EVIDENCE
REVIEW: POMPE DISEASE
On this page:
I. Overview
II. Rationale for
Review
III. Objectives
of Review
IV. Main Questions
V. Decision Model
and Development of Evidence Question/Outcome
Table
VI. Methods
VII. Results
VIII. Summary
IX. References
X. Appendix
I. OVERVIEW:
Pompe disease (OMIM #232300) is a lysosomal
storage disease caused by mutations in
the glucosidase alpha acid (GAA) gene
located on the long arm of chromosome
17q25.2-q25.3 and inherited in a classic
autosomal recessive manner. This genetic
mutation causes deficient acid alpha-glucosidase
enzyme activity ( Engel et al. 1973, Hirschhorn
1995, Raben, Plotz & Byrne 2002) which
is required for the degradation of some
cellular glycogen. As a result, glycogen
cannot effectively be removed from various
organ systems such as muscle, heart, and
lungs. Accumulation of glycogen in these
tissues results in progressive damage
and often life-threatening symptoms. Pompe
disease is also referred to as acid maltase
deficiency (AMD) and glycogen storage
disease type II (GSD-II).
Pompe and Putschar first described Pompe
disease in infants in 1932; Engel and
Dale subsequently described later-onset
disease. At present, the spectrum of this
disorder is generally divided into infantile-onset
and late-onset (Slonim et al. 2000, Kishnani
et al. 2006, Muller-Felber et al. 2007).
Infantile-onset can be further subdivided
into classic infantile-onset and non-classic
infantile-onset disease. Although non-classic
disease is associated with slightly longer
survival than classic disease, those with
untreated infantile Pompe disease die
by the third year of life after an illness
characterized by severe weakness, respiratory
insufficiency often requiring ventatitory
support, and cardiomyopathy.
There are over 200 known mutations of
the GAA gene, some of which are associated
with specific phenotypes of Pompe disease.
For example, a specific splicing mutation
(Huie et al. 1994) is associated with
late-onset disease and several different
mutations (e.g., nonsense, insertion/deletion,
splice mutations) are associated with
infantile-onset disease.(Kroos et al.
2008).
Case Definition
It is necessary to have a clear and explicit
case definition in order to evaluate any
condition. We have developed the following
case definition for infantile-onset Pompe
disease in children < 1 month of age.
For this report we did not develop a case
definition for late-onset Pompe disease
This case definition requires both laboratory
and clinical confirmation.
A. Laboratory Confirmation:
Either confirmed low enzyme activity
or genotypic confirmation, as described
below:
- Confirmed Low Enzyme Activity.
Low GAA from newborn screening
must be noted in a repeat specimen testing.
The following tissue testing may be used
for diagnosis:
- Cultured skin fibroblast enzyme
assay.
Complete deficiency (activity <1%
of normal controls) of GAA enzyme activity
is associated with classic infantile-onset
Pompe disease. Non-classic infantile cases
have levels of <2% of normal controls
(Kishnani et al. 2006). Adult (late-onset)
cases are variable but generally <
8% activity. (Reuser et al. 1978, Beratis,
Wilbur & Sklower 1983, McVie-Wylie
et al. 2008)
- Muscle enzyme activity.
Muscle biopsy is not usually part of
diagnosis because of the risk of the procedure
to infants. Secondarily, muscle biopsies
can be falsely normal in 20-30% of patient
biopsy specimens (Laforet et al. 2000,
Winkel et al. 2005).
- Peripheral blood lymphocytes or
mononuclear cell enzyme activity.
Leukocytes have been used to measure
GAA enzyme activity but alternate isoenzymes
such as maltase-glucoamylase may interfere
with the assay (Jack et al. 2006) Infantile-onset
disease will be <8 nmole/mg/protein
or <10% of the upper limit of normal.
- Whole blood enzyme assay.
GAA levels in Pompe disease can range
from 0.59 - 3.88 pmol/punch/hour in dried
blood spots.(Chamoles et al. 2004, Zhang
et al. 2006).
- Genotypic Confirmation.
In order for a patient to have confirmation
of Pompe disease by molecular genetic
diagnostics, two deleterious, disease
causing mutations (not a polymorphic variant)
must be present in trans; meaning
one mutation on each allele.(Pittis et
al. 2008). There is a fair amount of
genotype-phenotype variation.
There are other laboratory results that
are suggestive, but not diagnostic, of
Pompe disease, including creatine kinase
concentration,(Laforet et al. 2000, Kishnani
et al. 2006) and urine Hex4/oligosaccharides.
(An et al. 2005, Kallwass et al. 2007).
B. Clinical Confirmation:
- Cardiac Disease
Cardiac involvement is a hallmark of
classic infantile-onset Pompe disease,
but may not be present in non-classic
infantile-onset disease. Cardiomegaly
may be demonstrable in utero
or later.
Cardiac disease includes:
- Cardiomegaly or cardiomyopathy
- Left ventricular hypertrophy or EKG
changes (Kishnani et al. 2006)
- Elevated Plasma BNP (B-type natriuretic
peptide) (Soker, Kervancioglu 2005)
- Hypotonia
Hypotonia is variable and difficult to
assess in the first month of life.
II. RATIONALE
FOR REVIEW
The Advisory Committee (AC) directed the
Evidence Review Workgroup (ERW) to produce
this report for the nominated condition
of Pompe Disease. Pompe disease has been
nominated because of the following reasons:
- Newborn screening to identify Pompe
disease is possible by measuring GAA
enzyme activity in dried blood spots
by a variety of methods, including immunofluorescence
(Kallwass et al. 2007, Chien et al.
2008) and tandem mass spectrometry (MS/MS).(Gelb
et al. 2006, Meikle et al. 2006, Dajnoki
et al. 2008b)
- A large population-based pilot study
of newborn screening has recently been
completed in Taiwan (Chien et al. 2008).
- Studies have been published regarding
the effectiveness of enzyme replacement
therapy treatment for infantile-onset
Pompe disease with alglucosidase alfa
(rhGAA) (Kishnani et al. 2006, Kishnani
et al. 2007).
III. OBJECTIVES
OF REVIEW
This report updates a previously conducted
systematic review commissioned by the
Health Resources and Services Administration
for use by the Advisory Committee regarding
the potential benefits and harms of screening
for Pompe disease (Kemper et al. 2007).
The objectives of the current review are
to add more recent evidence to complement
the earlier review, with a focus on questions
of particular relevance to the AC. The
earlier review had several limitations:
- The impact of detecting late-onset
Pompe Disease in newborns was not considered.
- No peer-reviewed pilot screening data
were available.
- No cost-effectiveness analyses were
identified.
- Unpublished data were not systematically
sought for inclusion.
Thus, this review summarizes the earlier
review, provides greater in-depth information
about more recent published evidence,
and provides information from unpublished
data.
IV.
MAIN QUESTIONS
We sought to answer four over-arching
and critical questions arising from the
AC and nominating subcommittee to inform
recommendations concerning newborn screening
for Pompe disease:
- Do current screening tests effectively
and efficiently identify cases of Pompe
disease that may benefit from early
identification?
- Does intervention in newborns identified
by screening compared to those identified
clinically lead to improved health outcomes?
- What is the cost-effectiveness of
newborn screening for Pompe disease?
- What critical information is missing
that is needed to inform screening recommendations
for Pompe disease?
In the context of addressing these over-arching
questions, we also considered the following
specific questions:
- What is the natural history of Pompe
disease?
- What is the prevalence of Pompe disease?
- What are the methods of screening
and diagnosis?
- How accurate are the screening tests?
- What are the benefits of treatment?
- What is the relationship between treatment
outcomes and the timing of treatment
intervention?
- What are the potential harms of screening,
diagnosis, and treatment?
V.
DECISION MODEL AND DEVELOPMENT OF EVIDENCE
QUESTION/OUTCOME TABLE
In preparing this review, we separated
infantile-onset Pompe disease from late-onset
Pompe disease wherever possible. We only
considered screening test accuracy in
newborns and the effectiveness of treatment
begun in early childhood (i.e., by 2 years
of age). As described below, evidence
was gathered from a variety of sources.
However, the evidence table only summarizes
peer-reviewed published studies.
Figure 1. Conceptual Framework.
The conceptual framework illustrates
the salient factors in considering newborn
screening for Pompe disease addressed
by this review. Newborns can either
be screened or not screened. Those who
are screened may suffer adverse events,
including false positive or false negative
screens. Regardless of screening, individuals
may develop infantile- or late-onset Pompe
disease. Treatment, which impacts health
outcomes, may begin earlier for those
who are identified through screening.
Those who receive treatment may have associated
adverse effects.
VI. METHODS
For this report, we conducted a systematic
evidence review which updated the original
systematic review prepared for the use
of the AC. As in the original review,
we searched Medline for all studies published
in English from 1966 (the start of MEDLINE)
through July 2008 (updating the original
review by two years). Medline searches
were conducted using the National Library
of Medicine Medical Subject Headings term
“glycogen storage disease type II” and
the keywords “Pompe disease” and “Pompe’s
disease.” To ensure completeness of the
literature search, we reviewed reference
lists and the nomination form submitted
to the AC. We excluded research that
did not include human subjects, but did
consider all other study designs including
case reports, case series, and uncontrolled
intervention trials.
One author (ARK) abstracted the data
from articles to address the key questions
regarding the natural history and burden
of suffering related to Pompe disease,
methods for screening and diagnosis, effectiveness
of treatment, and accuracy of screening.
Due to the variations in study design
and the small sample size of most studies,
no quality score was assigned to the articles.
However, details regarding the study design,
study population, and sample size were
abstracted, and we report limitations
regarding specific studies in this review.
Articles that were included in the original
review were re-evaluated as part of this
update, and we report here the findings
from both the original review and the
update.
In addition to the systematic reviews
of published literature, one author (MFB)
interviewed subject matter experts to
identify unpublished data related to screening
methods, including MS/MS-based assays
and fluorescence-based assays, and the
effectiveness of treatment.
Subject matter expert were identified
by review of the scientific literature,
recommendation of the AC, and knowledge
of the ERW. Experts were asked to provide
primary data regarding in order for independent
evaluation (conducted by MFB). In order
to participate in this process, each investigator
submitted a standardized conflict of interest
form. The experts who contributed to
this review include:
- Deeksha Bali, PhD; Laboratory Director,
Duke University Glycogen Storage Disease
Lab, Durham NC.
- Olaf Bodamer, MD FACMG; Newborn
Screening Program, Division of Biochemical
Genetics, University Children's Hospital,
Vienna, Austria.
- Paul Wuh-Liang Hwu, MD; Taiwan Newborn
Screening Program, Department of Pediatrics
and Medical Genetics, National Taiwan
University Hospital.
- Joan Keutzer, PhD; Vice-President
of Scientific Affairs; Genzyme Corporation,
Cambridge, MA.
- Priya Kishnani, MD; Division Chief,
Medical Genetics, Duke University,
Durham, NC.
- Deborah Marsden, MBBS; Metabolism
Laboratory Director; Children’s Hospital
Boston; Director, Global Medical Affairs
–Myozyme, Genzyme Corporation, Cambridge
MA.
- Alfred E. Slonim MD, Clinical Professor
of Pediatrics. Division of Molecular
Biology. Columbia University Medical
College, New York.
We include findings arising from data
to which we were given complete access.
To help identify such data we began by
asking the experts the following questions:
Table 1. INITIAL EXPERT
SURVEY:
I. Screening.
- Have you developed a screening protocol?
If so, please describe your screening
protocol, including:
- What is your first tier test (e.g.,
fluorometry, mass spectrometry)?
- What, if anything, is your second
tier test (i.e., testing on the same
screening sample if the first tier
test is abnormal)?
- What subsequent testing do you perform
on a new sample from an individual
with an abnormal first tier/second
tier test (i.e., third tier testing)?
- What are the advantages and disadvantages
of your screening protocol?
- If your screening protocol has been
implemented, please describe your experience,
including:
- When screening began
- The number of children who have
been screened
- The total number of children that
had a positive screening test that
required a diagnostic evaluation
- The number of cases identified.
If possible, please characterize the
phenotype of these cases (e.g., classic
infantile, late-onset).
- The cost of screening. Because
costs can be determined in many different
ways, please outline what is included
in your calculation.
II. Diagnosis
- Do you have any data regarding the
distribution of the different phenotypes
of Pompe disease?
- At the time of initial diagnosis,
how do you predict the phenotype, especially
if the child was identified through
screening?
III. Treatment
- What is your treatment protocol for
presymptomatic late-onset Pompe disease
either diagnosed clinically or through
newborn screening?
- What are the major challenges to the
treating infantile Pompe disease?
- What unique outcomes data for the
treatment of Pompe disease, regardless
of phenotype, can you provide?
IV. Other Information
- Is there anything else about Pompe
disease that you would like to share
with us?
- Do you have any recommendations about
changing this form to make it easier
for others to use?
These surveys were reviewed by one member
of the ERW (MFB). Follow up telephone
interviews were conducted for additional
information.
VII. RESULTS:
Within this section we present results
from the systematic literature review
followed by information arising from data
obtained from the key experts. Tables
are provided within selected sections
highlighting important studies or evidence
obtained from the experts.
Overall, our literature search identified
717 articles. All abstracts were reviewed,
from which 26 were selected for inclusion
for this review (see Evidence Table) because
they met all inclusion criteria and directly
addressed one or more of the key questions.
Among these articles, four (Meikle et
al. 2006, Chien et al. 2008, Dajnoki et
al. 2008b, Kroos et al. 2008) were published
after the original systematic review and
four (Ausems et al. 1999a, Winkel et al.
2004, Hagemans et al. 2005, Winkel et
al. 2005) were not included in the initial
review because they addressed only late-onset
Pompe disease.
A. Natural History, including
Phenotype Variations
Pompe disease is divided into infantile
(classic or nonclassic) and late-onset
disease. The differences between these
conditions are described below.
1. Infantile-onset Pompe Disease
Systematic Review Findings
Symptoms typically develop around two
months of age and diagnosis is made by
five months of age. Patients with infantile-onset
Pompe disease generally exhibit poor feeding
and failure to thrive, gross motor delay
with muscle weakness, early respiratory
insufficiency, and significant cardiac
issues with the most severe concern being
cardiomyopathy. (van den Hout et al. 2003,
Kishnani et al. 2006). Without treatment,
the median age of death is nine months
due to cardiac dysfunction. (Kishnani
et al. 2006) Fewer than 10% survive past
24 months of age. (Kishnani et al. 2006)
Some with infantile-onset Pompe disease
may have longer survival. (Slonim et al.
2000) Those individuals
who develop symptoms in infancy, but who
survive longer, are considered to have
non-classic infantile-onset Pompe disease.
Newborn screening methods distinguish
classical from non-classic infantile onset
disease.
Table 2. Characterization of
Disease.
Study |
Design |
Subjects |
Comments |
Kishnani, 2006 |
Case
Series |
168
patients from Israel, Taiwan, North
America, or Europe with Pompe disease
who were diagnosed by 12 months
of age and who did not receive enzyme
replacement therapy. 45% were born
before 1995. |
Possible
selection bias – cohort was assembled
based on questionnaires sent to
physicians. This is the largest
natural history study. |
Slonim, 2000 |
Case
Series |
7 infants
referred to one US center and 15
infants for whom their pediatricians
consulted the center, all with non-classic
infantile-onset Pompe disease (later
age of onset: 4.8 + 2.9 months,
no cardiomegaly before 12 months
of age, traces of residual GAA activity
(<0.5%)). None were treated
with enzyme replacement therapy.
3/12 died (11 months, 13 months,
and 32 months), with the remainder
surviving past 2-years with gastrostomy
and tracheostomy. |
This
study has a small sample size and
is subject to selection bias. The
authors compared results to classic
infantile-onset cases. The methods
of case ascertainment do not allow
determination of the proportion
of classic vs. non-classic infantile-onset
Pompe disease. |
Van den Hout, 2003 |
Case
Series |
20 infantile-onset
cases diagnosed in Dutch centers
and 133 infantile-onset cases from
the literature. The 20 cases were
identified from 1980-1998. |
Methods
of assembly of the cases from the
literature are unclear. According
to the authors, much of the data
on the 20 infantile cases were incomplete. |
2. Late-onset Pompe Disease
Systematic Review Findings
Unlike with infantile-onset Pompe disease,
cardiomegaly is not typically present.
Late-onset Pompe disease is characterized
by muscle weakness and respiratory insufficiency.
A review of published case reports found
a wide range of death (median 25 years,
range 0.9-66 years), primarily due to
respiratory failure. (Winkel et al. 2005)
We could not directly determine the duration
of symptoms prior to diagnosis or death
from this review. However, the authors
state that “The deceased patients had
experienced their first symptoms significantly
earlier (at the age of 7, range 0-60 years
vs. 24 years…) and were significantly
younger at the time of diagnosis (24 years,
range 0.7-65 vs. 33 years…) than the patients
who were still alive at the time of description".
(Winkel et al. 2005) A study of a convenience
sample of individuals with late-onset
Pompe disease from a registry found that
the mean age of symptom development was
quite variable (28 + 14 years)
with an average age of diagnosis of 37+
13 years. (Hagemans et al. 2005) A separate
study of a convenience sample of individuals
with late-onset Pompe disease identified
through a registry reported that the odds
for wheelchair use increased by 13% for
each year that an individual has the disease.
Similarly, the odds of requiring respiratory
support increased 8% for each year. (Hagemans
et al. 2005)
Late-onset Pompe disease is highly variable
in both presentation and progression.
Natural history studies based on convenience
samples may be biased towards more significant
disease. For example, individuals with
slowly progressive or mild disease may
not be appropriately diagnosed; therefore,
such subjects would not be included in
studies. No studies were found that describe
the natural history of people with late-onset
disease detected through newborn screening
or prior to the development of symptoms,
and such individuals could have lower
severity disease than those identified
by symptoms at a later age.
- Prevalence of Pompe Disease
There are different ways to calculate
prevalence:
- Classical prevalence reporting:
This
is the number of cases of the condition
within the population at a particular
time or within a particular time period
divided by the population size. Classical
prevalence across an entire population
may underestimate the burden of infantile-onset
Pompe disease vs. late-onset Pompe
disease because those with infantile-onset
Pompe disease may not survive past
infancy
- Birth prevalence reporting: The
birth prevalence is a special case
of classical prevalence reporting.
It is the number of cases compared
to the total number of births over
a defined period of time. Birth prevalence
may better represent the burden of
infantile-onset Pompe disease assuming
that case ascertainment is effective.
- Estimated gene frequency with extrapolation
to the population burden of the condition:
The expected frequency of individuals
affected with an autosomal recessive
condition such as Pompe disease can
be estimated from the population prevalence
of heterozygotes. Since heterozygotes
are asymptomatic, such analyses are
usually based on carrier mutation
analysis from a large sample of unaffected
individuals.
Systematic Review Findings
There are 289 reported mutations associated
with Pompe disease.(Kroos et al. 2008)
Particular mutations have been associated
with certain clinical outcomes. For example,
a database of mutations collected in the
Netherlands including samples collected
from North America, Europe, and Asia,
has linked specific mutations to the severity
of disease based on the amount of GAA
enzyme produced, ranging from severe (i.e.,
minimal GAA enzyme production) to non-pathologic.
(Kroos et al. 2008) Although it is expected
that severe mutations would be associated
with infantile-onset Pompe disease, no
prospective studies have directly linked
mutation to clinical outcome. Similarly,
the relationship between less severe mutations
and the development of late-onset Pompe
disease is unclear. More specifically,
no mutations specifically and consistently
distinguish early vs late onset disease.
Carrier mutation analysis for seven mutations
associated with infantile and late-onset
Pompe disease conducted on 928 randomly
selected normal individuals in New York
suggested a total prevalence of Pompe
disease, regardless of type, to be about
1 case per 40,000. (Martiniuk et al. 1998)
No data were provided regarding estimates
of the relative distribution of infantile
vs. late-onset disease. A carrier mutation
analysis in the Netherlands conducted
on 3,043 anonymous newborn screening blood
spots identified 31 mutations and concluded
that the prevalence of infantile Pompe
disorder to be about 1 case per 138,000
and of late-onset Pompe disease to be
about 1 case per 57,000. (Ausems et al.
1999b) These estimates are associated
with very wide confidence intervals because
of the rarity of the conditions. Because
Pompe disease is rare, small mathematical
errors in estimates of the relative distribution
of gene frequencies could lead to significant
over- or under-estimates of prevalence.
For example, one of these studies (Martiniuk
et al. 1998) estimated that the seven
mutations assessed in their study accounted
for 29% of Pompe disease.
A recent report of a pilot population
screening program in Taiwan (Chien et
al. 2008) identified four cases of Pompe
disease out of 132,528 screened newborns,
for a prevalence of about 1 in 33,000.
Three of the newborns had cardiac involvement
at the time of diagnosis (i.e., classical
infantile-onset Pompe disease). The other
newborn did not have cardiac involvement
and did not develop muscle weakness until
9 months of age (i.e., nonclassical infantile-onset
Pompe disease). No cases of late-onset
Pompe disease were reported. The lack
of identification of late-onset cases
could be because the tiered screening
method eliminated those with late-onset
disease (e.g., those with marginal levels
of GAA tested negative at some point along
the screening cascade), that late-onset
disease is less common than suspected,
or the diagnostic methods employed in
the study do not identify those with late-onset
Pompe disease. Further details of the
screening process are described in our
evaluation of screening test characteristics
(Section J).
Table 3. Prevalence Estimates.
Study |
Design |
Subjects |
Estimated
Prevalence |
Comments |
Ausems,
1999 |
Cross-sectional |
3,043
anonymous dried blood spots in the
Netherlands screened for 3 mutations |
Infantile:
1/138,000 (95% CI: 43,169-1/536,482)
Late-onset: 1/57,000 (95% CI: 1/27,734-1/28,255)
Combined: 1/40,000 (95% CI: 17,622-1/100,073) |
No clinical
correlation. Only three mutations
were included. Very wide confidence
interval. This study suggests that
late-onset Pompe disease is 2 to
3 times more common than infantile-onset
disease. |
Ausems,
1999 – community Genetics |
Retrospective
Cohort in the Netherlands. |
Incidence
of Pompe disease between 1972 and
1996 |
Birth
prevalence of infantile Pompe disease:
1/101,000 (excluding prenatal diagnoses);
juvenile (onset after 1-year but
before 18-years): 1/53,000; adult:
1/53,000 |
These
estimates are dependent on case-finding.
The prevalence is similar to that
predicted based on gene frequency. |
Martiniuk,
1998 |
Cross-sectional |
928 randomly
selected adults in New York screened
for 7 mutations |
Combined
prevalence (infantile and late-onset):
1/40,000 (no confidence interval
provided) |
Published
as a research letter-to-the-editor.
|
Chien,
2008 |
Prospective |
132,538
newborns screened in Taiwan |
Infantile
Pompe (classical and nonclassical):
1/33,135
Late-onset: No cases detected |
Only
population-based prospective study
of screening |
Additional Findings from the Expert
Interviews:
Dr. Hwu reports that from the time of
the original publication above, the Taiwan
screening program has completed the flourometric-based
screening on a total of 206,008 infants.
Of this number screened, 0.3% have been
recalled for a second blood spot test,
and 0.04% of the total were required to
undergo confirmatory testing (a total
of 21.4% of the recalled tests). He reports
that of the 206,008 screened, 6 have infantile-onset
Pompe disease and 5 have late-onset Pompe
disease.
- Methods of Diagnosis
Systematic Review Findings
Diagnosis of Pompe disease can be made
by enzyme assay or the identification
of two mutations in the GAA gene associated
with severe reduction in the production
of GAA enzyme. (Kroos et al. 2008) Muscle
biopsy is not routinely done because of
lack of sensitivity in general and the
risk of anesthesia in patients with Pompe
disease. (Ing et al. 2004, Winkel et al.
2005) Skin fibroblast GAA enzyme activity
can be used to diagnose Pompe disease,
but is not practical for screening because
of expense, complexity, and time intensity
(i.e., up to 2 months before results are
available).
- Methods of Screening
Systematic Review Findings
Measurement of GAA enzyme activity in
whole blood dried on filter paper is possible.
Methods include fluorometric tests (Umapathysivam
et al. 2000, Chamoles et al. 2004, Jack
et al. 2006) and tandem mass spectroscopy
(MS/MS). (Gelb et al. 2006, Dajnoki et
al. 2008a)
In a study of MS/MS newborn screening
in Austria, 10,279 anonymous dried blood
spots were collected to define a pediatric
reference range. (Dajnoki et al. 2008a)
An adult reference range was developed
based on 229 samples submitted to the
laboratory for GAA enzyme analysis. The
sensitivity of the test was evaluated
against samples of 14 infantile-onset
and 15 late-onset patients. The assay
appropriately identified all cases of
Pompe disease, but could not differentiate
infantile from late-onset disease. Four
of the anonymous dried blood spots (0.04%)
tested positive. No subsequent testing
or clinical correlation is available.
A multiplexed immune-quantification assay
to detect eleven lysosomal storage disorders,
including Pompe disease has been developed.
(Meikle et al. 2006) In a study evaluating
30 dried blood spots from individuals
with Pompe disease, of whom three had
infantile-onset, 173 unaffected adults
and 426 unaffected newborns, the sensitivity
was 90% and the specificity >99%.
This study also reported test accuracy
for other lysosomal storage disorders
(e.g., Fabry disease and Gaucher disease).
The sensitivity for the lysosomal storage
disorders other than Pompe disease and
Gaucher disease were 100%. The sensitivity
for Gaucher disease was only 50%, based
on 12 patients.
A recent pilot test in Taiwan (Chien
et al. 2008)used a multi-tier test designed
to maximize sensitivity. Dried blood
spots were initially tested for GAA enzyme
using a fluorometric test. If the activity
was less than 55% of the mean, a second
test was conducted on the same dried blood
spot. If the GAA activity was <25%
and the ratio of total neutral glucosidase
activity (NAG) to GAA, which controls
for the quality of the sample, was >25
and =100, children were recalled for a
second blood spot. However, if the ratio
of NAG to GAA was >100, children were
recalled for diagnostic testing. Among
those children who had a second blood
spot, those who had GAA activity <8%,
percent total GAA inhibition > 80%
and NAG to GAA ratio > 60, were recalled
for diagnostic testing.
Among the 132,538 newborns tested, 8
were referred for diagnostic testing after
the first blood spot (0.006%); 1,093 required
a second blood spot (0.82%), of whom 113
(10.3%) were referred for diagnostic testing.
Among those who were referred for diagnostic
testing (including GAA assay, physical
examination, creatine kinase and creatine
kinase myocardial band assays), four were
found to have infantile Pompe disease
(3.5%). The authors are unaware of any
false-negative screening tests during
this time. No cases of late-onset Pompe
disease were detected.
Based on the GAA activity among the 117
false positive cases referred for diagnostic
testing, the authors suggest that the
cutoff for the NAG/GAA ratio for recalling
for a second blood spot can be increased
from 25 to 30 to decrease the recall rate
for a second blood spot to 0.37% with
no loss of sensitivity. Based on these
data, we generated the following table
illustrating the expected rates of recall
and diagnosis, assuming a population of
100,000 newborns:
Table 4. Expected rates of Recall
per 100,000:
|
Referred
for Diagnostic Confirmation after
the First Blood Spot |
Recalled
for Second Blood Spot |
Referred
for Diagnostic Confirmation after
the Second Blood Spot |
Cases
Diagnosed |
Original Criteria |
6 |
820
|
85 |
3 |
Increased NAG/GAA
Ratio |
6 |
370 |
38* |
3 |
*Assuming similar proportion to the original
criteria for referral rates for diagnostic
confirmation after the second blood spot.
- Feasibility and Acceptability
of Screening
Systematic Review Findings
The Taiwan pilot study suggested that
large-scale screening is feasible. However,
no data were presented regarding the costs
of screening or other challenges related
to implementing screening more broadly.
No data from the Taiwan pilot study were
reported regarding the acceptability of
screening to families or the harms associated
with false positive screens.
- Benefits of Treatment in Screen
Positive Individuals
Systematic Review Findings
Alglucosidase alfa, the FDA-approved form
of recombinant human GAA (rhGAA) can be
life saving for cases of infantile Pompe
disease. One study evaluated the impact
of treatment among a cohort of 18 children
with infantile Pompe disease diagnosed
before 27 weeks of age who were not ventilator
dependent. Among these children, who
had a median age of five months, all survived
the 52-week study period. Six required
ventilatory assistance, including three
who required endotracheal tube or tracheostomy.
Compared to historical controls, treatment
reduced the risk of death by 99% and reduced
the risk of death or the need for invasive
ventilation by 92%.(Kishnani et al. 2007)
Historical controls were used because
of ethical concerns about not treating
individuals. rhGAA treatment also appears
to be beneficial for individuals with
symptomatic late-onset Pompe disease.(Winkel
et al. 2004) We are unaware of any studies
that have evaluated the impact of presymptomatic
therapy in individuals with late-onset
Pompe disease.
Patients who do not produce any active
or inactive endogenous GAA (referred to
as cross-reacting immunologic material
[CRIM] negative) may produce higher and
more persistent titers of antibodies to
rhGAA, and thus have worse clinical outcomes.(Kishnani
et al. 2006) Among the cohort of 18 children,
16 developed IgG antibodies to rhGAA.
However, only 3 of the 18 (17%) were CRIM
negative. One of these patients made
no motor gains while on therapy.
Additional Evidence from Expert Review:
Active research is ongoing regarding the
prevalence of CRIM negative status in
infantile-onset patients at Duke University
(Drs. Kishnani/Bali). Within the Duke
repository of 86 patients with infantile
Pompe disease collected over the past
ten years, 19% were CRIM negative.
The Taiwan group has follow up data on
the five infants identified by newborn
screening, who had cardiomegaly on initial
evaluation and who were begun on enzyme
replacement treatment within the first
month or two of life. All of these
children have survived with essentially
normal growth and minimal motor impairment.
In comparison with 10 children in a group
treated later (not identified by newborn
screening but by clinical presentation),
there was no statistically significant
difference in mortality, but the early
treated group has had significantly earlier
walking than the late treated group.
Among the 10 in the later treated group,
two have died, although the analysis of
Kaplan-Meier survival curves did not indicate
a statistically significant difference
in mortality between the two populations.
.
A separate prospective cohort study of
rhGAA treatment enrolled 21 children with
Pompe disease between the ages of 6 and
36 months who developed symptoms by 12
months of age (corrected for prematurity).
Compared to historical controls, after
104 weeks of treatment the risk of death
was reduced by 79% and the risk of death
or invasive ventilation by 58%. About
60% of patients had improvement in motor
development and about 80% had improvement
in functional independence. The authors
conclude that rhGAA can “reduce the mortality…even
when treatment is started at a more advanced
stage of disease.” (Nicolino et al. In
Press). This study underscores the benefit
of rhGAA treatment, but does not provide
direct evidence about the benefit of beginning
therapy before the development of symptoms.
- Harms of Screening
Systematic Review Findings
We did not identify any studies of the
harms of screening, including the potential
harms associated with false positive or
false negative screens, or the potential
harms associated with identification of
presymptomatic late-onset Pompe disease.
- Harms of Diagnosis
Systematic Review Findings
We did not identify any studies of the
harms of diagnosis.
- Harms of Treatment
Systematic Review Findings
Patients who are CRIM negative may develop
antibodies that limit the effectiveness
of treatment, as described above.
- Cost-Effectiveness of Screening
or Treatment
Systematic Review Findings
We were not able to identify any study
of the cost-effectiveness of screening
or treatment for Pompe disease.
VIII. SUMMARY
Key findings:
Pompe disease affects about 1 in 30,000
to 1 in 50,000 individuals but may be
influenced by the underestimation of the
true prevalence of the infantile form
of Pompe, due to increased mortality in
the first 15 months and/or the lack of
capture of accurate diagnosis prior to
death. The ratio of infantile to late-onset
Pompe disease in newborns is unknown. No
cases of late-onset Pompe disease were
identified in the published reports from
the Taiwan screening program. The pilot
program in Taiwan showed that screening
is possible, but will have many false
positives.
Infantile Pompe disease is fatal, often
within the first fifteen months of life,
and treatment with enzyme replacement
therapy can be life saving. Indirect
evidence suggests that earlier treatment
for infantile Pompe disease improves health
outcomes. Further data are needed regarding
the long-term effectiveness of treatment.
Late-onset Pompe disease can be fatal.
However, late-onset Pompe disease is variable
in both age of onset and rate of progression.
It is unknown whether presymptomatic treatment
leads to better health outcomes for late-onset
Pompe disease.
Returning to the key questions:
- Do current screening tests
effectively and efficiently identify
cases of Pompe disease?
The pilot study in Taiwan suggests that
a highly sensitive enzyme assay using
dried blood spots is available to identify
cases of early infantile Pompe disease,
but with a relatively high number of false
positives. Other screening strategies
(e.g., MS/MS) have not undergone prospective
population-based pilot testing.
- Does intervention in newborns
or infants with pre-symptomatic or early
symptomatic Pompe disease improve health
outcomes?
Treatment of infantile-onset Pompe disease
is life saving. There is some concern
that treatment may induce an immune reaction
in those children who are CRIM negative
that would decrease the benefit of treatment.
However, without treatment, most children
with infantile-onset Pompe disease would
die between 12 and 24 months of life.
Long-term treatment studies of treating
infantile-onset Pompe disease are in progress.
The optimal time to begin treatment (e.g.,
presymptomatic vs. after the development
of symptoms) for late-onset Pompe disease
is not known.
- What is the cost-effectiveness
of newborn screening for Pompe disease?
We did not identify any cost-effectiveness
data. Charge data are available for rhGAA.
Other costs (e.g., costs of screening,
treatment) are not available, and we are
unaware of any data that quantify the
costs or utilities (quality-of-life measure)
associated with untreated Pompe disease,
treated Pompe disease, the harms of false
positives, and the relative benefits vs.
harms of diagnosing late-onset Pompe disease
during early infancy.
- What critical information
is missing that is needed to inform
screening recommendations for Pompe
disease?
We identified several domains with deficient
data, related to:
- Prevalence of Pompe disease:
A more accurate way to determine
prevalence would be through systematic
case finding. Such a study would help
determine the true distribution of infantile
vs. late-onset Pompe disease.
- Late-onset Pompe disease:
The relative distribution
of late-onset to infantile Pompe disease
is unknown. No data are available regarding
the benefits or harms of detecting late-onset
Pompe disease during infancy.
- Accuracy of Screening:
The pilot screening project in Taiwan
identified strategies to reduce the
false positive rate. Prospective data
are needed regarding this modified protocol.
Data are also needed regarding the accuracy
of other potential screening tests (e.g.,
ms/ms) when applied to a prospective
population based screening.
- Feasibility of Screening:
Data are needed regarding the ability
of other newborn screening laboratories
to offer Pompe disease screening.
- Benefit of Early Diagnosis:
Indirect evidence supports the benefit
of presymptomatic infantile-onset Pompe
disease. Direct evidence will require
evaluating long-term outcomes among
populations of screened and unscreened
neonates with Pompe disease.
- Acceptability of Screening:
No data are available regarding
the acceptability to consumers of screening.
This is especially important because
of the potential to diagnose late-onset
disease.
- Cost-Effectiveness: We
were unable to identify any cost-effectiveness
data that were extrapolated to US screening
centers; only charge data are available
for enzyme replacement therapy.
IX.
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X. APPENDIX
Table 5. Key findings from selected
articles (alphabetical by first author)
Author/Design |
Sample
Size/Population Characteristics |
Interventions/Independent
Variables |
Significant
Findings |
Amalfitano 2001;
Prospective Cohort |
3 infants
with Pompe disease |
Treatment
with rhGAA |
All
infants survived past one year;
cardiac status and strength improved.
One patient had decline in motor
development associated with anti-rhGAA-antibodies |
Ausems et al (1999);
Cross-sectional |
3,043
anonymous dried blood spots in the
Netherlands |
Gene
mutations associated with Pompe
disease |
The
frequency of infantile and late-onset
Pompe disease was predicted to be
1/40,000. |
Ausems et al (1999);
Case Series |
Case
finding in the Netherlands between
1972 and 1996 |
Prevalence
of Pompe disease |
Birth
prevalence of infantile Pompe disease:
1/101,000 (excluding prenatal diagnoses);
juvenile (onset after 1-year but
before 18-years): 1/53,000; adult:
1/53,000 |
†???
Chien et al (2008);
Prospective Cohort |
132,538
newborns in Taiwan between Oct 2005
and Mar 2007, with comparison to
the other children born in Taiwan
during this period |
Newborn
screening for Pompe disease |
Pompe
disease identified in 4 of the newborns
in the screened population. Although
a similar proportion was identified
in the unscreened population, diagnosis
in this group was later (3-6 months
vs. < 1 month). No false negative
screens were identified. Among
those screened, about 0.8% required
a second blood spot of whom about
10% were referred for diagnostic
testing. The authors suggest new
test cut-offs that may decrease
the false positive rate. |
Chamoles et al
(2000);
Cross-sectional |
Selected
samples from individuals with Pompe
disease and normal controls |
Ability
to measure GAA in dried blood spots |
Technique
is possible |
Dajnoki et al (2008);
Cross-sectional |
Population-based
samples to identify normal range
and 229 adults with suspected Pompe
disease, 14 with infantile-onset
Pompe disease and 15 with late-onset
Pompe disease |
Ability
to measure GAA by MS/MS in dried
blood spots |
Technique
is possible |
Hagemans et al
(2005);
Cross-sectional |
255
children and adults with late-onset
Pompe disease |
Reported
disease severity and duration |
Disease
duration predicted the need for
respiratory support and wheel chair
use more than the chronological
age of the affected individual. |
Jack et al (2006);
Cross-sectional |
14 patients
with Pompe disease |
Ability
to measure GAA |
13/14
cases were detected; 1 was intermediate |
Kishnani et al
(2006);
Case Series |
168
children with infantile Pompe disease |
Natural
history |
The
median age of symptom onset was
2 months (range 0 to 12 months)
and of death is 8.7 months (range
0.3 to 73.4 months). Early symptom
onset was associated with increased
risk of early death. |
Kishnani et al
(2007);
Prospective Cohort |
18 patients
with infantile Pompe disease |
Treatment
with enzyme replacement therapy
(rhGAA from Chinese hamster ovary
cells) |
All
patients survived to 18 months of
age, the study endpoint. Treatment
reduced the risk of 99% and the
risk of death or invasive ventilation
by 92%. CRIM-negative patients
may develop a higher immunologic
response to rhGAA, which could limit
its effectiveness. |
Klinge et al (2005);
(Neuromuscular Disorders)
Prospective cohort |
2 patients
with infantile Pompe disease |
†???
Treatment with rhGAA (rabbit milk) |
Dramatic
improvement in cardiomyopathy and
some improvement in motor skills.
Antibody formation was not associated
with motor declines |
Klinge et al (2005);
Prospective cohort |
As above |
As above |
Survival
at the end of this report was >
20 months |
Kroos et al (2008);
Cross-sectional |
Database
of mutations |
Mutation
analysis |
The
database has 189 unique mutations,
bringing the total number of reported
mutations to 289 |
Li et al (2004);
Cross sectional |
Selected
population of blood spots from individuals
with lysosomal storage disorders,
including Pompe disease and normal
controls |
Ability
to measure lysosomal enzymes in
dried blood spots |
The
laboratory technique is feasible
and accurate. |
Martiniuk et al
(1998);
Cross-sectional |
928
randomly selected adults in New
York. |
Gene
mutations associated with Pompe
disease |
The
frequency of infantile and late-onset
Pompe disease was predicted to be
1/40,000. |
Meikle et al (1999);
Case Series |
Cases
of lysosomal s †???torage disorders
in Australia from 1980-1996 |
Incidence
of lysosomal storage disorders |
21 cases
of Pompe were diagnosed in the postnatal
period, yielding a carrier frequency
of 1 in 191 and a prevalence of
1/146,000 |
Meikle et al (2006);
Cross-sectional |
30 blood
spots from individuals with Pompe
disease (3 infantile-onset), blood
spots from 173 adults and 426 newborns,
and blood spots from 81 individuals
with other lysosomal storage disorders |
Test
characteristics of a multiplexed
immune-quantification assay to detect
lysosomal storage disorders |
For
Pompe disease (infantile and late-onset),
the sensitivity is 90% and the specificity
is >99% |
Okumiya et al (2006);
Cross-sectional |
25 patients
with Pompe disease |
Ability
to assay GAA |
Technique
is possible |
Pinto et al (2004);
Case Series |
Population
of Portugal between 1982-2001 |
Prevalence
of lysosomal storage disorders,
including Pompe disease |
The
prevalence of Pompe disease was1/50,000 |
Poorthuis et al
(1999);
Case Series |
Population
of the Netherlands between 1970-1996 |
Prevalence
of lysosomal storage disorders,
including Pompe diseas |
†???
Birth
prevalence of infantile Pompe disease
1.3/100,000 and overall 1/50,000 |
Slonim et al (2000);
Case Series |
12 infants
with Pompe disease |
Natural
history |
Some
infants may have an atypical course
with survival beyond 12 months |
Umapathysivam et
al (2000);
Cross-sectional |
Selected
samples from individuals with lysosomal
storage disorders and normal controls |
Ability
to measure enzyme activity in dried
blood spots |
Technique
is possible |
Van den Hout et
al (2003);
Case Series |
20 cases
of infantile Pompe disease and 133
cases from the literature |
Natural
history |
Symptoms
start around 1.6 months with a median
age of death between 6 and 7.7 months.
Cardiomyopathy is significant. |
Van den Hout et
al (2004);
Case Series |
4 cases
of infantile Pompe disease |
Outcomes
of treatment with rhGLU |
All
children reached the age of 4 years.
There was motor improvement, but
respiratory improvement was variable.
CRIM-negative status was not associated
with worse outcomes. |
Winkel et al (2004);
Prospective Cohort |
3 p
†???atients with late-onset Pompe
disease (11-, 16-, and 32-years) |
Treatment
with enzyme replacement therapy
(rhGAA from rabbit milk) |
Pulmonary
function stabilized, fatigue improved,
and the least affected patient had
marked improvement in strength.
|
Winkel et al (2005);
Systematic Review of Case Reports |
225
case reports of late-onset Pompe
disease |
Age
of onset, symptoms, cause of death |
Most
patients (62%) had an age of onset
of 18-years or older. Motor/muscle
problems are the most common first
symptom (79.9%). The median age
of death is 24.5 years (range (0.9-66).
Respiratory failure is the most
frequent case of death (72%). |
Zhang et al (2006);
Cross-sectional |
Dried
blood spots from patients with Pompe
disease, heterozygotes, and normal
controls |
Ability
to measure GAA in dried blood spots |
Technique
is possible |
_________________________________________________________________________
November 14, 2008
Authors: Alex R. Kemper,
MD, MPH, MS and Marsha Browning, MD, MPH
Evidence Review Group: Chairperson,
James M. Perrin, MD
(MGH Center for Child and Adolescent Health
Policy)
Committee Members:
Marsha Browning, MD, MPH,
MMSc.
(Massachusetts General Hospital)
Anne Comeau, PhD
(University of Massachusetts)
Nancy Green, MD
(Columbia University)
Alex R. Kemper, MD, MPH,
MS
(Duke University)
Alixandra Knapp, MS
(MGH Center for Child and Adolescent Health
Policy)
Ellen Lipstein, MD
(MGH Center for Child and Adolescent Health
Policy)
Lisa Prosser, PhD
(University of Michigan)
Denise Queally, JD
(Consumer Representative)
This review was made possible by subcontract
number SC-07-028 to Massachusetts General
Hospital, Center for Child and Adolescent
Health Policy under prime contract number
HHSP23320045014XI to Altarum Institute,
from the Maternal and Child Health Bureau
(MCHB) (Title V, Social Security Act), Health
Resources and Services Administration (HRSA),
U.S. Department of Health and Human Services
(DHHS). |