The Physician’s Guide to Homozygous Familial ...

The National Organization for Rare Disorders NORD Guides for Physicians

The Physician’s Guide to

Homozygous Familial
Hypercholesterolemia (HoFH)

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Contents ©2014 National Organization for Rare Disorders®

Introduction

Welcome to the NORD Physician Guide to Homozygous Familial
Hypercholesterolemia (HoFH). The NORD Online Physician Guides are
written for physicians by physicians with expertise on specific rare disorders.
This guide was written by Dr. Dirk Blom, Head of Division of Lipidology,
Department of Medicine, University of Cape Town (see acknowledgements
for additional information).

NORD is a nonprofit organization representing all patients and families
affected by rare diseases. The information NORD provides to medical
professionals is intended to facilitate timely diagnosis and treatment for
patients.

HoFH is an inherited disorder of lipoprotein metabolism characterized by
marked elevation of low density lipoprotein cholesterol (LDL-C), xanthomata
and premature cardiovascular disease.

What Is Homozygous Familial
Hypercholesterolemia (HoFH)?

HoFH is an inherited disorder of lipoprotein metabolism characterized by
marked elevation of low density lipoprotein cholesterol (LDL-C), xanthomata
and premature cardiovascular disease. In most cases the underlying genetic
abnormality is mutation of both alleles of the LDL-receptor (LDLR) gene.

LDL is generated in the circulation by the delipidation and modification of
very low density lipoproteins (VLDL) secreted by the liver. Apolipoprotein
B100 (apoB100) is the major structural apoprotein of VLDL and LDL. LDL
is cleared from the circulation by hepatic LDLR with apoB100 acting as the
ligand for the receptor. The major pathophysiological abnormality in HoFH
is decreased LDL clearance although hepatic overproduction of apoB100-

1

containing lipoproteins may further exacerbate the hyperlipidaemia.

The worldwide prevalence of HoFH is generally estimated to be one in a
million while the prevalence of heterozygous familial Hypercholesterolemia
(HeFH) is estimated to be one in three- to five hundred, making the latter
one of the commonest severe monogenic disorders in medical practice.
The prevalence of HoFH is markedly increased in certain regions of the
world and may be as high as one in thirty thousand in some populations.
Populations with a very high prevalence of HoFH include Afrikaners in
South Africa, French Canadians, Christian Lebanese and Japanese from the
Hokuriku district. These regions are characterized by a high prevalence of
HeFH (estimated to be one in seventy to a hundred for Afrikaners in South
Africa) which results from founder effects that occur when small, isolated
populations increase in size rapidly with little outside genetic admixture.1

Symptoms and Signs

The majority of the literature on HoFH describes patient cohorts that were
identified using clinical definitions of HoFH. One of the important objectives
of clinical definitions was to distinguish severe HeFH from HoFH. The advent
of novel genetic techniques that can screen multiple genes rapidly for
mutations have broadened our understanding of HoFH indicating that, not
surprisingly, clinical definitions generally identify the more severely affected
patients within the HoFH spectrum. It is thus important to realize that there
are patients with genetic HoFH who are not as severely affected as in the
description of ‘classical HoFH’ given below.

The three cardinal clinical manifestations of HoFH are markedly elevated
levels of LDLC (often, but not invariably, exceeding 13 mmol/L (500 mg/dL)),
cutaneous as well as tendinous xanthomata and premature cardiovascular
disease.

HoFH is usually diagnosed in infancy or childhood but occasionally the
diagnosis may be delayed till later in life. The commonest childhood
presentation is with cutaneous xanthomata. If the diagnosis was missed in
childhood the first presentation may be with atherosclerotic cardiovascular
disease either in adolescence or as a young adult.

The physical signs of HoFH can be quite variable, but cutaneous
xanthomata are often noted in the first years of life. Most clinical definitions
of HoFH include the presence of cutaneous xanthomata before the age

2

of ten years as a diagnostic criterion. Planar xanthomata are often found
in skin creases or at other points of friction. Common sites for planar
xanthomata include the wrist, ankle, cubital fossa, popliteal fossa and natal
cleft. Planar xanthomata in the interdigital webspaces on the dorsum of the
hand (interdigital xanthomata) are pathognomonic of HoFH. Xanthelasma
are also commonly found in HoFH but are not diagnostically useful due
to their non-specific nature. Tuberous xanthomata are commonly found
at the elbows but can occur at other sites such as the knees or ankles as
well. Tendon xanthomata occur most commonly in the Achilles tendons
and the extensor tendons of the hands but can occur in other tendons as
well. Tendon xanthomata manifest later than cutaneous xanthomata and
are usually not found in infants and children. Arcus cornealis is a common
but non-specific finding in HoFH. Some of the physical features of HoFH are
illustrated below.

Interdigital xanthoma Xanthomata in buttock creases

Tuberous xanthoma at elbow

Planar xanthoma

Xanthomata in the popliteal fossa Achilles tendon xanthomata
3

Premature cardiovascular disease is a hallmark of HoFH. Patients may
develop ischemic heart disease in childhood. Survival beyond the second
or third decade was rare before the advent of statins and the addition of
apheresis to the therapeutic armamentarium.2 Supravalvular aortic stenosis
due to cholesterol deposition in the aortic root is a common complication
of HoFH and may require surgical correction. Coronary ostial stenosis
is a frequent finding at angiography in patients with HoFH. Although
diffuse atherosclerotic vascular damage is often seen on vascular imaging
studies, clinically overt disease in the non-coronary vasculature is relatively
uncommon. The clinical findings in the vasculature depend on the age of
the patient, the level of LDLC control achieved and a history of previous
interventions or complications. Frequent findings include an aortic outflow
murmur and bruits in multiple vascular territories.

Causes

HoFH is usually inherited in an autosomal co-dominant fashion but on
occasions may also be inherited recessively. The HoFH phenotype may result
from mutation of a single gene or more rarely may be the consequence
of mutations in several different genes involved in lipoprotein metabolism.
Currently four genes have been associated with the FH phenotype. All of
these genes are critical to LDLR function and mutations result in impaired LDL
clearance.

The commonest underlying molecular cause of the HoFH phenotype is
mutation of both LDLR alleles. The inheritance of HoFH due to mutations
in the LDLR is autosomal co-dominant. When HoFH is due to LDLR
mutations, both parents contribute one mutated allele. Patients may be true
homozygotes (the same mutation is found in both alleles) or compound
heterozygotes (a different mutation is found in each allele). Mutation of
only one LDLR allele causes heterozygous familial Hypercholesterolemia
(HeFH). The severity of the HeFH phenotype may vary considerably even
amongst patients carrying identical mutations as multiple other genetic and
environmental influences also influence LDLC concentration. The risk of a
couple who both carry one mutated LDLR allele of having a child with HoFH
is 25%, while the risk of a child with HeFH is 50% and the chance that a
child will not inherit a LDLR mutation is 25%.

Mutations in both alleles of the autosomal recessive Hypercholesterolemia
(ARH) adaptor protein 1 gene may also result in the HoFH phenotype.

4

The ARH adaptor protein 1 plays an important role in the clustering and
internalization of the LDLR from clathrin coated pits. HoFH secondary to ARH
adaptor protein mutations is an autosomal recessive disorder and mutation
carriers do not express the HeFH phenotype. The risk of two gene carriers
having an affected child is 25%. ARH adaptor protein 1 mutations were first
described in patients from Sardinia, where there is likely a founder effect, but
have subsequently been identified in patients from all over the world.

ApoB100 is the ligand for the LDLR and mutations that change the
conformation of the apoB100 binding region are associated with decreased
LDL binding and clearance. Mutation of one apoB allele is associated with
the HeFH phenotype. Homozygosity or compound heterozygosity for apoB
mutations is often associated with a less severe phenotype than that seen
with mutations of both LDLR alleles. 3,4

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzymatically
inactive serine protease that is predominantly secreted by hepatocytes.
PCSK9 targets LDLR for intracellular degradation and prevents their
recirculation. Gain-of-function mutations in PCSK9 are associated with LDL
Hypercholesterolemia while loss-of-function lower LDLC. Gain-of-function
PCSK9 mutations are associated with the HeFH phenotype in heterozygote
carriers. A few homozygotes and compound heterozygotes for PCSK9
mutations have been identified, but generally at least one of the mutations is
relatively mild and the identified phenotypes have not been extremely severe.4

Occasionally patients may have mutations in several genes involved in LDL
metabolism. For example the combined inheritance of a mutated LDLR allele
and a mutated PCSK9 allele has been described in association with the HoFH
phenotype.

Diagnosis

Patients with suspected HoFH, including patients with what clinically appears
to be severe HeFH with a poor response to lipid lowering therapy, should be
referred to a specialist lipid center so that an accurate diagnosis can be made.
Historically, the diagnosis of HoFH was based on the clinician identifying the
‘HoFH phenotype’ – what is now sometimes called ‘classical HoFH’. Although
there are no universally accepted clinical criteria for the diagnosis of HoFH a
common clinical definition1 of HoFH included the following:

5

• Cutaneous xanthomata before the age of ten years

• LDLC > 13 mmol/L before treatment or > 7.76 mmol/L despite treatment

• P henotypic features in keeping with HeFH in both parents
(for HoFH that is due to LDLR mutations)

The clinical diagnosis of HoFH could historically be confirmed by determining
LDL uptake in fibroblasts (or lymphocytes) or by identification of pathogenic
mutations in both alleles of the LDLR. Outside of specialized centers the clinical
diagnosis of HoFH was often not confirmed by specialized investigations,
as the required investigations were complex and not routinely available.
LDL uptake studies in cultured fibroblasts are complex and labor intensive
while early molecular genetics techniques were not able to screen genes
for mutations rapidly and efficiently. There are for instance more than 1500
reported pathogenic mutations in the LDLR alone. The advent of modern
genetic techniques that allow rapid and simultaneous screening of multiple
genes has changed the diagnostic paradigm for HoFH and a molecular genetic
diagnosis should now be sought in every suspected case. However, HoFH can
still be diagnosed using clinical criteria and treatment should not be withheld
because of lack of access to genetic testing or a delay in obtaining results as
not all health systems reimburse genetic testing.

Modern molecular genetic testing has confirmed that the spectrum of
severity of HoFH is wider than initially thought.3 A substantial proportion of
patients with genetically confirmed HoFH do not fulfill the clinical criteria
for diagnosis of ‘classical HoFH’, and genetic HoFH is likely underdiagnosed.
Without molecular genetic testing many patients with genetic HoFH may be
labeled by clinicians as patients with ‘severe HeFH’. Most of the available HoFH
literature describing cardiovascular outcomes and response to treatment is
based on HoFH cohorts that were identified clinically and may thus not always
be representative of patients with less severe phenotypes. The FDA recently
licensed two novel agents for the treatment of HoFH (see below) based on
trials where HoFH could be diagnosed clinically, although the diagnosis was in
fact confirmed by genetic testing in the vast majority of patients.5

Patients who carry mutations that render the LDLR completely non-functional
(receptor negative HoFH) often have a more severe phenotype and worse
prognosis than patients in whom there is some residual LDLR function
(receptor defective HoFH). Receptor negative patients also tend to respond
poorly if at all to therapies that act mainly by upregulating the LDLR. Knowing
the genotype and the functional impact of the mutation(s) may thus be useful

6

when selecting therapy based on the mechanism of action (requires residual
LDLR function or not).

Diagnosing HoFH requires a careful clinical, laboratory and family
evaluation followed by molecular genetic testing. Conditions that on
occasions may cause diagnostic difficulties for the non-expert include
dysbetalipoproteinaemia, sitosterolaemia, cerebrotendinous xanthomatosis
and secondary hyperlipidaemia. Dysbetalipoproteinaemia is characterized by
remnant accumulation and although the total cholesterol may be markedly
elevated there is concomitant hypertriglyceridaemia (often the molar ratio of
total cholesterol to triglycerides is around 2:1) and more detailed analysis of
the lipoprotein phenotype will reveal low levels of LDL with an accumulation
of remnant lipoproteins. It is also very unusual for dysbetalipoproteinaemia to
manifest in childhood. Sitosterolaemia is characterized by the accumulation
of plant sterols (phyosterols) and may present with cutaneous xanthomata
and high total cholesterol in childhood. It is a recessive disorder and normal
lipid levels in the parents of a child with HoFH should alert the clinician to
this diagnosis. The diagnosis can be confirmed by measuring plant sterols.
Cerebrotendinous xanthomatosis is associated with prominent tendon
xanthomata but the diagnosis is usually obvious as LDLC is not markedly
elevated in the face of early-onset cataracts and neurological degeneration.

Treatment

The treatment of HoFH is complex and patients should be referred to a
specialized lipid unit that is experienced in the treatment of such patients.
Referral to a specialized unit also offers patients the best chance of access
to novel therapies. Atherosclerotic complications tend to be proportional
to the duration and severity of LDL Hypercholesterolemia (‘cholesterol-year
score’). Because LDLC is so high in patients with HoFH they may reach the
‘cholesterol exposure burden’ at which atherosclerosis is likely to occur
in childhood or early adolescence. Early and aggressive LDLC control is
therefore the major therapeutic goal when treating patients with HoFH.

Treatment for HoFH is usually started at the time of diagnosis and may be
started in infants as young as one year. No lipid-lowering therapies are
licensed for use in such young patients and parents should thus always
be informed and counseled about the risks and benefits of off-label
prescribing. Statins remain the backbone of therapy in HoFH although
they are less effective than in patients with HeFH or other forms of

7

Hypercholesterolemia. Individual responses may vary widely and can range
from virtually no response to a 50% reduction in LDLC. Receptor defective
patients generally achieve a 25% LDLC reduction while the average
reduction in receptor negative patients is usually only around 15%. The
main mechanism by which statins lower LDLC is LDLR upregulation but high
dose statins also decrease hepatic lipoprotein synthesis due to decreased
availability of cholesterol in the hepatocyte. This second mechanism
probably accounts for the response seen in receptor negative patients.
HoFH patients are generally prescribed high to maximal doses (adjusted for
body mass) of potent statins such atorvastatin or rosuvastatin.

Ezetimibe lowers LDLC by a further 10-20% in patients with HoFH on
statins.6 It is generally safe and well tolerated and is routinely prescribed in
combination with statins even in very young patients. Other lipid lowering
therapies such as bile acid sequestrants, niacin, omega-3 fatty acids and
fibrates are used on occasions but there is little published evidence to
support their use. When multiple lipid-lowering therapies are prescribed
concomitantly patients should be monitored carefully for adverse effects
and drug interactions. Therapies that do not lower LDLC further should be
discontinued.

LDLC levels are inadequately controlled in almost all HoFH patients receiving
conventional lipid-lowering therapy. In a recent review of a large cohort of
HoFH patients from South Africa the mean on-treatment LDLC was 11.7
mmol/L (a 26% reduction from the untreated baseline).2 Until December
2012 when lomitapide and subsequently mipomersen (January 2013) were
approved for use in HoFH by the FDA the only other therapeutic options
were apheresis or liver transplantation. Partial ileal bypass, portocaval
shunting and gene therapy were utilized in the past but have been
abandoned due to poor efficacy and/or unacceptable side effects.

The first apheresis therapy was plasma exchange but techniques that
remove lipoproteins more specifically (lipoprotein apheresis) have replaced
plasma exchange in most areas of the world. Lipoprotein apheresis
typically lowers LDLC by about 45%, but results may vary considerably
depending on the plasma volume treated and the frequency at which the
procedure is performed. There are no controlled cardiovascular outcome
trials of apheresis in patients with HoFH, but cohort and retrospective
studies suggest that outcomes are improved and apheresis is considered
standard of care for HoFH in most parts of the world. 7 Because apheresis

8

is costly, imposes a significant treatment burden on patients and is often
only available in specialized centers, not all patients have access to this
therapy. Apheresis only reduces LDLC transiently and LDLC rebounds
relatively rapidly in the first few days following the procedure. If apheresis
is performed infrequently (once every two weeks or less) the vasculature
continues to be exposed to significant amounts of LDL.

Advances in surgical techniques and immunosuppression have resulted in
significantly improved survival rates for liver transplant recipients. Because
the liver is the major site of LDL uptake transplantation may normalize or
reduce LDLC levels very significantly. The limited availability of donor organs
and concerns about long term immunosuppression has restricted the
numbers of patients receiving liver transplants.

Lomitapide and mipomersen are two novel therapies for HoFH that
reduce lipoprotein production and do not rely on functional LDLR for their
effect. Lomitapide is an oral inhibitor of microsomal triglyceride transfer
protein (MTP). MTP is required for the production of apoB-containing
lipoproteins in the intestines and liver. Mutation of both MTP alleles causes
abetalipoproteinaemia - a condition characterized by fat malabsorption,
very low or absent levels of apoB-containing lipoproteins and neurological
damage secondary to vitamin E deficiency in peripheral tissues which
depend on vitamin E transported in apoB-containing lipoproteins. MTP
inhibition was first explored as a therapeutic option for lowering lipids more
than 30 years ago, but subsequently abandoned in favor of statins. More
recently there has been renewed interest in MTP inhibition and in a pilot
study with six HoFH patients lomitapide monotherapy reduced LDLC by
51%. 8 This study was followed by a larger phase 3 study in which patients
remained on their baseline lipid-lowering therapy including apheresis. In
this single-arm, open-label study involving 29 HoFH patients older than 18
years lomitapide reduced LDLC by a further 50% on top of baseline therapy
at week 26. 9

The side effects of lomitapide relate to its mechanism of action. Inhibition
of MTP in the intestines may result in nausea, bloating and diarrhea
especially if oral fat intake is high. Gastrointestinal symptoms were frequent
in the initial phases of the trial but decreased in severity and frequency
as the trial progressed. Hepatotoxicity is one of the complications of
lomitapide therapy. Specifically, hepatic inhibition of MTP may result
in hepatic steatosis and transaminitis. In the phase 3 study hepatic fat

9

measured by magnetic resonance spectroscopy increased from 1% at
baseline to 8.3% at week 78 with large individual variations. Transaminitis
with alanine aminotransferase (ALT) greater than five times the upper limit
normal was seen in four patients and was managed successfully in all
patients either by dose reduction or by temporary interruption of lomitapide
dosing.

Lomitapide, as an adjunct to a low-fat diet and other lipid-lowering
treatments including LDL apheresis, is currently approved for use in adult
patients with HoFH in the United States, Europe, Canada and Mexico.

In countries where lomitapide has been approved regulatory authorities
have imposed conditions (risk mitigation programs) on the prescription
of lomitapide. Although there are variations in the labels among the
countries where the drug has been approved, the general principles are
that lomitapide should only be prescribed for patients with HoFH who
are older than 18 years and physicians prescribing lomitapide need to be
knowledgeable about its use and potential adverse effects. Hepatic function
needs to be monitored closely; patients should receive dietary advice and
vitamin E and essential fatty supplements; and patients should restrict
intake (1 drink/ day) or avoid alcohol completely. In addition, because
lomitapide is a substrate of cytochrome (CYP) 450 3A4, very close attention
should be paid to possible drug interactions with concomitant medications.
A registry study (Lomitapide Observational Worldwide Evaluation Registry,
or LOWER) is being conducted to evaluate the long-term effects of
lomatipide.

Mipomersen is an antisense oligonucleotide that targets apoB100 mRNA.
ApoB100 mRNA that is bound to mipomersen is degraded by ribonuclease
H and less apoB100 protein is synthesized which in turn inhibits hepatic
production of apoB100-containing lipoproteins. Mipomersen was studied
in a double-blind, placebo controlled of 51 HoFH patients older than 12
years not receiving apheresis. The dose of mipomersen was 200 mg once
a week by subcutaneous injection except for patients weighing less than
50 kg who received 160 mg once a week. The mean LDLC reduction was
25% although responses ranged from no response to more than 80%
LDLC reduction. 10 The major adverse effects of mipomersen are injection
site reactions, transaminitis, flu-like symptoms and hepatic steatosis.
Mipomersen was licensed for use in adult HoFH by the FDA (subject to a
risk mitigation program) but not by the EMA. Because mipomersen was

10

studied in a HoFH population not receiving apheresis its use in conjunction
with apheresis is not recommended. Patients receiving mipomersen require
regular liver function monitoring and alcohol intake should be restricted to
a maximum of 1 drink per day.

There is as yet no cardiovascular outcome data for lomitapide and
mipomersen. These drugs were licensed based on their ability to lower
LDLC, the very high and poorly responsive levels of LDLC that characterize
HoFH and the known association between LDLC lowering and improved
cardiovascular outcomes. Hepatic steatosis is a complication intrinsic to the
mechanism of action of both drugs and they should thus not be prescribed
together. The long term outcome of the hepatic steatosis associated with
lomitapide and mipomersen is as yet unknown and careful long term
follow up of each patient is required. Potential complications of hepatic
steatosis may include steatohepatitis and ultimately cirrhosis. However, the
substantial LDLC lowering and expected cardiovascular benefit outweighs
the potential risks in patients with HoFH.

Despite optimal therapy many patients require cardiac interventional
procedures. Such procedures should ideally only be performed by
cardiologists and surgeons experienced in the management of patients with
HoFH. Aortic root and valve surgery in patients with HoFH poses particular
technical challenges due to the extensive cholesterol deposits that may be
present.

Investigative Therapies

PCSK9 inhibition is a novel lipid lowering strategy and increases the
number of LDLR on hepatocytes by reducing PCSK9 mediated lysosomal
degradation of internalized LDLR. Several approaches to PCSK9 inhibition
are currently being explored in clinical trials with monoclonal antibodies, the
furthest advanced along the development pathway. The trials completed
thus far have shown large (>50%) and consistent reductions in LDLC with
good tolerability in multiple populations including patients with HeFH.11
Antibodies have mostly been given by subcutaneous injection once every
two to four weeks. The results of a small pilot study involving eight patients
with HoFH were reported recently. In this study evolocumab 420 mg two
weekly reduced LDLC by 26% in the six receptor defective patients. The
two receptor negative patients did not respond at all. 12 A larger double-
blind study is currently ongoing and results are expected in mid-2014.

11

The predominant effect of cholesterol ester transfer protein (CETP)
inhibitors is to raise high density lipoprotein cholesterol (HDLC) but some
CETP inhibitors also lower LDLC. An ongoing study is evaluating the use of
anacetrapib in patients with HoFH. Other therapeutic approaches that are
being evaluated for HoFH include infusion of apolipoprotein A1 mimetic
peptides and mesenchymal stem cell transplantation.

References

1. Raal FJ, Santos RD. Homozygous familial hypercholesterolemia: Current perspectives on
diagnosis and treatment. Atherosclerosis. 2012;223(2):262-268.

2. Raal FJ, Pilcher GJ, Panz VR, et al. Reduction in mortality in subjects with homozygous
familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation.
2011;124(20):2202-2207.

3. Sjouke B, Kusters DM, Kindt I, et al. Homozygous autosomal dominant
hypercholesterolaemia in the netherlands: Prevalence, genotype-phenotype relationship, and
clinical outcome. Eur Heart J. First published online: February 28, 2014.

4. Mabuchi H, Nohara A, Noguchi T, et al. Molecular genetic epidemiology of homozygous
familial hypercholesterolemia in the hokuriku district of japan. Atherosclerosis.
2011;214(2):404-407.

5. Rader DJ, Kastelein JJ. Lomitapide and mipomersen: Two first-in-class drugs for reducing
low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia.
Circulation. 2014;129(9):1022-1032.

6. Gagne C, Gaudet D, Bruckert E, Ezetimibe Study Group. Efficacy and safety of ezetimibe
coadministered with atorvastatin or simvastatin in patients with homozygous familial
hypercholesterolemia. Circulation. 2002;105(21):2469-2475.

7. Thompson GR. The evidence-base for the efficacy of lipoprotein apheresis in combating
cardiovascular disease. Atheroscler Suppl. 2013;14(1):67-70.

8. Cuchel M, Bloedon LT, Szapary PO, et al. Inhibition of microsomal triglyceride transfer protein
in familial hypercholesterolemia. N Engl J Med. 2007;356(2):148-156.

9. Cuchel M, Meagher EA, du Toit Theron H, et al. Efficacy and safety of a
microsomal triglyceride transfer protein inhibitor in patients with homozygous familial
hypercholesterolaemia: A single-arm, open-label, phase 3 study. Lancet. 2013;381(9860):40-46.

10. Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor,
for lowering of LDL cholesterol concentrations in patients with homozygous familial
hypercholesterolaemia: A randomised, double-blind, placebo-controlled trial. Lancet.
2010;375(9719):998-1006.

11. Stein EA, Raal F. Reduction of low-density lipoprotein cholesterol by monoclonal antibody
inhibition of PCSK9. Annu Rev Med. 2014;65:417-431.

12. Stein EA, Honarpour N, Wasserman SM, Xu F, Scott R, Raal FJ. Effect of the proprotein
convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial
hypercholesterolemia. Circulation. 2013;128(19):2113-2120.

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Resources

Familial Hypercholesterolemia (FH) Foundation
1515 Hope Street, Suite 204
South Pasadena, CA 91030
Telephone: (626) 465-1234
E-mail: [email protected]
Web: www.thefhfoundation.org

The National Lipid Association
6816 Southpoint Parkway
Suite 1000
Jacksonville, FL 32216
Telephone: (904) 998-0854
Web: https://www.lipid.org/
www.lipid.org/nla/familial-hypercholesterolemia-screening-diagnosis-and-
management-pediatric-and-adult-patients

GeneReviews®
www.ncbi.nlm.nih.gov/books/NBK174884

National Organization for Rare Disorders (NORD)
PO Box 1968
55 Kenosia Avenue
Danbury, CT 06813-1968
Telephone: (203) 744-0100 or (800) 999-NORD
E-mail: [email protected]
Web: www.rarediseases.org

Clinical Centers and Medical Experts

View the FH Foundation’s list of medical advisors here:
www.thefhfoundation.org/about-us/scientific-advisory-board

13

Acknowledgements

NORD is grateful to the following medical expert for serving as author of
this Physician Guide:
Dr. Dirk Blom
Head of Division of Lipidology
University of Cape Town
5th Floor
Chris Barnard Building
UCT Health Sciences Faculty
Anzio Road
7925 Observatory
South Africa
This NORD Physician Guide was made possible by an educational grant
from Aegerion Pharmaceuticals.

14

NORD Guides for Physicians For information on rare disorders
and the voluntary health organi-
#1 The Pediatrician’s Guide to zations that help people affected
Tyrosinemia Type 1 by them, visit NORD’s web site at
www.rarediseases.org or call
#2 The Pediatrician’s Guide to Ornithine (800) 999-NORD or
Transcarbamylase Deficiency...and (203) 744-0100.
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#5 The Physician’s Guide to • Referrals to support groups and
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#7 The Physician’s Guide to Giant • Medication assistance programs
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other medical professionals
#11 The Physician’s Guide to
The Homocystinurias Contact NORD at
[email protected].
#12 The Physician’s Guide to National Organization for
Treacher Collins Syndrome Rare Disorders (NORD)
PO Box 1968
#13 The Physician’s Guide to Danbury, CT 06813-1968
Urea Cycle Disorders
Phone: (203) 744-0100
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Myelofibrosis Fax: (203) 798-2291

#15 The Physician’s Guide to This NORD Physician Guide
Lipodystrophy Disorders was made possible by an
educational grant from Aegerion
#16 The Physician’s Guide to Pharmaceuticals.
Pompe Disease

#17 The Physician’s Guide to
Gaucher Disease

#18 The Physician’s Guide to
Infantile Spasms

#19 Homozygous Familial
Hypercholesterolemia (HoFH)

These booklets are available free of charge. To obtain
copies, call or write to NORD or download the text from
www.NORDPhysicianGuides.org.

Patient Support NORD is grateful to the following
and Resources medical expert for serving as
author of this Physician Guide:
National Organization for
Rare Disorders (NORD) Dr. Dirk Blom
55 Kenosia Avenue Head of Division of Lipidology
PO Box 1968 University of Cape Town
Danbury, CT 06813-1968 5th Floor
Phone: (203) 744-0100 Chris Barnard Building
Toll free: (800) 999-NORD UCT Health Sciences Faculty
Fax: (203) 798-2291 Anzio Road
7925 Observatory
www.rarediseases.org South Africa
[email protected]
This NORD Physician Guide was made
possible by an educational grant from
Aegerion Pharmaceuticals.

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