Niemann-Pick Disease Figure 1: Lipid-trafficking Defects in Niemann-Pick Type C Disease11 A
Unesterified cholesterol
B
Extracellular Intracellular
Unesterified cholesterol
Extracellular Intracellular
Lysosome Early endosome Late endosome Late endosome X
Esterified cholesterol
NPC1 NPC2 ER X NPC1/NPC2 deficiency
A: Normally, lipoprotein cholesterol particles enter the endosomal network, where unesterified cholesterol and companion lipids are then trafficked from late endosomes and lysosomes to the Golgi apparatus, endoplasmic reticulum and other intracellular compartments. B: Niemann-Pick (NP) C1 or NPC2 defects inhibit the transport of unesterified cholesterol and sphingolipids from late endosomes and lysosomes, leading to their accumulation at these sites. ER = endoplasmic reticulum.
Table 1: Clinical Signs of Niemann-Pick Type C Disease in Adulthood
Clinical Sign Ataxia
Vertical supranuclear ophthalmoplegia Cognitive disorder Dysarthria
Movement disorder Splenomegaly Psychiatric Dysphagia Pyramidal
Hepatomegaly Epilepsy Deafness Cataplexy
Presentation in Patients (n=67*) (%)
76 75 61 63 58 54 45 37 19 19 16 4 4
*n=68 for splenomegaly and hepatomegaly. Data reproduced from Sevin et al., 2007.9
associated with the toxic production of GM gangliosides, particularly GM2 and GM3 gangliosides,29
in neurons that appear to underpin the neurological and psychiatric consequences of the illness.9
Currently, over 230 disease-causing mutations of the Npc1 gene have been identified, with a subset of mutations specifically affecting the cysteine-rich luminal loop of the protein.9
This not uncommonly
results in the ‘variant’ biochemical phenotype, and is often associated with less severe defects in cellular LDL cholesterol trafficking than the ‘classic’ phenotype.8,30
variant phenotype occurs more frequently in later-onset disease9
may account for the slower illness course seen in many adults. Signs and Symptoms
Clinically, NPC is an extremely heterogeneous disease and its presentation varies greatly among patients. A review of 13 adult cases from a comprehensive study and 55 other cases of NPC examined the frequency of a number of commonly occurring clinical characteristics (see Table 1).9
In adult patients, the first indication may
soluble protein that is localised to lysosomes and is also secreted.22 With a putative cholesterol-binding domain,23
NPC2 is also involved in
the transport of sterols between multiple intracellular organelles, and mutations affecting the area around this domain impair binding and movement of cholesterol within the cell.24
Although either of two different protein mutations may be responsible for NPC, both result in identical disease phenotypes that are biochemically and clinically almost indistinguishable.11
Evidence
suggests that NPC1 and NPC2 function in the same pathway to regulate intracellular lipid transport.25
A reduction or loss of function in either of
these proteins results in lipid-trafficking defects and an accumulation of unesterified cholesterol, glycosphingolipids and other lipid components in the late endosomes and lysosomes of most cell types (see Figure 1).8,19,20,26–28
These lipids are then unable to reach their
intended destinations, which include the Golgi apparatus and the endoplasmic reticulum. This leads to negative cellular effects in the liver, spleen and brain.11
In neurons, a number of metabolic functions
are disrupted, which in turn leads to cytoskeletal dysfunction, ectopic dendritogenesis, meganeurites and altered myelination. NPC is
84
be a motor sign such as tremor, ataxia, vertical gaze palsy or dystonia resulting in disturbances to speech, swallowing, vision, gait and fine motor control. As these symptoms may be rather subtle at onset, it is not uncommon for patients not to be aware of them; instead, family members and friends may notice slight alterations in the way the patient walks and/or talks.
By contrast, non-motor signs can also be the first notable sign in adult NPC. This includes major neuropsychiatric illnesses, often in the form of a schizophrenia-like psychotic disorder.12
Data from case studies suggest that this and
ER Golgi Early endosome Lysosome X Golgi
However, NPC can also
present as a mood disorder and may occasionally follow childhood attention-deficit disorders. An initial psychotic disease can sometimes precede the onset of any motor symptoms by up to 10 years.3
While
most, if not all, adult patients show difficulties in vertical gaze (vertical supranuclear ophthalmoplegia) at disease onset, NPC remains heterogeneous in its clinical manifestations and the initial presentation of adult patients may be motor or neuropsychiatric in nature.9,12 Because of this clinical heterogeneity, adult NPC patients may present to psychiatrists as well as neurologists. Motor symptoms that occur after the initial presentation of psychiatric illness are not uncommonly
EUROPEAN NEUROLOGICAL REVIEW
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