Download MPS I

E M O RY G E N E T I C S N E W S L E T T E R FA X • J A N . 2 0 0 7
DEPARTMENT OF HUMAN GENETICS • DIVISION OF MEDICAL GENETICS • EMORY UNIVERSITY SCHOOL OF MEDICINE • ATLANTA, GEORGIA
GENETIC
take the
©2007
CHALLENGE
test your knowledge of clinical genetics
What is your diagnosis?
What is Your Diagnosis?
Caucasian
CHIEF COMPLAINT
A 12 month old Caucasian male presents with
the following history:
31 y.o.
29 y.o.
12 months
•
•
•
•
Developmental delay
Unusual facial features
Gibbus deformity
Skeletal changes prompting concern of a
skeletal dysplasia
• Failure to thrive
Te s t y o u r s e l f :
answer these
questions before
reading the
answers on
page 2.
1. Which of the following tests are likely
to lead to a clear diagnosis?
A. Enzyme assay for alpha-L-iduronidase
B . Urinary glycosaminoglycans (GAGs)
analysis
C. Gene sequence analysis for the
IDUA gene
D. All of the above
PA S T M E D I C A L H I S T O RY
The patient is the product of an uneventful
f i r s t p r e g n a n c y. H e h a d a n i n g u i n a l h e r n i a
repaired at 5 months of age. His diet
consists of soy formula due to lactose
intolerance. He has had no major illnesses
and does not take any medications. He was
able to support himself on his forearms in
prone position at 3 months of age, and was
rolling over at 4 months, but was not able to
sit unsupported until 10 months. He is not
yet crawling, cruising, or walking.
2. What is the most likely diagnosis for
your patient?
A. A c h o n d r o p l a s i a
B. Gaucher disease type I
C . Mucopolysaccharidosis type I (Hurler)
D. Glycogen storage disease (Pompe)
E. I-cell disease
PHYSICAL EXAM
3 . What is the recurrence risk for this disorder?
A. 1 % o r l e s s
B. 25%
C. 50%
D. 100%
Yo u n o t e t h a t t h e p a t i e n t h a s c o a r s e f a c i a l
features, corneal clouding, and mild
macroglossia. The patient has
hepatosplenomegaly and a thoracolumbar
gibbus. His fingers are short with unilateral
c l a w i n g o f t h e 3 rd d i g i t .
4 . Is prenatal testing an option for the family’s
future pregnancies?
A. No, prenatal diagnosis is not available
for this disorder
B . Ye s , t h r o u g h b i o c h e m i c a l s t u d i e s
by CVS or amniocentesis
C . Ye s , t h r o u g h m o l e c u l a r s t u d i e s b y
CVS or amniocentesis
D . Yes, but only if the familial mutations
have previously been identified in
the affected child
ADDITIONAL ASSESSMENTS
Based on the history and physical exam,
you suspect that the patient has a
l y s o s o m a l s t o r a g e d i s o r d e r. T h e r e f o r e , y o u
order a skeletal radiologic survey that
identifies features consistent with
dysostosis multiplex.
FA M I LY H I S T O RY
See pedigree. Patient’s parents do not have
any known relatives in common. The family
shares with you that they are planning to
conceive a second pregnancy within the
n e x t y e a r.
continued next page
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sulfate. GAGs are complex
polysaccharides that are an important
component of the extracellular matrix
and connective tissues throughout the
b o d y. D e f i c i e n c y o f t h i s e n z y m e l e a d s t o
accumulation of GAGs in the lysosome,
ultimately resulting in cell, tissue and
organ dysfunction.
If you answered 1) D, 2) C,
3) B, and 4) C&D for each
question, congratulations!
Yo u h a v e m a s t e r e d t h i s m o n t h ' s
Genetic Challenge!
FINAL DIAGNOSIS
Mucopolysaccharidosis type I (MPS I)
[question 2]. The urine MPS screen
revealed abnormal glycosaminoglycans
(GAGs) of 196.4 mg GAG/gm creatinine
(normal is 2.9 - 80.5). Qualitative GAGs
identified included dermatan sulfate,
chondroitin 4-sulfate, and chondroitin-6
sulfate. The enzyme assay for alpha-Liduronidase revealed an enzyme level in
leukocytes of 0 pmol/hr/mg protein
(control range of 100-350 pmol/min/mg
protein).
MPS I occurs in severe, intermediate,
and milder forms that cover a broad
spectrum of symptoms and disease
progression. MPS I is now considered a
spectrum of disease, though in the past,
it was divided into three subtypes based
on disease severity: “Hurler” for severe
MPS I, “Hurler-Scheie” for intermediate
MPS I, and “Scheie” for mild MPS I. The
heterogeneity of MPS I disease
demonstrates a wide range of clinical
involvement marked by umbilical and
inguinal hernias, skeletal abnormalities,
recurrent and persistent upper
respiratory tract infections, coarse
f a c i a l f e a t u r e s , a r t h r o p a t h y,
hydrocephalus, spinal root and
peripheral nerve entrapment, obstructive
airway disease, sleep apnea, hearing
l o s s , m a s s i v e h e p a t o s p l e n o m e g a l y,
corneal clouding, glaucoma, retinal
d e g e n e r a t i o n , o p t i c a t r o p h y, c a r d i a c
valvular and ischemic myocardial
damage. As MPS I progresses,
complications become debilitating and
often life threatening.
FOLLOW UP
After a quick search on the internet, you
find that there is a lysosomal storage
disease center in your area that can
assist you with coordination of patient
care, genetic counseling, discussion of
treatment options, and participation in
r e s e a r c h t r i a l s . Yo u p r o v i d e t h e f a m i l y
with information about treatment options
for their son, including enzyme
replacement therapy and hematopoietic
s t e m c e l l t r a n s p l a n t a t i o n . Yo u a l s o m a k e
referrals to obtain baseline studies
including echocardiogram, PT
assessment to assess range of motion,
developmental assessment, pulmonary
function tests, MRI/CT for liver and
spleen volumes, hearing exam, and
brain/spine MRI.
DIAGNOSIS
The diagnosis of MPS I is demonstrated
by deficient activity of the lysosomal
enzyme alpha-L-iduronidase in
peripheral blood leukocytes, cultured
f i b r o b l a s t s , o r p l a s m a . H o w e v e r, t h e
amount of residual enzyme does not
p r e d i c t d i s e a s e s e v e r i t y. Te s t i n g f o r
urinary GAGs (qualitatively or
quantitatively) is a useful preliminary
test; if abnormal, a MPS disorder is likely
[question 1].
ABOUT
MUCOPOLYSACCHARIDOSIS
TYPE I
MPS I is a progressive, autosomal
recessive genetic disorder resulting
from a defect in the gene for the
lysosomal enzyme α-L-iduronidase. The
genetic defect leads to a partial or
complete deficiency of α-L-iduronidase
a n d , s u b s e q u e n t l y, p r o g r e s s i v e
accumulation of the glycosaminoglycans
(GAGs), dermatan sulfate and heparan
MOLECULAR TESTING
MPS I is caused by mutations in the
iduronidase-A (IDUA) gene on
chromosome 4. For some mutations,
genotype-phenotype correlations do
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nervous system manifestations of this
disease. Aldurazyme® is administered
intravenously at a dose of 0.58 mg/kg,
typically on an outpatient basis once per
week.
exist. Gene sequencing for MPS I is
clinically available through Emory
Genetics Laboratory and both mutations
are detected in >95% of patients. Once
the underlying gene mutation(s) has
been identified by sequencing, family
members can have carrier testing and
couples can have prenatal testing,
targeted for the specific gene
mutation(s) [question 4]. For couples
with a family history of MPS I but no living
affected relatives available for testing,
sequencing is available for the couple to
clarify genetic counseling concerning
their carrier risk. Couples who have had
an affeced child with MPS I are obligate
carriers and have a 1 in 4 or 25% risk for
recurrence in future pregnancies
[question 3].
REFERENCES & ADDITIONAL
I N F O R M AT I O N :
Emory Genetics Laboratory
h t t p : / / w w w. g e n e t i c s . e m o r y. e d u / t e s t i n g /
test.php?test_id=138
Gene Reviews
h t t p : / / w w w. g e n e t e s t s . o r g / q u e r y ? d z = m p s 1
Aldurazyme Information
h t t p : / / w w w. a l d u r a z y m e . c o m /
National MPS Society
- w w w. m p s s o c i e t y. o r g
T R E AT M E N T O P T I O N S
T h e r e i s n o c u r e f o r M P S I . C u r r e n t l y, a
hematopoietic stem cell transplant
(HSCT) from bone marrow or umbilical
cord blood is the only proven therapy
that can stabilize neurocognitive
development and improve survival in
patients with MPS I. Bone marrow
transplant is most advantageous when
performed on a patient with minimal
symptoms of MPS I (typically before 2
years of age). HSCT has its own
associated risks for complications,
including developing graft versus host
disease. The risk of severe
complications and death varies
depending upon several factors,
including pulmonary function and
whether there is a related versus
u n r e l a t e d d o n o r.
Another available treatment option for
MPS I is enzyme replacement therapy
with Aldurazyme®. This drug is the only
enzyme replacement therapy available
that treats the underlying cause of MPS I.
Aldurazyme has been shown to improve
pulmonary function, endurance and
functional capacity as well as decrease
g l y c o s a m i n o g l y c a n s ( G A G, t h e
accumulated substrate), and reduce
hepatomegaly in patients with this
d i s o r d e r. T h e t h e r a p y h a s n o t b e e n
evaluated for effects on the central
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Ta k e t h e G e n e t i c C h a l l e n g e ! f e a t u r e s o n e o r m o r e g e n e t i c c a s e s p e r m o n t h t o t e s t y o u r k n o w l e d g e o f
clinical genetics. We hope you find these cases interesting and educational. Questions or comments,
p l e a s e c a l l : 1 - 8 0 0 - 3 6 6 - 1 5 0 2 o r v i s i t u s o n t h e w e b a t : w w w. g e n e t i c s . e m o r y. e d u . T h i s i s s u e o f “ Ta k e t h e
Genetic Challenge!” was written by Heather Clark, MS, CGC, with edits by Daniel Gruskin, MD.
Emory Department of Human Genetics
revolutionizing patient care
through human genetics research
If you have additional questions regarding MPS I or other lysosomal storage disorders, call the
Emory Lysosomal Storage Disease Center at (404)778-8565 or 1-800-200-1524,
or fill out the information below,
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