Niemann-Pick Disease Type C
Niemann-Pick disease type C (NPC) is an extremely rare genetic disorder arising from build up of glycosphingolipids particularly in the Central Nervous System. These build up in toxic quantities as unesterified cholesterol, causing structural and functional damage in cells and tissues. NPC is pan-ethnic and arises at irregular intervals across populations, regardless of race, although genetic isolates (clusters) have been identified in Nova Scotia, Colorado, and New Mexico. It is believed that NPC arises in 1 case per every 120,000 births (source: Marie T. Vanier, Orphanet Journal of Rare Disease, 2010 Jun 3;5 (1):16) . However, it is considered highly likely that this is an underestimate due to a mixture of factors – chiefly, failure to recognise the clinical characteristics and a previous lack of definitive diagnostic tests.
Based on molecular genetic testing, NPC is now divided into two subtypes − NPC1 and NPC2 − as each is caused by a different gene mutation. These names are currently preferred, as they relate back to the mutated genes responsible for the clinical phenotype. Niemann-Pick disease type D (NPD), previously and still sometimes used to describe the genetic isolate from Nova Scotia, should no longer be considered as a separate condition as it is biochemically and clinically indistinguishable from NPC, and is now known to result from mutations in the NPC1 gene. NPC has an extremely varied clinical presentation, but is characterised by a range of progressive neurological problems that become severe and limiting at late stages of the disease. It can present, either with or without associated hepatosplenomegaly (enlarged liver and spleen) in infants, children or adults, and is characterized by eye movement abnormalities, dysphagia (difficulty in swallowing) and dysarthria (slurred, irregular speech), ataxia (lack of muscle control) and progressive cognitive dysfunction (progressive intellectual decline) leading to dementia.
When Helen and Pete Carter found out that their gorgeous three year old daughter, Hollie, suffers from the rare, fatal, condition, Niemann-Pick Type C, they bravely decided to start the “Hope for Hollie” Campaign to help Hollie and other children like her. The Campaign has gone from strength to strength and has so far raised over £38,000 to support the work of the NPDG (UK). To learn more about the ‘Hope for Hollie’ Campaign, visit their website www.hopeforhollie.co.uk . A recent addition to the website is a forum, which aims to provide a support network for parents and carers of those affected by Niemann-Pick diseases, enabling them to share their knowledge and experience. To join the forum click here.
What, typically, is the age when NPC becomes apparent?
NPC is present in an individual from the moment of conception but is not necessarily apparent. The symptoms are often related to the age when the disease takes hold and, this is in itself an extremely variable factor ranging from birth to old age. It is possible that babies have died prior to birth and been undiagnosed or diagnosed in a ‘blanket’ manner, eg liver disease.
Similarly, people with very late onset may be incorrectly diagnosed with a disease such as Alzheimer’s. Since awareness of the disease has increased and diagnosis has been improved, the age profile of the disease is beginning to look different to that of a few years ago. What was once considered to be a childhood disease is now, equally, beginning to look like a disease of adults. Information on numbers of people affected, age of onset and progression has been collected in a number of countries and this will help to provide a better picture in due course.
How is NPC diagnosed?
If NPC is suspected clinically a skin biopsy is taken and grown in a sterile environment which takes about 6 weeks. When sufficient tissue is available it is stained with filipin which causes the lipid filled lysosomes to fluoresce in affected cells A second test to look at the rate of cholesterol esterification (how the cell processes the cholesterol) is also done. The whole process usually takes about 12 weeks. Meanwhile, a blood test to check for raised chitotriosidase levels may be done as this is raised in most (but not all) NPC patients.
Is there any treatment?
At present treatment is aimed at symptoms ie. Anticonvulsants for seizures. There is currently no treatment or cure for NPC.
Clinical trials are in progress to look at the effects of Miglustat, a medication that may slow down the progression of the disease (see Research).
In Summary - the symptoms of NPC
Symptoms vary with age of onset and may include:
- jaundice at (or shortly after) birth
- an enlarged spleen and/or liver (hepatosplenamegaly)
- difficulty with upward and downward eye movements (Vertical Supranuclear Gaze Palsy).
- unsteadiness of gait, clumsiness, problems in walking (ataxia)
- difficulty in posturing of limbs (dystonia)
- slurred, irregular speech (dysarthria)
- learning difficulties and progressive intellectual decline (Cognitive dysfunction - "dementia")
- sudden loss of muscle tone which may lead to falls (cataplexy)
- tremors accompanying movement and, in some cases, seizures
Type C is the most variable form of the disease. Symptoms may appear and then disappear. Some symptoms may never appear. The rate of progression of the disease is different from person to person. The rate of progress for an individual will change over time.
Type C is often incorrectly diagnosed. Some of the common errors are:
- Attention Deficit Disorder (ADD)
- Learning Disability
- Delayed Development
Vertical Supranuclear Gaze Palsy (VSGP or VGP) is highly suggestive of Type C. VSGP is the inability to move the eyes up and down. Parents often notice this when their child walks up and down stairs, watches TV while sitting on the floor, or in similar situations - the child tilts their head to see instead of moving their eyes. Liver or spleen problems in the first few months after birth are also highly suggestive of Type C.