VOLUME

In the last issue of Bangkok Med J 2018, Vol. 14(1): page 57-62, we reported an aborted sudden coronary death in a veryyoung man, age of 29 years.¹ Although he had no other atherosclerotic risk factors, severe hypercholesterolemia was noted withLDL cholesterol of 186 mg/dl, tendinous xanthoma and family history of dyslipidemia, suggestive of an inherited condition.By clinical criteria, he was diagnosed with familial hypercholesterolemia (FH).^2-4

FH is an inherited hypercholesterolemia, caused by mutations in any of the three major genes encoding cholesterol traffickingproteins including LDL receptor (LDLR), APOB (the ligand for the LDLR) and PCSK9 (the regulator of LDLR’s turnover),required for hepatic clearance of plasma LDL.⁴ Figure 1 below summarizes the effect of mutations resulting in reduced ordysfunctional LDLR, malfunction of APOB, or excessive function of PCSK9. The fourth gene, LDLRAP1, controls productionof a chaperone protein that carries the LDLR on the sinusoidal side of the hepatocyte.⁵ All of these changes have been reportedto cause lifelong exposure to hypercholesterolemia, xanthomatosis, premature atherosclerosis, and sporadic sudden coronarydeath at a young age, as in our reported case.^2-4 Prevalence of heterozygous mutations in LDLR, APOB, and PCSK9 mutationsis > 90%, ~5%, and ~1%, respectively among patients with genetically determined FH.⁶ Further detail of FH has beensummarized in this Journal by Shapiro and Fazio.⁴

Figure 1: In A, LDL cholesterol (yellow circles) is carrying by normal APOB (blue segment) and is internalized by thehepatocyte via the action of normal LDL receptor (dark blue LDLR in A). Mutations in LDLR (black LDLR in B) or ApoB(orange segment in B), and in PCSK9 (C) impair hepatic LDL transport and result in lifelong hypercholesterolemia.

We now report on the result of genetic analysis performed on blood DNA from our patient. No mutation was found in APOB,LDLRAP1 or PCSK9. However, a heterozygous mutation was found in the LDLR: c1241T>G (p.Leu414Arg). This mutationchanges the amino acid at position 414, where the highly co nserved leucine is substituted by arginine. This L414R mutationhas been previously reported in several Chinese patients but was designated differently as L393R in some publications.^7-9 It iscategorized as likely pathogenic and likely related to hypercholesterolemia in this patient, since it is predicted to be disruptiveto the function of LDLR protein by three prediction algorithms (SIFT, PolyPhen-2 and Align-GVGD) and is also found at a verylow allele frequency of 0.001% in ExAc database (rs748554592). The functional effect of this mutation is uncertain due to thelocation of L414R is in the beta strand region but outside of the calcium binding EGF-like domain.¹⁰ It might be hypothesizedto interfere with LDLR protein folding and thus LDLR recycling. The patient and family members have been informed andgenetic counselling is provided.

This case illustrates the importance of properly diagnosing familial hypercholesterolemia in younger patients to implementaggressive preventive therapy and reduce the risk of cardiac complications including sudden death. In addition, the case supportsour contention that a prospectively designed cohort study is necessary to determine the true prevalence of FH and its mutationspectrum in the Thai population.