Deficiency of the lysosomal enzyme acid sphingomyelinase (ASM; E.C. 220.127.116.11), caused by mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene, results in storage of sphingomyelin in lysosomes and altered cell signaling at the cell membrane. The disorder has an autosomal recessive pattern of inheritance and is extremely rare. The estimated birth prevalence reported for The Netherlands is 0.53 per 100.000, which is consistent with other reports of 0.5 up to 1 per 100.000.
Complete absence of ASM activity results in the rapidly fatal infantile-onset Niemann Pick disease type A or infantile neurovisceral ASMD (MIM 257200). These infants present with failure to thrive and progressive neurological manifestations ultimately leading to death in early childhood.
The more attenuated form, Niemann Pick type B or chronic visceral ASMD (MIM 607616) is characterized by hepatosplenomegaly, pulmonary involvement and the absence of neurological symptoms. Patients often survive into adulthood. An intermediate phenotype of Niemann Pick type B , also referred to as chronic neurovisceral ASMD, has been described with a combination of prominent visceral disease and slow progression of mild neurological features. Because of the overlap in clinical presentations, the disorder is best regarded a single entity with a phenotypic spectrum.
Pathophysiology and phenotypes
Tissues affected by sphingomyelin storage are the spleen, liver and lungs. Sphingomyelin accumulation in brain is only seen in Niemann Pick disease type A. The infants have hepatosplenomegaly , lung involvement and progressive neurological manifestations leading to feeding difficulties and recurrent pulmonary infections. These infants ultimately die of respiratory failure or liver failure.
In the more attenuated form, Niemann Pick type B ,key features are hepatosplenomegaly and restrictive lung disease due to pulmonary involvement. Thrombocytopenia is often present due to splenomegaly and possibly bone marrow infiltration. Bone symptoms are less frequent but joint involvement has been described. Lipid profiles typically show low HDL cholesterol levels and mildly elevated LDL cholesterol levels. This atherogenic lipid profile may result in premature atherosclerosis, as is described in many of these patients. Other complications of this phenotype are hepatic fibrosis and eventually cirrhosis.
Currently the only treatment available for all phenotypes of Niemann Pick type A/B is supportive care. In severely affected infants with Niemann Pick type A this may consist of placement of a feeding tube and treatment of recurrent infections.
Patients with the attenuated form Niemann Pick type B are treated with cholesterol lowering agents such as statins to reduce atherogenic lipid profiles. Liver transplantation has been performed in patients with end-stage liver failure.
Unfortunately there is no specific treatment for Niemann Pick type A/B . Two case reports of allogeneic bone marrow transplantation or HSCT for Niemann Pick type A and B have been described, which were not successful.
Enzyme replacement therapy
Enzyme replacement therapy with recombinant ASM (olipudase alfa, Sanofi Genzyme) is under clinical evaluation for patients with Niemann Pick type B, the attenuated phenotype. Preliminary data show promising results.
SPHINX is officially acknowledged as center of expertise for Niemann Pick disorders. All Dutch patients with Niemann Pick type B will be referred to us after diagnosis for patient care and research.
The Amsterdam UMC participates in several research projects such as the international enzyme replacement trial.
More information on this and other research projects can be found in the research section.