Niemann-Pick disease type C, late infantile neurologic onset

Niemann-Pick disease type C (NPC) with late infantile neurologic onset is a rare lysosomal storage disorder characterized by impaired intracellular lipid trafficking, leading to the accumulation of unesterified cholesterol and glycosphingolipids in various tissues, particularly the brain, liver, and spleen. NPC is caused by mutations in the NPC1 gene (approximately 95% of cases) or the NPC2 gene (approximately 5% of cases). The late infantile neurologic onset form typically presents between ages 2 and 6 years and is distinguished from other NPC subtypes by the timing of neurological symptom appearance. Children with this form commonly develop progressive cerebellar ataxia (difficulty with coordination and balance), dysarthria (slurred speech), vertical supranuclear gaze palsy (difficulty moving the eyes vertically), gelastic cataplexy (sudden loss of muscle tone often triggered by laughter), dysphagia (swallowing difficulties), and progressive cognitive decline. Hepatosplenomegaly (enlargement of the liver and spleen) may be present from early life or may have resolved by the time neurological symptoms emerge. Seizures can also occur. The disease follows a progressive neurodegenerative course, and children with late infantile onset generally experience a more rapid neurological decline compared to those with later-onset forms. 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 manifestations in some patients. Miglustat is approved in the European Union and several other countries for the treatment of progressive neurological manifestations in NPC. Supportive and symptomatic management remains essential and includes physical therapy, speech therapy, management of seizures, and nutritional support. Arimoclomol has also been investigated in clinical trials. Research into additional therapies, including intrathecal cyclodextrin (2-hydroxypropyl-β-cyclodextrin), is ongoing.

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