Review Identifies Elevated Cancer Prevalence in Patients With ASMD

A small cohort of patients with acid sphingomyelinase deficiency (ASMD) showed higher rates of cancer compared with the general population, according to recent findings.

Acid sphingomyelinase deficiency (ASMD) is a rare inherited lysosomal storage disease that can progress rapidly in infancy or chronically in either infancy or adulthood. Patients with chronic ASMD typically show hepatosplenomegaly, secondary anemia, thrombocytopenia, and interstitial lung disease (ILD). According to a recent review published in the Journal of Clinical Medicine, patients with chronic ASMD may also be at a higher risk of cancer.

Acid sphingomyelinase is an enzyme that breaks down sphingomyelin. ASMD, also known as Niemann-Pick disease types A and B (NPD-A and B), causes sphingomyelin to accumulate in all cells, particularly reticuloendothelial and hepatocyte cells. In NPD-A, the more severe infantile form, neurons are also affected. There are no approved disease-modifying therapies for ASMD, so treatment of the disease includes symptom management. Enzyme replacement therapies have seen promising results in clinical trials.

“Malignancies have been described sporadically in ASMD patients without any specific warning,” the study authors wrote. “However, the role of ASM deficiency in cancer development has already been suggested.” In the review, they retrospectively studied medical records of 31 adult NPD-B patients to gauge the prevalence of cancer in the cohort.

A total of 12 female and 19 male patients at a median age of 48.7 years were included in the study, which took place in France. All patients were 18 years of age or older and had an enzymatically or genetically proven diagnosis of ASMD. Median age at ASMD diagnosis was 8.1 years. A clinical assessment during final follow-up or cancer diagnosis included measures of spleen diameter, ILD severity based on carbon monoxide diffusing capacity of the lung (DLCO) adjusted for hemoglobin, adrenal gland abnormality, family status, tobacco use, and alcohol use.

The overall cancer prevalence was 16.1%. Five patients in the cohort were diagnosed with cancer (1 female patient with breast cancer, 2 males with lung cancer, 1 male with thyroid cancer, and 1 male with bladder cancer). In the overall cohort, 3 patients died, all of whom died from cancer. Splenectomy and tobacco exposure were associated with cancer occurrence, while alcohol, gender, and family status were not associated with cancer occurrence. Splenectomy has also been found to worsen ASMD overall in past studies.

Patients with cancer tended to have worse ASMD symptoms, such as larger spleen size than patients without cancer (25 cm vs. 18 cm). They also had significantly lower DLCO values (29.5% vs. 58.5%; normal value is >80%), despite similar ASM activity in both groups. DLCO values were inversely associated with cancer occurrence, and spleen size was almost significantly correlated with cancer occurrence. However, a multivariate regression analysis found that DLCO and spleen size may not correlate with cancer occurrence, but with each other.

Compared with the estimated rate of cancer in France (2.3%, according to the Global Cancer Observatory), the prevalence of cancer in the study cohort was significantly elevated. The authors hypothesize that ASMD severity may be linked with cancer risk, although 3 of the 5 cancers in the cohort were associated with a mutation that is generally linked to a milder form of ASMD.

Acid sphingomyelinase and ceramide levels play roles in carcinogenesis, the authors note. Acid sphingomyelinase breaks sphingomyelin down into ceramide and phosphocholine, and an imbalance of ceramide and its metabolites may have pro-tumor effects based on prior studies. Therefore, ASMD may inhibit anti-tumor response.

A larger cohort and comparisons to a smoker population would be necessary to confirm the review’s findings, but the authors suggest that quitting tobacco and limiting exposure to carcinogens should be a priority for ASMD patients. Careful cancer screening should also be prioritized in patients with ASMD.


Mauhin W, Levade T, Vanier MT, et al. Prevalence of cancer in acid sphingomyelinase deficiency. J Clin Med. Published online October 28, 2021. doi:10.3390/jcm10215029