November 2011
26
decline is more variable and psychotic episodes may occur. Dysphagia is a major problem often
requiring gastrotomy. Dementia usually occurs in the teenage years. Death, often from pulmonary
complications, may occur in teenage years or early adulthood.
Juvenile or adult presentation (> 12 years)
:
In juvenile and adults the progressive neurological
manifestations are the most prominent feature, including ataxia, dystonia, dysphagia, dysartria,
seizures, cataplexy and cognitive deterioration (dementia). Psychosis and other neuropsychiatric
symptoms are not uncommon and may be the presenting symptom. Paresis of the vertical gaze
and visceromegaly may be absent. And even adult patients with isolated splenomegaly have been
described. Juvenile and adult onset patients show a much slower rate of neurological
deterioration.
Diagnosis
In patients suspected to have NPC, screening should comprise evaluation for characteristic
neurological as well as systemic features by medical history, clinical examination and regular
laboratory test. Confirmation of the diagnoses requires biochemical and molecular genetic testing.
The key laboratory diagnostic tests are performed on a skin fibroblast culture. Filipin staining
demonstrates unesterified cholesterol accumulation in lysosomes after LDL-loading, showing a
‘
classical’ storage pattern in 85% of cases. A lesser level of storage is seen about 15% ‘variant
biochemical phenotypes’. Another biochemical test measures the rate of cholesterol ester
formation, which is very low in the classical phenotype. Genetic studies can be used for further
confirmation of the diagnoses, especially in patients with a variant biochemical phenotype. Genetic
studies can also be undertaken if clinical symptoms are very suggestive of a diagnosis of NPC, even
with a negative result from filipin testing.
8,10
Due to the rapid advances in DNA analysis it is likely that filipin staining will soon be replaced by
mutation analysis as a first line investigation.
Furthermore, the recent discovery of plasma oxysterol markers, which correlated with the age of
disease onset, disease severity and therapy response, are promissing.
11
Treatment
Since it is likely that irreversible damage of the neuronal pool has occurred by the time diagnosis is
made, disease stabilization is likely the best attainable goal for long-term disease modifying
therapy.
8
This in addition to symptom control and palliative care which still is a main feature (and
till recently the only) in the treatment of NPC.
N-butyldeoxynojirimycin (Miglustat) is the first and only approved therapy for patients with NPC.
Miglustat is a small iminosugar molecule that reversibly inhibits glycosphingolipid synthesis. A
prospective clinical trail
12
and retrospective study
13
have demonstrated clinically relevant
beneficial effect of Miglustat on neurological disease progression in adult, juvenile and pediatric
patient with NPC. The magnitude of this effect was greater in patients diagnosed in juveniles and
adults compared with those diagnosed in early childhood. It was well-tolerated and safe. The
effects of Miglustat on the systemic manifestation of NPC have not yet been investigated in clinical
trials.
8,14
The symptomatic treatment consists of optimizing the general condition and treating the clinical
neurological and neuropsychiatric features and complications (malnutrition, aspiration
pneumonia). This includes pharmacotherapy to alleviate neurological symptoms such as epilepsy,
cataplexie, dystonia; tube feeding in patients who are malnourished or at risk of aspiration due to
dysfagia; and treatment for aspiration pneumonia.
Lipid-lowering drugs and bone marrow transplantation have been ineffective in halting the
neurologic progression.
9
Although lipid-lowering drugs significantly improved liver cholesterol