Dr. Julius King Kwedhi,

ЦИОП, 4th Year

Objectives

Review Lipoproteins

Familial Hypercholesterolemia, a Genetic Disorder

Pathophysiology of FH

Types of FH

FH Clinical Presentation

Diagnosis & Management

Treatment

Lipoproteins

LDL Endocytosis

LDL Endocytosis

Definition

• Familial hypercholesterolemia (FH) is an autosomal dominant disorder that causes severe elevations in total cholesterol and low-density lipoprotein cholesterol (LDLc).

A Genetic Disorder

HoFH HeFH

Epidemiology of FH

4 Known Genes Involved

Single Nucleotide Polymorph

isms

rs7566605,(Insulin-induced

gene 2 (INSIG2),

Chromosome2)

rs854560, (Paraoxonases

1(PON1 gene),

Chromosome2)

rs505151

(PCSK9 gene,

Chromosome1)

rs12720762, APOB gene,

Chromosome 19

Chromosome 19

FH is an autosomal dominant disorder

Mutations in the LDL receptor gene on Chromosome 19

Pathophysiology

3 Forms of FH

Familial Hypercholesterolemi

a

Autosomal Dominant

Hypercholesterolemia

Autosomal dominant

hypercholesterolemia,

type B

Autosomal recessive

hypercholesterolemia

2 Types of FH

FLDB = Familial ligand defective apoB-100 , CHD = Coronary Heart Disease

Homozygous FH Heterozygous FH

Symptomatic in Childhood Symptomatic mainly in Adulthood

Normal Triglycerides Normal Triglycerides

LDLc >600 mg/dL LDLc Usually >250 mg/dL<20 yrs: LDLc>200 mg/dL is FH/ (FLDB)Adults >20 yrs: >290-300 mg/dL

Total Cholesterol >600 mg/dL Total Cholesterol>250 mg/dL

Two major genetic defects in

LDL metabolism

One major genetic defect in LDL

metabolism

Tendon and cutaneous

xanthomas often before age 10

years

Arcus cornealis and Achilles tendon

xanthomas often present

CHD onset in childhood CHD onset 30-60 years

Poorly responsive to drugs;

apheresis often indicated

Most respond to drugs, but individual

response variable

Lipoproteins Distribution

Signs & Symptoms

Achilles Tendons Xanthomas

Corneal Arcus

Metacarpal PhalangealExtensor Tendons Xanthoma

Tendon Xanthomas

Xanthelasmas

The Urgency!

“For untreated FH homozygotes, the prognosis is down-right tragic. Heart

attacks have been documented in 2-year-old infants and more frequently at ages 8,

10, and 12 due to extremely aggressive coronary atherosclerosis. Untreated, most FH homozygotes will have heart attacks in their late teens, and few will survive past

their 20s.”

- Bob Carlson, MHA, Biotechnol Healthc Senior Contributing Editor

Routine Lipid Screening

Prenatal testing for pregnancies at high risk

Serial single-gene testing

Multi-gene panel testing

LaboratoryGenetic testing can identify genetic mutations associated with FH

Treatment

HMG-CoAReductaseInhibitors (Statins)

Vitamins

Bile acid Sequestrant

s (resins)

Lipid-Lowering Agents, Other

PCSK9 Inhibitors

Liver Transplantat

ion

Portacavalanastomosis

Estrogen replacement Therapy in

postmenopausal women

LDL Apheresis

Treatment

Interindividual Variations

Gene Therapy

FH Management

References1. July M, & Olajide OB. (2017). Familial Hypercholesterolemia Clinical Presentation . Medscape.

http://emedicine.medscape.com/article/121298-clinical

2. Jeffrey S. (2016). Very High LDL Seldom Caused By FH Gene Variants. Medscapehttp://www.medscape.com/viewarticle/861390

3. Gidding SS, et al. (2015). The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association. AHA Journals. 2015;132:2167-2192. http://circ.ahajournals.org/content/132/22/2167

4. Belgian Artherosclerosis Society. (2015). Prevention : Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. http://www.lipidclub.be/newsletter.php

5. SNPedia. (2016). Familial Hypercholesterolemia. https://www.snpedia.com/index.php/Familial_hypercholesterolemia

6. SNPedia. (2011). Hypercholesterolemia. https://www.snpedia.com/index.php/Hypercholesterolemia

7. Soutar AK, Naoumova RP. (2004). Autosomal recessive hypercholesterolemia. Semin Vasc Med. 4(3):214-8. https://www.ncbi.nlm.nih.gov/pubmed/15630633

8. Youngblom E, Pariani M, & Knowles JW. (2016). Familial Hypercholesterolemia. GeneReviews [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK174884/

9. Sharifi M, et al. (2016). Cardiovascular biomarkers in monogenic familial hypercholesterolaemia and polygenic hypercholesterolaemia. Artherosclerosis Journal. 2016.09.055 http://www.atherosclerosis-journal.com/article/S0021-9150(16)31369-7/abstract

10. Orsó E1, Ahrens N, Kilalić D, & Schmitz G. (2009). Familial hypercholesterolemia and lipoprotein(a) hyperlipidemia as independent and combined cardiovascular risk factors. PubMed. 2009 Dec 29;10(5):74-8. https://www.ncbi.nlm.nih.gov/pubmed/20129380

11. Novelli G, et al. (2008). Genetic tests and genomic biomarkers: regulation, qualification and validation. Clin Cases Miner Bone Metab. 2008 May-Aug; 5(2): 149–154. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781197/

12. Brumit ML. (2014). Heterozygous vs Homozygous FH. Familial Hypercholesterolemia Foundation. https://thefhfoundation.org/heterozygous-vs-homozygous-fh

13. Familial Hypercholesterolemia Foundation. (N/A). About HoFH. https://thefhfoundation.org/about-fh/homozygous-familial-hypercholesterolemia

14. Staff FH Foundation. (2016). FH and Personalized Medicine. The Familial Hypercholesterolemia Foundation. March 10, 2016. https://thefhfoundation.org/fh-and-personalized-medicine

15. Huber J. (2016). Familial hypercholesterolemia: A genetic disease in need of early testing. Stanford Medicine. http://scopeblog.stanford.edu/2016/04/26/familial-hypercholesterolemia-a-genetic-disease-in-need-of-early-testing/

16. National Human Genome Research Institute. (2013). Learning About Familial Hypercholesterolemia. https://www.genome.gov/25520184/