A Personalized Medicine Approach is Best for Patients with Homozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is an autosomal semi-dominant condition characterized by biallelic pathogenic variants impacting low-density lipoprotein receptor (LDLR) function. Affected individuals have severely elevated LDL cholesterol, early onset atherosclerotic heart disease and/or aortic stenosis, and characteristic clinical findings. While the cause is known and diagnosis is relatively simple, real-world HoFH care presents many complexities, including genetic heterogeneity and the diverse personal and social circumstances that influence care.

Brief communication: Strong concordance of the North American Familial Chylomicronemia Syndrome Score with a positive genetic diagnosis in patients from the Balance study.

Background: Patients with familial chylomicronemia syndrome (FCS) are often misdiagnosed. A positive genetic diagnosis is considered definitive, but clinical scoring systems can also identify affected patients. The North American FCS (NAFCS) Score is intended to identify patients likely to have positive DNA testing, but its sensitivity has not been quantified.

Neurodegeneration in familial chylomicronemia syndrome.

Background And Objectives: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder associated with markedly elevated triglyceride concentration and acute pancreatitis, but neuropathic pain and cognitive dysfunction are also increasingly recognized. This study undertook detailed quantification of somatic and autonomic neuropathy in participants with FCS.

Methods: Sixteen individuals with FCS and 16 age and sex-matched controls underwent assessment of the lipid profile, neuropathic symptoms and disability, vibration perception, corneal confocal microscopy (CCM), and cardiac autonomic reflex testing.

Heterozygous pathogenic PPARG variants in patients with severe hypertriglyceridemia.

Background: Heterozygous pathogenic variants in PPARG cause familial partial lipodystrophy type 3 (FPLD3; Mendelian Inheritance in Man [MIM] #604367), a heritable form of insulin resistance with multiple metabolic disturbances including hypertriglyceridemia. We investigated the prevalence of FPLD3 individuals in our cohort of patients with multifactorial chylomicronemia syndrome (MCS).

Methods: We used our targeted DNA sequencing panel to screen the PPARG gene in 182 clinically diagnosed MCS patients.

Ambroxol as a Treatment for Parkinson Disease Dementia: A Randomized Clinical Trial.

Importance: Carrying a variation in the gene for β-glucocerebrosidase is a major risk factor for Parkinson disease dementia (PDD), and raising β-glucocerebrosidase levels lowers α-synuclein in cell and animals. Ambroxol is a chaperone for β-glucocerebrosidase, which increases the levels of β-glucocerebrosidase.

Objective: To examine the safety and tolerability of ambroxol in PDD, test the efficacy of ambroxol in improving or slowing the progression of cognitive deficits, and acquire pharmacological data.

Regional free-water diffusion is more strongly related to neuroinflammation than neurodegeneration.

Introduction: Recent research has suggested that neuroinflammation may be important in the pathogenesis of neurodegenerative diseases. Free-water diffusion (FWD) has been proposed as a non-invasive neuroimaging-based biomarker for neuroinflammation.

Methods: Free-water maps were generated using diffusion MRI data in 367 patients from the Ontario Neurodegenerative Disease Research Initiative (108 Alzheimer's Disease/Mild Cognitive Impairment, 42 Frontotemporal Dementia, 37 Amyotrophic Lateral Sclerosis, 123 Parkinson's Disease, and 58 vascular disease-related Cognitive Impairment).

Characterization of familial chylomicronemia syndrome in a compound heterozygote for 2 APOA5 nonsense variants.

Objective: A 3-year-old patient presented with severe hypertriglyceridemia and suspected familial chylomicronemia syndrome. Genetic analysis of the patient's DNA revealed the presence of 2 different heterozygous nonsense variants in the APOA5 gene encoding apolipoprotein (apo) A-V, namely p.Q275X and p.

Association between vascular risk factors burden and neurodegenerative diseases: results from ONDRI.

Background: Vascular risk factors are common in older adults and contribute to brain damage, can manifest as increased white matter hyperintensities (WMH), and associated with future risk of stroke and dementia. However, their prevalence, effect across different neurodegenerative diseases, and association with WMH remains underexplored.

Objective: To investigate the association between vascular risk burden, and brain white matter integrity, across five neurodegenerative conditions.

Efficacy and Safety of Inclisiran in Adolescents With Genetically Confirmed Homozygous Familial Hypercholesterolemia: Results From the Double-Blind, Placebo-Controlled Part of the ORION-13 Randomized Trial.

Background: Homozygous familial hypercholesterolemia (HoFH) is a genetic disease characterized by high levels of low-density lipoprotein cholesterol (LDL-C) present from birth, leading to early-onset and progressive atherosclerotic cardiovascular disease. Early treatment initiation is crucial for cardiovascular risk reduction; however, many patients do not reach LDL-C treatment goals. Inclisiran, a small interfering RNA targeting hepatic PCSK9 (proprotein convertase subtilisin/kexin type 9), is effective and well tolerated in adult patients with hyperlipidemia; however, it has not yet been studied in pediatric patients.

Implementation strategies for improving the care of familial hypercholesterolaemia from the International Atherosclerosis Society: next steps in implementation science and practice.

Familial hypercholesterolaemia (FH) is the most common monogenic condition associated with premature atherosclerotic cardiovascular disease. Early detection and initiation of cholesterol lowering therapy combined with lifestyle changes improves the prognosis of patients with FH significantly. The International Atherosclerosis Society (IAS) published a new guidance for implementing best practice in the care of FH.

Genetic Testing in Adults over 50 Years with Chronic Kidney Disease: Diagnostic Yield and Clinical Implications in a Specialized Kidney Genetics Clinic.

Genetic causes of chronic diseases, once considered rare in adult-onset disease, now account for between 10 and 20% of cases of chronic kidney disease (CKD). Confirming a genetic diagnosis can influence disease management; however, the utility of genetic testing in older adults remains poorly understood, partly due to age-based restrictions on testing access. To better evaluate the diagnostic yield and clinical utility of genetic testing in this population, we analyzed data from adults aged ≥50 years with CKD who were assessed in a specialized kidney genetics clinic.

Familial chylomicronemia syndrome: An expert clinical review from the National Lipid Association.

Familial chylomicronemia syndrome (FCS) is a rare Mendelian autosomal recessive disorder (MIM 238600) characterized by extreme and sustained hypertriglyceridemia due to profound reduction of lipoprotein lipase (LPL) activity. This expert opinion statement synthesizes current knowledge on the definition, pathophysiology, genetics, prevalence, diagnosis, and management of FCS. FCS typically manifests at a young age with persistent severe hypertriglyceridemia-defined as ≥10 mmol/L (≥885 mg/dL), or ≥1000 mg/dL (≥11.

What is the phenotype of heterozygous lipoprotein lipase deficiency?

Purpose Of Review: Genetic testing of patients with severe hypertriglyceridemia often identifies a single heterozygous pathogenic variant in the LPL gene. The complex and variable phenotype associated with this genotype is the topic of this review.

Recent Findings: Previous research showed that heterozygosity for lipoprotein lipase deficiency is associated with reduced but variable post heparin lipolytic activity alongside inconsistent plasma lipid phenotypes ranging from normal to mild-to-moderate to severe hypertriglyceridemia.

Futility of plasmapheresis, insulin in normoglycaemic individuals, or heparin in the treatment of hypertriglyceridaemia-induced acute pancreatitis.

There is a well-established link between the severity of hypertriglyceridaemia and acute pancreatitis and long-term triglyceride-lowering therapies known to prevent episodes of acute pancreatitis. Therefore, it has been assumed, without firm evidence, that rapid lowering of plasma triglycerides would be an effective strategy for reducing the clinical severity of acute pancreatitis and improving health outcomes. Therapies, such as intravenous heparin, intravenous insulin in normoglycaemic individuals (with glucose to prevent hypoglycaemia), and plasmapheresis, continue to be widely used as therapeutic interventions to rapidly reduce serum triglyceride concentration.

Effect of Targeting ApoC-III With Plozasiran on Lipoprotein Particle Size and Number in Hypertriglyceridemia.

Background: Plozasiran, an investigational siRNA targeting hepatic apoC-III, reduces triglyceride-rich lipoproteins (TRLs). The impact of plozasiran on lipoprotein particle numbers and sizes is unknown. However, reductions in the number of TRL particles (TRL-P) and a shift to possibly less atherogenic large low-density lipoprotein particles (LDL-P) are expected.

Association of Plasma Biomarkers With Longitudinal Atrophy and Microvascular Burden on MRI Across Neurodegenerative and Cerebrovascular Diseases.

Background And Objectives: Plasma biomarkers of Alzheimer disease (AD), neuroinflammation, and neurodegeneration are increasingly being used in clinical trials for diagnosis and monitoring of dementia. However, their association with longitudinal structural brain MRI changes, an important outcome measure across neurodegenerative and cerebrovascular diseases, is less known. We investigated how baseline plasma biomarkers reflect MRI markers of progression over time in patients with neurodegenerative and cerebrovascular diseases.

Polygenic risk score for coronary artery disease predicts atherosclerotic cardiovascular disease in familial hypercholesterolemia.

Background: Patients with familial hypercholesterolemia (FH) are at increased risk of atherosclerotic cardiovascular disease (ASCVD). However, this risk is heterogeneous, and the contribution of several clinical risk factors has been well demonstrated in this population. The proportion of the risk conferred by the accumulation of common small effect variants in coronary artery disease (CAD) susceptibility genes remains to be determined.

Reappraisal of statin primary prevention trials: implications for identification of the statin-eligible primary prevention patient.

Background And Aims: Identification of patients eligible for primary prevention statin therapy is complex, often relying upon risk algorithms that diverge internationally. Our goal was to develop a simpler global definition of statin-eligible primary prevention patients.

Methods: Randomized clinical trials (RCTs) cited in North American and European dyslipidemia guidelines justifying primary prevention statins for cardiovascular risk reduction were critically reappraised according to eligibility criteria and characteristics of actual enrollees.