Familial chylomicronemia syndrome (ORPHA:444490)
A rare genetic hyperlipidemia characterized by excessive increase in plasma triglyceride levels due to the accumulation of chylomicrons, which manifests biochemically as severe hypertriglyceridemia. Clinical manifestations include recurrent episodes of acute pancreatitis, abdominal pain, nausea, fatigue, diarrhea, hepatosplenomegaly, eruptive xanthomas, lipemia retinalis and failure to thrive. Children may be asymptomatic with later onset of symptoms. The condition is not associated with severe atherosclerosis.
Epidemiology
Familial chylomicronemia syndrome (FCS) has an estimated prevalence of 1/300,000 (ranging from 1/100,000 to 1/1,000,000 in Europe and North America). Founder effects are seen in Quebec and the Cayman Islands.
Clinical description
Presentation in infancy includes failure to thrive, abdominal pain, nausea and vomiting progressing to acute pancreatitis. Symptoms and signs include fatigue, irritability, lipemia retinalis, eruptive xanthomas on trunk, back and gluteal region, and hepatosplenomegaly. Lipemic plasma indicates severely elevated plasma triglyceride levels due to pathological presence of chylomicrons (>10 mmol/L or >875 mg/dL).
Etiology
Most FCS patients have bi-allelic loss-of-function variants in LPL encoding lipoprotein lipase. Other minor causal genes encoding factors that interact with LPL, including apolipoprotein (apo) A-V (APOA5), apo C-II (APOC2), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) and lipase maturation factor 1 (LMF1).
Diagnostic methods
Definitive diagnosis is made by DNA sequencing. Biochemical methods are non-specific with technical performance challenges.
Differential diagnosis
In young adults, multifactorial (polygenic) chylomicronemia is 50 to 100 times as common as FCS and is associated with many secondary factors, hepatosteatosis, renal impairment or proteinuria. Patients with autoimmune diseases can develop antibodies against GPIHBP1 and develop chylomicronemia secondarily. Patients with undiagnosed partial lipodystrophy may present with chylomicronemia and pancreatitis.
Antenatal diagnosis
Antenatal diagnosis is not commonly offered, since FCS is manageable with dietary intervention.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (i.e. parents of a known FCS child or where both individuals are known carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
The mainstay of treatment is fat restriction, reducing total fat to <10% of calories or <20 grams per day, in combination with weight maintenance, exercise, and avoidance of processed foods, alcohol and smoking. Standard lipid-lowering medications and plasmapheresis are ineffective. Volanesorsen (apo C-III antisense oligonucleotide) is available in the EU but not North America; similar agents are in development.
Prognosis
Some patients have lived for six decades after the initial FCS diagnosis with minimal sequelae reportedly by adhering to a strict diet. Chylomicrons are not atherogenic, so atherosclerosis is uncommon in FCS patients, unlike other severe hypertriglyceridemia patients.

                            Last update: 
                            March 2023


                            - Expert reviewer(s): 
                            Dr Robert HEGELE