Exome Analysis of a New Disease-causing Mutation in a Preterm Neonate with NP-C Disease

Niemann-Pick C disease (NP-C) is an ultra-rare, autosomal recessive, neurovisceral lysosomal lipid storage disorder (LSD) with impaired intracellular lipid trafficking, and an estimated incidence of approximately 1:/90.000 live births [Wassif CA et al. Genet Med 2016; 18(1): 41–48]. Disease severity in most patients is dependent on the degree of neurological involvement, but neurological abnormalities are typically preceded by systemic signs (i.e., cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood) as well non-immune hydrops [Whybra C et al. Orphanet J Rare Dis 2012; 8; 7: 86]. The first neurological symptoms vary with age of onset and include delay in developmental motor milestones, gait disturbances, falls, clumsiness, cataplexy, school problems, and ataxia. The most characteristic sign is vertical supranuclear gaze palsy. Cataplexy, seizures and dystonia as well as dementia are other common features; in adults, psychiatric problems may occur as well [Rohanizadegan M et al., Cold Spring Harb Mol Case Stud 2017; 21; 3: a002147]. Due to the extreme rarity of NP-C disease, establishing a correct diagnosis is challenging, and is often realized only with a substantial delay [Vanier MT., Orphanet J Rare Dis 2010; 5: 16]. Here, we report a case of neonatal NP-C disease diagnosed by prenatal exome analysis, demonstrating a new disease-causing mutation.