Endocrine Abstracts

Heterozygous (monoallelic) familial hypercholesterolemia (HeFH) is a monogenic disorder that affects one in 300 people. The majority of cases of FH are caused by inherited mutations in the LDLR gene, which encodes the LDLR. Less commonly, the heterozygous FH phenotype can be caused by mutations in other genes, specifically PCSK9, which encodes proprotein convertase subtilisin/kexin type 9. As many as 30% of patients do not survive their first myocardial infarction (MI). We present a HeFH patient with a rare mutation of LDLr. A 67-year-old woman with FH has been treated for the past 30 years with statins in the maximum tolerated dose. Last 10 years, on Rosuvastatin 40 mg, and cholesterol absorption inhibitor Ezetimibe 10 mg. Her past history revealed that she underwent percutaneous coronary interventions (PCI) with stent implantation on the left anterior descending artery 15 years ago and carotid endarterectomy. Her family history included premature coronary artery disease: her brother had MI in his forties, required the placement of 3 bypasses. Both daughters have FH. For determining the presence of a hetero or homozygous form of FH for the purpose of applying appropriate therapy, molecular genetic diagnostics using Next Generation Sequencing method was conducted. The analysis included all coding sequences (exons) and boundary exon/intron sequences in genes defined according to phenotypic characteristic present in the patient. The clinical target encompassed nine genes in the panel for FH. The conducted analysis revealed the presence of a likely pathogenic heterozygous variant in the LDLr gene c.858C>A, p. (Ser286Arg), NM 000527.5. This variant has an expected allelic frequency of 0.0028%. Following the results, she became eligible for treatment with a PCSK9 inhibitor, and she was approved for adjuvant biweekly treatment with Repatha® (evolocumab) 140 mg. Follow-up results showed a reduction: total cholesterol from 4.93 to 3.9 mmol/l; and LDL-C from 2.59 to 1.48 mmol/l. Treatment with PCSK9 inhibitor was combined with Rosuvastatin 20 mg and Ezetimibe 10 mg daily. We confirm the observations that, in compound heterozygous HeFH patients who receive stable background lipid-lowering treatment and do not undergo apheresis, biweekly treatment with evolocumab 140 mg was well tolerated and significantly reduced LDL-C.