Download Lysosomal Storage Diseases and Enzyme Replacement

VOLUME 29
C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M
Lysosomal Storage Diseases and Enzyme Replacement Therapy
Enzymes are proteins that play
critical roles in the body. Made
from amino acids, an enzyme is
a catalyst — it makes a specific
action happen in the body. There
are three categories of enzymes:
food enzymes, which are derived
from raw foods and initiate the
digestive process; digestive
enzymes, which digest food; and
metabolic enzymes, which catalyze
cellular function.
Each cell in the body requires
a specific enzyme to initiate a
chemical reaction that the cell needs
to work properly. Each enzyme
works on one specific chemical
reaction rapidly and efficiently.
Enzymes can generally be
recognized by their name; most are
named by adding “-ase” to the root
name of the molecule the enzyme
is acting upon. For example, lipase
catalyzes the breakdown of a lipid;
sucrase is the enzyme that starts the
process of breaking down sucrose
into the usable sugars glucose
and fructose. If an enzyme is either
missing or dysfunctional, whatever
function that enzyme was supposed
to initiate does not happen; thus,
the patient has a related disease.
Lysosomal storage diseases
(LSDs) are caused by problems with
lysosomal enzymes. Inside each
cell, lysosomal enzymes are held
within sacs (or organelles) called
lysosomes. Lysosomal enzymes
break down large molecules,
such as glycolipids and glycogen,
into functional units. When any
lysosomal enzyme is not functioning
properly, whatever substrate was
to be broken down accumulates
in the cells of various tissues and
organs, eventually leading to cellular
degeneration and progressive tissue
and organ dysfunction. Lysosomal
storage diseases (LSDs) are
characterized by the deficiency of a
lysosomal enzyme.
For patients with LSDs, successful
cellular function requires
replacement of the enzyme that is
not functioning properly. Intravenous
enzyme replacement therapy
(ERT) refers to the infusion of a
specific enzyme directly into a vein
to replace the patient’s missing,
deficient, or ineffective enzyme.
Mucopolysaccharidoses –
A Group of LSDs
One group of inherited LSDs is the
mucopolysaccharidoses (MPSs).
Lysosomal enzymes help digest
foods such as certain carbohydrates
and fats (lipids). In people with MPS
disorders, missing or malfunctioning
lysosomal enzymes cause an
accumulation throughout the body
of certain complex carbohydrates
known as mucopolysaccharides
or glycosaminoglycans, ultimately
resulting in damage.
The MPSs are inherited diseases,
some of which have prevalence
Figure 1. Inheritance Pattern for MPSs
Autosomal recessive
Carrier
father
Affected
child
Affected
Carrier
mother
Carrier
child
Carrier
child
Unaffected
child
Unaffected
Image source: http://kintalk.org/files/2012/07/recessive-inheritance.jpg
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Carrier
within certain ethnicities. Most are
autosomally recessive. (See Figure
1.) This means that two defective
genes are necessary to get the
disease, and therefore, a person
must have inherited the defective
gene from both parents. If a person
inherits a defective gene from one
or the other parent only, he or she is
a carrier (more commonly known as
a heterozygote).
Types of MPSs
More than 50 disorders in the MPS
category have been identified, and
while each individual disease is rare,
as a group they have an estimated
incidence of 1 in 6,500–7,700
live births.1 While there are some
similarities between the diseases,
there are also unique effects
depending on the specific enzyme
affected. And while the treatment
is the same in that the enzyme
needs to be replaced, the drug with
which it is replaced is unique to the
specific disease. See Table 1 for a
list of the MPSs for which ERT is
currently available.
Fabry Disease
Fabry disease is caused by a
lack or deficiency of the enzyme
alpha galactosidase A (a-GAL A).
A genetic mutation in the gene
that controls a-GAL A production
causes a poor breakdown of
lipids, leading to a harmful
accumulation of lipids in the
cardiovascular system, autonomic
nervous system, kidneys, and
eyes. This accumulation of
lipids— particularly one lipid called
globotriaosylceramide (GL-3)—
can lead to circulatory problems
and increase the risk of stroke or
heart attack.
Fabry is an x-linked recessive
disorder, which means that if a male
inherits a defective x gene, he will
have the disorder. If a female inherits
a defective x gene, she will be a
heterozygote. With most diseases,
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Table 1. Mucopolysaccharidoses Treated with ERT
Disease
Missing/Deficient Enzyme
Enzyme
Replacement
Therapy
Fabry disease
Alpha-galactosidase A — agalsidase beta
Fabrazyme®
Gaucher disease
Glucocerebrosidase — alglucerase
Ceredase®
Cerezyme®
VPRIV®
Hunter syndrome
Iduronate-2 sulfatase-idursulfase
Elaprase®
Hurler-Scheie syndromes
Alpha-iduronidase-laronidase
Aldurazyme®
Maroteaux-Lamy syndrome
Arylsulfatase B-galsulfase
Naglazyme®
Pompe disease
Alglucosidase alpha
Myozyme®
a heterozygote is unaffected by the
disorder and is symptom-free. This
is not always true in the case of
Fabry disease.
Symptoms of Fabry disease vary,
and are typically more significant
in males than females. They
may include episodes of pain in
the hands and feet, skin rash,
decreased ability to sweat, and
clouding of the corneas (does
not affect vision). Since the fat
accumulates gradually over years,
symptoms also develop over time.
After about age 30, patients may
also experience nausea, vomiting,
and diarrhea; cardiac problems
including heart failure, arrhythmias,
heart attack, and valvular disease;
central nervous system symptoms
such as stroke, headaches,
dizziness, and numbness and
tingling; gradual hearing loss
or ringing in the ear; and renal
dysfunction or failure. In fact, Fabry
disease is often first diagnosed
when the patient presents with renal
insufficiency.
Treatment of Fabry disease
includes the replacement of the
missing a-GAL A enzyme with
the recombinant (man-made)
preparation agalsidase beta
(Fabrazyme). Fabrazyme is dosed
at 1 mg/kg IV every two weeks
over four to five hours. The infusion
rate can be increased as tolerated.
Infusion reactions can happen, and
pre-treatment with an antipyretic
and an antihistamine is common.
C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M The life expectancy of patients
with Fabry disease is often 20
years less than normal in men, and
15 years less in women. Death is
often secondary to renal failure or
a cardiac or cerebrovascular event,
and typically occurs in the late fifties
or sixties.2
Gaucher Disease
Gaucher (pronounced “go-SHAY”)
disease is the most common of the
MPSs. People with Gaucher disease
do not have enough of the enzyme
glucocerebrosidase, which helps the
body break down glucocerebroside,
a type of fat molecule. As a result,
glucocerebroside is not broken
down or digested, and dangerous
levels of undigested fat build up
in the patient’s spleen, liver, bone
marrow, and sometimes the brain,
resulting in a number of potential
symptoms.
As described in Table 2 below, there
are three types of Gaucher disease,
with key differences between the
types. It is important to recognize,
too, that the signs and symptoms
vary between individuals, even with
the same type of disease.
There is currently no available
treatment for type 2 Gaucher
disease. Patients with type I disease
who present with mild symptoms
may not require treatment. However,
for symptomatic patients with
type 1 or type 3 Gaucher disease,
replacement of the missing enzyme
(glucocerebrosidase) is the standard
VOLUME 29
of care. The three current ERT drugs
for Gaucher disease are:
yy Alglucerase – injection
(Ceredase®)
yy Imiglucerase (Cerezyme®)
yy Velaglucerase alfa (VPRIV®)
ERT is administered intravenously
every two weeks, over one to
two hours. ERT can alleviate
and, in some cases, even reverse
the effects of Gaucher disease.
With ERT, there is a risk of
hypersensitivity reaction, and
premedication is common. Patients
also have the potential to develop
Ig (immunoglobulin) antibodies,
usually within the first six months of
therapy. This results in the need for
intermittent monitoring throughout
the first year.
In addition to ERT, there are two
available oral medications for the
treatment of Gaucher disease.
Miglustate (Zavesca®) may be
indicated for the treatment of adult
patients with mild to moderate
type 1 Gaucher disease for whom
ERT is not a therapeutic option
(for instance, because of allergy,
hypersensitivity, or poor venous
access). As opposed to ERT, which
replaces the missing enzyme,
miglustate functions as substrate
reduction therapy, reducing the
production of fatty substances.
One important potential adverse
effect is the development of
peripheral neuropathy. Neurological
evaluations at baseline and every six
months are recommended.
Eliglustat (Cerdelga®) is another
oral agent. Similar to miglustate,
Eliglustat — a glucosylceramide
synthase inhibitor — reduces
production of the lipid
glucosylceramide. Thus,
there is less to accumulate.
Hunter Syndrome
The normal function of the enzyme
iduronate-2-sulfatase is to cause
lysosomes to break down complex
sugars called glycosaminoglycans.
The body requires these sugars
to build structures such as bone,
cartilage, tendons, corneas,
skin, and connective tissue, and
to lubricate joints. With Hunter
syndrome, the enzyme does
not work properly. Undigested
glycosaminoglycans collect in
the cells, blood, and connective
tissues, leading to progressive and
permanent damage.
There are two distinct forms
of Hunter syndrome — early
onset and late onset. Early onset
disease presents with severe
symptoms, and physical and mental
development peaks at two to four
years of age. Symptoms of late
onset disease are milder, typically
presenting after age 10 and often
not until adulthood.
Symptoms for both types of Hunter
syndrome vary in terms of both
incidence and severity. For early
onset disease, symptoms can
include:
yy Delayed development
and short stature
Table 2. Symptoms of the Three Types of Gaucher Disease
Type
1
Incidence /Age of
Onset
yy Most common
type (~90%) /Can
appear at any age,
average around
age 30
Possible Symptoms
yy Easy bruising
yy Nose bleeds
yy Fatigue
yy Enlarged liver and spleen
yy Skeletal abnormalities (bone thinning, pain, fractures)
Primary
Treatment
Complications / Prognosis
yy In mild cases,
may require no
treatment
yy Bleeding disorders
yy Enzyme
replacement
therapy
yy Bone pain
yy Increased risk of certain cancers, such as
multiple myeloma
yy Near-normal life expectancy
yy Lung and kidney injury
yy Delayed puberty
yy Yellow spots in eyes (pingueculae)
yy No brain involvement
2
yy Rare/Appears in
infancy
yy Liver and spleen enlargement
by three months of age
yy None available
yy Bone pain
yy Bleeding disorders
yy Widespread and rapidly progressive brain damage
yy Increased risk of certain cancers, such as
multiple myeloma
yy Cognitive deterioration (such as mental retardations,
dementia)
yy Seizures
yy Rigidity
yy Abnormal gait
yy Seizures
yy Swallowing difficulties
yy Death by age two years
3
yy Rare/Appears in
childhood, early
teens
yy Chronic, more slowly progressive
yy Liver and spleen enlargement
yy Milder, gradually progressive brain involvement
yy Enzyme
replacement
therapy
yy Bone pain
yy Bleeding disorders
yy Skeletal abnormalities
yy Increased risk of certain cancers, such as
multiple myeloma
yy Cognitive deterioration
yy Heart valve calcifications
yy Abnormal eye movement disorders
yy If survival to the teens, numerous additional
years likely
yy Loss of muscle coordination
yy Blood disorders
VOLUME 29 C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M | 3
yy Intellectual disability
yy Aggressive behavior
yy Changing facial features such
as thickening of the lips, tongue,
and nostrils, broadening of the
nose, protrusion of the tongue
yy Skeletal abnormalities such as
claw-like hands, abnormal bone
size or shape, joint stiffness
yy Spasticity
yy Carpal tunnel syndrome
yy Enlarged liver and spleen
yy Sleep apnea
yy High blood pressure
yy Visual changes
yy Progressive hearing loss
In late onset disease, symptoms
may include varying degrees of:
yy Abnormal bone size or shape
and other skeletal irregularities,
but less severe than in early
onset
yy Shorter stature, but to
a lesser degree than in
early onset
yy Poor peripheral vision
yy Joint stiffness
yy Hearing loss
yy Carpal tunnel syndrome
yy Sleep apnea
Enzyme replacement for
Hunter syndrome is done using
iduronate-2 sulfatase-idursulfase
(Elaprase), administered weekly
by IV over about three hours. The
infusion time may be gradually
decreased if the patient remains
free of signs of hypersensitivity.
It may also need to be longer
depending on patient tolerance,
but cannot exceed eight hours.
This therapy comes with a black
box warning for risk of anaphylaxis,
as life-threatening anaphylactic
reactions have been observed.
About 50% of patients develop
anti-idursulfase IgG antibodies,
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which increase the risk of infusionrelated reactions.
expectancy with Sheie syndrome is
close to normal.
Hurler-Scheie Syndromes
Treatment for all three syndromes
is recombinant alpha-iduronidaselaronidase (Aldurazyme) ERT
and is aimed at slowing disease
progression. Weekly infusions
typically require premedication, and
monitoring is required.
The Hurler-Scheie (pronounced
“shay”) syndromes are three
variations of another MPS. In
order of severity, they are Hurler
syndrome, Hurler-Sheie syndrome,
and Sheie syndrome. The genetic
abnormality in this set of diseases
causes a deficiency of the
alpha-L-iduronidase enzyme.
Patients with these diseases present
with varying degrees of many of
the same symptoms described for
Hunter syndrome. In the severe
form, symptoms include short
stature and coarse facial features
such as a broad flat nose, flat face,
long head with a bulging forehead,
thick lips, an enlarged tongue,
and poorly formed, widely spaced
teeth. Noisy breathing, chronic
runny nose, and ear infections are
common due to the flattened nose
and thickened soft tissues in the
nasal passages. Weakening of the
heart muscle and valves commonly
leads to heart disease.
Hydrocephalus commonly presents,
and corneal clouding may develop.
Importantly, with Hurler syndrome,
progressive mental retardation
occurs, with peak intelligence
achieved at about age two, after
which there is a progressive
regression of skills until death.
Patients rarely live beyond 10 years.
Patients with Hurler-Scheie typically
present with normal intelligence
but also have progressive physical
involvement, short stature, and
a significantly decreased life
expectancy.
Patients with Scheie syndrome
typically have normal intelligence,
stature, and life expectancy, but
other physical symptoms occur,
such as stiff joints and corneal
clouding. These symptoms usually
start after five years of age. Life
C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M Maroteaux-Lamy Syndrome
Maroteaux-Lamy syndrome, also
known as mucopolysaccharidosis
type VI or MPS VI, is characterized
by complete or partial lack
of activity of the enzyme
arylsulfatase B (also called
N-acetylgalactosamine-4-sulfatase).
This causes the accumulation of
complex carbohydrates called
glycosaminoglycans.
The symptoms and severity of
Maroteaux-Lamy syndrome can
vary dramatically from one person
to another, and range from mild
to severe and life-threatening.
Symptoms are progressive and
can include coarse facial features;
impaired bone formation and
growth; dwarfism; enlarged tongue
and thick lips; corneal clouding,
which, if severe enough, can impair
vision; hearing loss; an abnormally
enlarged liver and/or spleen; cardiac
disease; and restrictive pulmonary
disease. Symptoms usually begin
around age two to three years.
Intelligence is usually not affected.
Treatment for Maroteaux-Lamy
syndrome is weekly infusions, over
four hours, of the ERT galsulfase
(Naglazyme). Pre-medication is
usually required. Sleep apnea is not
an uncommon adverse effect, and
requires monitoring.
Pompe Disease
Pompe disease results from a
defective gene that causes a
deficiency of the enzyme acid
alpha-glucosidase (GAA). Glycogen,
a form of sugar that is stored in the
VOLUME 29
muscle cells, builds up in the body.
As excess glycogen accumulates, it
interferes with normal cell function
and causes continuous damage
to cells, resulting in worsening
muscle weakness that can affect
movement, breathing, and in infants,
heart function.
Pompe disease affects people
of all ages, from infancy through
adulthood, although there are two
forms of the disease with distinct
differences. With infantile onset,
patients have a complete GAA
deficiency, and the primary site of
glycogen accumulation is in the
heart muscle. With adult-onset
Pompe disease, GAA activity is
between 1% and 40% of normal
levels, with glycogen accumulation
occurring primarily in the skeletal
and respiratory muscles.
Patients with infantile onset may
present with:
yy Cardiac hypertrophy
yy Severe muscle weakness
»» Floppiness due to loss
of muscle tone
»» Head lag
yy Respiratory difficulties
yy Enlarged liver and tongue
yy Feeding problems
yy Cardiac failure
yy Frequent pulmonary infections
yy Failure to meet motor milestones
yy Poor weight gain and failure
to thrive
Patients with adult onset disease
may present with:
yy Progressive muscle weakness
»» Trunk and proximal
lower limbs
yy Delayed motor milestones and
progressive loss
yy Gait abnormalities; difficulty
walking or climbing stairs;
frequent falls; arthralgia
VOLUME 29 yy Lordosis, kyphosis, or scoliosis
yy Respiratory difficulties; exertional
dyspnea
yy Morning headache and daytime
sleepiness
yy Nocturnal hypoventilation
yy Poor weight gain and
maintenance
yy Eventual loss of ambulation
and mechanical ventilation, and
premature death
Pompe disease is treated with
the enzyme alglucosidase alfa
(Myozyme). Myozyme infusion is
typically given via one dose every
two weeks. It is administered
over about four hours, depending
on how the patient tolerates the
infusion. This agent also has a black
box warning for life-threatening
anaphylactic reaction. Severe
allergic and immune-mediated
reactions have been observed. In
addition, patients with compromised
cardiac or respiratory function
may be at risk for serious acute
exacerbation of this compromised
function due to infusion reactions,
and require additional monitoring.
Enzyme Replacement
Therapy Administration
While not a cure for LSDs, ERT can
impact both symptoms and disease
progression. Most disease-related
complications of LSDs cannot be
reversed by ERT, so early diagnosis
and treatment is critical in order to
prevent their development.
Patients who require ERT need
lifetime treatment. ERT is given
by IV through either a peripheral
line or a central line. Most patients
require an infusion every two weeks,
although patients with Hunter or the
Hurler-Scheie syndromes typically
require weekly infusions. Treatment
is usually infused over two to six
hours, depending on the specific
therapy, the patient’s weight, and
whether or not the patient has or
has had a reaction to the infusion.
Since patients often develop
antibodies to their ERT, there is
potential for infusion reactions,
including anaphylaxis. Most of
the time, infusion reactions can
be managed by decreasing the
rate of the infusion, as well as
providing an anti-fever medication
and an antihistamine prior to the
infusion. This treatment is called
pre-medication, and it is usually
required. Because there are no other
medications to treat these diseases,
the risk of infusion reaction is
cautiously accepted.
Infusions are often given in a
controlled setting, such as an
outpatient clinic or ambulatory
infusion suite. After a period of
infusions without infusion-related
reactions, some patients may
be able to infuse in their homes.
However, due to the therapyspecific complexity and potential
adverse effect profile, the majority
of ERTs require a nursing presence
for the entire length of drug
administration.
Other Treatment
Options
Blood cell transplantation (bone
marrow or umbilical cord) may be
an option, with or without ERT,
especially when performed early in
the course of disease.3
In addition to the ERT available for
the above-mentioned diseases,
enzyme replacement options
continue to be developed for other
enzyme disorders as well. Route
of administration is also being
evaluated, with particular focus
on intrathecal enzyme delivery.
Current therapy has limited impact
on improving central nervous
system manifestations related to
the neuronopathic forms of the
diseases.t
*Do not use the information in this article
to diagnose or treat a health problem or
disease without consulting a qualified
physician. Patients should consult their
C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M | 5
physician before starting any course
of treatment or supplementation,
particularly if they are currently under
medical care, and should never
disregard medical advice or delay in
seeking it because of something set
forth in this publication.
References
1. American Society of Gene and Cell Therapy.
www.asgct.org/general-public/educationalresources/gene-therapy-and-cell-therapyfor-diseases/lysosomal-storage-diseases.
Accessed March 19, 2015.
2. Golfomitsos C, Sengupta A, Prasad U, Gray S.
Fabry disease. Br J Cardiol. 2012;19(1):41-45.
3. Martino S. Therapy for lysosomal storage
disorders: a matter for stem cells. Int J Stem
Cell Res Transplant. 2015;3(1e) 1-2.
Bibliography
• Alroy J, Lyons JA. Lysosomal storage
diseases. Jl Inborn Errors Metab
& Screening. March 28, 2014.
doi:10.1177/2326409813517663. http://iem.
sagepub.com/content/2/2326409813517663.
full. Accessed June 10, 2015.
•Fong CT. Lysosomal storage disorders.
www.merckmanuals.com/professional/
pediatrics/inherited-disorders-of-metabolism/
lysosomal-storage-disorders. Updated February
2010. Accessed June 10, 2015.
•Kruer MC. Lysosomal storage disease.
Medscape reference. http://emedicine.
medscape.com/article/1182830. Updated
October 18, 2013. Accessed June 10, 2015.
•Nagueh SF. Contemporary reviews in
cardiovascular medicine: Anderson-Fabry
disease and other lysosomal storage disorders.
Circulation. 2014; 130:1081-1090.
•Ortolano S, Vieitez I, Navarro C, Spuch C.
Treatment of lysosomal storage diseases:
recent patents and future strategies. Recent
Pat Endocr Metab Immune Drug Discov.
2014;8(1):9-25.
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C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M VOLUME 29
Self-Assessment Quiz: Lysosomal Storage Diseases and Enzyme
Replacement Therapy
LEARNING GOAL
LEARNING OBJECTIVES
To gain knowledge of lysosomal
storage diseases, including signs,
symptoms, and outcomes, as well
as therapy considerations, with
a focus on enzyme replacement
therapies.
At the end of this program, the reader will be able to:
1. Identify the primary role of enzymes.
2. Describe the impact of missing or ineffective enzymes.
3. Identify and discuss enzyme replacement therapies for lysosomal storage
diseases.
SELF-ASSESSMENT QUESTIONS
In the Quiz Answers section on the next page, circle the correct answer for each question. To obtain two (2.0)
contact hours toward CE credit, the passing score is 100%. Return your Self-Assesment Quiz to Coram via email,
fax or mail. See the next page for details on how to return to your quiz. Please allow approximately seven days to
process your test and receive your certificate upon achieving a passing score.
1. Enzymes are essential catalysts for specific
activities in the body.
a.True
b.False
2. More than __ disorders in the MPS category have
been identified so far, with treatments available for
only a few.
a.20
b.40
c.50
3. Lysosomal storage disorders are:
a.Inherited via an autosomal dominant pathway.
b.Inherited via an autosomal recessive pathway.
c.Neither A nor B.
4. In people with MPS disorders, missing or
malfunctioning lysosomal enzymes cause:
a.An accumulation of certain complex
carbohydrates.
b.A deficiency of certain complex carbohydrates.
c.A and B.
5. Each lysosomal storage disorder requires its own
specific enzyme replacement therapy.
a.True
b.False
VOLUME 29 6. Unlike most carriers of inherited diseases,
a carrier of Fabry disease:
a.Will remain free of symptoms of the disease.
b.May present with symptoms of the disease.
7. Enzyme replacement therapy (ERT) is primarily
administered to:
a.Replace the missing or deficient enzyme.
b.Cure the disease.
c.Reverse most complications of disease.
d.A and C.
e.B and C.
8. ERT is administered:
a.Intravenously for a lifetime.
b.Orally for a lifetime.
c.A or B.
9. Patients often develop antibodies to their ERT,
creating potential for infusion reactions, including
anaphylaxis.
a.True
b.False
10.Infusion reactions can often be managed by:
a.Decreasing the rate of the infusion.
b.Pre-medicating with an antipyretic and
an antihistamine.
c.A and B.
C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M | 7
VOLUME 29
C O R A M ’ S C O N T I N U I N G E D U C AT I O N P R O G R A M
Lysosomal Storage Diseases and Enzyme Replacement Therapy
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