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Pathological manifestations of Niemann-Pick type C disease

Neuropathology

In Niemann-Pick type C (NP-C), lipids accumulate in neurons and glial cells, causing neuropathological changes, including:1

Meganeurite formation (distortion of neuron shape)

Ectopic dendritogenesis (extensive growth of new ectopic dendrites),2 altering neurotransmission leading to the neurologic symptoms of NP-C.1

Neurofibrillary tangles (NFTs), a feature of Alzheimer's disease, are found in the basal ganglia, hypothalamus, brain stem and spinal cord of most juvenile or adult cases of NP-C.3 In addition, amyloid precursor protein (APP) processing is altered, leading to beta-amyloid deposition in the brain.1

Brain atrophy, suggestive of neurodegeneration, is seen in some areas, for example the Purkinje cells of the cerebellum, in patients with particularly slow progressing NP-C or in those with end-stage disease.1,4

Several structural neurologic findings in patients with NP-C have been reported, using different imaging modalities:

Magnetic resonance imaging

Atrophy of cortical and subcortical structures, corpus callosum, and brainstem6

White matter hyperintensities6

Gray matter reductions in the hippocampus, parahippocampal regions, thalamus, insular cortex, and cerebellum7,8

Widespread changes in white matter affecting the majority of primary commissural, association, and corticofugal/corticopetal tracts7,9

Significantly reduced area and thickness of the corpus callosum10

Midbrain atrophy on sagittal imaging11

Positron emission tomography

Progressive hypometabolism in the cerebral, cerebellar, and thalamic regions12, and the frontal, parietal and temporal cortices13

Visceral pathology

Visceral histopathologic features vary considerably in terms of severity and extent. They are characterized by:

Foam cells (lipid-laden macrophages)

Sea-blue histiocytes in the spleen, liver, lung, lymph nodes, and bone marrow.5

The most prominent symptom is hepatosplenomegaly, which occurs predominantly in early and late infantile forms of NP-C. Isolated splenomegaly is often present in adulthood and is detected with an abdominal ultrasound.5

There may also be foam cell infiltration of the lungs in infancy, leading to respiratory failure.1,5

References

  1. Wraith JE, Imrie J. Understanding Niemann-Pick disease type C and its potential treatment. UK Blackwell Publishing, 2007.
  2. Zervas M, Dobrenis K, Walkley S. Neurons in Niemann-Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations. J Neuropathol Exp Neurol 2001;60:49–64.
  3. Suzuki K, Parker CC, Pentchev PG, et al. Neurofibrillary tangles in Niemann-Pick disease type C. Acta Neuropathol 1995;89:227–38.
  4. Walkley SU. Cellular pathology of lysosomal storage disorders Brain Pathol 1998;8:175–93.
  5. 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, pp3611–33.
  6. Sevin M, Lesca G, Baumann N, et al. The adult form of Niemann-Pick disease type C. Brain 2007;130:120–33.
  7. Walterfang M, Fahey M, Desmond P, et al. White and gray matter alterations in adults with Niemann-Pick disease type C: A cross-sectional study. Neurology 2010;75:49.
  8. Walterfang M, Abel LA, Desmond P, et al. Cerebellar volume correlates with saccadic gain and ataxia in adult Niemann-Pick type C. Mol Genet Metab 2013;108:85–9.
  9. Patterson MC, Hendriksz CJ, Walterfang M, et al., on behalf of the NP-C Guidelines Working Group. Recommendations for the diagnosis and management of Niemann–Pick disease type C: An update. Mol Genet Metab 2012;106:330–44.
  10. Walterfang M, Fahey M, Abel L, et al. Size and Shape of the Corpus Callosum in Adult Niemann-Pick Type C Reflects State and Trait Illness Variables. Am J Neuroradiol 2011;32:1340–6. 
  11. Walterfang M, Macfarlane MD, Looi JCL, et al. Pontine-to-midbrain ration indexes ocular-motor function and illness stage in adult Niemann-Pick disease type C. Eur J Neurol 2012;19:462–7.
  12. Pineda M, Perez-Poyato MS, O'Callaghan M, et al. Clinical experience with miglustat therapy in pediatric patients with Niemann-Pick disease type C: a case series. Mol Genet Metab 2010;99:358–66.
  13. Kumar A, Chugani HT. Niemann-Pick Disease Type C: Unique 2-Deoxy-2[18F] Fluoro-D-Glucose PET Abnormality. Pediatr Neurol 2011;44:57–60.