Improvements in Awareness and Testing Have Led to a Threefold Increase Over 10 Years in the Identification of Monogenic Diabetes in the U.K

This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this recordAims/hypothesis: Maturity Onset Diabetes of the Young (MODY) is a rare monogenic form of diabetes. In 2009, >80% of UK cases were estimated to be misdiagnosed. Since then, there have been a number of initiatives to improve the awareness and detection of MODY including education initiatives (Genetic Diabetes Nurse (GDN) programme), the MODY probability calculator, and targeted next generation sequencing (tNGS). We aimed to examine how the estimated prevalence of MODY, and other forms of monogenic diabetes diagnosed outside the neonatal period, has changed over time and how the initiatives have impacted case finding. Research design and Methods: UK referrals for genetic testing for monogenic diabetes diagnosed >1y of age from 01/01/1996 to 31/12/2019 were examined. Positive-test rates were compared for referrals reporting involvement of the GDNs/MODY calculator with those that did not. Results: A diagnosis of monogenic diabetes was confirmed in 3860 individuals, >3-fold higher than 2009 (01/01/1996-28/02/2009; n=1177). Median age at diagnosis in probands was 21y. GDN involvement was reported in 21% of referrals; these referrals had a higher positive-test rate than those without GDN involvement (32% v 23%, p<0.001). MODY calculator usage was indicated on 74% of eligible referrals since 2014; these referrals had a higher positive-test rate than those not using the calculator (33% v 25%, p=0.001). 410 (10.6%) cases were identified through tNGS. Monogenic diabetes prevalence was estimated to be 248 cases/million (double that estimated in 2009 due to increased case-finding). 3 Conclusions: Since 2009, referral rates and case diagnosis have increased three-fold. This is likely to be the consequence of tNGS, GDN education and the MODY calculator

South Asian individuals with diabetes who are referred for MODY testing in the UK have a lower mutation pick-up rate than white European people.

This article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text via the publisher's site.Published (Open Access

Increased cerebral functional connectivity in ALS:A resting-state magnetoencephalography study

Objective We sought to assess cortical function in amyotrophic lateral sclerosis (ALS) using noninvasive neural signal recording. Methods Resting-state magnetoencephalography was used to measure power fluctuations in neuronal oscillations from distributed cortical parcels in 24 patients with ALS and 24 healthy controls. A further 9 patients with primary lateral sclerosis and a group of 15 asymptomatic carriers of genetic mutations associated with ALS were also studied. Results Increased functional connectivity, particularly from the posterior cingulate cortex, was demonstrated in both patient groups compared to healthy controls. Directionally similar patterns were also evident in the asymptomatic genetic mutation carrier group. Conclusion Increased cortical functional connectivity elevation is a quantitative marker that reflects ALS pathology across its clinical spectrum, and may develop during the presymptomatic period. The amelioration of pathologic magnetoencephalography signals might be a marker sensitive enough to provide proof-of-principle in the development of future neuroprotective therapeutics

Altered cortical beta-band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

Continuous rhythmic neuronal oscillations underpin local and regional cortical communication. The impact of the motor system neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) on the neuronal oscillations subserving movement might therefore serve as a sensitive marker of disease activity. Movement preparation and execution are consistently associated with modulations to neuronal oscillation beta (15–30 Hz) power. Cortical beta‐band oscillations were measured using magnetoencephalography (MEG) during preparation for, execution, and completion of a visually cued, lateralized motor task that included movement inhibition trials. Eleven “classical” ALS patients, 9 with the primary lateral sclerosis (PLS) phenotype, and 12 asymptomatic carriers of ALS‐associated gene mutations were compared with age‐similar healthy control groups. Augmented beta desynchronization was observed in both contra‐ and ipsilateral motor cortices of ALS patients during motor preparation. Movement execution coincided with excess beta desynchronization in asymptomatic mutation carriers. Movement completion was followed by a slowed rebound of beta power in all symptomatic patients, further reflected in delayed hemispheric lateralization for beta rebound in the PLS group. This may correspond to the particular involvement of interhemispheric fibers of the corpus callosum previously demonstrated in diffusion tensor imaging studies. We conclude that the ALS spectrum is characterized by intensified cortical beta desynchronization followed by delayed rebound, concordant with a broader concept of cortical hyperexcitability, possibly through loss of inhibitory interneuronal influences. MEG may potentially detect cortical dysfunction prior to the development of overt symptoms, and thus be able to contribute to the assessment of future neuroprotective strategies. Hum Brain Mapp 38:237–254, 2017. © 2016 Wiley Periodicals, Inc

Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL).

Mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL) is an autosomal dominant systemic disorder characterized by prominent loss of subcutaneous fat, a characteristic facial appearance and metabolic abnormalities. This syndrome is caused by heterozygous de novo mutations in the POLD1 gene. To date, 19 patients with MDPL have been reported in the literature and among them 14 patients have been characterized at the molecular level. Twelve unrelated patients carried a recurrent in-frame deletion of a single codon (p.Ser605del) and two other patients carried a novel heterozygous mutation in exon 13 (p.Arg507Cys). Additionally and interestingly, germline mutations of the same gene have been involved in familial polyposis and colorectal cancer (CRC) predisposition

Altered cortical beta‐band oscillations reflect motor system degeneration in amyotrophic lateral sclerosis

Continuous rhythmic neuronal oscillations underpin local and regional cortical communication. The impact of the motor system neurodegenerative syndrome amyotrophic lateral sclerosis (ALS) on the neuronal oscillations subserving movement might therefore serve as a sensitive marker of disease activity. Movement preparation and execution are consistently associated with modulations to neuronal oscillation beta (15–30 Hz) power. Cortical beta‐band oscillations were measured using magnetoencephalography (MEG) during preparation for, execution, and completion of a visually cued, lateralized motor task that included movement inhibition trials. Eleven “classical” ALS patients, 9 with the primary lateral sclerosis (PLS) phenotype, and 12 asymptomatic carriers of ALS‐associated gene mutations were compared with age‐similar healthy control groups. Augmented beta desynchronization was observed in both contra‐ and ipsilateral motor cortices of ALS patients during motor preparation. Movement execution coincided with excess beta desynchronization in asymptomatic mutation carriers. Movement completion was followed by a slowed rebound of beta power in all symptomatic patients, further reflected in delayed hemispheric lateralization for beta rebound in the PLS group. This may correspond to the particular involvement of interhemispheric fibers of the corpus callosum previously demonstrated in diffusion tensor imaging studies. We conclude that the ALS spectrum is characterized by intensified cortical beta desynchronization followed by delayed rebound, concordant with a broader concept of cortical hyperexcitability, possibly through loss of inhibitory interneuronal influences. MEG may potentially detect cortical dysfunction prior to the development of overt symptoms, and thus be able to contribute to the assessment of future neuroprotective strategies. Hum Brain Mapp 38:237–254, 2017. © 2016 Wiley Periodicals, Inc

Characteristics of maturity onset diabetes of the young in a large diabetes center.

Published as an e-pub ahead of print 8th June 2015.Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes caused by a mutation in a single gene, often not requiring insulin. The aim of this study was to estimate the frequency and clinical characteristics of MODY at the Barbara Davis Center. A total of 97 subjects with diabetes onset before age 25, a random C-peptide ≥0.1 ng/mL, and negative for all diabetes autoantibodies (GADA, IA-2, ZnT8, and IAA) were enrolled, after excluding 21 subjects with secondary diabetes or refusal to participate. Genetic testing for MODY 1-5 was performed through Athena Diagnostics, and all variants of unknown significance were further analyzed at Exeter, UK. A total of 22 subjects [20 (21%) when excluding two siblings] were found to have a mutation in hepatocyte nuclear factor 4A (n = 4), glucokinase (n = 8), or hepatocyte nuclear factor 1A (n = 10). Of these 22 subjects, 13 had mutations known to be pathogenic and 9 (41%) had novel mutations, predicted to be pathogenic. Only 1 of the 22 subjects had been given the appropriate MODY diagnosis prior to testing. Compared with MODY-negative subjects, the MODY-positive subjects had lower hemoglobin A1c level and no diabetic ketoacidosis at onset; however, these characteristics are not specific for MODY. In summary, this study found a high frequency of MODY mutations with the majority of subjects clinically misdiagnosed. Clinicians should have a high index of suspicion for MODY in youth with antibody-negative diabetes.This article is freely available via Open Access. Click on the 'Additional Link' above to access the full text via the publisher's site.098395/Wellcome Trust/United Kingdo