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Neurometabolic Disorders Efficient Investigation and Differential Diagnosis of Childhood Onset Niemann-Pick Type C Alasdair Parker Consultant Paediatric Neurologist, Department of Paediatric Neurology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK Abstract Niemann-Pick disease type C (NPC) is a fatal, neurodegenerative, lysosomal storage disorder. It is rare with a broad phenotypic spectrum and variable age of onset. This complicates diagnosis, which is often delayed by several years after presentation of the first symptoms. It is a treatable condition if detected early, therefore reliable means of diagnosis are essential. Clinical diagnosis of NPC involves identifying characteristic neurological features, taking a detailed history of the patient’s details, and must be confirmed by biochemical and/or genetic testing. The key laboratory diagnostic test for NPC is filipin staining of cultured skin fibroblasts, which shows free cholesterol accumulation in lysosomes resulting from impaired intracellular cholesterol transport. Genetic testing for mutations in the NPC1 and NPC2 genes is also important for confirmation of the diagnosis. However, there is an unmet need for cheaper diagnostic tests with greater specificity and sensitivity. Keywords Filipin, lysosomal storage disorder, Niemann-Pick type C (NPC), NPC1, NPC2, progressive intellectual, neurological deterioration, genetic analysis Disclosure: Alasdair Parker is a member of the Niemann-Pick Type C advisory panel for which he receives an honorarium from Actelion. He has also received remuneration from Actelion for developing and running workshops and lectures. Acknowledgement: Editorial assistance was provided by Touch Briefings and funded by Actelion. Received: 10 September 2012 Accepted: 17 September 2012 Citation: European Neurological Review, 2012;7(3):153–9 Correspondence: Alasdair Parker, Consultant Paediatric Neurologist, Child Development Centre, Box 107, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK. E: Support: The publication of this article was funded by Actelion. The views and opinions expressed are those of the author and not necessarily those of Actelion. Niemann-Pick disease type C (NPC) is a rare, autosomal recessive, neurodegenerative disorder occurring in all ethnic groups, with an estimated minimal incidence of 0.82 per 100,000 live births. 1 This figure is likely to be an underestimation due to failure to recognise the clinical characteristics and initiate appropriate tests. NPC is a devastating disorder, characterised by a variety of progressive and disabling neurological/psychiatric symptoms and leading to premature death. 2 In the terminal phase, patients are immobile and require tube feeding. 3 The emotional and economic burden imposed by NPC on patients, families and society is disproportionate to the rarity of the disease. 3 (LDL)-derived, unesterified cholesterol. 1 Genetic studies found that mutations in two genes, NPC1 (reported in 90–95 % of patients) and NPC2 (~5 % of patients), play a role in the disrupted transport of unesterified cholesterol, sphingolipids and glycosphingolipids. When there is mutation within one of these genes, accumulation of cholesterol in late endosomes and lysosomes within the spleen, liver and brain occurs. 3,5,6 The wide clinical spectrum of NPC was not recognised until the early 1990s, particularly regarding rapidly fatal cases in infants, and no specific laboratory tests had been available making accurate diagnosis challenging. Delayed presentation of NPC in adolescents and adults has further added to the misdiagnosis of this disorder. Since awareness of the disease and diagnostic techniques have improved, what was once considered to be a childhood condition is now increasingly recognised as an illness affecting individuals of all ages. NPC is a heterogeneous condition with an age at onset ranging from the perinatal period to as late as 50 years of age or older; juvenile onset (ages 6–15 years) is the most common. 1 The age of onset has a major impact on the severity and the course of the disease although progression is linear and independent of this variable (see Figure 1). 2,7 The different ages of disease onset can be used to define the disorder: the generally accepted categories are pre/perinatal, early-infantile, late-infantile, juvenile, and adolescent/adult. 3 Apart from a subset of patients that die at birth, most patients follow a progressive and ultimately fatal neurological disease course. The lifespan of affected individuals can vary from days to years with many dying between 10 and 25 years of age. 1 The biochemistry behind NPC was elucidated in 1984 following studies on cholesterol metabolism. 4 It is a cellular lipid trafficking disorder characterised by lysosomal accumulation of low-density lipoprotein While diagnosis of this rare condition is not difficult per se, mis-/delayed diagnoses are common – possibly due to poor clinical examination and inappropriate tests being performed. Timely detection of NPC is © TOUCH BRIEFINGS 2012 153