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

Posted on April 3, 2017

A range of disorders are associated with schizophrenia-like psychosis or “secondary schizophrenia” at higher than expected rates than the 0.5-1.0% rate seen in the general population. Disorders such as epilepsy and Huntington’s disease, with pathology affecting grey matter regions such as the medial temporal lobe, the basal ganglia and the prefrontal cortex, have long been known as illnesses with elevated rates of schizophrenia-like presentation. Pathology in these key grey matter regions is thought to disrupt crucial fronto-subcortical and fronto-limbic connectivity, leading to the classical impairments in reality testing seen in schizophrenia patients.

A number of neurometabolic disorders, where basic cellular metabolic or enzymatic processes are disrupted, have also been associated with significantly elevated rates of schizophrenia-like psychosis. Some disorders are associated with psychotic illness in up to 50% of young adult patients. The first well-described illness, metachromatic leukodystrophy, is a disorder that affects fronto-temporal myelination. Like many neurometabolic disorders, the degree of biochemical disruption impacts the age of onset and severity of progression; severe deficits thus commonly present in young childhood with seizures, mental retardation and developmental delay; mid-childhood with attentional deficit and school failure; and middle to late age with a (frontal-)subcortical dementia.

However, it is when the significant biochemical impact occurs during the “psychotogenic window” – largely between age 15-30 – that schizophrenia-like psychosis much more commonly occurs. During this period, a number of “late” neurodevelopmental changes are occurring, particularly in cortico-cortical myelination, and in particular in refining connectivity between frontal, temporal and subcortical tracts.

Disruption to the finely-tuned temporal synchrony between grey matter regions that this facilitates appears to be particularly psychotogenic, and is known as the “disconnectivity hypothesis” of schizophrenia. This is consistent with the large amount of literature that suggests that disruption to myelination at a genetic and microstructural level, and white matter tracts at a macrostructural level, underpin at least some the pathological changes seen in schizophrenia patients.

References

The neuropsychiatry of Niemann-Pick type C disease in adulthood

Walterfang et al. The neuropsychiatry of Niemann-Pick type C disease in adulthood. J Psychiatry Clin Neurosci 18: 158-170, 2006.

Neuropsychiatry of inborn errors of metabolism

Walterfang et al. The neuropsychiatry of inborn errors of metabolism. J Inher Met Dis 36: 687-702, 2013.

Secondary psychosis induced by metabolic disorders

Bonnot et al. Secondary psychosis induced by metabolic disorders. Front Neurosci 9:177, 2015.

Diagnostic and treatment implications of psychosis secondary to treatable metabolic disorders in adults

Bonnot et al. Diagnostic and treatment implications of psychosis secondary to treatable metabolic disorders in adults: a systematic review. Orphanet J Rare Dis 9:65, 2014.

Development of a suspicion index to aid diagnosis of Niemann-Pick disease type C

Wijburg et al. Development of a suspicion index to aid diagnosis of Niemann-Pick disease type C. Neurology 78: 1560-1567, 2012.

White and grey matter alterations in adults with Niemann-Pick disease type C

Walterfang et al. White and grey matter alterations in adults with Niemann-Pick disease type C: a cross-sectional study. Neurology 75: 49-56, 2010.