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Circulation. Heart Failure Sep 2015Despite the substantial overlap of obesity and metabolic disease, there is heterogeneity with respect to cardiovascular risk. We sought to investigate preclinical...
BACKGROUND
Despite the substantial overlap of obesity and metabolic disease, there is heterogeneity with respect to cardiovascular risk. We sought to investigate preclinical differences in systolic and diastolic function in obesity, and specifically compare obese individuals with and without metabolic syndrome (MS).
METHODS AND RESULTS
Obese individuals without cardiac disease with (OB/MS+, n=124) and without (OB/MS-, n=37) MS were compared with nonobese controls (n=29). Diastolic function was assessed by transmitral and tissue Doppler. Global longitudinal strain (LS) and time-based dyssynchrony were assessed by speckle tracking. Both OB/MS- and OB/MS+ groups had similar ejection fraction but worse systolic mechanics as assessed by LS and dyssynchrony when compared with nonobese controls. Specifically, OB/MS- had 2.5% lower LS (SE, 0.7%; P=0.001 in multivariable-adjusted analyses) and 10.8 ms greater dyssynchrony (SE, 3.3 ms; P=0.002), and OB/MS+ had 1.0% lower LS (SE, 0.3%; P<0.001) and 7.8 ms greater dyssynchrony (SE, 1.5 ms; P<0.001) when compared with controls. Obesity was associated with impaired diastolic function regardless of MS status, as evidenced by greater left atrial diameter and left ventricular mass although diastolic dysfunction was more pronounced in OB/MS+ than in OB/MS- individuals.
CONCLUSIONS
Obesity is associated with subclinical differences in both systolic and diastolic function regardless of the presence or absence of MS although MS seems to be associated with worse diastolic dysfunction. When compared with controls, metabolically healthy obese had lower LS, greater dyssynchrony, and early diastolic dysfunction, supporting the notion that obesity per se may have adverse cardiovascular effects regardless of metabolic disease.
Topics: Adult; Diastole; Echocardiography, Doppler; Female; Heart Ventricles; Humans; Male; Metabolic Syndrome; Obesity; Risk Factors; Stroke Volume; Systole; Ventricular Dysfunction, Left; Ventricular Function, Left
PubMed: 26175540
DOI: 10.1161/CIRCHEARTFAILURE.114.002026 -
Journal of Clinical Research in... Apr 2023Homozygous or compound heterozygous mutations in insulin receptor gene (INSR) lead to marked insulin resistance and hyperglycaemia in Donohue syndrome and...
Homozygous or compound heterozygous mutations in insulin receptor gene (INSR) lead to marked insulin resistance and hyperglycaemia in Donohue syndrome and Rabson-Mendenhall syndrome, conditions which are associated with significant morbidity early in life. On the other hand, heterozygous INSR gene mutations result in milder phenotype known as type A insulin resistance syndrome. While presentation in adults with this condition is well reported, phenotypes in infant are less well-characterized. We herein report an infant presenting with hyperinsulinemic hypoglycaemia who did not respond to diazoxide therapy. She was subsequently found to carry heterozygous INSR gene mutation. Our patient was a female infant born at 29 weeks of gestation who developed recurrent hypoglycaemia in early infancy. Workup showed hyperinsulinism and she was started on first-line therapy with diazoxide and high-calorie feeds. However, continuous blood glucose monitoring showed post-prandial hyperglycaemia followed by rapid fall to hypogylcaemia. Whole exome sequencing was performed to investigate for diazoxide-unresponsive hyperinsulinism, which revealed a likely pathogenic mutation in the INSR gene c.1246C>T p. (R416X). This nonsense mutation was inherited from the father. With the molecular diagnosis, diazoxide was stopped and she followed a diet with low glycaemic-index food. Subsequent monitoring showed stable glucose profile. Our case highlights the importance to consider type A insulin resistance syndrome when no mutation could be identified in the ABCC8/KCNJ11 genes in diazoxide-unresponsive hyperinsulinism. With autosomal dominant inheritance, cascade screening should be performed in family members to identify those harbouring the mutation as they are at risk of early onset diabetes.
PubMed: 37074094
DOI: 10.4274/jcrpe.galenos.2023.2022-12-10 -
Pediatric Research Jan 2023We hypothesised that the clinical characteristics of hospitalised children and young people (CYP) with SARS-CoV-2 in the UK second wave (W2) would differ from the... (Observational Study)
Observational Study
BACKGROUND
We hypothesised that the clinical characteristics of hospitalised children and young people (CYP) with SARS-CoV-2 in the UK second wave (W2) would differ from the first wave (W1) due to the alpha variant (B.1.1.7), school reopening and relaxation of shielding.
METHODS
Prospective multicentre observational cohort study of patients <19 years hospitalised in the UK with SARS-CoV-2 between 17/01/20 and 31/01/21. Clinical characteristics were compared between W1 and W2 (W1 = 17/01/20-31/07/20,W2 = 01/08/20-31/01/21).
RESULTS
2044 CYP < 19 years from 187 hospitals. 427/2044 (20.6%) with asymptomatic/incidental SARS-CoV-2 were excluded from main analysis. 16.0% (248/1548) of symptomatic CYP were admitted to critical care and 0.8% (12/1504) died. 5.6% (91/1617) of symptomatic CYP had Multisystem Inflammatory Syndrome in Children (MIS-C). After excluding CYP with MIS-C, patients in W2 had lower Paediatric Early Warning Scores (PEWS, composite vital sign score), lower antibiotic use and less respiratory and cardiovascular support than W1. The proportion of CYP admitted to critical care was unchanged. 58.0% (938/1617) of symptomatic CYP had no reported comorbidity. Patients without co-morbidities were younger (42.4%, 398/938, <1 year), had lower PEWS, shorter length of stay and less respiratory support.
CONCLUSIONS
We found no evidence of increased disease severity in W2 vs W1. A large proportion of hospitalised CYP had no comorbidity.
IMPACT
No evidence of increased severity of COVID-19 admissions amongst children and young people (CYP) in the second vs first wave in the UK, despite changes in variant, relaxation of shielding and return to face-to-face schooling. CYP with no comorbidities made up a significant proportion of those admitted. However, they had shorter length of stays and lower treatment requirements than CYP with comorbidities once those with MIS-C were excluded. At least 20% of CYP admitted in this cohort had asymptomatic/incidental SARS-CoV-2 infection. This paper was presented to SAGE to inform CYP vaccination policy in the UK.
Topics: Humans; Child; Adolescent; SARS-CoV-2; COVID-19; Pandemics; Prospective Studies; Coronavirus Infections; United Kingdom
PubMed: 35449394
DOI: 10.1038/s41390-022-02052-5 -
Open Forum Infectious Diseases Feb 2022There is mounting evidence for the presence of postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), but there is limited...
BACKGROUND
There is mounting evidence for the presence of postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), but there is limited information on the spectrum, magnitude, duration, and patterns of these sequelae as well as their influence on quality of life.
METHODS
We assembled a cohort of adults with a documented history of SARS-CoV-2 RNA positivity at ≥2 weeks past onset of coronavirus disease 2019 (COVID-19) symptoms or, if asymptomatic, first positive test. At 4-month intervals, we queried physical and mental health symptoms and quality of life.
RESULTS
Of the first 179 participants enrolled, 10 were asymptomatic during the acute phase of SARS-CoV-2 infection, 125 were symptomatic but not hospitalized, and 44 were symptomatic and hospitalized. During the postacute phase, fatigue, shortness of breath, concentration problems, headaches, trouble sleeping, and anosmia/dysgeusia were most common through 8 months of observation. Symptoms were typically at least somewhat bothersome and sometimes exhibited a waxing-and-waning course. Some participants experienced symptoms of depression, anxiety, and post-traumatic stress, as well as difficulties with performance of usual activities. The median visual analogue scale rating of general health was lower at 4 and 8 months compared with pre-COVID-19. Two clusters of symptom domains were identified.
CONCLUSIONS
Many participants report bothersome symptoms following onset of COVID-19 with variable patterns of persistence and impact on quality of life. The substantial variability suggests the existence of multiple subphenotypes of PASC. A rigorous approach to the prospective measurement of symptoms and functional manifestations sets the stage for the next phase of research focusing on the pathophysiologic causes of the various subgroups of PASC.
PubMed: 35106317
DOI: 10.1093/ofid/ofab640 -
American Journal of Medical Genetics.... Jan 2021Genetic diseases are a major cause of neonatal morbidity and mortality. The clinical differential diagnosis in severely ill neonates, especially in premature infants, is...
Genetic diseases are a major cause of neonatal morbidity and mortality. The clinical differential diagnosis in severely ill neonates, especially in premature infants, is challenging. Next generation sequencing (NGS) diagnostics is a valuable tool, but the turnaround time is often too long to provide a diagnosis in the time needed for clinical guidance in newborn intensive care units (NICU). To minimize turnaround time, we developed an ultra-rapid whole genome sequencing pipeline and tested it in clinical practice. Our pilot case, was a preterm infant presenting with several crises of dehydration, hypoglycaemia and hyponatremia together with nephrocalcinosis and hypertrophic cardiomyopathy. Whole genome sequencing was performed using a paired-end 2x75bp protocol. Sequencing data were exported after 50 sequencing cycles for a first analysis. After run completion, the rapid-sequencing protocol, a second analysis of the 2 x 75 paired-end run was performed. Both analyses comprised read-mapping and SNP-/indel calling on an on-site Edico Genome DRAGEN server, followed by functional annotation and pathogenicity prediction using in-house scripts. After the first analysis within 17 h, the emergency ultra-rapid protocol identified two novel compound heterozygous variants in the insulin receptor gene (INSR), pathogenic variants in which cause Donohue Syndrome. The genetic diagnosis could be confirmed by detection of hyperinsulinism and patient care adjusted. Nonetheless, we decided to pursue RNA studies, proving the functional effect of the novel splice variant and reduced expression levels of INSR in patients skin fibroblasts.
Topics: Antigens, CD; Dehydration; Female; Genetic Diseases, Inborn; High-Throughput Nucleotide Sequencing; Humans; Hypoglycemia; Infant; Infant Mortality; Infant, Newborn; Infant, Premature; Intensive Care Units, Neonatal; Male; Molecular Sequence Annotation; Polymorphism, Single Nucleotide; Protein Isoforms; Receptor, Insulin; Whole Genome Sequencing
PubMed: 33048476
DOI: 10.1002/ajmg.a.61917 -
Journal of Pediatric Endocrinology &... Nov 2022Rabson Mendenhall syndrome (RMS) is a rare form of insulin resistance syndrome caused by insulin receptor mutation. In term of severity, it lies at an intermediate...
OBJECTIVES
Rabson Mendenhall syndrome (RMS) is a rare form of insulin resistance syndrome caused by insulin receptor mutation. In term of severity, it lies at an intermediate point on spectrum of insulin resistance with Donohue syndrome flanking the severe and Type A insulin resistance at the mild end. We are reporting a 3.5-month-old boy with RMS along with its management challenges in a resource limited country.
CASE PRESENTATION
An infant presented at 3.5-month of an age with failure to thrive and fluctuating blood glucose level (hyperglycaemia and hypoglycaemia) along with clinical features of insulin resistance. He was found to have raised HbA1C, high insulin and C peptide level and a homozygous mutation in gene c.1049C>T, (p.Ser350 Leu) confirming the diagnosis of RMS. He was managed with long-acting insulin (Detemir) along with frequent feeding.
CONCLUSIONS
RMS in resource limited countries could be managed with frequent feeding along with insulin. Early diagnosis and management can improve long term outcome.
Topics: Infant; Male; Humans; Donohue Syndrome; Insulin Resistance; Receptor, Insulin; Insulin; Mutation
PubMed: 36106528
DOI: 10.1515/jpem-2022-0214 -
MedRxiv : the Preprint Server For... Mar 2021As the coronavirus disease 2019 (COVID-19) pandemic continues and millions remain vulnerable to infection with severe acute respiratory syndrome-coronavirus-2...
BACKGROUND
As the coronavirus disease 2019 (COVID-19) pandemic continues and millions remain vulnerable to infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), attention has turned to characterizing post-acute sequelae of SARS-CoV-2 infection (PASC).
METHODS
From April 21 to December 31, 2020, we assembled a cohort of consecutive volunteers who a) had documented history of SARS-CoV-2 RNA-positivity; b) were ≥ 2 weeks past onset of COVID-19 symptoms or, if asymptomatic, first test for SARS-CoV-2; and c) were able to travel to our site in San Francisco. Participants learned about the study by being identified on medical center-based registries and being notified or by responding to advertisements. At 4-month intervals, we asked participants about physical symptoms that were new or worse compared to the period prior to COVID-19, mental health symptoms and quality of life. We described 4 time periods: 1) acute illness (0-3 weeks), 2) early recovery (3-10 weeks), 3) late recovery 1 (12-20 weeks), and 4) late recovery 2 (28-36 weeks). Blood and oral specimens were collected at each visit.
RESULTS
We have, to date, enrolled 179 adults. During acute SARS-CoV-2 infection, 10 had been asymptomatic, 125 symptomatic but not hospitalized, and 44 symptomatic and hospitalized. In the acute phase, the most common symptoms were fatigue, fever, myalgia, cough and anosmia/dysgeusia. During the post-acute phase, fatigue, shortness of breath, concentration problems, headaches, trouble sleeping and anosmia/dysgeusia were the most commonly reported symptoms, but a variety of others were endorsed by at least some participants. Some experienced symptoms of depression, anxiety, and post-traumatic stress, as well as difficulties with ambulation and performance of usual activities. The median visual analogue scale value rating of general health was lower at 4 and 8 months (80, interquartile range [IQR]: 70-90; and 80, IQR 75-90) compared to prior to COVID-19 (85; IQR 75-90). Biospecimens were collected at nearly 600 participant-visits.
CONCLUSION
Among a cohort of participants enrolled in the post-acute phase of SARS-CoV-2 infection, we found many with persistent physical symptoms through 8 months following onset of COVID-19 with an impact on self-rated overall health. The presence of participants with and without symptoms and ample biological specimens will facilitate study of PASC pathogenesis. Similar evaluations in a population-representative sample will be needed to estimate the population-level prevalence of PASC.
PubMed: 33758895
DOI: 10.1101/2021.03.11.21252311 -
Journal of Clinical Research in... Aug 2023Mutations in the gene result in rare inherited syndromes causing insulin resistance, such as leprechaunism (Donohue syndrome), Rabson-Mendenhall syndrome and insulin...
Mutations in the gene result in rare inherited syndromes causing insulin resistance, such as leprechaunism (Donohue syndrome), Rabson-Mendenhall syndrome and insulin resistance type A. Leprechaunism is an autosomal recessive disorder associated with extreme insulin resistance that leads to hyperinsulinemia, impaired glucose homeostasis, fasting hypoglycemia and postprandial hyperglycemia. Impaired insulin action causes prenatal and postnatal growth retardation. Lipoatrophy, dysmorphic facies, hypertrichosis, macrogenitosomia and hypertrophy of internal organs are also present. A male infant with congenital insulin resistance was born at term after a normal pregnancy with a weight of 1905 g (<3 c), a length of 48 cm (<3 c), and an Apgar score of 10. Intrauterine growth retardation, transient hypoglycemia, pneumonia, urinary tract infection and heart defects [patent foramen ovale (PFO); patent ductus arteriosus (PDA)] were diagnosed after birth. At 5 weeks of age, he was admitted to the regional hospital with severe fever, diarrhea and dehydration. Hyperglycemia was observed (672 mg/dL), and insulin was administered. He was referred to a hospital at 7 weeks of age for suspected neonatal diabetes and hypertrophic cardiomyopathy. The physical examination revealed a loud systolic heart murmur, tachycardia, tachypnea, dysmorphic facies, hypertrichosis, acanthosis nigricans, hypotonia, swollen nipples and enlarged testicles. Glycemic fluctuations (50-250 mg/dL) were observed. The serum insulin concentration was high (maximum 1200 IU/mL) at normoglycemia. Ultrasound of the heart confirmed progressive hypertrophic cardiomyopathy. Leprechaunism was confirmed by genetic analysis of , in which a novel c.320C>G; p. Thr107Arg homozygous missense mutation was found in exon 2.
Topics: Female; Humans; Infant; Infant, Newborn; Male; Antigens, CD; Cardiomyopathy, Hypertrophic; Diabetes Mellitus; Donohue Syndrome; Facies; Hyperglycemia; Hypertrichosis; Hypoglycemia; Insulin; Insulin Resistance; Mutation; Receptor, Insulin
PubMed: 34965699
DOI: 10.4274/jcrpe.galenos.2021.2021.0256 -
Primary Care Diabetes Feb 2021To report on Rabson-Mendenhall Syndrome (RMS) diagnosed in Kuwait.
AIM
To report on Rabson-Mendenhall Syndrome (RMS) diagnosed in Kuwait.
METHODS
A toddler (18 months old) was referred with high plasma insulin and dysmorphic features suggestive of RMS including coarse facial features with globular nose, full lips and furrowed tongue. His skin was hyperkeratotic with hypertrichosis. His sister (aged 13.5 years) was diagnosed with diabetes at 9 years of age and treated with metformin and insulin. She presented with similar dysmorphic features, extensive acanthosis nigricans, dental abnormalities and bilateral nephrocalcinosis. The children were born to non-consanguineous parents. Blood samples were sent for genetic testing in a reference laboratory.
RESULTS
Both children were found to be homozygous for the p.Arg141Trp missense variant (p.Arg114Trp if numbered according to pro-receptor sequence) in the alpha subunit of the insulin receptor.
CONCLUSIONS
These cases demonstrate the importance of raising awareness among healthcare professionals to ensure rapid referral of patients with characteristic physical features of RMS and severe insulin resistance for genetic testing. Unfortunately, treatment of RMS patients remains a challenge with poor prognosis and short life expectancy usually caused by diabetes-related complications. Genetic testing confirms the diagnosis and allows informed genetic counseling of parents considering future pregnancies.
Topics: Acanthosis Nigricans; Donohue Syndrome; Female; Follow-Up Studies; Humans; Infant; Insulin Resistance; Kuwait; Male; Siblings
PubMed: 32843252
DOI: 10.1016/j.pcd.2020.07.012 -
Endocrinology Jun 2015Donohue syndrome (DS) is characterized by severe insulin resistance due to mutations in the insulin receptor (INSR) gene. To identify molecular defects contributing to...
Donohue syndrome (DS) is characterized by severe insulin resistance due to mutations in the insulin receptor (INSR) gene. To identify molecular defects contributing to metabolic dysregulation in DS in the undifferentiated state, we generated mesenchymal progenitor cells (MPCs) from induced pluripotent stem cells derived from a 4-week-old female with DS and a healthy newborn male (control). INSR mRNA and protein were significantly reduced in DS MPC (for β-subunit, 64% and 89% reduction, respectively, P < .05), but IGF1R mRNA and protein did not differ vs control. Insulin-stimulated phosphorylation of INSR or the downstream substrates insulin receptor substrate 1 and protein kinase B did not differ, but ERK phosphorylation tended to be reduced in DS (32% decrease, P = .07). By contrast, IGF-1 and insulin-stimulated insulin-like growth factor 1 (IGF-1) receptor phosphorylation were increased in DS (IGF-1, 8.5- vs 4.5-fold increase; INS, 11- vs 6-fold; P < .05). DS MPC tended to have higher oxygen consumption in both the basal state (87% higher, P =.09) and in response to the uncoupler carbonyl cyanide-p-triflouromethoxyphenylhydrazone (2-fold increase, P =.06). Although mitochondrial DNA or mass did not differ, oxidative phosphorylation protein complexes III and V were increased in DS (by 37% and 6%, respectively; P < .05). Extracellular acidification also tended to increase in DS (91% increase, P = .07), with parallel significant increases in lactate secretion (34% higher at 4 h, P < .05). In summary, DS MPC maintain signaling downstream of the INSR, suggesting that IGF-1R signaling may partly compensate for INSR mutations. However, alterations in receptor expression and pathway-specific defects in insulin signaling, even in undifferentiated cells, can alter cellular oxidative metabolism, potentially via transcriptional mechanisms.
Topics: Cell Survival; Cells, Cultured; DNA, Mitochondrial; Female; Flow Cytometry; Humans; Induced Pluripotent Stem Cells; Infant; Infant, Newborn; Insulin Resistance; Male; Mesenchymal Stem Cells
PubMed: 25811318
DOI: 10.1210/en.2014-1403