Natural course in Dutch patients with Sanfilippo syndome (MPS III)

Mucopolysaccharidosis III (Sanfilippo syndrome) comprises 4 related inborn
errors of lysosomal degradation of the glycosaminoglycan heparan sulphate. The
lysosomal enzymes deficient in Sanfilippo syndrome (MPS III) are involved in
the breakdown of heparan sulfate. Accumulation of heparan sulfate, an essential
component of nerve cell membranes, results in progressive mental deterioration,
which is the main symptom of Sanfilippo syndrome.
All types of MPS III are characterized by progressive mental deterioration and
behavioral problems with only mild facial dysmorphisms and mild somatic
disease.

MPS III disease is a rare debilitating and fatal disorder for which until now
only symptomatic treatment is available. Therefore clinical data have only been
reported on small numbers of patients and information on the natural course of
the disease is limited.
This lack of knowledge on the natural history of the Sanfilippo syndrome is
limiting physicians and other health professionals who wish to counsel parents
of MPS III children regarding the management of this disorder.
In addition, if and when causal therapy (e.g. intracerebral enzyme replacement
therapy or gene therapy) becomes available, precise knowledge on the natural
course of the disorder is essential to study efficacy.

The first aim of this study is to extend clinical knowledge on Sanfilippo
syndrome. This has several important reasons:
*Clinical knowledge helps the physician to provide better care to patients
diagnosed with this incurable disease and to counsel parents and other family
members.
*Because Sanfilippo is a heritable disease it is important to obtain the
correct diagnosis as early as possible. This can only be achieved if physicians
are familiar with the disease and/or if this knowledge is readily available.
*Presently Sanfilippo is still an incurable disease. It is however expected
that therapy will be developed in the nearby future. Pre-clinical studies on
enzyme replacement and gene therapy have already been initiated. To make it
possible to evaluate these therapies in the future the natural course of the
disease should be accurately surveyed.

The second aim of the study is expanding knowledge on the biochemical aspects,
especially on excretion of GAG*s in Sanfilippo patients. This has several
reasons:
*Currently the initial diagnosis of all types of MPS III is based on
demonstration of increased concentrations of GAG*s in the urine. GAG excretion
is known to vary with age and time. Increased knowledge on the pattern of GAG*s
excretion througout the day and in different age groups can indicate the best
moment to collect urine in patient with suspection of Sanfilippo syndrome and
improve diagnostics.
*The most frequently used assay to demonstrate increased GAG excretion in urine
is the DMB test. Urinary excretion of GAGs is only mildly elevated in some
Sanfilippo patients and it is suspected that the sensitivity of the DMB test
alone in detecting Sanfilippo patients may not be sufficient. We therefore
intend to study the accuracy of the DMB-test and, if possible, improve this
diagnostic technique.

In deceased patients:

-Study of medical records
Many of the deceased patients were previously described by Prof.J.J.P. van de
Kamp in 1979 and lived in institutions. With permission of the physician of
these institutions medical records will be retrieved and studied to gather
follow-up data on these patients.

In living patients:

-Parents or Legal representatives will be asked to fill out 5 questionnaires.
Patients are once seen in the out patients clinic and will once be visited by a
psychologist at home.

Questionaires
-A questionaire on medical history
-The child behaviour checklist to evaluate behaviour
-A questionaire to assess Quality of life in patients with MPS III and parents.
Age appropriate and validated Questionaires (TACQOL/TAPQOL) will be used.
-Pediatric Evaluation of Disability Inventory (PEDI): this questionnaire
assesses the functional ability of children on three scales: Self Care,
Mobility and Social Function.
-A questionaire to evaluate parents opinion on neonatal screening for
Sanfilippo syndrome in the future

2. Physical examination

3. Developmental testing including psychological testing
Psychomotor development will be assessed using specific tests, appropriate for
different age groups and severity of the mental handicap. These tests will be
done in the home environment.

4. Photographs and Film
Of all patients photographs and a short film will be made. Photographs and film
will be used to asses dysmorfic features in MPS III.

Biochemical/molecular analyses

5. Urinary glycosaminoglycan analysis
Several (3) urine samples will be collected by collecting bag. 100 mL of urine
will be frozen and used for glycosaminoglycan analysis.

6. DNA analysis:
If possible about 2-10 ml EDTA-blood will be collected for DNA isolation.
Mutational analysis will be done in the Erasmus MC, Rotterdam.
In those patients, where DNA-analyses was previously done, no blood will be
drawn.
If blood is drawn for DNA-analysis, 5 ml blood is drawn in addition. This
additional blood sample will be used for glycosaminoglycan analysis.

There are no risks associated with participation in the study, except for the
risk of a hematoma after drawing blood.

The extend of the burden for the patients participating in the study is
relatively low. Patients are once seen in the out patient clinic and a
developmental test is done in the home environment.

Blood is only drawn if DNA analysis in not yet done, and urine can be collected
and frozen at home.