Chronic visceral acid sphingomyelinase deficiency (ORPHA:77293)
A rare autosomal recessive, chronic, acid sphingomyelinase deficiency characterized clinically by onset in childhood with hepatosplenomegaly, growth retardation, interstitial lung disease and absence of neurodegenerative disorders.
Epidemiology
Epidemiological data is not available specifically for Niemann-Pick disease type B (NPD-B); however, the estimated birth prevalence of acid sphingomyelinase deficiency (both NPD types A and B combined) is between 1/167,000-250,000 in Europe.
Clinical description
NPD-B is characterized by hepatosplenomegaly with progressive hypersplenism and stable liver dysfunction, gradual deterioration in pulmonary function, osteopenia, and atherogenic lipid profile. Most patients are diagnosed in infancy or childhood. The degree of hepatosplenomegaly ranges from mild to massive. Those with significant organomegaly have hypersplenism with secondary thrombocytopenia. Pulmonary involvement is common in affected individuals of all ages. Most affected individuals have evidence of interstitial lung disease. Abnormal linear growth and delayed skeletal maturation are common in children and adolescents, and can result in significant short stature in adulthood. A proatherogenic lipid profile is seen early in the disease course and some patients develop coronary artery disease. Neurologic manifestations occur infrequently and most of patients had minor and non-progressive findings. Up to one third of individuals with NPD-B have a cherry-red macula.
Etiology
NPD-B is caused by mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene (locus 11p15.4), leading to decreased activity of acid sphingomyelinase (ASM), which results in lysosomal accumulation of sphingomyelin (SM) and secondary elevation of cholesterol and other lipids.
Diagnostic methods
The diagnosis of NPD-B is established by detection of biallelic pathogenic variants in SMPD1 and/or residual acid sphingomyelinase enzyme activity (in peripheral blood lymphocytes, cultured skin fibroblasts or dry blood spots (DBS)). The de-acylated form of sphingomyelin (lyso-SPM) is increased in NPD-B and could be measured in plasma and DBS. Histology shows lipid-laden macrophages (foam-cells) in the bone marrow.
Differential diagnosis
Differential diagnosis includes other lysosomal storage diseases such as Gaucher disease, GM2-gangliosidosis, Niemann-Pick disease type C, lysosomal acid lipase deficiency, hematological malignancy, and primary hepatic disease (e.g., fatty liver, autoimmune, chronic hepatitis B-related, cryptogenic cirrhosis).
Antenatal diagnosis
Prenatal diagnosis for pregnancies at increased risk is possible by testing of ASM enzyme activity or by DNA- analysis if both SMPD1 pathogenic variants in the family are known.
Genetic counseling
NPD-B is inherited in an autosomal recessive manner. Genetic counseling should be offered to at-risk couples informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Currently, only supportive care is available for patients with NPD-B and includes management of coagulopathy and end-stage liver disease manifestations; supplemental oxygen for symptomatic pulmonary disease, and treatment of hyperlipidemia and osteopenia/osteoporosis. Enzyme replacement therapy (ERT) with recombinant human acid sphingomyelinase is in clinical development for the treatment of the non-neurologic manifestations of the disease.
Prognosis
Patients with NPD-B may live till late childhood or early adulthood. However, they develop many complications of the disease, significantly affecting the quality of life. The leading cause of death is progressive loss of pulmonary function.

                            Last update: 
                            April 2021


                            - Expert reviewer(s): 
                            Dr Ekaterina ZAKHAROVA