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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
  1. Timothy M Reynolds1,2,
  2. Clare Mewies1,
  3. John Hamilton3,
  4. Anthony S Wierzbicki4
  5. on behalf of the PATHFINDER Project Collaboration group
    1. 1 Department of Chemical Pathology, Queen’s Hospital, Burton, UK
    2. 2 Division of Health Sciences, Wolverhampton University, Wolverhampton, UK
    3. 3 Biochemistry Department, Queen Elizabeth University Hospital Laboratory, Glasgow, UK
    4. 4 Department of Metabolic Medicine/Chemical Pathology, Guy’s & St Thomas’ Hospitals, London, UK
    1. Correspondence to Professor Timothy M Reynolds, Department of Chemical Pathology, Queen’s Hospital, Burton DE13 0RB, UK; tim.reynolds{at}


    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.

    • inherited metabolic disease
    • lysosomal acid lipase
    • screening
    • atherosclerosis cardiovascular disease
    • hepatic disease
    • cirrhosis

    Statistics from


    • Handling editor Tahir S Pillay.

    • Contributors TMR conceived of the project, wrote the protocol, negotiated funding, arranged approvals and wrote the manuscript. ASW assisted in writing the manuscript and was involved in discussions at protocol-writing stage. CM administered the project, ensured collaborating centres had supplies and collected results. JH analysed dried blood spot samples.

    • Funding This work was supported by an investigator grant from Synageva BioPharma Ltd., 1A Local Board Road, Watford, Hertfordshire, WD17 2JP, UK. Research nurses funded by the National Institute of Health Research.

    • Competing interests TMR is currently in receipt of project grants from: Synageva BioPharma Ltd., 1A Local Board Road, Watford, Hertfordshire, WD17 2JP, UK; Genzyme Therapeutics Ltd, 4620 Kingsgate, Cascade Way, Oxford Business Park South, Oxford OX4 2SU, UK; Shire, Hampshire International Business Park, Chineham, Basingstoke, Hampshire, RG24 8EP, UK. Other authors have no competing interest to declare.

    • Ethics approval This study was ethically reviewed and approved by the National Research Ethics Service (NRES) Committee East Midlands – Leicester (reference number 12/EM/0321) on 27 September 2012 and NRES Committee East Midlands – Northampton (reference number 14/EM/1153) on 15 October 2014.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement Data can be obtained by contacting the chief investigator, Timothy M Reynolds.

    • Collaborators PATHFINDER Project Collaboration group: Dr Patrick Deegan, Addenbrooke’s Hospital; Dr Alan Jones, Heart of England; Dr Taruna Likari, Ipswich Hospital; Dr Adie Viljoen, Lister Hospital, Stevenage; Dr David James, Musgrove Park Hospital, Taunton; Professor Rousseau Gama, New Cross, Wolverhampton; Dr Nigel Capps, Princess Royal, Telford; Professor Timothy M Reynolds, Queen’s Hospital, Burton; Dr Tristan Richardson, Royal Bournemouth Hospital; Jackie Smith, Russells Hall Hospital, Dudley; Dr Kevin Evans, Stafford Hospital; Dr Anthony Wierzbicki, St Thomas’ Hospital, London; Dr Anthony Fryer, University Hospital North Mids; Dr Farial Alubaidi, Kings Mill Hospital.

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