Biliary atresia as initial manifestation of Niemann Pick C1 disease

Abstract

Niemann Pick Type C1 (NPC1) is a severe neurodegenerative disease with letal prognosis. Several atypical manifestations has been published so far. We report a now 3 y old boy, who was born after uneventful pregnancy and birth. Postpartum the boy presented hypoglycaemia and intermittent direct hyperbilirubinaemia. The liver biopsy showed a severe cholestasis with ductopenia without proliferation of bile ducts but also additional features like periductal infiltrations and a giant cell hepatitis. These changes are compatible with intrahepatic bile duct hypoplasia and extrahepatic bile duct atresia. Due to progressive cholestasis a Kasai surgery was performed at the age of 2 months. During the second year of life the boy developed a severe dystrophy, recurrent pulmonal infections due to swallowing difficulties and loss of abilities like independent sitting and speaking few words. At the age 3y the boy presented muscular hypotonia at rest and spastic movements, positive Babinski sign, horizontal nystgamus, tremor, fasciculations of the tongue and hepatosplenomegaly. The brain MRT showed leukodystrophy. Bone marrow analysis showed foam cells. The positive filipin test in fibroblasts, indicating pathological accumulation of cholesterol in the golgi and lysosomes, confirmed the diagnosis of NPC1. Sequencing of the NPC1 gene presented a novel homozygous missense mutation G1240R in the c-terminal transmembrane domain. This amino acid is conserved down to drosophila. The NPC1 protein has a function in the cholesterol homoestasis of the cell, mutations in the NPC1 protein are causing accumulation of sphingolipis in lysosomes.