Timothy C. Hain, MD • Page last modified: January 6, 2018
The eponym Niemann-Pick disease refers to a rare group of patients who present with varying degrees of lipid storage and foam cell infiltration in tissues, as well as overlapping clinical features including hepatosplenomegaly, pulmonary insufficiency and/or central nervous system (CNS) involvement. (Schuchman and Desnick, 2017)
Niemann-Pick type C (NMC)is a rare degenerative neurological/visceral (organ) disorder characterized by gait ataxia, problems thinking, psychiatric problems, and slowing or inability to generate voluntary saccadic eye movements. The most characteristic aspect of NMC is an inability to move the eyes, but the first symptom of NMC is usually unsteadiness and falling. As the other symptoms of NMC are common (i.e. unsteadiness), logically one should be searching for patients with slow eye movements, and/or hepatomegaly.
Although NPC is rare (i.e. roughly 1/20,000), it has been the subject of an immense number of papers in the world literature (about 2000 have it in the title as of 2018).
NPC is rather similar to PSP, or progressive supranuclear palsy, which also has vertical saccadic disturbances (the most specific clinical sign).
NPC is a genetic disease and appears in families. The disease can present in adults, where it is called "late".
Visceral -- there may be hepatomegaly or splenomegaly. This is a highly specific symptom (Pineda et al, 2016). This can be identified with scans of the abdomen, or sometimes with a good physical examination (the clinician has to think of looking for this of course).
Oculomotor problems -- vertical supranuclear saccadic palsy (Blundell et al, 2017). As is the situation with PSP, slow vertical saccades appear first, often followed by impairment of horizontal saccades, and eventually horizontal gaze. Vertical saccadic palsies presents early and may be the only sign of NPC in adults. This is also a highly specific symptom (Pineda et al, 2016). In our practice in Chicago, we have the equipment to measure vertical saccades very accurately (part of rotatory chair test).
Balance -- ataxia is common but nonspecific. Ataxia at an early age (i.e. less than 40) increases the change of NPC. Dystonia is also found in NPC, especially in those with juvenile and adult onset. Dystonia is far more specific than ataxia. The vestibular system is normal in NPC (Bremova et al, 2016).
Cognitive -- as NPC can present at any age, the terminology of cognitive disturbance varies -- in children, it is called "intellectual disability" or "developmental delay". In adults, it may be called dementia. As NPC is a progressive disease, there should be progressive deterioration. Similar to PSP, there may be a "frontotemporal dementia". Heitz described neuropsychological testing in NPC (2017). Cognitive impairment is common at all ages. We are dubious that there is a need to measure this common symptom with neuropsychological testing when attempting to diagnose NPC, as it is so nonspecific.
Psychiatric -- Psychosis and "atypical schiophrenia" are found in NPC. This is also common at all ages and not at all specific.
So logically, if one finds a supranuclear palsy in a relatively young person with ataxia, it would be reasonable to also check for hepatomegaly.
NPC is a genetic disease caused by autosomal recessive mutations in NPC1 or NPC2 (95% and 4%). There are at least 700 variants, of whom only about 400 are pathogenic. This can make things difficult when a patient is positive for a new mutation.
As NPC is autosomal recessive, it is mainly found in inbred populations, as it is more probable that two rare genes will combine in this situation. Ashkenazi Jewish patients are an example of this type of population (Levran et al, 1991). Other examples of inbred populations are French-Canadians and Appalachian dwellers.
There are several other Niemann-Pick diseases (NPD). There are two distinct metabolic abnormalities that account for NPD. The first is due to the deficient activity of the enzyme acid sphingomyelinase (ASM; "types A & B" NPD), and the second is due to defective function in cholesterol transport ("type C" NPD). Type A NPD patients exhibit hepatosplenomegaly in infancy and profound CNS involvement. They rarely survive beyond 2-3years of age. Type B patients also have hepatosplenomegaly and pathologic alterations of their lungs, but there are usually no CNS signs (Schuchman and Desnick, 2017).
NPC is suspected by detecting progressive symptoms including psychiatric, balance, cognitive, oculomotor and visceral areas. Genetic testing or NPC biomarkers are confirmatory tests. Biomarkers include oxysterols, and several other chemicals. Practically however, one would never get these tests without a high suspicion of NPC.
The filipin staining test, which is the historic "gold standard" for NPC diagnosis, is no longer favored as the initial laboratory test.
Well, clinically, they are close. The both have supranuclear gaze palsy. NPC includes hepatomegaly, which is not a feature of PSP. NPC has more psychiatric issues than PSP. Patients with PSP are usually fairly sensible. NPC includes dystonia in some, but this is not a part of PSP.
NPC is a progressive illness.
Miglustat therapy can be considered. It currently is the only approved therapy for NPC. Miglustat reversibly inhibits glucosylceramide synthase.