Null syndrome

Null syndrome, also known as Niemann-Pick disease type C2 (NPC2), is a rare autosomal recessive lysosomal storage disorder classified under the sphingolipidoses (ICD-10: E75.2). It is caused by mutations in the NPC2 gene, which encodes a small soluble lysosomal protein essential for intracellular cholesterol trafficking. Deficiency of the NPC2 protein leads to abnormal accumulation of unesterified cholesterol and glycosphingolipids within lysosomes and late endosomes, primarily affecting the brain, liver, spleen, and lungs. Clinical features are similar to Niemann-Pick disease type C1 and include progressive neurological deterioration with cerebellar ataxia, vertical supranuclear gaze palsy, dysarthria, dysphagia, cognitive decline, and gelastic cataplexy. Hepatosplenomegaly is common and may present in infancy or early childhood. Some patients present with neonatal cholestatic jaundice or fatal neonatal liver disease. A severe neonatal-onset pulmonary form with respiratory failure has also been described, which appears to be more frequent in NPC2 than in NPC1 disease. Treatment is primarily supportive and symptomatic. Miglustat (Zavesca), a substrate reduction therapy that inhibits glucosylceramide synthase, has been approved in some countries for the treatment of progressive neurological manifestations in Niemann-Pick disease type C and may slow neurological progression. Multidisciplinary management including speech therapy, physiotherapy, and nutritional support is essential. Research into intrathecal therapies, gene therapy, and other disease-modifying approaches is ongoing. Prognosis varies depending on age of onset, with earlier onset generally associated with more rapid disease progression.

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