Niemann-Pick disease type C

Niemann-Pick disease type C (NPC) is a rare, progressive neurovisceral lysosomal storage disorder caused by impaired intracellular lipid trafficking, leading to the accumulation of unesterified cholesterol and glycosphingolipids in the brain, liver, spleen, and other tissues. It is also known as NPC, Niemann-Pick type C, or juvenile dystonic lipidosis. The disease is caused by mutations in either the NPC1 gene (approximately 95% of cases) or the NPC2 gene (approximately 5% of cases). NPC affects multiple body systems, most prominently the central nervous system and the visceral organs. Clinical presentation is highly variable and depends on the age of onset. In the neonatal and infantile period, patients may present with prolonged neonatal jaundice, hepatosplenomegaly, and liver failure. In childhood and later, the hallmark features are progressive neurological deterioration including cerebellar ataxia, dysarthria, dysphagia, vertical supranuclear gaze palsy (VSGP), gelastic cataplexy (sudden loss of muscle tone triggered by laughter), cognitive decline, and psychiatric symptoms. Seizures and dystonia may also occur. Hepatosplenomegaly may be present but can be subtle or absent in later-onset forms. The disease follows a progressive course, with neurological decline being the primary driver of morbidity and mortality. The age of neurological onset is the strongest predictor of disease severity: early infantile forms progress rapidly, while adolescent and adult-onset forms may have a more protracted course. Diagnosis is supported by filipin staining of cultured fibroblasts showing impaired cholesterol esterification, plasma biomarkers such as oxysterols (notably cholestane-3β,5α,6β-triol) and lysosphingomyelin-509, and confirmed by molecular genetic testing of NPC1 and NPC2. The only disease-specific approved therapy is miglustat (Zavesca), a substrate reduction therapy that inhibits glucosylceramide synthase and has been shown to stabilize or slow the progression of neurological symptoms in some patients. Arimoclomol has also been investigated in clinical trials. Supportive care including management of seizures, swallowing difficulties, and psychiatric symptoms is essential. Research into intrathecal cyclodextrin (2-hydroxypropyl-β-cyclodextrin) and gene therapy is ongoing.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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