Psychiatric Manifestations of Niemann-Pick Disease

Daniel Webber, Hans H Klünemann
European Psychiatric Review, 2011;4(1):25-31
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Abstract

Niemann-Pick disease type C (NPC) is a rare and fatal inherited disease caused by mutations in either the NPC1 or NPC2 genes and leads to the inhibition of unesterified cholesterol glycosphingolipids transport and intracellular accumulation in the spleen, liver and brain. NPC affects both infants and adults with neurological symptoms varying with age of onset. Symptoms include mental retardation (infantile period), gait problems, cataplexy and ataxia with the most common characteristic being vertical supranuclear gaze palsy. People with NPC, presenting with neuropsychiatric symptoms in combination with delayed onset of other NPC-like symptoms, are often misdiagnosed as other major psychiatric disorders and may thus be prescribed inappropriate treatments. Non-motor signs often precede the first notable clinical motor symptoms in adult NPC including neuropsychiatric illness in the form of schizophrenia-like psychotic disorders, paranoia, hallucinations and aggressive behaviours. Improved awareness of NPC and its symptoms among clinicians is essential for better disease detection, since patients diagnosed with chronic psychiatric illness and concomitant neurological impairments managed with antipsychotic drugs may have this disease.

Acknowledgement: Editorial assistance was provided by Touch Briefings.
Support: The publication of this article was funded by Actelion. The views and opinions expressed are those of the authors and not necessarily those of Actelion.
Keywords
Glycosphingolipids, lipid storage disorder, neurological, neuropsychiatric disorder, Niemann-Pick disease type C
Disclosure Hans H Klünemann is a member of the Actelion advisory board and has received speaker fees.
Received: March 02, 2011 Accepted May 14, 2011
Correspondence: Hans H Klünemann, Neurologist and Psychiatrist, Department of Psychiatry, Universitätsstr. 84, University of Regensburg School of Medicine, 93053 Regensburg, Germany. E: hans.kluenemann@medbo.de
Prevalence of Niemann-Pick Disease

The term Niemann-Pick disease encompasses a rare and heterogeneous group of autosomal recessive lysosomal lipid storage disorders characterised by abnormalities in unesterified cholesterol accumulation in late endosomes and lysosomes of the spleen, liver, lungs, bone marrow and brain.1,2 Symptoms may include lack of muscle coordination, brain degeneration, learning problems, loss of muscle tone, increased sensitivity to touch, spasticity, feeding and swallowing difficulties and an enlarged spleen and liver. The disease currently has four related types. Type A, the most common type, occurs in infants, while type B involves an enlarged liver and spleen and usually occurs in adolescence. Type A and B are caused by insufficient activity of an enzyme called sphingomyelinase, leading to the build up of toxic amounts of sphingomyelin.1,2 Type C may appear early at infancy, adolescence or up to the eighth decade of adulthood.3 Affected individuals have only moderate enlargement of the spleen and liver, but brain damage may be extensive and cause vertical supranuclear gaze palsy, difficulty in walking and swallowing and progressive loss of vision and hearing. Types C and D are characterised by a mutation in the NPC1 and NPC2 gene that disrupts the transport of cholesterol between brain cells. Niemann-Pick disease type C (NPC) is panethnic. NPC is estimated to occur in one in 150,000 births in France, UK and Germany while figures of one in 50,000 have been reported in Australia and the Netherlands.4–8 The age of onset in NPC is wide ranging. Fatal cases can have a perinatal onset but also occur into adulthood; they can present with a broad clinical spectrum of disease symptoms that are not disease specific or limited to specific stages of disease development. This results in difficulties in diagnosing NPC and consequently the prevalence is possibly underestimated.4,9 Furthermore, specific diagnostic assays for NPC were not widely available until the early 1990s, which has historically limited NPC detection and awareness.7

Pathological Manifestation

Significant advances in the understanding of NPC and potential treatments have occurred as a result of the discovery of genetic mutations in either the NPC1 or NPC2 genes. People with NPC commonly have mutations in NPC1 (95%), encoding a large membrane bound glycoprotein, which results in intracellular accumulation of unesterifed cholesterol and sphingolipids.10–12 The remaining 5% of people have mutations in NPC2, which encodes a small lysosomal protein that binds cholesterol with high affinity.13,14

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