The underdiagnosis of lysosomal acid lipase deficiency (LAL-D) might not be as common as initially thought, according to a preprint published in Research Square.

Kwok and colleagues aimed to study the effectiveness of testing lysosomal acid lipase (LAL) activity in a dried blood spot (DBS) as a screening tool for LAL-D. The sample included patients with suggestive clinical or paraclinical findings of LAL-D from either a liver or lipid and diabetic clinic from 8 centers in the UK.

Blood samples from a fingerpick or venous access allowed to determine LAL activity which diagnosed LAL-D with a resulting 0.03 nmol/punch/h or less in the DBS. Individuals with LAL activity of 0.25 nmol/punch/h or lower, and/or beta-galactosidase activity >85 pmol/punch/h, and/or a pathological liver biopsy consistent with LAL-D also underwent genetic testing.

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Despite sampling 1730 participants and conducting 27 genetic tests, no individuals were diagnosed with LAL-D. Although these results came up as unexpected, they still yield valuable information regarding this disease.

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“Our results do not suggest that a significant number of patients being seen in Lipid, Diabetic or Liver Clinics have undiagnosed [LAL-D]. However, given the ease of diagnostic testing using a DBS and the potential availability of [enzyme replacement therapy], testing for [LAL-D] is probably still recommended in atypical cases albeit not as first line,” the authors said.

The great impact that novel enzyme replacement therapies have on patients with LAL-D has increased the interest of healthcare providers to diagnose this disease promptly. However, determining such cases and carriers requires genetic methods that result in costly, hence the need to develop faster and more accessible screening methods.

“It is thought that [LAL-D} is an under-diagnosed condition but, even using the triggers for LAL testing of combined dyslipidaemia and liver dysfunction, the detection rate remains low,” the authors said. “A recent epidemiological study looking at the incidence of all currently known LAL mutations has given an estimated prevalence of 1 in 177,000 therefore confirming it to be within the ultra-rare classification of diseases.”


Kwok S, Soran H, Barr M. Detection of lysosomal acid lipase deficiency in tertiary referral centers. Published online February 11, 2022. doi:10.21203/