Newborn screening for acid sphingomyelinase deficiency in Illinois.

Background

Acid Sphingomyelinase Deficiency (ASMD) is a rare lysosomal storage disorder caused by reduced activity of the acid sphingomyelinase (ASM) enzyme; due to biallelic variants in the SMPD1. There are 3 distinct phenotypes, which are differentiated based on age of onset and manifestations. While there is no cure for ASMD, comprehensive care guidelines and enzyme replacement therapy are available, making an early diagnosis crucial. Newborn screening (NBS) for ASMD is possible through measurement of ASM activity in dried blood spots.

Methods

Following a one-year pilot study, Illinois (IL) was the first in the US to initiate statewide NBS for ASMD on 06/01/2015. In IL, infants with low ASM activity (<15% of daily median) are referred to metabolic centers for further diagnostic evaluation.

Results

Since 2014, we have evaluated 7 patients with positive newborn screens. All were subsequently diagnosed with ASMD or suspected ASMD through enzymatic and genetic testing. Our NBS population includes one sibling pair and 5 other unrelated patients. On diagnostic testing, all patients had deficient ASM activity (range: 0.12-0.26, reference range: >0.30 nmol/hr). The sibling pair was compound heterozygous for two well-characterized SMPD1 variants, Q294K and R610del, predictive of Type B disease. The other 5 patients had genotypes that were novel or with conflicting reports in the literature. Monitoring is conducted on an annual or biannual basis, which includes a combination of physical exam, laboratory investigations and imaging.

Conclusion

There are multiple conclusions that can be drawn from our data. First, NBS for ASMD is very specific: all that have screened positive through the NBS program were found to have low ASM enzyme and biallelic SMPD1 variants. However, we cannot rule out the possibility of a pseudodeficiency. Second, we observed many novel genotypes in our patients, making the prognostication of their phenotype difficult.