Natural history of Niemann-Pick disease type C in a multicentre observational retrospective cohort study
Section snippets
1. Introduction
Niemann-Pick disease type C (NP-C) is a rare, devastating and fatal genetic disorder that is inherited in autosomal recessive manner. NP-C is pan-ethnic and arises sporadically across populations, regardless of gender and race [1]. The estimated incidence of NP-C is 1 in 150,000 live births [2], [3]. However, this is likely an underestimation, due to high fatality rates and the wide clinical heterogeneity of the disease.
Approximately 90–95% cases of NP-C arise from mutations in the NPC1 gene,
2.1. Study design
This was an international, multicentre, observational retrospective cohort study. Seven expert centres from six countries participated in the study. All untreated patients with NP-C at each participating centre were included. All patients were required to have a confirmed diagnosis of NP-C based on biochemical and/or molecular genetic laboratory tests. The observation period ended in August 2008.
Physicians were asked to complete a web-based questionnaire for each patient. The questionnaire was
3.1. Patients
Data were collected from 57 patients. Of these, 28 were from a UK centre, 17 were from two French centres, four each were from Switzerland and Taiwan, and two each were from Italy and Germany.
Patient demographics and baseline characteristics are summarised in Table 2. The mean (SD) age at diagnosis was 10.7 (9.6) years, and the mean (SD) age at the last visit was 16.2 (10.6) years. The proportions of patients aged <6 years, 6–11 years and ⩾12 years at diagnosis were 40.3%, 21.0%, and 38.6%,
4. Discussion
In this cohort of 57 NP-C patients neurological disease progressed in a continuous, unbroken manner in most patients. The rate of deterioration was similar across the four individual parameters of the disability scale; ambulation, manipulation, language and swallowing deficits. Among patients with a time interval of at least 1 year between diagnosis and the last follow-up visit, the vast majority of patients (86%) demonstrated a measurable progression in neurological disease during the
Acknowledgments
The authors thank Peter Schieber, Actelion Pharmaceuticals Ltd., for his assistance with data collection.
This research was funded by Actelion Pharmaceuticals Ltd. Actelion Pharmaceuticals Ltd. was involved in the study design and data analysis and interpretation. Medical writing assistance for the manuscript development was provided by Alpha-Plus Medical Communications Ltd. All authors read, contributed to and approved this manuscript. The decision to submit this article to peer review, for
References (23)
- et al.
Structure and function of the NPC2 protein
Biochim. Biophys. Acta
(2004) - et al.
Intracellular trafficking of Niemann-Pick C proteins 1 and 2: obligate components of subcellular lipid transport
Biochim. Biophys. Acta
(2004) - et al.
Niemann-Pick disease types C and D
Neurol. Clin.
(1989) Glycosphingolipid levels in an unusual neurovisceral storage disease characterized by lactosylceramide galactosyl hydrolase deficiency: lactosylceramidosis
J. Lipid. Res.
(1972)- et al.
Lactosylceramidosis: lactosylceramide galactosyl hydrolase deficiency and accumulation of lactosylceramide in cultured skin fibroblasts
J. Pediatr.
(1971) - et al.
Consequences of NPC1 and NPC2 loss of function in mammalian neurons
Biochim. Biophys. Acta
(2004) - et al.
Niemann-Pick C disease in Spain: clinical spectrum and development of a disability scale
J. Neurol. Sci.
(2006) - et al.
Niemann-Pick disease type C: a lipid trafficking disorder
- et al.
Prevalence of lysosomal storage disorders
JAMA
(1999) - et al.
Niemann-Pick disease type C
Clin. Genet.
(2003)
Complementation studies in Niemann-Pick disease type C indicate the existence of a second group
J. Med. Genet.
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