Niemann-Pick disease type C, adult neurologic onset

Niemann-Pick disease type C (NPC) with adult neurologic onset is a rare lysosomal storage disorder caused by mutations in the NPC1 gene (approximately 95% of cases) or the NPC2 gene (approximately 5% of cases). These mutations impair intracellular lipid trafficking, leading to the accumulation of unesterified cholesterol and glycosphingolipids in lysosomes and late endosomes of cells throughout the body, particularly in the brain, liver, and spleen. While NPC can present at any age, the adult-onset neurologic form typically manifests after age 15 and often in the second or third decade of life, though diagnosis is frequently delayed due to the subtlety and variability of early symptoms. The adult neurologic onset form is characterized by progressive neurological deterioration. Key clinical features include cerebellar ataxia (difficulty with coordination and balance), vertical supranuclear gaze palsy (impaired voluntary vertical eye movements, especially downward gaze), dysarthria (slurred speech), dysphagia (difficulty swallowing), cognitive decline, and psychiatric manifestations. Psychiatric symptoms — including psychosis, depression, behavioral disturbances, and cognitive impairment resembling early-onset dementia — are particularly prominent in the adult-onset form and may precede other neurological signs by years, often leading to initial misdiagnosis as a primary psychiatric disorder. Hepatosplenomegaly (enlargement of the liver and spleen) may be present but is often less pronounced or absent in adult-onset cases compared to childhood forms. Dystonia, gelastic cataplexy (sudden loss of muscle tone triggered by laughter or strong emotions), and seizures may also occur. The only disease-specific approved therapy is miglustat (Zavesca), which inhibits glucosylceramide synthase and has been shown to stabilize or slow the progression of neurological symptoms in some patients. Miglustat is approved in the European Union and several other countries for the treatment of progressive neurological manifestations of NPC. Management is otherwise supportive and multidisciplinary, involving neurologists, psychiatrists, speech therapists, physiotherapists, and other specialists. Arimoclomol has been investigated in clinical trials but did not meet its primary endpoint. Early diagnosis and initiation of treatment are important, as neurological damage is progressive and largely irreversible. Genetic counseling is recommended for affected families.

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