Niemann Pick Type C – What Can a Neurometabolic Disorder Tell Us About The Underlying Pathophysiology of Schizophrenia?

WHAT IS NIEMANN-PICK DISEASE TYPE C?

In the last decade another neurometabolic disorder has been increasingly recognized as a cause of “secondary” schizophrenia. Niemann-Pick disease type C (NPC) is a recessive neurovisceral disorder affecting intracellular cholesterol trafficking, and occurs in 1:100,000 individuals in a pan ethnic distribution.

Dysfunction of the NPC1 protein, which participates in lysosomal sterol trafficking, in 95% of affected patients results in an intracellular cholesterol “traffic jam” that significantly disrupts neuronal function and structure, and also myelination.

The cerebellum is affected first, but a number of other subcortical grey matter structures (thalamus, basal ganglia and hippocampus) are also impacted, and white matter disruption is widespread.

These are the areas where abnormal levels of GM2 and GM3 gangliosides accumulate; in addition, Alzheimer-like neurofibrillary tangles (NFTs) also accumulate in these same regions, other than the cerebellum.

Figure 1

Filipin staining of cultured fibroblasts, to demonstrate intracellular cholesterol levels. A healthy individual demonstrating little staining.

Figure 2

A “classical” biochemical NPC juvenile patient, showing intense perinuclear cholesterol accumulation

Figure 3

A “variant”, adult-onset patient showing less intense accumulation. It is the variant patients that present later, and are more likely to develop a psychotic illness.

THE CLINICAL PICTURE OF NIEMANN-PICK DISEASE TYPE C ACROSS THE LIFE SPAN

It may present in-utero, in infancy, childhood or early or late adulthood, depending on the degree of biochemical deficit. Although historically thought to be a paediatric disorder (being called “childhood Alzheimer’s disease” in Western countries), where it presents with cholestasis, splenomegaly and a movement disorder characterized by ataxia and dystonia. Increasingly it has been recognized that up to half of diagnoses are made in adults, and it is this group that particularly presents with neuropsychiatric presentation – in up to half of all individuals.

Figure 4

The clinical picture of NPC across the lifespan.

These patients often present with an early-onset psychotic illness (frequently in adolescence) that only partially responds to treatment, often with significant residual symptoms in spite of high-dose neuroleptic treatment.

It is common for patients to present with a decade of resistant psychosis before a frank neurological disorder emerges; typically, patients develop ataxia and dysarthria, but also dystonia, and this can – for some patients, for many years – be wrongly attributable to antipsychotic medication EPSE.

Figure 5

Assessing for VSGP. If only pursuit movements are tested, saccadic impairment may be missed, and the diagnosis delayed. Reprinted from Mengel et al. Orphanet J Rare Dis 2013

THE DIAGNOSIS OF NIEMANN-PICK DISEASE TYPE C

The diagnosis of NPC in adults rests on clinical suspicion (particularly in the setting of a family history – such an affected sibling or consanguinity), and then diagnosis at an established metabolic referral centre.

Historically, this was done via a complex skin biopsy and biochemical challenge, but now testing is often done directly genetically, with sequencing of the NPC1 and NPC2 genes, or using a simple blood measure of oxidized sterol species (oxysterols). Neuroimaging often reveals non-specific cortical atrophy, combined with atrophy of the cerebellum and/or corpus callosum.

One TGA-approved treatment, the oral iminosugar miglustat, has shown some slowing of the disease, and Australian patients are currently participating in a trial of intrathecal cyclodextrin, a cyclical sugar that has shown significant promise in animal NPC models.

At the Royal Melbourne Hospital Neuropsychiatry Unit, we have seen 16 adult patients with this disease over the last 17 years, with our first four patients all presenting with a psychotic illness.

This group of patients has allowed us to close investigate brain structure and function, with the aim of attempting to not just understand why these patients present so frequently with psychotic symptoms, but also to see if this pathology sheds light on the underlying pathophysiology of schizophrenia proper.

NEUROIMAGING IN NIEMANN-PICK DISEASE TYPE C

We have shown that NPC patients demonstrate significant impairments in grey matter in areas that are known to be pathophysiologically affected in schizophrenia. In a study published in Neurology in 2010, we showed reductions in the hippocampus, thalamus, caudate nucleus and cerebellum in adult NPC patients compared to a large control group, consistent with animal NPC models and the scattered few human neuropathological cases published.

We also showed widespread impairments to white matter tracts using diffusion tensor imaging (DTI); impairments in both axial and radial diffusivity demonstrated that changes to both myelination and axonal structure underpinned these changes.

Figure 6

Regions in red show areas of neuronal loss in NPC

Figure 7

Reductions in fractional anisotropy (FA) are widespread (areas of impairment are shown on a green skeleton; red areas showing areas of reduced white matter integrity). In the right images are measures of axial diffusivity (AD), showing widespread axonal structural changes in yellow, and radial diffusivity (RD) in orange, which indexes myelination

We have also shown that there are reductions in the corpus callosum in areas connecting frontal and temporal regions, similar to the patterns seen in schizophrenia; and the regions of subcortical volume change are again somewhat homologous to changes seen in our schizophrenia patients.

Figure 8

Significance map of where reductions are seen in the callosum, the brain’s largest white matter structure, in cross-section; anterior regions are to the left.

Figure 9

Significance map showing reductions in caudate nucleus in both cognitive and motor regions, consistent with both the dystonia and frontal-subcortical cognitive impairment seen in the illness. Much of the hippocampal volume loss seen in the posterior body.

NPC in adults appears to be an archetypal “secondary schizophrenia”; when the neurometabolic impairment is mild, it starts to disrupt frontal-subcortical and cortico-cortical connectivity subtly enough to disrupt the delicate temporal synchrony that maintains reality testing. This probably occurs through direct impairments to myelination as well as to changes to key grey matter relay centres crucial to this process. As it progresses, more frank motor disturbance and cognitive impairment supervene, at which point the diagnosis can be more readily considered.

WHY IS IT RELEVANT TO CLINICAL PRACTICE?

The relevance for practising psychiatrists is that, increasingly, a number of secondary schizophrenias are not just treatable symptomatically, but their underlying pathophysiology may be reversible with new treatments.

NPC is one of the few current neurodegenerative disorders where at least one illness-modifying treatment is available. Thus, it is imperative that psychiatrists maintain a high index of suspicion for atypicality and “red flags” that may assist in differentiating “primary” schizophrenia from a “secondary” type, whose underlying cause may be readily treatable.

One tool to assist clinicians is the NPC Suspicion Index, which scores symptoms highly suspicious of the disease and was generated using a pool of NPC patients, other metabolic and neurological disorders and healthy controls. This provides a guide for clinicians as to symptom and/or sign combinations that may be indicative of disease.

Figure 10

The NPC suspicion index – a score of greater than or equal to 70 is highly suspicious of NPC.

CONCLUSION

For psychiatrists, it remains important to differentiate illness presentations consistent with common major mental disorders but to also remain vigilant for the “red flags” of a secondary illness (atypical onset, course, treatment response, and concomitant cognitive or neurological symptoms). Remaining proficient in

Remaining proficient in a neurological examination is also crucial, as often the first specialist port-of-call for these patients is their psychiatrist, with whom the responsibility to detect reversible causes of illness rests.

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