MIXED DONOR CHIMERISM AND LOW LEVEL IDURONIDASE
EXPRESSION MAY BE ADEQUATE FOR NEURODEVELOPMENTAL
JENNIFER CONWAY, MD, SARAH DYACK, MD, FRCPC, FCCMG, BRUCE N. A. CROOKS, MB, CHB, BSC, MRCP,
Hurler syndrome is a lysosomal storage disease resulting in fatal cardiac or neurologic sequelae unless alpha-iduronidase
production is reconstituted with hematopoietic stem cell transplantation. We report on a 4-year, 6-month-old boy with mixeddonor chimerism and low enzyme levels but a normal neurodevelopmental trajectory. (J Pediatr 2005;147:106-8)
Children with Hurler syndrome lack the lysosomal enzyme alpha-L-iduronidase. This results in glycosaminoglycan
(GAG) accumulation with progressive mental retardation and death.Recombinant alpha-L-iduronidase appears toameliorate some of the systemic effects in Hurler syndrome, but hematopoietic stem cell transplantation remains the only
means of preventing the neurologic deterioration.
Children with Hurler syndrome have normal intelligence at birth, but on average their IQ declines by 2 standard deviations
within the first 2 years of life (30-point decrease in IQ).The negative correlation between age and IQ has been found to besignificant (r = 20.82, P # .0003).Good neuropsychological outcomes after bone marrow transplantation (BMT) aredependent on multiple factors including age at transplantation (<24 months), mental developmental indexes >70 beforetransplantation, adequate engraftment (as measured by full donor chimerism), and posttransplantation iduronidase activity.We report the case of a patient with Hurler syndrome in whom a good neurologic outcome was achieved in spite of poor sustainedengraftment and very low serum alpha-L-iduronidase activity after BMT.
At 9 months of age, the patient presented with coarse facies and a lumbar gibbus. He
had dysostosis multiplex and a positive mucopolysaccharide (MPS) screen result. Hurlersyndrome was confirmed by the absence of alpha-L-iduronidase activity in peripheralblood leukocytes. He had a homozygous mutation of his IDUA gene, W402X, common tothose with a severe Hurler phenotype.
At 15 months of age, the patients underwent BMT from a male matched related
donor. Conditioning regimen included cyclophosphamide (50 mg/kg 3 4 doses), busulfan(based on targeted AUC 18mg/kg divided every 6 hours over 4 days), and low-dose totalbody irradiation (300 cGy). The patient was transplanted with 5.6 3 108 nucleated cells/
kg. He had no unexpected transplant-related toxicity and specifically no central nervous
After BMT, his musculoskeletal abnormalities persisted but were stable, his facial
the IWK Health Centre and DalhousieUniversity, Halifax, Nova Scotia.
features softened, and airway obstruction resolved. An echocardiogram obtained 2 years
after transplantation showed resolution of both his atrial septal defect and mild valvular
2005; accepted Mar 3, 2005.
Reprint requests: Conrad Fernandez
Initially he fully engrafted. He was followed by chimerisms on whole blood and
alpha-L-iduronidase levels on unfractionated peripheral leukocytes. He expressed normal
levels of alpha-L-iduronidase after transplantation but failed to sustain these beyond 4
9700, Halifax, Nova Scotia B3K 6R8Canada. E-mail:
months after BMT. The patient has remained at very low levels of activity (
0022-3476/$ - see front matterCopyright ª
2005 Elsevier Inc. All rightsreserved.
Based on clinical evaluation and developmental achieve-
Table. Measured levels of alpha-L-iduronidase and
ments, it was felt that his pretransplantation development was
normal. He sat at 6½ months, stood at 7 months, had singlewords at 10 months, and walked at 13 months. Two years after
BMT (age 3 years, 3 months), a formal neuropsychologicalevaluation demonstrated development in the normal range.
Full Scale intelligence testing revealed average intelligence
(45th percentile). There was a minor discrepancy between his
verbal (average range) and performance intelligence (low-
average range). He had mild difficulties with visual spatial
skills, primarily with block design. His language skills were
normal on the Token Test for children.
His most-recent evaluation at age 4 years 5 months
revealed dramatic improvements on the Peabody Develop-
mental Motor Skills, with an age equivalent of 41 months.
(This minor delay was attributed to his Hurler syndrome–
induced flexion contractures of his fingers). He continued to
do well in school and was communicating in both English and
*Alpha iduronidase enzyme activity was measured using a standardized
French. Repeat neuropsychological testing at that time
assay on unfractionated peripheral blood leukocytes.
revealed average full-scale intelligence with no discrepancy
Chimerism was determined by restriction fragment length polymorphism
on the recipient’s whole blood sample.
between his verbal and performance skills.
zBelieved to be secondary to assay problems.
central levels of GAGs before and after BMT in a patient with
Hurler syndrome is a progressive disease that leads to
Hurler syndrome. After BMT, peripheral enzyme activity was
coarse facial features, corneal clouding, hernias, hepatospleno-
greater than 50% of normal (13 nmol/mg/protein/h with
megaly, skeletal deformities, and progressive mental retarda-
normal 28 ± 7) but never achieved complete engraftment. At
tion.Death results from heart disease or respiratory failure
the patient’s 2-year follow-up, in spite of low enzyme activity,
the levels of central GAGs were stable, routine neuroimaging
Cleary and Wraitshowed that normal developmental
results were normal, and the child had a 28-point increase in
milestones over the first year of life were achieved by all of
IQ.This is the first neuroimaging evidence that peripheral
their patients. However, neurodevelopment does not continue
enzyme activity may be limited in predicting CNS enzyme
along a normal trajectory after the first year.Therefore
activity. Our case adds support to this notion.
our patient should have had evidence of neurologic deterio-
Limitations of this report include that it may be too
ration if there were inadequate cerebral alpha-L-iduronidase
early to predict our patient’s ultimate neurologic outcome,
although if enzyme activity in the CNS were inadequate, he
The rationale for BMT lies in the provision of donor
should have shown cognitive decline by age 4. Although de-
histiocytes that migrate to the central nervous system (CNS),
layed or minimal cognitive problems are seen in attenuated
differentiate into microglial cells, and provide an ongoing
forms of MPS1, such as Hurler-Scheie syndrome, our patient
source of functional enzyme.We postulate that this
presented with significant symptoms before 1 year of age,
occurred in our patient at sufficient levels to provide neuro-
and his IDUA mutations are associated with a severe MPS1
protection in spite of an inadequate peripheral engraftment.
phenotype. Thus we are confident he has Hurler syndrome.
Peters et showed that iduronidase activity post BMT
Our case illustrates that normal peripheral blood alpha-
less than or equal to that of a heterozygous carrier donor (~50%)
L-iduronidase levels may not be required to sustain normal
was associated with a poor neurologic outcome (Mental
neuropsychological development in patients with Hurler
Development Index [MDI] #80). A statistically significant
syndrome after BMT. If techniques can be developed to
correlation was subsequently found between MDI at follow-up
identify prospectively those patients who are destined to
and peripheral enzyme activity in these patients (0.59, P
have a good neurologic outcome in spite of low peripheral
Other studies have reported adequate developmental outcomes
blood alpha-L-iduronidase levels (for example by functional
in children with less than 90% chimerism (although all had at
neuroimaging or other central nervous system biochemical
least 50% chimerism).Our patient’s outcome suggests
markers), we may avoid the morbidity and mortality of a
that even very low levels of peripheral enzyme activity level can
be associated with normal development.
Data regarding the presence of alpha-iduronidase
activity in the CNS after BMT is indirectly derived from
cerebrospinal fluid and neuroimaging stTakahashi
Cleary MA, Wraith JE. The presenting features of mucopolysaccha-
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The Journal of Pediatrics
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International Journal of Dermatology, Vol. 35, No. 9, September 1996 PHARMACOLOGY AND THERAPEUTICS JOLANTA B. SCHMIDT, M.D., MARTINA BINDER, M.D., GABRIELE DEMSCHIK, M.D., CHRISTIAN BIEGLMAYER, PH.D., AND ANGELIKA REINER, M.D. Conclusions. Both estrogen compounds were found to be highly Background. The coincidence of climacteric symptoms and the effective in preventing or