Newborn Screening Test Shows Promise for Detecting Late Infantile Batten Disease, Study Shows

Researchers have developed a new newborn screening test that uses dried blood spots to more accurately diagnose late infantile Batten disease, along with six other lysosomal storage disorders.

Findings were published in the study, “Multiplex Tandem Mass Spectrometry Enzymatic Activity Assay for Newborn Screening of the Mucopolysaccharidoses and Type 2 Neuronal Ceroid Lipofuscinosis,” in the journal Clinical Chemistry.

Late infantile Batten disease, also called CLN2 or Jansky-Bielschowsky disease, belongs to the group of lysosomal storage disorders caused by deficiencies in enzymes that break down waste molecules in cellular structures called lysosomes.

CLN2 is caused by a deficiency, or loss of function, of the tripeptidyl peptidase 1 (TPP1) enzyme due to mutations in the TPP1 gene. As a result, waste molecules accumulate in brain cells, leading to nerve damage and cell death.

Late infantile Batten disease now has an approved enzyme replacement therapy called Brineura, and early diagnosis is crucial to allow for treatment and prevent further degeneration. However, a delay in diagnosis is common due to nonspecific symptoms, low disease awareness, and limited access to diagnostic testing in some regions.

While it is recommended that analysis of TPP1 enzyme activity be performed in white blood cells, these samples are particularly sensitive to temperature extremes or to delays in shipping, potentially reducing the reliability of the analysis.

Since dried blood spot samples are more resistant to these factors, they are likely to become the sample of choice for newborn screening approaches to detect CLN2 disease.

Researchers at Washington University in St. Louis developed a multiple diagnostic test for newborn screening that can detect defects in seven lysosomal enzymes, including TPP1, in dried blood spots.

It is based on a powerful method, called liquid chromatography combined with tandem mass spectrometry (LC-MS/MS), that separates all the molecules in a sample and detects their levels of activity with a high degree of specificity and sensitivity.

The diagnostic test was developed to detect the levels of TPP1 enzyme, as well as six other lysosomal enzymes associated with different types of lysosomal storage disorders called mucopolysaccharidoses (MPS).

The screening was performed in 62 healthy newborns, four adults, seven CLN2 patients, and seven patients who had two different types of MPS.

Among the seven lysosomal enzymes analyzed, TPP1 had the highest activity in healthy newborns, and the lowest (3.7% of the normal mean activity) in CLN2 patients. TPP1 activity in CLN2 patients was also lower than in patients affected by other lysosomal storage disorders.

According to the researchers, this diagnostic test can more accurately and effectively distinguish newborns with CLN2 from healthy ones.

“We hope that the large analytical range of LC-MS/MS enzymatic assays will lead to a separation of affected individuals from those with pseudodeficiencies as well as to estimate the severity of the disease, for example early vs late onset forms,” the researchers wrote.