Identification of rare diseases by screening a population selected on the basis of routine pathology results-the PATHFINDER project: lysosomal acid lipase/cholesteryl ester storage disease substudy.

AIMS: Lysosomal acid lipase deficiency (LALD) is an autosomal recessive disorder of cholesterol ester storage associated with hepatic disease, cirrhosis and accelerated atherosclerosis. Its prevalence in the general population, patients with dyslipidaemia and raised transaminases is unclear. This study attempted to identify the prevalence of LALD from patients with abnormal results in laboratory databases.

METHODS

Electronic laboratory databases were interrogated to identify from clinical biochemistry records patients with a phenotype of low high-density lipoprotein-cholesterol (≤0.85 mmol/L; 33 mg/dL) and with elevated alanine or aspartate transaminases (≥60 IU/L) on one occasion or more over a 3-year time interval. Patients were recalled, and a dried blood spot sample was collected for lysosomal acid lipase determination by a fluorimetric enzyme assay. Histopathology databases of liver biopsies were interrogated for patients with features of 'microvesicular cirrhosis' or 'cryptogenic cirrhosis' in the report. Histological blocks were sampled, and samples were analysed by next-generation sequencing for the presence of mutations in the LAL gene.

RESULTS

Samples were obtained from 1825 patients with dyslipidaemia and elevated transaminases. No cases of LALD were identified. Liver biopsies were obtained from six patients. DNA extraction was successful from four patients. Two patients were homozygous for the LAL c.46A>C;p.Thr16Pro unclassified variant in exon 2.

CONCLUSIONS

Pathology databases hold routine information that can be used to identify patients with specific patterns of results or those who had biopsies to allow targeted testing for possible causes of disease. Biochemical screening suggests that the gene frequency of LAL deficiency in adults is less than 1 in 100.