Niemann-Pick disease type C Orphanet Journal of Rare Diseases

Niemann-Pick C disease (NP-C) is a neurovisceral atypical lysosomal lipid storage disorder with an estimated minimal incidence of 1/120 000 live births. The broad clinical spectrum ranges from a neonatal rapidly fatal disorder to an adult-onset chronic neurodegenerative disease. The neurological involvement defines the disease severity in most patients but is typically preceded by systemic signs (cholestatic jaundice in the neonatal period or isolated spleno- or hepatosplenomegaly in infancy or childhood). The first neurological symptoms vary with age of onset: delay in developmental motor milestones (early infantile period), gait problems, falls, clumsiness, cataplexy, school problems (late infantile and juvenile period), and ataxia not unfrequently following initial psychiatric disturbances (adult form). The most characteristic sign is vertical supranuclear gaze palsy. The neurological disorder consists mainly of cerebellar ataxia, dysarthria, dysphagia, and progressive dementia. Cataplexy, seizures and dystonia are other common features. NP-C is transmitted in an autosomal recessive manner and is caused by mutations of either the NPC1 (95% of families) or the NPC2 genes. The exact functions of the NPC1 and NPC2 proteins are still unclear. NP-C is currently described as a cellular cholesterol trafficking defect but in the brain, the prominently stored lipids are gangliosides. Clinical examination should include comprehensive neurological and ophthalmological evaluations. The primary laboratory diagnosis requires living skin fibroblasts to demonstrate accumulation of unesterified cholesterol in perinuclear vesicles (lysosomes) after staining with filipin. Pronounced abnormalities are observed in about 80% of the cases, mild to moderate alterations in the remainder ("variant" biochemical phenotype). Genotyping of patients is useful to confirm the diagnosis in the latter patients and essential for future prenatal diagnosis. The differential diagnosis may include other lipidoses; idiopathic neonatal hepatitis and other causes of cholestatic icterus should be considered in neonates, and conditions with cerebellar ataxia, dystonia, cataplexy and supranuclear gaze palsy in older children and adults. Symptomatic management of patients is crucial. A first product, miglustat, has been granted marketing authorization in Europe and several other countries for specific treatment of the neurological manifestations. The prognosis largely correlates with the age at onset of the neurological manifestations.

At a glance: the largest Niemann-Pick type C1 cohort with 602 patients diagnosed over 15 years

Identification of Niemann–Pick type C disease in the group of ataxias of unclear origin in adults - Klyushnikov - Annals of Clinical and Experimental Neurology

Imaging of neuroinflammation in adult Niemann-Pick type C disease

Rapid Diagnosis of 83 Patients with Niemann Pick Type C Disease and Related Cholesterol Transport Disorders by Cholestantriol Screening - eBioMedicine

Clinical disease progression and biomarkers in Niemann–Pick disease type C: a prospective cohort study, Orphanet Journal of Rare Diseases

Journal of Rare Disorders: Diagnosis & Therapy

Adult‐onset Niemann–Pick disease type C masquerading as spinocerebellar ataxia - Vo - 2022 - Molecular Genetics & Genomic Medicine - Wiley Online Library

Severely impaired CTL killing is a feature of the neurological disorder Niemann-Pick disease type C1 - ScienceDirect

Patient with Niemann-Pick disease type C: over 20 years' follow-up

Infantile form of Niemann-Pick disease type C with demyelination: An uncommon feature

Patient with Niemann-Pick disease type C: over 20 years' follow-up

Niemann-Pick disease type C, Orphanet Journal of Rare Diseases

Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1–2 trial - The Lancet