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Open Access Highly Accessed Review

Niemann-Pick disease type C symptomatology: an expert-based clinical description

Eugen Mengel1*, Hans-Hermann Klünemann2, Charles M Lourenço3, Christian J Hendriksz4, Frédéric Sedel5, Mark Walterfang6 and Stefan A Kolb7

Author Affiliations

1 Department of Lysosomal Storage Disorder, Villa Metabolica, Center for Paediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany

2 Department of Psychiatry, University of Regensburg, 93053 Regensburg, Germany

3 Medical Genetics Service, Clinics Hospital of Ribeirão Preto, University of São Paulo, São Paulo, Brazil

4 Manchester Academic Health Science Centre (MAHSC), University of Manchester, Salford Royal Hospital NHS Foundation Trust, Stott Lane, Manchester M6 8HD UK

5 Department of Neurology and Reference Center for Lysosomal Diseases, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France

6 Department of Neuropsychiatry, Royal Melbourne Hospital and Melbourne Neuropsychiatry Center, University of Melbourne, 3050 Melbourne, Australia

7 Actelion Pharmaceuticals Ltd, 4123 Allschwil, Switzerland

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Orphanet Journal of Rare Diseases 2013, 8:166  doi:10.1186/1750-1172-8-166

Published: 17 October 2013

Abstract

Niemann-Pick disease type C (NP-C) is a rare, progressive, irreversible disease leading to disabling neurological manifestations and premature death. The estimated disease incidence is 1:120,000 live births, but this likely represents an underestimate, as the disease may be under-diagnosed due to its highly heterogeneous presentation. NP-C is characterised by visceral, neurological and psychiatric manifestations that are not specific to the disease and that can be found in other conditions. The aim of this review is to provide non-specialists with an expert-based, detailed description of NP-C signs and symptoms, including how they present in patients and how they can be assessed. Early disease detection should rely on seeking a combination of signs and symptoms, rather than isolated findings. Examples of combinations which are strongly suggestive of NP-C include: splenomegaly and vertical supranuclear gaze palsy (VSGP); splenomegaly and clumsiness; splenomegaly and schizophrenia-like psychosis; psychotic symptoms and cognitive decline; and ataxia with dystonia, dysarthria/dysphagia and cognitive decline. VSGP is a hallmark of NP-C and becomes highly specific of the disease when it occurs in combination with other manifestations (e.g. splenomegaly, ataxia). In young infants (<2 years), abnormal saccades may first manifest as slowing and shortening of upward saccades, long before gaze palsy onset. While visceral manifestations tend to predominate during the perinatal and infantile period (2 months–6 years of age), neurological and psychiatric involvement is more prominent during the juvenile/adult period (>6 years of age). Psychosis in NP-C is atypical and variably responsive to treatment. Progressive cognitive decline, which always occurs in patients with NP-C, manifests as memory and executive impairment in juvenile/adult patients. Disease prognosis mainly correlates with the age at onset of the neurological signs, with early-onset forms progressing faster. Therefore, a detailed and descriptive picture of NP-C signs and symptoms may help improve disease detection and early diagnosis, so that therapy with miglustat (Zavesca®), the only available treatment approved to date, can be started as soon as neurological symptoms appear, in order to slow disease progression.

Keywords:
Niemann-Pick disease type C; Lysosomal lipid storage disease; Splenomegaly; Ataxia; Dystonia; Vertical supranuclear gaze palsy; Gelastic cataplexy; Cognitive impairment; Diagnosis