Progression of Niemann-Pick disease type C in a paediatric patient

A 17-year-old boy experienced daily seizures and cataplectic episodes. Audiometry revealed hearing loss on the left. Somatosensory evoked potential test showed prolonged cortical responses and central conduction, with weaker right-side cortical response. Minor liver enlargement, dysphagia, rapidly progressing learning disability, memory issues, and increased clumsiness with walking difficulties were present. The first neurological symptoms appeared at 6 years of age.

MRI showed dilatation of the ventricles and sulci, more pronounced in the frontal and parietal areas, indicative of moderate cerebral atrophy.

Additionally, there was mild reduction in volume of both hippocampi, and a markedly reduced midbrain to pons ratio.

T2 and FLAIR imaging revealed mildly hyperintense signal of the periventricular white matter, particularly in the parieto-occipital region and adjacent to the anterior horns of the lateral ventricles.

Niemann-Pick disease type C (NPD-C) is an autosomal recessive lysosomal storage disorder within the Niemann-Pick disease spectrum. This categorization is based on clinical signs, notably hepatosplenomegaly and varying levels of involvement of the central nervous system [1]. Epidemiologically, NPD-C follows an autosomal recessive inheritance pattern, with a minimal estimated incidence of 1 in 120,000 live births [2]. The disease's clinical presentation spans a wide age range, from the neonatal period through adulthood. Phenotypes are categorized by the age of onset and the progression rate of neurological symptoms.

Hepatobiliary manifestations present differently at various ages. In the neonatal period, cholestatic liver failure is observed. During infancy and childhood, hepatosplenomegaly becomes evident.

Neurological symptoms also manifest differently across age groups. Neonates and infants experience delayed developmental milestones. Childhood reveals symptoms like ataxia, falls, supranuclear vertical gaze palsy, and cognitive impairment affecting school performance. Adolescents and adults exhibit ataxia, supranuclear vertical gaze palsy, psychiatric disorders, and cognitive impairment mimicking dementia.

Radiographic features of Niemann-Pick disease type C are limited, with MRI being the preferred imaging method. MRI abnormalities encompass cerebral atrophy, notably in the frontal lobe, as well as cerebellar atrophy [2,3]. Additionally, a hyperintense T2 signal in the parieto-occipital periventricular white matter may also be appreciated [3]. In adult-onset cases, deep grey matter and hippocampal atrophy have been reported [4] and reduced midbrain to pons ratio may also be observed [5].

The diagnosis is suspected based on clinical features and oxysterol biomarker screening. It is confirmed with genetic testing, if two mutated alleles are found in genes NPC1 or NPC2 [6]. Miglustat, the only disease modifying drug in use, has the potential to slow down the advancement of neurological symptoms in patients with later neurological onset (non-infantile forms). However, it is not indicated in profound neurological disease or in pre-symptomatic patients [7,8]. While NPD-C generally leads to premature death, the rate of disease progression varies widely. Notably, the age of onset for systemic symptoms such as hepatosplenomegaly doesn't reliably predict outcomes. In contrast, the emergence of neurological symptoms correlates with survival: individuals experiencing an earlier onset of neurological signs tend to have a shorter life expectancy [2].

Written informed patient consent for publication has been obtained.