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Neurology Jan 2020
PubMed: 31862782
DOI: 10.1212/WNL.0000000000008828 -
Histology and Histopathology Jul 2024Hyperinsulinemic hypoglycemia (HH) of pancreatic origin includes congenital hyperinsulinism (CHI), insulinoma, insulinomatosis, and adult-onset non-insulinoma persistent... (Review)
Review
Hyperinsulinemic hypoglycemia (HH) of pancreatic origin includes congenital hyperinsulinism (CHI), insulinoma, insulinomatosis, and adult-onset non-insulinoma persistent hyperinsulinemic hypoglycemia syndrome (NI-PHHS). In this review, we describe the genotype-histotype-phenotype correlations in HH and their therapeutic implications. CHI can occur from birth or later on in life. Histologically, diffuse CHI shows diffuse beta cell hypertrophy with a few giant nuclei per islet of Langerhans, most frequently caused by loss-of-function mutations in or . Focal CHI is histologically characterized by focal adenomatous hyperplasia consisting of confluent hyperplastic islets, caused by a paternal mutation combined with paternal uniparental disomy of 11p15. CHI in Beckwith-Wiedemann syndrome is caused by mosaic changes in the imprinting region 11p15.4-11p15.5, leading to segmental or diffuse overgrowth of endocrine tissue in the pancreas. Morphological mosaicism of pancreatic islets is characterized by occurence of hyperplastic (type 1) islets in one or a few lobules and small (type 2) islets in the entire pancreas. Other rare genetic causes of CHI show less characteristic or unspecific histology. HH with a predominant adult onset includes insulinomas, which are pancreatic insulin-producing endocrine neoplasms, in some cases with metastatic potential. Insulinomas occur sporadically or as part of multiple endocrine neoplasia type 1 due to mutations. mutations may histologically lead to insulinomatosis with insulin-producing neuroendocrine microadenomas or neuroendocrine neoplasms. NI-PHHS is mainly seen in adults and shows slight histological changes in some patients, which have been defined as major and minor criteria. The genetic cause is unknown in most cases. The diagnosis of HH, as defined by genetic, histological, and phenotypic features, has important implications for patient management and outcome.
Topics: Humans; Congenital Hyperinsulinism; Phenotype; Mutation; Pancreatic Neoplasms; Hyperinsulinism; Insulinoma; Hypoglycemia; Genotype; Genetic Association Studies
PubMed: 38305063
DOI: 10.14670/HH-18-709 -
Advances in Genetics 2020Potassium channels are a heterogeneous group of membrane-bound proteins, whose functions support a diverse range of biological processes. Genetic disorders arising from... (Review)
Review
Potassium channels are a heterogeneous group of membrane-bound proteins, whose functions support a diverse range of biological processes. Genetic disorders arising from mutations in potassium channels are classically recognized by symptoms arising from acute channel dysfunction, such as periodic paralysis, ataxia, seizures, or cardiac conduction abnormalities, often in a patient with otherwise normal examination findings. In this chapter, we review a distinct subgroup of rare potassium channelopathies whose presentations are instead suggestive of a developmental disorder, with features including intellectual disability, craniofacial dysmorphism or other physical anomalies. Known conditions within this subgroup are: Andersen-Tawil syndrome, Birk-Barel syndrome, Cantú syndrome, Keppen-Lubinsky syndrome, Temple-Baraitser syndrome, Zimmerman-Laband syndrome and a very similar disorder called Bauer-Tartaglia or FHEIG syndrome. Ion channelopathies are unlikely to be routinely considered in the differential diagnosis of children presenting with developmental concerns, and so detailed description and photographs of the clinical phenotype are provided to aid recognition. For several of these disorders, functional characterization of the genetic mutations responsible has led to identification of candidate therapies, including drugs already commonly used for other indications, which adds further impetus to their prompt recognition. Together, these cases illustrate the potential for mechanistic insights gained from genetic diagnosis to drive translational work toward targeted, disease-modifying therapies for rare disorders.
Topics: Abnormalities, Multiple; Andersen Syndrome; Cardiomegaly; Channelopathies; Child; Craniofacial Abnormalities; Fibromatosis, Gingival; Hallux; Hand Deformities, Congenital; Humans; Hypertrichosis; Intellectual Disability; Muscle Hypotonia; Nails, Malformed; Osteochondrodysplasias; Potassium Channels; Thumb
PubMed: 32560786
DOI: 10.1016/bs.adgen.2020.03.002 -
Journal of the American College of... Apr 2020
Topics: Andersen Syndrome; Humans; Mutation; Risk Assessment
PubMed: 32299590
DOI: 10.1016/j.jacc.2020.03.005 -
European Journal of Neurology Aug 2022Andersen-Tawil syndrome (ATS) is a skeletal muscle channelopathy caused by KCNJ2 mutations, characterized by a clinical triad of periodic paralysis, cardiac arrhythmias...
BACKGROUND AND PURPOSE
Andersen-Tawil syndrome (ATS) is a skeletal muscle channelopathy caused by KCNJ2 mutations, characterized by a clinical triad of periodic paralysis, cardiac arrhythmias and dysmorphism. The muscle phenotype, particularly the atypical forms with prominent permanent weakness or predominantly painful symptoms, remains incompletely characterized.
METHODS
A retrospective clinical, histological, electroneuromyography (ENMG) and genetic analysis of molecularly confirmed ATS patients, diagnosed and followed up at neuromuscular reference centers in France, was conducted.
RESULTS
Thirty-five patients from 27 unrelated families carrying 17 different missense KCNJ2 mutations (four novel mutations) and a heterozygous KCNJ2 duplication are reported. The typical triad was observed in 42.9% of patients. Cardiac abnormalities were observed in 65.7%: 56.5% asymptomatic and 39.1% requiring antiarrhythmic drugs. 71.4% of patients exhibited dysmorphic features. Muscle symptoms were reported in 85.7%, amongst whom 13.3% had no cardiopathy and 33.3% no dysmorphic features. Periodic paralysis was present in 80% and was significantly more frequent in men. Common triggers were exercise, immobility and carbohydrate-rich diet. Ictal serum potassium concentrations were low in 53.6%. Of the 35 patients, 45.7% had permanent weakness affecting proximal muscles, which was mild and stable or slowly progressive over several decades. Four patients presented with exercise-induced pain and myalgia attacks. Diagnostic delay was 14.4 ± 9.5 years. ENMG long-exercise test performed in 25 patients (71.4%) showed in all a decremental response up to 40%. Muscle biopsy performed in 12 patients revealed tubular aggregates in six patients (associated in two of them with vacuolar lesions), dystrophic features in one patient and non-specific myopathic features in one patient; it was normal in four patients.
DISCUSSION
Recognition of atypical features (exercise-induced pain or myalgia and permanent weakness) along with any of the elements of the triad should arouse suspicion. The ENMG long-exercise test has a high diagnostic yield and should be performed. Early diagnosis is of utmost importance to improve disease prognosis.
Topics: Andersen Syndrome; Delayed Diagnosis; Humans; Mutation; Myalgia; Paralysis; Retrospective Studies
PubMed: 35460302
DOI: 10.1111/ene.15369 -
Circulation Research Apr 2024Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K channel Kir2.1. The extracellular Cys...
BACKGROUND
Andersen-Tawil syndrome type 1 is a rare heritable disease caused by mutations in the gene coding the strong inwardly rectifying K channel Kir2.1. The extracellular Cys (cysteine)-to-Cys disulfide bond in the channel structure is crucial for proper folding but has not been associated with correct channel function at the membrane. We evaluated whether a human mutation at the Cys-to-Cys disulfide bridge leads to Kir2.1 channel dysfunction and arrhythmias by reorganizing the overall Kir2.1 channel structure and destabilizing its open state.
METHODS
We identified a Kir2.1 loss-of-function mutation (c.366 A>T; p.Cys122Tyr) in an ATS1 family. To investigate its pathophysiological implications, we generated an AAV9-mediated cardiac-specific mouse model expressing the Kir2.1 variant. We employed a multidisciplinary approach, integrating patch clamping and intracardiac stimulation, molecular biology techniques, molecular dynamics, and bioluminescence resonance energy transfer experiments.
RESULTS
Kir2.1 mice recapitulated the ECG features of ATS1 independently of sex, including corrected QT prolongation, conduction defects, and increased arrhythmia susceptibility. Isolated Kir2.1 cardiomyocytes showed significantly reduced inwardly rectifier K+ (I) and inward Na+ (I) current densities independently of normal trafficking. Molecular dynamics predicted that the C122Y mutation provoked a conformational change over the 2000-ns simulation, characterized by a greater loss of hydrogen bonds between Kir2.1 and phosphatidylinositol 4,5-bisphosphate than wild type (WT). Therefore, the phosphatidylinositol 4,5-bisphosphate-binding pocket was destabilized, resulting in a lower conductance state compared with WT. Accordingly, on inside-out patch clamping, the C122Y mutation significantly blunted Kir2.1 sensitivity to increasing phosphatidylinositol 4,5-bisphosphate concentrations. In addition, the Kir2.1 mutation resulted in channelosome degradation, demonstrating temporal instability of both Kir2.1 and Na1.5 proteins.
CONCLUSIONS
The extracellular Cys-to-Cys disulfide bond in the tridimensional Kir2.1 channel structure is essential for the channel function. We demonstrate that breaking disulfide bonds in the extracellular domain disrupts phosphatidylinositol 4,5-bisphosphate-dependent regulation, leading to channel dysfunction and defects in Kir2.1 energetic stability. The mutation also alters functional expression of the Na1.5 channel and ultimately leads to conduction disturbances and life-threatening arrhythmia characteristic of Andersen-Tawil syndrome type 1.
Topics: Humans; Mice; Animals; Andersen Syndrome; Mutation; Myocytes, Cardiac; Cardiac Conduction System Disease; Disulfides; Phosphatidylinositols
PubMed: 38497220
DOI: 10.1161/CIRCRESAHA.123.323895 -
Therapeutic Advances in Endocrinology... 2020Hypoglycaemia remains an inevitable risk in insulin-treated type 1 diabetes and type 2 diabetes and has been associated with multiple adverse outcomes. Whether... (Review)
Review
Hypoglycaemia remains an inevitable risk in insulin-treated type 1 diabetes and type 2 diabetes and has been associated with multiple adverse outcomes. Whether hypoglycaemia is a cause of fatal cardiac arrhythmias in diabetes, or merely a marker of vulnerability, is still unknown. Since a pivotal report in 1991, hypoglycaemia has been suspected to induce cardiac arrhythmias in patients with type 1 diabetes, the so-called 'dead-in-bed syndrome'. This suspicion has subsequently been supported by the coexistence of an increased mortality and a three-fold increase in severe hypoglycaemia in patients with type 2 diabetes receiving intensive glucose-lowering treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Studies have investigated the association between hypoglycaemia-induced cardiac arrhythmias. In a rat-model, severe hypoglycaemia resulted in a specific pattern of cardiac arrhythmias including QT-prolongation, ventricular tachycardia, second- and third-degree AV block and ultimately cardiorespiratory arrest. In clinical studies of experimentally induced hypoglycaemia, QTc-prolongation, a risk factor of ventricular arrhythmias, is an almost consistent finding. The extent of QT-prolongation seems to be modified by several factors, including antecedent hypoglycaemia, diabetes duration and cardiac autonomic neuropathy. Observational studies indicate diurnal differences in the pattern of electrocardiographic alterations during hypoglycaemia with larger QTc-prolongations during daytime, whereas the risk of bradyarrhythmias may be increased during sleep. Daytime periods of hypoglycaemia are characterized by shorter duration, increased awareness and a larger increase in catecholamines. The counterregulatory response is reduced during nightly episodes of hypoglycaemia, resulting in prolonged periods of hypoglycaemia with multiple nadirs. An initial sympathetic activity at plasma glucose nadir is replaced by increased vagal activity, which results in bradycardia. Here, we provide an overview of the existing literature exploring potential mechanisms for hypoglycaemia-induced cardiac arrhythmias and studies linking hypoglycaemia to cardiac arrhythmias in patients with diabetes.
PubMed: 32489579
DOI: 10.1177/2042018820911803 -
Ugeskrift For Laeger Sep 2022The use of peripheral nerve blocks carries a small risk of most often temporary direct damage to the peripheral nerves. Due to lack of research and differing opinions... (Review)
Review
The use of peripheral nerve blocks carries a small risk of most often temporary direct damage to the peripheral nerves. Due to lack of research and differing opinions regarding the potential of nerve blocks delaying the diagnosis of acute compartment syndrome, there is currently no consensus between anaesthetic- and orthopaedic associations regarding the use of peripheral nerve blocks in patients at risk of acute compartment syndrome. More interdisciplinary research is needed to inform and promote an evidence-based discussion of the subject, as argued in this review.
Topics: Anesthesia, Conduction; Compartment Syndromes; Humans; Nerve Block; Peripheral Nerves
PubMed: 36205160
DOI: No ID Found -
Current Cardiology Reports Aug 2020The development of biventricular repair and conversion pathways for patients with borderline hypoplastic heart disease represents an area of recent inquiry and... (Review)
Review
PURPOSE OF REVIEW
The development of biventricular repair and conversion pathways for patients with borderline hypoplastic heart disease represents an area of recent inquiry and innovation. This review summarizes emerging techniques and novel treatment algorithms for borderline hypoplastic heart disease with a focus on surgical advances within the last 10 years.
RECENT FINDINGS
Many patients with borderline hypoplastic heart disease are amenable to primary biventricular repair, or biventricular conversion following single-ventricle palliation coupled with ventricular rehabilitation strategies. New insights into the potential for growth and recovery of borderline ventricles have been uncovered. However, questions remain regarding optimal patient selection and the long-term outcomes of select patient groups treated with single-ventricle palliation versus biventricular repair/conversion or transplantation. Efforts to direct a greater proportion of borderline hypoplastic heart patients towards a biventricular circulation are accelerating and represent important avenues for progress and future research in the field of congenital heart disease.
Topics: Heart Defects, Congenital; Heart Ventricles; Humans; Hypoplastic Left Heart Syndrome; Palliative Care; Retrospective Studies
PubMed: 32770360
DOI: 10.1007/s11886-020-01363-5 -
The Psychiatric Clinics of North America Mar 2021Catatonia was first described by Karl Ludwig Kahlbaum in 1874, occurring in association with other psychiatric and medical disorders. However, in the nineteenth century... (Review)
Review
Catatonia was first described by Karl Ludwig Kahlbaum in 1874, occurring in association with other psychiatric and medical disorders. However, in the nineteenth century the disorder was incorrectly classified as a subtype of schizophrenia. This misclassification persisted until the publication of DSM-5 in 2013 when important changes were incorporated. Although the etiology is unknown, disrupted gamma-aminobutyric acid has been proposed as the underlying pathophysiological mechanism. Key symptoms can be identified under 3 clinical domains: motor, speech, and behavioral. Benzodiazepines and electroconvulsive therapy are the only known effective treatments. Timely recognition and treatment have important outcome, and sometimes lifesaving, implications.
Topics: Autism Spectrum Disorder; Benzodiazepines; Catatonia; Electroconvulsive Therapy; Humans; Schizophrenia
PubMed: 33526232
DOI: 10.1016/j.psc.2020.11.002