Clinical Guidance

As most pathogenic LPL variants have been reported in individual case reports or small case series, reliable systematic correlation of genotype-phenotype relationships is challenging. There are no known genotype-phenotype correlations.

Source: GeneReviews — "Familial Lipoprotein Lipase Deficiency"

Diagnostic Criteria

Suggestive Findings

Familial lipoprotein lipase (LPL) deficiency should be suspected in individuals (particularly those age 40 years) with the following clinical and supportive laboratory findings.

Clinical findings

• Recurrent acute pancreatitis

• Eruptive cutaneous xanthomata

• Hepatosplenomegaly

Supportive laboratory findings

• Impaired clearance of chylomicrons from plasma causing the plasma to have a milky (lactescent or lipemic) appearance

• Plasma triglyceride concentrations greater than 2000 mg/dL in the untreated state, regardless of fasting status

Establishing the Diagnosis

The diagnosis of LPL deficiency is established in a proband by the identification of biallelic pathogenic variants in LPL on molecular genetic testing . A consensus diagnostic algorithm has been published (see Figure 3).

Source: GeneReviews — "Familial Lipoprotein Lipase Deficiency"

Differential Diagnosis

Familial lipoprotein lipase (LPL) deficiency should be considered in young persons with the chylomicronemia syndrome, defined as abdominal pain, eruptive xanthomata, plasma triglyceride concentrations greater than 2000 mg/dL, and fasting lipemic plasma. However, the majority of individuals with chylomicronemia and plasma triglyceride concentration greater than 2000 mg/dL do not have familial LPL deficiency; rather, they have one of the more common genetic disorders of triglyceride metabolism (i.e., familial combined hyperlipidemia and monogenic familial hypertriglyceridemia). Hypertriglyceridemia can also be polygenic, due to both heterozygous rare large-effect variants and accumulations of common rare small-effect variants in several genes and loci . With such genetic predisposition, clinical expression of chylomicronemia typically requires the presence of secondary, non-genetic factors . Secondary causes of hypertriglyceridemia include: diabetes mellitus; paraproteinemia and lymphoproliferative disorders; use of alcohol; and therapy with estrogen, glucocorticoids, selective serotonin reuptake inhibitors, atypical antipsychotic agents, isotretinoin, or certain antihypertensive agents. In one series of 123 individuals evaluated for marked hypertriglyceridemia, 110 had an acquired cause of hypertriglyceridemia combined with a common genetic form of hypertriglyceridemia, five had familial LPL deficiency, five had other rare genetic forms of hypertriglyceridemia, and three had an unknown cause . Other than LPL deficiency, the chylomicronemia syndrome may be caused by biallelic pathogenic variants in apolipoprotein C-II (APOC2), apolipoprotein A-V (APOA5), lipase maturation factor 1 (LMF1) or GPIHBP1 . Table 2. Genetic Causes of Primary Monogenic Chylomicronemia

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with familial lipoprotein lipase (LPL) deficiency, measurement of plasma triglyceride concentration is recommended. Consultation with a clinical geneticist and/or genetic counselor may also be considered.

Treatment of Manifestations

Medical nutrition therapy. Morbidity and mortality can be prevented by maintaining plasma triglyceride concentration at less than 2000 mg/dL; a good clinical goal is less than 1000 mg/dL . Restriction of dietary fat to no more than 20 g/day or 15% of total energy intake is usually sufficient to reduce plasma triglyceride concentration and to keep the individual with familial LPL deficiency free of symptoms. Medium-chain triglycerides may be used for cooking, as they are absorbed directly into the portal vein without becoming incorporated into chylomicron triglyceride. The success of therapy depends on the individual's acceptance of the fat restriction, including both unsaturated and saturated fat. Note: Fish oil supplements, which are effective in disorders of excess hepatic triglyceride production, are not effective in LPL deficiency and are contraindicated . The enlarged liver and spleen can return to normal size within one week of lowering of triglyceride concentrations. The xanthomas can clear over the course of weeks to months. Recurrent or persistent eruptive xanthomas indicate inadequate therapy.

Source: GeneReviews — "Familial Lipoprotein Lipase Deficiency"

Clinical Guidance

Avoidance of agents known to increase endogenous triglyceride concentration such as alcohol, oral estrogens, diuretics, isotretinoin, glucocorticoids, selective serotonin reuptake inhibitors, and beta-adrenergic blocking agents is recommended. Fish oil supplements are contraindicated as they contribute to chylomicron levels.

Source: GeneReviews — "Familial Lipoprotein Lipase Deficiency"

Therapies Under Investigation

LPL gene therapy is available in Europe and the US for the treatment of familial LPL deficiency. It consists of the LPL Ser447Ter variant in an adeno-associated virus serotype 1 (alipogene tiparvovec). Twenty percent of the general population has the Ser447Ter allelic variant, which results in a prematurely truncated LPL that is associated with increased lipolytic function and an anti-atherogenic lipid profile and can therefore be regarded as a naturally occurring gain-of-function variant (reviewed by ). Note that the standard nomenclature for this variant is NP_000228.1:p.Ser474Ter (NM_000237.2:c.1421CG).

Source: GeneReviews — "Familial Lipoprotein Lipase Deficiency"

Surveillance Guidelines

Plasma triglyceride levels need to be followed over time to evaluate the affected individuals success in following the very low-fat dietary recommendations. When the triglyceride level is above 1000 mg/dL, a fasting sample is not required for this evaluation. Other components of the lipid profile do not need to be routinely measured. Affected individuals who develop abdominal pain need to contact their physician.

Source: GeneReviews — "Familial Lipoprotein Lipase Deficiency"