Two successful pregnancies -in patients taking Volanesorsen for familial chylomicronemia syndrome.

Familial chylomicronemia syndrome (FCS) is a rare inherited disorder characterized by severe hypertriglyceridemia, posing a heightened risk of acute pancreatitis. Recently, Volanesorsen, an APOC3 antisense oligonucleotide, gained approval for FCS treatment in the UK. Caution is advised during pregnancy due to limited safety data, although animal studies show no toxicity/teratogenicity. Two case scenarios are presented: In the first case, a patient with FCS continued Volanesorsen injections without having thrombocytopenia during an unplanned pregnancy until third trimester, maintaining triglyceride control. Upon discovering the pregnancy at 38 weeks, Volanesorsen was ceased, and a low-fat diet reinstated. Despite a heightened risk of pancreatitis, no episodes of pancreatitis occurred during the pregnancy. In the second case, stopping Volanesorsen before conception led to elevated triglycerides, and an episode of acute pancreatitis at 22 weeks, despite strict very low-fat diet and fibrate therapy from 14 weeks. At 23 weeks, Volanesorsen was reintroduced concurrently with regular therapeutic plasma exchange. No further episodes of pancreatitis occurred. In both case, fetal health was maintained throughout pregnancy, fetal scans revealed no anomalies, and planned C-sections delivered healthy babies without congenital issues. Both babies are well and developing normally at 24 and 19 months.

Long-term effects of volanesorsen on triglycerides and pancreatitis in patients with familial chylomicronaemia syndrome (FCS) in the UK Early Access to Medicines Scheme (EAMS).

BACKGROUND AND AIMS: The VOL4002 study assessed the efficacy and safety of volanesorsen in 22 adults with genetically confirmed familial chylomicronaemia syndrome (FCS) treated in the UK Early Access to Medicines Scheme (EAMS), with ("prior exposure") or without ("treatment naive") previous treatment in the APPROACH and/or APPROACH-OLE volanesorsen phase 3 studies. METHODS: Data collection focused on triglyceride (TG) levels, platelet counts and pancreatitis events. Pancreatitis incidence during volanesorsen treatment was compared against the 5-year period preceding volanesorsen exposure. Volanesorsen 285 mg was self-administered subcutaneously once every 2 weeks. RESULTS: Individual patient volanesorsen exposure ranged from 6 to 51 months (total cumulative exposure, 589 months). Among treatment-naive patients (n = 12), volanesorsen treatment resulted in an averaged median 52% reduction (-10.6 mmol/L) from baseline (26.4 mmol/L) in TG levels at 3 months, which were maintained through time points over 15 months of treatment (47%-55% reductions). Similarly, prior-exposure patients (n = 10) experienced a 51% reduction (-17.8 mmol/L) from pre-treatment baseline (28.0 mmol/L), with reductions of 10%-38% over 21 months of treatment. A comparison of pancreatitis event rates found a 74% reduction from the 5-year period before (one event/2.8 years) and during (one event/11.0 years) volanesorsen treatment. Platelet declines were consistent with observations in phase 3 clinical trials. No patient recorded a platelet count <50 × 109/L. CONCLUSIONS: This longitudinal study supports the efficacy of volanesorsen in patients with FCS for lowering TG levels over treatment periods up to 51 months with no apparent safety signals related to increased duration of exposure.

Atherosclerosis in Fabry Disease-A Contemporary Review.

Fabry disease (FD) is a lysosomal storage disorder characterised by a deficiency in the enzyme α-galactosidase A resulting in sphingolipid deposition which causes progressive cardiac, renal, and cerebral manifestations. The case illustrates a patient with FD who died suddenly, and medical examination demonstrated myocardial scarring and prior infarction. Angina is a frequent symptom in FD. Our own data are consistent with registry data indicating a high prevalence of risk factors for coronary artery disease (CAD) in FD that may accelerate conventional atherosclerosis. Patients with FD also have a higher high-density lipoprotein (HDL)/total cholesterol (T-Chol) ratio which may further accelerate atherosclerosis through expression of early atherosclerotic markers. Patients with FD may develop CAD both via classical atherosclerosis and through formation of thickened fibrocellular intima containing fibroblasts with storage of sphingolipids. Both mechanisms occurring together may accelerate coronary stenosis, as well as alter myocardial blood flow. Our data supports limited data that, although coronary flow may be reduced, the prevalence of epicardial coronary stenosis is low in FD. Microvascular dysfunction and arterial wall stress from sphingolipid deposition may form reactive oxygen species (ROS) and myeloperoxidase (MPO), key atherosclerotic mediators. Reduced myocardial blood flow in FD has also been demonstrated using numerous imaging modalities suggesting perfusion mismatch. This review describes the above mechanisms in detail, highlighting the importance of modifying cardiovascular risk factors in FD patients who likely develop accelerated atherosclerosis compared to the general population.

Acute Confusion as an Initial Presentation of SARS-CoV-2 Infection.

BACKGROUND AND PURPOSE: The respiratory manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been extensively documented. There is emerging evidence that coronavirus disease 2019 (COVID-19) has number of other presenting features which might not be related to the severity of the respiratory disease. We have previously described a case of hypoactive delirium as the first manifestation of COVID-19 without profound lung disease. Here we present five cases of elderly patients, without a prior history of dementia and had no overt COVID-19-related pneumonia, who presented with the acute onset of delirium as the primary manifestation of COVID-19. METHODS: This retrospective, single-center study performed a health informatics search to produce a list of patients who were admitted with acute confusion and tested positive for the SARS-CoV-2 virus between March 1 and June 30, 2020. The electronic medical admission notes were screened for all patients with confusion who tested positive for SARS-CoV-2. Patients with a history of dementia and a high risk of delirium were excluded, such as severe COVID-19-related pneumonia or any other infection, malignancy, drugs, or severe illness of any kind. RESULTS: During the first wave of the COVID-19 pandemic our hospital experienced just over 3,000 SARS-CoV-2 positive patients, and 45 of them had documented confusion upon admission. Secondary causes for their acute confusion were excluded. Five patients were identified as having delirium as the initial presentation of COVID-19-related illness without significant COVID-19-related pneumonitis. None of them had overt chest symptoms or a previous history of confusion, and the 3 patients who underwent head CT scans had normal findings. CONCLUSIONS: This case series illustrates the importance of recognizing acute confusion as the first manifestation of COVID-19 in susceptible individuals.

A case series of cerebral venous thrombosis as the first manifestation of homocystinuria.

Background: Cerebral venous thrombosis (CVT) is an important cause of stroke particularly in younger patients and potentially fatal if diagnosis is delayed. The presentation of symptoms is highly variable and consequently the diagnosis and underlying cause is often delayed or overlooked. Homocystinuria, a rare autosomal recessive disorder is an identified risk factor for CVT. Purpose: A timely diagnosis and treatment of the underlying cause of CVT could result in improved outcome and prevent further events. This case series describes the clinical course of six adults presented with unprovoked CVT, in whom the diagnosis of underlying homocystinuria was delayed with adverse consequences. We aim to highlight the importance of recognising homocystinuria as an underlying cause of CVT and offer a practical approach to the diagnosis and management. Methods: This is a retrospective case series of a cohort of 30 consecutive patients seen in a UK tertiary referral centre. Result: Six out of 30 patients presented with CVT prior to homocystinuria diagnosis. The mean and range of age at the time of the first CVT episode was 22.6 (range 11-31) years. The mean ±SD age at diagnosis of homocystinuria as the underlying cause was 26 ± 4.2 years. The time between first CVT and diagnosis of homocystinuria ranged from 1.6 to 11 years resulting in a delay to introduction of effective treatment and, in some cases, a further large vessels thrombotic event. Conclusion: Physician awareness of homocystinuria as an underlying cause for an unprovoked CVT will facilitate timely introduction of effective treatment to prevent a further event.