task relative to control peers (EMMdifference = 5.70, 95% CI 0.51–11.00, p = 0.03), but performance of the PreDM1 group was better than that of the manifest DM1 group (EMMdifference = 5.60, 95% CI 0.11–11.00, p = 0.05). Hypersomnolence in PreDM1 was intermediate between controls (EMMdifference = −1.70, 95% CI −3.10–0.35, p = 0.01) and manifest DM1 (EMMdifference = −2.10, 95% CI −3.50–0.60, p = 0.006).ConclusionsOur findings highlight key CNS and functional deficits associated with PreDM1, offering insight in early disease course.

Analysis of daily energy, protein, fat, and carbohydrate intake in citrin-deficient patients: Towards prevention of adult-onset type II citrullinemia

Patients with citrin deficiency during the adaptation/compensation period exhibit diverse clinical features and have characteristic diet of high protein, high fat, and low carbohydrate. Japanese cuisine typically contains high carbohydrate but evaluation of diet of citrin-deficient patients in 2008 showed a low energy intake and a protein:fat:carbohydrate (PFC) ratio of 19:44:37, which indicates low carbohydrate consumption rate. These findings prompted the need for diet intervention to prevent the adult onset of type II citrullinemia (CTLN2). Since the publication of the report about 10 years ago, patients are generally advised to eat what they wish under active dietary consultation and intervention. In this study, citrin-deficient patients and control subjects living in the same household provided answers to a questionnaire, filled-up a maximum 6-day food diary, and supplied physical data and information on medications if any. To study the effects of the current diet, the survey collected data from 62 patients and 45 controls comparing daily intakes of energy, protein, fat, and carbohydrate. Food analysis showed that patient's energy intake was 115% compared to the Japanese standard. The confidence interval of the PFC ratio of patients was 20–22:47–51:28–32, indicating higher protein, higher fat and lower carbohydrate relative to previous reports. The mean PFC ratio of female patients (22:53:25) was significantly different from that of male patients (20:46:34), which may explain the lower frequency of CTLN2 in females. Comparison of the present data to those published 10 years ago, energy, protein, and fat intakes were significantly higher but the amount of carbohydrate consumption remained the same. Regardless of age, most patients (except for adolescents) consumed 100–200 g/day of carbohydrates, which met the estimated average requirement of 100 g/day for healthy individuals. Finally, patients were generally not overweight and some CTLN2 patients were underweight although their energy intake was higher compared with the control subjects. We speculate that high-energy of a low carbohydrate diet under dietary intervention may help citrin-deficient patients attain normal growth and prevent the onset of CTLN2.

Quantitative muscle MRI as a sensitive marker of early muscle pathology in myotonic dystrophy type 1.

Quantitative muscle MRI as a sensitive marker of early muscle pathology and disease progression in adult-onset myotonic dystrophy type 1. The utility of muscle MRI as a marker of muscle pathology and disease progression in adult-onset myotonic dystrophy type 1 (DM1) was evaluated. This prospective, longitudinal study included 67 observations from 36 DM1 patients (50% female), and 92 observations from 49 healthy adults (49% female). Lower-leg 3T magnetic resonance imaging (MRI) scans were acquired. Volume and fat fraction (FF) were estimated using a three-point Dixon method, and T2-relaxometry was determined using a multi-echo spin-echo sequence. Muscles were segmented automatically. Mixed linear models were conducted to determine group differences across muscles and image modality, accounting for age, sex, and repeated observations. Differences in rate of change in volume, T2-relaxometry, and FF were also determined with mixed linear regression that included a group by elapsed time interaction. Compared with healthy adults, DM1 patients exhibited reduced volume of the tibialis anterior, soleus, and gastrocnemius (GAS) (all, P < .05). T2-relaxometry and FF were increased across all calf muscles in DM1 compared to controls. (all, P < .01). Signs of muscle pathology, including reduced volume, and increased T2-relaxometry and FF were already noted in DM1 patients who did not exhibit clinical motor symptoms of DM1. As a group, DM1 patients exhibited a more rapid change than did controls in tibialis posterior volume (P = .05) and GAS T2-relaxometry (P = .03) and FF (P = .06). Muscle MRI renders sensitive, early markers of muscle pathology and disease progression in DM1. T2 relaxometry may be particularly sensitive to early muscle changes related to DM1.

The application of scales and characteristics of disability in the common genotypes of Charcot-Marie-Tooth disease

Objective: To analyze the correlations among different common scales for evaluating the severity of the first-visit Charcot-Marie-Tooth disease (CMT), and explore the cross-sectional characteristics of neurological dysfunction in patients with four common genotypes (CMT1A, CMT1X, CMT2A and MPZ-related CMT) at their first visits. Methods: A total of 117 genetically confirmed CMT patients (aged ≥10 years) from the Department of Neurology of the Third Xiangya Hospital from 2009 to 2019 were included in the study, which consisted of 45 CMT1A, 41 CMT1X, 19 CMT2A, and 12 MPZ-related CMT patients. Clinical data of these patients at first visits were collected and neurological deficits were evaluated by Charcot-Marie-Tooth Neuropathy Score (CMTNS), Charcot-Marie-Tooth Examination Score (CMTES), Overall Neuropathy Limitation Scale (ONLS) and Functional Disability Scale (FDS). Spearman's correlation was performed to analyze the relationship between CMTNS, CMTES, ONLS and FDS. The age of onset, duration of disease, scores of CMTNS, CMTES, ONLS and FDS were compared among four genotypes. Results: In the 117 CMT patients, the male to female ratio was 1.79/1, and the age of onset was (19±13) years. The duration of disease was 10(3, 15) years, and the scores of CMTNS, CMTES, ONLS and FDS were 11.4±6.2, 8.8±5.7, 2.7±1.4 and 2.6±1.3, respectively. There was a significant correlation between CMTES, ONLS, FDS and CMTNS in the overall CMT patients and four subtypes respectively (r≥0.40, P<0.05). CMTNS, CMTES and ONLS scores of four subtypes showed positive correlations with duration of disease (P<0.05), but FDS scores of CMT1A, CMT1X and MPZ-related CMT patients exhibited no correlation with duration of disease (P>0.05) at their first visits. The age of onset in CMT2A patients was younger than that of the patients with the other three genotypes (P<0.05), furthermore, the scores of four scales in early-onset CMT2A patients were higher than those of adult-onset type CMT2A patients (CMTNS: P=0.031, CMTES: P=0.048, ONLS: P=0.042, FDS: P=0.047). In CMT1X patients, the males had higher scores than those of females for all four scales (CMTNS: P=0.028, CMTES: P=0.014, ONLS: P=0.023, FDS: P=0.002). Conclusions: CMTNS, CMTES and ONLS could be used in natural history studies and clinical trials according to the different clinical situations. In the four genotypes, CMT2A patients have younger age of onset, and the earlier the age of onset, the severer the dysfunction. Moreover, male CMT1X patients relatively have severer neurological dysfunction than female patients.

Liver Transplantation for Metabolic Liver Disease Patients: A Single-Center Experience

Introduction: Metabolic liver disease (MLD) is life threatening. The efficacy of liver transplantation (LT) for MLD patients are well reported. There are some options of surgical procedures, but a few reports of collecting data was reported from a single-center. Here we present our experiences of LT procedures including deceased donor (DD) LT, living donor (LD) LT and auxiliary partial orthotopic liver transplantation (APOLT), and outcome in those patients. Methods: Medical records of 61 MLD adult (≧18 years old) recipients underwent LT in our institute were reviewed retrospectively. Perioperative factors were investigated. The patient survival rate was calculated. Results: The causes of LT were familial amyloid polyneuropathy in 42, adult-onset type 2 citrullinemia in 17, glycogen storage disease in 1 and Wilson's disease in 1. The median age at LT was 37.1 (range 18.8 to 58.4) years old. All DDLT recipients received whole liver graft (n=7). In all LDLT cases (n=54), the left liver grafts were used. The median volume of graft was 392g that was correspond to 38.0% of the recipient standard liver volume (range 230 (22.1) to 580g (58.8%)). In 18 cases of those, APOLT was selected because of extremely small size of graft or expectation of future gene therapy. The 10-year survival rate of MLD recipients was 86.8%. Conclusions: Even though a graft is relatively small, LT for MLD patients could be successfully achieved with APOLT. The 10-year survival rate of MLD recipient in our institute was thought to be satisfactory.

Psychosocial and social factors related to self-care agency in patients with adult-onset type 1 diabetes

Psychosocial and social factors related to self-care agency in patients with adult-onset type 1 diabetes

The Absence of Islet Autoantibodies in Clinically Diagnosed Older-Adult Onset Type 1 Diabetes Suggests an Alternative Pathology, Advocating for Routine Testing in This Age Group

Objective: Islet autoantibodies at diagnosis are not well studied in older-adult onset (>30years) type 1 diabetes due to difficulties of accurate diagnosis. We used a type 1 diabetes genetic risk score (T1DGRS) to identify type 1 diabetes aiming to evaluate the prevalence and pattern of autoantibodies in older-adult onset type 1 diabetes. Methods: We used a 30 variant T1DGRS in 1866 white-European individuals to genetically confirm a clinical diagnosis of new onset type 1 diabetes. We then assessed the prevalence and pattern of GADA, IA2A and ZnT8A within genetically consistent type 1 diabetes across three age groups ( 30years (n=588)). Findings: In autoantibody positive cases T1DGRS was consistent with 100% type 1 diabetes in each age group. Conversely in autoantibody negative cases, T1DGRS was consistent with 93%(56/60) of 30years having type 1 diabetes. Restricting analysis to genetically consistent type 1 diabetes showed similar proportions of positive autoantibodies across age groups (92% 30years)[p=0.87]. GADA was the most common autoantibody in older-adult onset type 1 diabetes, identifying 95% of autoantibody positive cases versus 72% in those <18years. Interpretation: Older adult-onset type 1 diabetes has identical rates but different patterns of positive autoantibodies to childhood onset. In clinically suspected type 1 diabetes in older-adults, absence of autoantibodies strongly suggests non-autoimmune diabetes. Our findings suggest the need to change guidelines from measuring islet autoantibodies where there is diagnostic uncertainty to measuring at least GADA in all suspected adult type 1 diabetes cases. Funding Statement: NJT is funded by a Wellcome Trust funded GW4 PhD (220601/Z/20/Z). M.N.W. is supported by the Wellcome Trust Institutional Support Fund (WT097835MF). KAP is a Wellcome Trust fellow (219606/Z/19/Z) and the genetic risk score analysis in ADDRESS-2 was funded by Diabetes wellness Research foundation pump priming grant. ADDRESS-2 is co-funded by Diabetes UK (grant numbers 09-0003919, 15-005234 & 19/0006119) and the Juvenile Diabetes Research Foundation (grant numbers 9-2010-407 & 3-SRA-2015-35-A-N), supported by the NIHR Clinical Research Network and hosted by Imperial College London. S.M. is currently supported by a Future Leaders Mentorship award from the European Federation for the Study of Diabetes. NO is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College London. DJ is funded by the NIHR CRN. Declaration of Interests: We declare no competing interest. Ethics Approval Statement:Ethics for the ADDRESS2 study was granted by the South Central – Berkshire NHS Research Ethics Committee on the 03/10/2010, ref: 10/H0505/85. Ethics for monogenic testing in the ADDRESS2 cohort by the East of England – Essex Research Ethics Committee on the 14/7/2016, ref 16/EE/0306

Dietary Management, Clinical Status and Outcome of Patients with Citrin Deficiency in the UK.

Background: Little is known about the optimal dietary treatment for citrin deficiency. Our aim is to describe the management of UK citrin deficiency patients. Methods: A longitudinal retrospective review was performed. Data were collected from medical records on presenting signs and symptoms, dietary management and clinical outcome. Results: data were collected on 32 patients from 21 families. 50% were females (16/32). Median age at diagnosis was 4 y (5 days–35 y) with 12 patients diagnosed in the neonatal period with neonatal intrahepatic cholestasis (NICCD), eight later in childhood (FTTDCD) and 12 by family screening based on index cases from five families. No patient had adult-onset type II citrullinemia. The patient age at the time of data collection was a median of 11 y (1–44 y). 91% (29/32) of patients had normal physical and neurological development, 47% (15/32) experienced recurrent unexplained abdominal pain and 9% (3/32) episodes of hypoglycaemia. Siblings had different phenotypes (5 families had > 1 affected patient). Most patients preferred high protein foods, limiting sugar-containing foods. Only 41% (13/32) were prescribed a low CHO, high protein, high fat diet (restriction varied) and two used medium chain triglyceride (MCT) supplements. No patient was prescribed drug therapy. Twenty-five per cent (8/32) of patients were underweight and 41% (13/32) had height <−1 z-scores. Conclusions: patients presented with various phenotypes, symptoms and suboptimal growth. Symptoms and biochemical markers improved with age, but height remained low in some. More research is necessary to assess the effectiveness of dietary approaches in improving clinical outcomes and symptoms in citrin deficiency.

Encoding of facial expressions in individuals with adult-onset myotonic dystrophy type 1

ABSTRACT Introduction: Emotional issues are often reported among individuals with myotonic dystrophy type 1 (DM1) and some studies have suggested that deficits in ability to quickly encode emotions may contribute to these problems. However, poor performance on emotion encoding tasks could also be explained by a more general cognitive deficit (Full Scale IQ [FSIQ]), rather than a specific deficit in emotional processing. Since individuals with DM1 are known to exhibit difficulties in general cognitive abilities, it is important to account for FSIQ when evaluating emotion encoding. The aim of this study was to compare emotion encoding abilities between individuals with and without DM1, while adjusting for the impact of general cognitive abilities (FSIQ). Methods: The sample included 35 individuals with adult-onset DM1 and 54 unaffected adults who completed assessments of emotion encoding abilities (Ekman faces test) and general cognitive abilities (Wechsler Adult Intelligence Scale-IV). Performance on the emotion encoding task was operationalized as proportion correct and response time. Group differences in proportion correct were evaluated with generalized linear regression, while linear regression models were used to determine the effect of group on response time. Models were adjusted for age, sex, and FSIQ. The false discovery rate (FDR) was applied to control false positives due to multiple comparisons (pfdr ). Results: No significant group differences were observed for emotion encoding abilities (all pfdr > 0.13). FSIQ was significantly associated with proportion correct and with response time (all pfdr < 0.05). Conclusions: Emotion encoding appears intact in individuals with DM1 and variation in the ability to encode facial expressions was associated with FSIQ. Further research is required to address the relationship between general cognitive abilities and emotion encoding abilities among DM1 patients.

Metabolic basis and treatment of citrin deficiency.

Citrin deficiency is a hereditary disorder caused by SLC25A13 mutations and manifests as neonatal intrahepatic cholestasis (NICCD), failure to thrive and dyslipidemia (FTTDCD), and adult-onset type II citrullinemia (CTLN2). Citrin is a component of the malate-aspartate nicotinamide adenine dinucleotide hydrogen (NADH) shuttle, an essential shuttle for hepatic glycolysis. Hepatic glycolysis and the coupled lipogenesis are impaired in citrin deficiency. Hepatic lipogenesis plays a significant role in fat supply during growth spurt periods: the fetal period, infancy, and puberty. Growth impairment in these periods is characteristic of citrin deficiency. Hepatocytes with citrin deficiency cannot use glucose and fatty acids as energy sources due to defects in the NADH shuttle and downregulation of peroxisome proliferator-activated receptor α (PPARα), respectively. An energy deficit in hepatocytes is considered a fundamental pathogenesis of citrin deficiency. Medium-chain triglyceride (MCT) supplementation with a lactose-restricted formula and MCT supplementation under a low-carbohydrate diet are recommended for NICCD and CTLN2, respectively. MCT supplementation therapy can provide energy to hepatocytes, promote lipogenesis, correct the cytosolic NAD+ /NADH ratio via the malate-citrate shuttle and improve ammonia detoxification, and it is a reasonable therapy for citrin deficiency. It is very important to administer MCT at a dose equivalent to the liver's energy requirements in divided doses with meals. MCT supplementation therapy is certainly promising for promoting growth spurts during infancy and adolescence and for preventing CTLN2 onset. Intravenous administration of solutions containing fructose is contraindicated, and persistent hyperglycemia should be avoided due to glucose intoxication for patients receiving hyperalimentation or with complicating diabetes.

Lessons for the clinical nephrologist: dietary management of adult-onset type II citrullinemia in chronic kidney disease: a nutritional dilemma.

Lessons for the clinical nephrologist: dietary management of adult-onset type II citrullinemia in chronic kidney disease: a nutritional dilemma.

AGC2 (Citrin) Deficiency—From Recognition of the Disease till Construction of Therapeutic Procedures

Can you imagine a disease in which intake of an excess amount of sugars or carbohydrates causes hyperammonemia? It is hard to imagine the intake causing hyperammonemia. AGC2 or citrin deficiency shows their symptoms following sugar/carbohydrates intake excess and this disease is now known as a pan-ethnic disease. AGC2 (aspartate glutamate carrier 2) or citrin is a mitochondrial transporter which transports aspartate (Asp) from mitochondria to cytosol in exchange with glutamate (Glu) and H+. Asp is originally supplied from mitochondria to cytosol where it is necessary for synthesis of proteins, nucleotides, and urea. In cytosol, Asp can be synthesized from oxaloacetate and Glu by cytosolic Asp aminotransferase, but oxaloacetate formation is limited by the amount of NAD+. This means an increase in NADH causes suppression of Asp formation in the cytosol. Metabolism of carbohydrates and other substances which produce cytosolic NADH such as alcohol and glycerol suppress oxaloacetate formation. It is forced under citrin deficiency since citrin is a member of malate/Asp shuttle. In this review, we will describe history of identification of the SLC25A13 gene as the causative gene for adult-onset type II citrullinemia (CTLN2), a type of citrin deficiency, pathophysiology of citrin deficiency together with animal models and possible treatments for citrin deficiency newly developing.