Natural course of Niemann-Pick disease type C in the Netherlands

NPC is a rare neurodegenerative disease with an approximated minimal incidence
of 1:150.000 births. The primary defect Niemann-Pick type C (NPC) lies in
mutations of the genes NPC1 (found in approximately 95% of NPC patients) and on
NPC2 (found in about 4% of patients). In healthy individuals, NPC1 and NPC2
cooperate smoothly in realizing outbalanced intracellular lipid transport. In
NPC the intracellular transport of unesterified cholesterol, glycosphingolipids
and sphingosine is impaired, leading to the accumulation of unesterified
cholesterol, sphingomyelin, bis (monoacylglycero)phosphate, glycoshingolipids
and sphingosine in liver and spleen. In the central nervous system, levels of
glucosylceramide, lactosylceramide, GM2 and GM3 gangliosides are markedly
increased.

Due to structural damage to (neuro)visceral tissue, clinical features of NPC
involve a broad range of aspecific systemic, neurological and psychiatric
symptoms. Considering this extreme heterogeneous clinical presentation,
recognising NPC in patients can be a challenging task for physicians and
therefore may lead to underdetection and even misdiagnosis of NPC.

Although the onset of clinical signs and symptoms of NPC can occur at any age,
mostly children and adolescents are affected. Systemic manifestions such as
fetal hydrops, hepatosplenomegaly, prolonged cholestasis, respiratory failure
and hepatic failure mostly arise early in life, whereas psychiatric symptoms
including schizophrenia and depression are generally found in adolescent and
adult NPC patients. The neurological signs and symptoms of NPC include central
hypotonia, hearing loss, seizures, cataplexy, vertical supranuclear gaze palsy,
progressive ataxia, dystonia, dysphagia and dysarthria. These neurological
findings have a dramatic influence on disease prognosis. The younger the age at
onset of neurological symptoms, the faster will be the rate of deterioration,
consequently increasing the risk of premature death.

The recent EU-commission approval of *Miglustat* as a disease-modifying drug
for NPC, entails significant benefits for NPC patients, as the drug delays the
onset of neurological symptoms and prolongs the survival during pre-clinical
studies.

NPC patients need regular follow up by their physicians in order to measure
respons to therapy and the disease course. Unfortunately, there is a lack of
biochemical markers for monitoring follow up.

The first aim of this study is to extend clinical knowledge on NPC. This has
several reasons:

1) The heterogeneous clinical presentation of NPC makes extensive clinical
knowledge amongst physicians a prerequisite in preventing diagnostic delay.
Considering the acceleration of disease progression after the onset of
neurological signs and symptoms, recognising patients as early as possible is
crucial for the treatment and prognosis of NPC patients.
2) Given the chronic and in general invalidating nature of the disease,
clinical knowledge is essential in counselling and supporting parents and other
care-providers of NPC patients.
3) Because NPC is an inheritable disease, not only NPC patients, but also their
families need accurate and up-to-date information that requires extensive
knowledge of the physician.
4) With the recent developments in therapeutic options, extensive clinical
knowledge can play a key role in improving not only the disease outcomes, but
also the compliance in NPC patients.


The second aim of this study is to expand knowledge the genetic aspects on NP-
C. This has several reasons:

1) Genetic testing provides essential information about treatment modalities
and prenatal diagnostic measurements. Diagnostic measurements for NPC require
time-consuming tests that need to be performed in specialized laboratories and
need accurate interpretation by specialists. Increasing the rate of sequencing
the NPC1 and NPC2 genes can shorten the diagnostic delay, and help the
physician to treat patients according to their specific genetic defect more
rapidly. Expanding knowledge on the relation between genotype and phenotype
will help.
2) Very little is known about the different genotypes in the Netherlands.
Collecting information of the genetic mutations in Dutch NPC patients,
increases knowledge on the relation between genotype and the course of the
disease with or without treatment of Miglustat.

In deceased NPC patients, treating physicians will be asked their permission
for medical records to be retrieved and studied on follow-up data of

In living NPC patients, parents or legal representatives will be asked to fill
out seven questionnaires:
1) A questionnaire on medical history
2) A questionnaire to evaluate behaviour.
3) Functional adaptive behaviour as measured by the Vineland Adaptive
Behavioral Scales, Second Edition (VABS-II).
4) A questionnaire to assess the functional ability of the patients. The
validated *NPC functional disability rating scale* will be used.
5) A questionnaire to screen general cognitive impairment. The *Minimal
Minds State Examination* will be used.
6) A questionnaire to evaluate cognitive domains that are commonly affected in
NPC. The *Frontal Assessment Battery Scale* will be used.
7) A special short test for retrieval of non-specific information will be
used.



Patients will be examinated once in the outpatient clinic by a medical
practitioner. The physical examination includes:
* General appearance
* Skin
* Head and neck
* Lymph nodes
* Eyes
* Ears nose and throat
* Heart
* Lungs
* Abdomen
* Extremities, joints and back
* Neurological and mental status

All patients will be photographed and filmed for clinical assessment of NPC.

With the permission of parents or legal representatives of patients, genetic
sequencing of NPC1 and NPC2 will be performed if initial biochemical testing
results were dubious or difficult to interpret. This will be assessed by
sampling 2-10 ml EDTA blood of the patients. Mutational analysis will be
performed in the laboratory of the Academic Medical Center in Amsterdam.

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 genetic sequencing showed inconclusive
results.