Niemann-Pick disease type C, severe perinatal form

Niemann-Pick disease type C, severe perinatal form (also known as NPC severe perinatal form) is the most severe clinical presentation of Niemann-Pick disease type C (NPC), a rare lysosomal storage disorder caused by mutations in the NPC1 or NPC2 genes. These genes encode proteins essential for intracellular cholesterol and lipid trafficking. When these proteins are dysfunctional, unesterified cholesterol and glycosphingolipids accumulate in lysosomes and late endosomes, leading to progressive cellular damage across multiple organ systems. This severe perinatal form manifests in the neonatal period, often presenting before or shortly after birth with fetal hydrops (abnormal fluid accumulation in fetal tissues), severe hepatosplenomegaly, progressive liver failure with cholestatic jaundice, and ascites. Affected neonates may also develop respiratory failure due to pulmonary involvement. The liver disease is rapidly progressive and often fatal within the first weeks to months of life, distinguishing this form from the later-onset variants of NPC that are characterized primarily by progressive neurological deterioration. Some infants may also exhibit hypotonia and feeding difficulties. Currently, there is no cure for the severe perinatal form of NPC. Miglustat, a substrate reduction therapy approved for the neurological manifestations of NPC in some countries, has limited applicability in this form due to the rapid and predominantly visceral disease course. Management is primarily supportive and palliative, focusing on nutritional support, management of liver failure, and respiratory care. The prognosis for the severe perinatal form is very poor, with most affected infants succumbing to the disease in early infancy. Genetic counseling is recommended for affected families.

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