Glycerol Kinase Gene Variant as a Cause of Pseudohypertriglyceridemia and Apparent Poor Response to Plozasiran

TL;DR

A rare genetic variant in the glycerol kinase gene can cause misleadingly high triglyceride levels and an apparent poor response to treatment.

Contribution

This case report identifies a glycerol kinase gene variant as a cause of pseudohypertriglyceridemia and apparent treatment resistance to plozasiran.

Findings

A loss-of-function variant in the GK gene led to elevated free glycerol levels, falsely increasing triglyceride measurements.

Correcting for free glycerol revealed mild hypertriglyceridemia and a significant treatment response to plozasiran.

APOC3 inhibition does not affect free glycerol concentration, highlighting the need for additional diagnostic measures in non-responders.

Abstract

Severe hypertriglyceridemia (HTG) is characterized by plasma triglyceride (TG) levels >500 mg/dL (SI: 5.7 mmol/L) (reference range, <150 mg/dL [SI: <1.7 mmol/L]) and is linked to cardiovascular disease and pancreatitis risk. Treatment typically involves dietary restrictions and lipid-lowering medications. Glycerol kinase deficiency (GKD) is a rare genetic disorder that causes pseudo-HTG.

In SHASTA-2, a study of patients with severe HTG, most subjects (>90%) treated with plozasiran, an apolipoprotein C-III (APOC3) small interfering RNA (siRNA), achieved TG levels <500 mg/dL (SI: 5.7 mmol/L), below the risk threshold for acute pancreatitis. We report herein a case study of a 65-year-old male apparently not responding to plozasiran. The patient was shown to carry a loss-of-function variant in the GK gene resulting in GKD, with high free glycerol (40.24 mg/dL or 4.37 mmol/L) (reference range, 0.03-0.13 mmol/L) that contributed to an overestimation of TG concentration. After correcting for free glycerol, the patient was noted to have had mild HTG, with plozasiran treatment decreasing real TG values by up to 71%.

This case report suggests that in the absence of response to APOC3 inhibition, measuring free glycerol could be clinically relevant. It also highlights that APOC3 inhibition has no effect on free glycerol concentration.

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