Pathophysiology

Neuropathology

At the gross level, the brain often shows signs of atrophy, with severe changes seen in patients with slowly progressive forms of NPC. Neuropathologic changes associated with glycosphingolipid accumulation range from distortion of neurone shape (meganeurite formation) to extensive growth of new, ectopic dendrites, possibly linked to ganglioside sequestration (Figure 3).^2,3 Such changes can affect the larger basal ganglia and thalamic neurones.¹

Neurofibrillary tangles (NFTs), possibly linked to dysregulation of cholesterol metabolism, are consistent findings in the CNS of patients with a prolonged clinical course. These NFTs are similar to those seen in Alzheimer’s disease, but are distributed throughout different regions of the CNS. Whilst Alzheimer brain shows NFTs concentrated in certain regions of the cerebral cortex, NFTs in NPC brain are more numerous in the basal ganglia, hypothalamus, brain stem and spinal cord (Figure 4).^1,4

Neuroaxonal dystrophy has also been observed, and as the disease progresses, neurodegeneration can become apparent in some brain regions, particularly in Purkinje fibres in the cerebellum.³ The cerebral white matter is usually unaffected.¹ The basis of selective neuronal vulnerability is not yet known.

Figure 3. Ectopic dendritogenesis in NPC (reproduced with permission from Walkley and Suzuki³)

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Figure showing ectopic dendritogenesis in cortical pyramidal neurones. Feline NPC neurones display a range of axon hillock changes associated with ectopic dendrites. Human NPC neurones display more severe morphological abnormalities; meganeurites can be 3–5 times larger that the soma and contain long, meandering ectopic dendrites. Such pathology can lead to aberrant neurotransmission that contributes to cognitive impairment and / or seizures.

Figure 4. Neurofibrillary tangles in NPC (Reproduced with permission from Suzuki et al.⁴)

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NFT distribution in parallel swollen storage neurons. Characteristic paired helical filaments are found in the swollen perikarya and in meganeurites, as well as in neurones without swollen perikarya.

References:
1. Patterson MC, Vanier MT, Suzuki K et al. Niemann–Pick disease, type C: a lipid trafficking disorder. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease, 8th ed, 2001. New York: McGraw-Hill, Ch 145, pp 3611–33.
2. Zervas M, Dobrenis K, Walkley SU. Neurons in Niemann–Pick disease type C accumulate gangliosides as well as unesterifi ed cholesterol and undergo dendritic and axonal alterations. J Neuropathol Exp Neurol 2001a;60:49–64.
3. Walkley SU, Suzuki K. Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochim Biophys Acta 2004;1685:48–62.
4. Suzuki K, Parker CC, Pentchev PG et al. Neurofibrillary tangles in Niemann–Pick disease type C. Acta Neuropathol (Berl) 1995;89:227–38.

Niemann-Pick Knowledge Centre
(Type C)