Natural course, effects of enzyme therapy and health economic aspects in patients with mucopolysaccharidosis type I, II and VI. Long-term folloe-up of untreated patients and patients receiving commercially available Aldurazyme, Elaprase and Naglazyme.

The mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders, all
caused by the deficiency of a specific enzyme required for the stepwise
degradation of glycosaminoglycans (GAGs). The deficiency of one of these
enzymes results in accumulation of partially degraded GAG's in the lysosomes of
various tissues. For example, in MPS I and II the storage products are
dermatan and heparan sulphate; in MPS VI only dermatan sulphate accumulates.
The clinical features of the mucopolysaccharidoses involve different organ
systems. In all MPS there is a chronic and progressive clinical course leading
ultimately to premature death. Characteristic symptoms are coarse facial
features, skeletal deformities and an enlargement of the liver and the spleen.
Furthermore, hearing, vision and joint range of motion may be impaired and
patients may have cardiac and respiratory problems. In the severe forms of MPS
I and II mental retardation is also present, while in MPS VI the central
nervous system does not seem to be involved. The MPS are rare diseases with an
estimated birth prevalence in the Netherlands of 1 in 22.000 for all MPS
together.

Until recently, no therapy was available for patients with MPS I, II and VI.
Recently enzyme therapy was registered for treatment of these disorders.
However, information about the effect of enzyme therapy is limited. Further
research is essential to determine the precise effects of enzyme therapy.
Furthermore it is necessary to increase the knowledge on the natural course of
MPS I, II and VI to measure these effects.

Although the follow-up time and number of treated patients are still limited,
it is expected that an earlier
start of treatment will lead to better outcome. Furthermore, for patients with
the severe Hurler
phenotype of MPS I hematopoietic stem cell therapy (HSCT) is the treatment of
choice. This
treatment should be given before the age of 2 years, but preferably even sooner
after birth.
If diagnosis could be moved forward to the first month of life, MPS I-Hurler
patients would be
detected long before the critical age for HSCT of 2 years, and both HSCT for
Hurler patients
and ERT for the other patient groups could be started sooner. An obvious way to
reduce
diagnostic delay for the MPSes would be universal newborn screening.

the objective of the current study is to evaluate the safety and efficacy of
enzyme therapy in the Dutch population of patients with MPS I, II and VI; to
compare this to the natural course of these diseases; to make an inventory of
the direct and indirect costs of the MPS and the effects of enzyme therapy on
these costs. and to make guidelines to safely install enzyme therapy at home.
Finally, we will study whether newborn screening for MPS I, II and VI in The
Netherlands is possible.

This study is a therapeutic intervention study with a registered product.
Patients will be followed for at least 3 years (with a maximum duration untill
the 2013) by general/neurological examination, combined with additional
examination of endurance, pulmonary function, cardiac size and function, size
of liver and spleen, joint mobility, vision and hearing, quality of life and
mental and social functioning.
For the substudy on newborn screening, the bloodspots of patients with MPS I,
II and VI, parents of patients with MPS I, II and VI and anonymous Guthrie
cards from the RIVM (National Institute for Public Health and the Environment)
will be analysed with a fluorimetric method and tandem mass spectometry. To
study the mental development of patientens with MPS siblings of patients will
be assessed once.

MPS I patients, participating in the therapeutic part of the study will receive
infusions with Aldurazyme, MPS II patient with Elaprase and MPS VI patients
with Naglazyme. These medications are registered (orphan)drugs for treatment of
MPS I, II and VI. Patients will be treated once a week at the Erasmus Medical
Center/ Sophia Children's Hospital.

Except for the risks involved with a skin biopsy no specific risks excist.
Patients, participating in the therapeutic part of the study, will visit the
hospital once every week to receive their treatment. All other examinations
will be combined with infusion visits.
For the substudy on newborn screening, blood will be drawn once from the
parents of patients with mucopolysaccharidosis type I, II and VI to prepare
blood spots in which enzyme activity will be measured. To minimize the burden
and time investment the mental development of siblings will be assessed during
a regulare visit of the patient to the hospital.