Pediatric liver transplantation for neonatal-onset Niemann-Pick disease type C: Japanese multicenter experience.

Niemann-Pick disease type C (NPC) is a rare autosomal recessive inherited disease characterized by lysosomal accumulation of free cholesterol in macrophages within multiple organs. Infantile-onset NPC often presents with jaundice and hepatosplenomegaly from birth, but these symptoms usually improve during early childhood, and it rarely progresses to liver failure. We report three cases from different hospitals in Japan; the patients developed neonatal-onset NPC, and liver transplantation (LT) was performed as a life-saving procedure. LT was performed at 19 days, 59 days, and 4 months of age, respectively. The last patient was diagnosed with NPC before LT, while the first two patients were diagnosed with neonatal hemochromatosis at LT. In these two patients, the diagnosis of NPC was made more than a year after LT. Even though oral administration of miglustat was started soon after the diagnosis of NPC, all patients showed neurological regression and required artificial respiratory support. All patients survived more than one year after LT; however, one patient died due to tracheal hemorrhage at 4.5 years of age, and another one patient was suspected as recurrence of NPC in liver graft. In conclusion, while LT may be a temporary life-saving measure in patients with neonatal-onset NPC leading to liver failure, the outcome is poor especially due to neurological symptoms. A preoperative diagnosis is thus critical.

Developmental outcome post allogenic bone marrow transplant for Niemann Pick Type C2.

Niemann Pick Type C2 (NPC2) is a rare autosomal recessive disease caused by mutations in the NPC2 gene (OMIM 601015). Clinically, NPC2 presents in most cases in the neonatal period with inflammatory lung disease, which may lead to death in the first year. If patients survive the neonatal period, they may develop a severe neurological disease. Here we present the developmental and neurological follow up at 5 years of age of a child with NPC2 successfully treated with allogenic bone marrow transplantation (BMT) at the age of 16 months. A homozygous p.E20X sequence variation previously associated with a severe phenotype was identified. In contrast to the previously reported patients with the same mutations, our patient has no respiratory compromise and has made some developmental progress (especially gross motor), though is significantly delayed (particularly in speech and language). Haematopoietic stem cell transplantation (HSCT) could be considered for patients with this mutation as long as performed early in the course of the disease.

Successful allogeneic bone marrow transplant for Niemann-Pick disease type C2 is likely to be associated with a severe 'graft versus substrate' effect.

Niemann-Pick disease type C2 (NPC2) is caused by the inherited deficiency of a lysosomal cholesterol transport protein, NPC2 protein. Many cases of NPC2 present in early infancy with inflammatory lung disease, with subsequent severe neurological disease and death in early childhood. This disease is theoretically correctable by bone marrow transplantation (BMT), as the NPC2 protein is small and soluble and secreted and recaptured by the mannose-6-phosphate pathway. In this report we describe the first successful allogeneic bone marrow transplantation for this condition in a 16-month-old boy homozygous for the NPC2 p.E20X mutation, which has hitherto been reported to cause disease with a severe phenotype. During BMT there was an initial improvement of the established respiratory illness, with the immune suppression associated with transplant conditioning, but there was subsequent marked deterioration at the time of immune reconstitution and donor cell engraftment. This 'graft versus substrate' reaction was managed with intensive immune suppressant therapy, and it gradually resolved as the substrate was cleared by the engrafted donor macrophages. All immune suppression was withdrawn 18 months after transplantation, and his respiratory illness has resolved. He walked independently at 24 months and is continuing to reach development milestones after receiving his transplant. We conclude that the successful treatment of Niemann-Pick C2 therefore seems likely to be associated with a severe post-transplantation 'graft versus substrate' reaction that requires intense immune suppression before eventual resolution.