9 Identifying Np-C Early in Paediatric Patients

Abstract

Niemann-Pick disease, type C (NP-C) is an autosomal recessive, progressive and ultimately fatal, neurovisceral lysosomal storage disorder involving the accumulation of unesterified cholesterol and glycolipids. Two genes (NPC1 and NPC2) are involved in its pathogenesis. The estimated incidence of NP-C is 1:150,000 live births; however, the true incidence is probably significantly higher, as there is ample evidence that many patients remain undiagnosed. Clinical presentation in NP-C is extremely heterogenous, often resulting in misdiagnosis. The first signs and symptoms may occur from the prenatal period; through to childhood and late adulthood. The absence of a simple diagnostic test for NP-C precludes the inclusion of the disease in general metabolic screening panels. The following signs and symptoms should lead to inclusion of NP-C in a differential diagnosis in paediatric patients: prolonged unexplained neonatal jaundice; hepatosplenomegaly or isolated splenomegaly; and neurological signs including vertical supranuclear gaze palsy, ataxia and/or dystonia, seizures and/or cataplexia, and early and progressive dementia. At present, definitive diagnosis depends on demonstrating impaired cholesterol transport and homeostasis in cultured skin fibroblasts followed by genetic testing for mutations in NPC1 and NPC2. A simple diagnostic tool based on a scoring system for various visceral, neurological and psychiatric signs and symptoms is currently being developed to facilitate decision-making regarding the need for diagnostic biochemical or genetic studies for NP-C. With the recent approval of miglustat (Zavesca®) as disease-modifying therapy for NP-C, treatment can now be aimed toward stabilising neurological disease. Early diagnosis of NPC has, thus, become even more important.