Considerations for Familial Chylomicronemia Diagnosis in the Era of Next-Generation Sequencing: A Latin American Perspective

Abstract Familial chylomicronemia syndrome (FCS) is an autosomal recessive disorder, characterized by alterations in the catabolism of chylomicrons and by increased levels of plasma triglycerides. It has been shown that about 60-90% of FCS patients have biallelic mutations in the LPL gene and the remaining patients have mutations in genes encoding proteins closely related to LPL function. The objective of this manuscript is to illustrate the different clinical scenarios of FCS presentation, and to guide practitioners on the usefulness of genetic tests in each of them. To this end, several published papers about recommendations for the diagnosis of FCS are discussed briefly, in addition to the presentation of several hypothetical cases, highlighting different clinical presentations and possible associated genetic findings. These cases illustrate the multiplicity of potential aspects of family history, clinical manifestations, biochemical parameters, and patterns of genetic variants found in genomic analyses of FCS.

Familial chylomicronemia syndrome: A comprehensive clinical and genetic approach

Abstract The familial chylomicronemia syndrome (FCS) is characterized by very high levels of circulating triglycerides. FCS is caused by lipoprotein lipase (LPL) deficiency resulting from homozygous or biallelic loss-of-function variants in the LPL or other related genes. Here, we report a case of severe hypertriglyceridemia refractory to conventional therapy in a male patient diagnosed at 33 years of age. LPL activity was below 20%. During the clinical course, the patient developed severe acute pancreatitis in addition to other complications. Two heterozygous variants (c.984G>A and c.1139+6T>C) which had not been previously reported in the major databases were identified in the LPL gene. Treatment with volanesorsen was proposed based on its approved indication as an adjunct to diet in adult patients with confirmed FCS and at high risk for pancreatitis. Volanesorsen was effective and well-tolerated, and the patient did not experience abdominal pain or any other manifestations. The assessment of genetic characterization is essential to guide treatment decisions during follow-up, in addition to the patient's history, their comorbidities and clinical stigmas.

Hipertrigliceridemia grave y síndrome de quilomicronemia familiar: una revisión de la literatura reciente / Severe hypertriglyceridemia and familial chylomicronemia syndrome: a review of recent literature

Resumen La hipertrigliceridemia (HTG) es un problema que se presenta con frecuencia en la práctica clínica. Su prevalencia en adultos es cercana al 10%. El espectro varía desde una predisposición que resulta en HTG solo en presencia de sobrepeso considerable o consumo excesivo de alcohol hasta mutaciones graves muy raras que pueden conducir a HTG grave en la infancia, incluso en ausencia de factores adicionales, como en el síndrome de quilomicronemia familiar (FCS, familial chylomicronemia syndrome). Este es un trastorno autosómico recesivo poco frecuente del metabolismo del quilomicrón que causa una importante elevación de los triglicéridos (>10 mmol/885 mg/dl). Esta condición está asociada con un riesgo significativo de pancreatitis aguda recurrente. La aproximación diagnóstica se logra mediante la caracterización fenotípica, y el hallazgo de la alteración genética ayuda a dar un diagnóstico más preciso. Además, se ha propuesto una puntuación clínica para el diagnóstico de FCS, pero necesita más validación. Las opciones de tratamiento disponibles para reducir los triglicéridos, como los fibratos y los ácidos grasos omega-3, no son eficaces en los pacientes con FCS. Actualmente, el único tratamiento sigue siendo una dieta de por vida muy baja en grasas, que reduce la formación de quilomicrones. Finalmente, los inhibidores de la apolipoproteína C-III están en desarrollo y podrían constituir opciones de tratamiento para estos pacientes. Considerando lo anterior, el objetivo de este artículo es realizar una revisión general sobre la HTG grave, con énfasis en el FCS, basados en la literatura disponible más reciente.

Abstract Hypertriglyceridemia (HTG) is a problem that occurs frequently in clinical practice. Its prevalence in adults is close to 10% and it varies between regions. The spectrum ranges from a disposition that results in HTG only in the presence of considerable overweight and/or excessive alcohol consumption to very rare serious mutations that can lead to severe HTG in childhood, even in the absence of additional factors such as familial chylomicronemia syndrome (FCS). This is a rare autosomal recessive disorder of chylomicron metabolism that causes a severe elevation in triglyceride levels (>10 mmol/885 mg/dL). This condition is associated with a significant risk of recurrent acute pancreatitis. Because this is a genetic condition, the optimal diagnostic strategy remains the genetic test. In addition, a clinical score for the diagnosis of FCS has been proposed but it needs further validation. Available treatment options to lower triglycerides, such as fibrates or omega-3 fatty acids, are not effective in patients with FCS. Currently, the cornerstone of treatment remains a very low-fat, lifetime diet that reduces chylomicron formation. Finally, apolipoprotein C-3 inhibitors are under development and may eventually be treatment options for these patients. The objective of this article is to carry out a general review of severe HTG, with an emphasis on FCS and based on the most recent available literature.

Familial chylomicronemia syndrome-induced acute necrotizing pancreatitis during pregnancy

Abstract Acute pancreatitis is a rare condition in pregnancy, associated with a high mortality rate. Hypertriglyceridemia represents its second most common cause.We present the case of a 38-year-old woman in the 24th week of gestation with a history of hypertriglyceridemia and recurrent episodes of pancreatitis. She was admitted to our hospital with acute pancreatitis due to severe hypertriglyceridemia. She was stabilized and treated with fibrates. Despite her favorable clinical course, she developed a second episode of acute pancreatitis complicated by multi-organ dysfunction and pancreatic necrosis, requiring a necrosectomy. The pregnancy was ended by cesarean section, after which three plasmapheresis sessions were performed. She is currently asymptomatic with stable triglyceride levels. Acute pancreatitis due to hypertriglyceridemia represents a diagnostic and therapeutic challenge in pregnant women, associated with serious maternal and fetal complications. When primary hypertriglyceridemia is suspected, such as familial chylomicronemia syndrome, the most important objective is preventing the onset of pancreatitis.