Niemann-Pick Disease


Niemann-Pick Disease Type C in Adulthood – A Psychiatric and Neurological Disorder


Mark Walterfang1 and Dennis Velakoulis2 1. Consultant Neuropsychiatrist; 2. Consultant Neuropsychiatrist, and Director, Neuropsychiatry Unit, Royal Melbourne Hospital and Melbourne Neuropsychiatry Centre, University of Melbourne


Abstract


Niemann-Pick disease type C (NPC) is a rare neurovisceral lipid storage disorder resulting from autosomal recessively inherited loss-of-function mutations in either Npc1 or Npc2. This disrupts intracellular lipid transport, leading to the accumulation of lipid products in the late endosomes and lysosomes. Affecting both children and adults, it exhibits a less rapid disease course in older patients, where it is characterised by slow cognitive decline, neuropsychiatric illness, ataxia and dystonia. As NPC is heterogeneous in presentation, it is often misdiagnosed as other movement or psychiatric disorders, highlighting the need for better awareness of this disease among clinicians. NPC is a progressive disorder and the only currently available disease-specific drug for its treatment is miglustat, which has shown positive outcomes in clinical studies. While other medications have been tested in animal models with encouraging results, they have yet to be trialled in human subjects.


Keywords


Niemann-Pick disease type C (NPC), adult-onset, lipid storage disorder, genetic mutation, neuropsychiatric disorder, miglustat, vertical gaze palsy, misdiagnosis, glycosphingolipids, progressive disorder


Disclosure: Mark Walterfang has served on local and international advisory boards for Actelion, which is the manufacturer of miglustat (Zavesca). Dennis Velakoulis has no conflicts of interest to declare. Received: 25 May 2010 Accepted: 14 June 2010 Citation: European Neurological Review, 2010;5(1):83–7 Correspondence: Mark Walterfang, Consultant Neuropsychiatrist, Neuropsychiatry Unit, Level 2, John Cade Building, Royal Melbourne Hospital, Corner Grattan St and Royal Parade, Melbourne 3050, Australia. E: mark.walterfang@mh.org.au


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.


Niemann-Pick disease type C (NPC) is a rare and fatal neurovisceral lipid storage disorder that affects both children and adults. Whereas the disease in children is characterised by mental retardation, seizures and often rapid neurodegeneration, in adults the disease is characterised by slow cognitive decline, major neuropsychiatric illness and the development of ataxia and dystonia.1


The data are limited in terms of the epidemiology of NPC. This disease is pan-ethnic, and two genetic isolates have been described in French Arcadians in Nova Scotia and Spanish Americans in South Colorado.2 The prevalence of NPC in the general population has been estimated at between one in 100,000 and one in 150,000 live births,3–6 the incidence in the genetically isolated populations is higher.2,7


although Of


these cases, approximately 20% experience symptomatic onset during adolescence and adulthood,8


resulting in an estimated adult


prevalence of one in 500,000 to one in 750,000. Although adult onset is technically defined as symptoms presenting at 18 years of age or over, it may be more relevant to separate both adolescent- and adult- onset from childhood-onset NPC. In the adolescent-onset group, the first obvious neurological or psychiatric symptoms appear at 13–14 years of age, and this group of patients is generally phenotypically different from the early-onset (infantile or juvenile) patient group.8–10


While there is no exact figure for the mean age at onset of adult NPC, most patients develop initial signs during the second or third decade,11


© TOUCH BRIEFINGS 2010


although presentation in the sixth decade has been reported.9


Like


childhood and adolescent NPC, adult NPC is a progressive disorder and patients usually succumb to illness in their late 30s or 40s.11


The


atypical presentation of NPC in adults often leads to its misdiagnosis as other movement disorders or major psychiatric illness.9,11,12


Given


the progressive nature of NPC, the high likelihood of misdiagnosis and the presence of available treatment, it is important to increase awareness of this disease among clinicians and provide better knowledge of its manifestation and management.


Pathogenesis of Niemann-Pick Disease Type C NPC results from autosomal recessively inherited loss-of-function mutations in either Npc1 (chromosome location 18q11)9,13 (chromosome location 14q24.3).9,14


patients are found to have mutations in the Npc1 gene,13


encodes a multipass transmembrane protein, NPC1, localised to the late endosome and lysosome.15–17 sensing domain,18


This protein contains a sterol-


and the traditional view is that NPC1 co-ordinates the transport of low-density lipoprotein (LDL)-derived unesterified cholesterol from late endosomes and lysosomes to other intracellular compartments,19,20


or Npc2


Approximately 95% of NPC which


although more recent evidence suggests its primary chaperone role is with sphingosine and that loss of function results in cholesterol accumulation indirectly via altered calcium homeostasis.21


mutations in Npc2.14


Conversely, approximately 5% of NPC patients exhibit The gene product of Npc2, NPC2, is a small,


83


Page 1  |  Page 2  |  Page 3  |  Page 4  |  Page 5  |  Page 6  |  Page 7  |  Page 8  |  Page 9  |  Page 10  |  Page 11  |  Page 12  |  Page 13  |  Page 14  |  Page 15  |  Page 16  |  Page 17  |  Page 18  |  Page 19  |  Page 20  |  Page 21  |  Page 22  |  Page 23  |  Page 24  |  Page 25  |  Page 26  |  Page 27  |  Page 28  |  Page 29  |  Page 30  |  Page 31  |  Page 32  |  Page 33  |  Page 34  |  Page 35  |  Page 36  |  Page 37  |  Page 38  |  Page 39  |  Page 40  |  Page 41  |  Page 42  |  Page 43  |  Page 44  |  Page 45  |  Page 46  |  Page 47  |  Page 48  |  Page 49  |  Page 50  |  Page 51  |  Page 52  |  Page 53  |  Page 54  |  Page 55  |  Page 56  |  Page 57  |  Page 58  |  Page 59  |  Page 60  |  Page 61  |  Page 62  |  Page 63  |  Page 64  |  Page 65  |  Page 66  |  Page 67  |  Page 68  |  Page 69  |  Page 70  |  Page 71  |  Page 72  |  Page 73  |  Page 74  |  Page 75  |  Page 76  |  Page 77  |  Page 78  |  Page 79  |  Page 80  |  Page 81  |  Page 82  |  Page 83  |  Page 84  |  Page 85  |  Page 86  |  Page 87  |  Page 88  |  Page 89  |  Page 90  |  Page 91  |  Page 92  |  Page 93  |  Page 94  |  Page 95  |  Page 96  |  Page 97  |  Page 98  |  Page 99  |  Page 100  |  Page 101  |  Page 102  |  Page 103  |  Page 104  |  Page 105  |  Page 106  |  Page 107  |  Page 108  |  Page 109  |  Page 110  |  Page 111  |  Page 112  |  Page 113  |  Page 114  |  Page 115  |  Page 116