Niemann-Pick type C (NPC) is a progressive genetic neurovisceral storage disorder that affects individuals across the age range. 70% of patients are children, but 30% of affected individuals have the onset of their disorder in adolescence or adulthood. Onset in early adulthood often confers an increased risk of developing a psychiatric illness, and the illness may first present in young adults as a psychotic illness such as schizophrenia or bipolar disorder.

In adults, NPC presents with difficulties with speech and swallowing, eye movement, walking and manual dexterity, and individuals also develop changes in cognition. Testing for NCP in the Australia-Pacific region is undertaken by the National Referral Laboratory for Lysosomal Peroxisomal Disorders at the Womens and Childrens Hospital in Adelaide.

Our patients and families affected by NPC have worked with us to examine into how NPC affects brain function in adults, which have provided new insights into brain structure and function in NPC.

A review publication on the link between NPC and psychiatric illness can be found here, in full text.
Walterfang et al. The neuropsychiatry of Niemann-Pick type C disease in adulthood. J Neuropsychiatry Clin Neurosci 18: 158-170, 2006.

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Image above: images of filipin-stained cultured fibroblasts in a healthy control (left) and an NPC patient (right). Fibroblasts in NPC show punctate perinuclear cholesterol accumulation, not seen in the healthy control.

We have undertaken a suite of studies using brain imaging in adult NPC to better understand brain-behaviour relationships in this disorder. This has occurred in collaboration with:

  • Professor Patricia Desmond (Royal Melbourne Hospital Department of Radiology)
  • Dr Michael Fahey (Monash Children's Hospital and Royal Melbourne Hospital Neurogenetics Clinic)
  • Dr Chris Adamson and Dr Marc Seal (Murdoch Children's Research Institute)
  • Dr Michael Fietz (Womens and Children's Hospital, Adelaide)
  • Dr Larry Abel and Dr Liz Bowman (Department of Optometry and Vision Sciences, University of Melbourne)
  • Professor David Reutens (Queensland Brain Institute, Brisbane)
  • Associate Professor Jeff Looi (Australian National university, Canberra)
  • Dr Brian Patenaude (Stanford University, USA)
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We showed that there are widespread changes to white matter in adult NPC as detected by diffusion tensor imaging (DTI), challenging the notion that NPC was only a "grey matter disease". In this study we also demonstrated specific reductions to subcortical regions (hippocampus, thalamus and striatum) in addition to cerebellar changes that map to neuropathological changes seen in human and adult models of NPC. This was the first group analysis of adult NPC patients, and shed significant light on the nature of brain changes in adult NPC patients.

This paper, published in Neurology in 2010, can be found here.
Walterfang et al. White and gray matter alterations in adults with Niemann-Pick disease type C: a cross-sectional study. Neurology 75: 49-56, 2010.
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The red areas on the white matter "skeleton" demonstrate where NPC patients' white matter showed lower integrity than controls. Green areas on the skeleton showed no difference.
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The coloured areas within grey matter regions taken in five horizontal slices of the brain show where grey matter volume was significantly smaller in NPC patients than control subjects.
We extended on this to demonstrate that the corpus callosum, the major white matter bundle connecting the brain's two hemispheres, showed that the callosum is globally thinnger in NPC (reflecting reduced connectivity) and that particular shape changes reflected reduced connectivity in frontal, temporal and parietal regions. These changes in shape were similar to those seen in patients with psychotic illness, and may go some way to explain the high rate of psychotic illness in NPC.

Walterfang et al. Size and shape of the corpus callosum in adult Niemann-Pick type C reflects state and trait illness variables.
Am J Neuroradiol 32: 1340-1346, 2011.
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The corpus callosum in cross-section, with the frontal regions on the left. The orange-red colours highlight regions where the thickness was reduced disproportionately, in regions connecting frontal, temporal and parietal association cortex.
With A/Prof Jeff Looi we then examined midbrain structure, which has been shown to be altered in other disorders associated with vertical gaze palsy, including progressive supranuclear palsy (PSP). We showed changes similar to, but not as great as, those changes in PSP in adults with NPC, but demonstrated that these changes were significant correlates with illness progression and ocular-motor function.

MacFarlane et al. Pontine-to-midbrain ratio indexes ocular-motor function and illness stage in adult Niemann-Pick type C. In press, Eur J Neurol.
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Sagittal section of the midbrain. The pontine-midbrain ratio reflects the ratio between area 2 (green) of the pons and 3 (yellow) of the midbrain.
We are also examining subcortical brain structures in NPC, and in unpublished work have demonstrated significant reductions in volume in hippocampus, thalamus and striatum, which correlate strongly with symptomatic and cognitive variables in adult patients.
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Representative image of a healthy control, with regions of interest shown in different colours.
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Representative image of an NPC patient, with the same regions of interest shown. The thalamus (green), hippocampus (yellow) and striatum (light & dark blue and pink) were shown to be significantly reduced in NPC patients.

One of the characteristic findings in NPC are abnormalities of gaze. Vertical gaze is often significantly impaired when individuals become symptomatic; however horizontal gaze is less impaired, and can be used as a measure of illness progress and change.

In work with Dr Larry Abel, we showed that peak velocity and gain in adult NPC patients differed significantly from controls, and indexed illness stage and severity. A link to the full text of this article can be found here.

Abel et al. Saccades in adult Niemann-Pick type C reflect frontal, brainstem and biochemical deficits. Neurology 24: 1083-1086, 2009.

In as-yet unpublished work, we have also shown significant changes with pharmacological treatment in a group of adult patients with NPC.
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Graph of velocity vs amplitude in adult NPC. Normal controls are at the top, with patients P1, P2 and P3's saccadic function worsening with an increase in illness severity.
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Sagittal section of the brainstem illustrating connections of the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), which controls gaze function and is affected in NPC. Image provided courtesy of Dr Larry Abel.

With Dr Wendy Kelso from the unit, we are analysing years of neuropsychological data in adult NPC patients to determine the relationships between brain changes, illness progression and cognition. We aim to map the distinctive neuropsychological pattern of illness progression, how this affects NPC patients' functioning in their daily life, and how this may be affected by treatment.
With Danielle Schubiger, senior speech pathologist at the Royal Melbourne Hospital, we have collated a large sample of video fluoroscopy data analysing longitudinal swallowing function in patients at a range of illness severities, and changes that may occur with treatment.