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

Reynolds, Tim; Mewies, Clare; Hamilton, John; Wierzbicki, Anthony S.

doi:10.1136/jclinpath-2017-204727

Cited by 12 publications

(7 citation statements)

References 15 publications

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“…A recent UK-based study among a cohort (n-1825 patients) with dyslipidaemia and elevated transaminases failed to identify a case of LAL deficiency. 8 Liver biopsies from six of the study patients enabled DNA extraction from four cases; two of these were found to be homozygous for the LAL c.46A>C;p.Thr16Pro…”

Section: Diagnosis and Differential Diagnosismentioning

confidence: 99%

<p>Lysosomal Acid Lipase Deficiency: Therapeutic Options</p>

Pastores¹,

Hughes²

2020

DDDT

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Lysosomal acid lipase (LAL) deficiency is a metabolic (storage) disorder, encompassing a severe (Wolman disease) and attenuated (Cholesterol ester storage disease) subtype; both inherited as autosomal recessive traits. Cardinal clinical features include the combination of hepatic dysfunction and dyslipidemia, as a consequence of cholesteryl esters and triglyceride accumulation, predominately in the liver and vascular and reticuloendothelial system. Significant morbidity can arise, due to liver failure and/or atherosclerosis; in part related to the severity of the underlying gene defect and corresponding enzyme deficiency. Diagnosis is based on demonstration of decreased LAL enzyme activity, complemented by analysis of the cognate gene defects. Therapeutic options include dietary manipulation and the use of lipid-lowering drugs. Sebelipase alfa, a recombinant enzyme replacement therapy, has garnered regulatory approval, following demonstration of improvements in diseaserelevant markers and clinical benefit in clinical trials, which included increased survival in the most severe cases.

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Section: Diagnosis and Differential Diagnosismentioning

confidence: 99%

<p>Lysosomal Acid Lipase Deficiency: Therapeutic Options</p>

Pastores¹,

Hughes²

2020

DDDT

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“…As such, it is worthwhile to investigate LALdeficiency in young lean-NAFLD patients with severe hypercholesterolemia (LDL higher than 160 mg/dL or 130 mg/dL in patients taking lipid-lowering drugs; and HDL lower than 40 mg/dL in men and 50 mg/dL in women), with cryptogenic cirrhosis, or with liver biopsy that shows microvesicular steatosis [152] . In fact, one third of patients with microvesicular steatosis or cryptogenic cirrhosis may have LAL-deficiency [153] .…”

Section: Hepatic Steatosis As a Manifestation Of Other Liver Diseasesmentioning

confidence: 99%

Nonalcoholic fatty liver disease in lean subjects: is it all metabolic-associated fatty liver disease?

Machado¹

2020

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“…Identification of patients with rare diseases is problematic as the possibility of the rare disease has to be considered before a highly specialist test is ordered. The PATHFINDER project is based on the premise of using routine laboratory results to identify patients who should be tested for inherited errors of metabolism 6‐8 . The objective of this study was to use a biomarker panel comprising ferritin concentration, ALP levels and platelet count for initial screening to identify patients with potential GD from primary care or outpatient laboratory samples.…”

Section: Introductionmentioning

confidence: 99%

Screening for patients with Gaucher's disease using routine pathology results: PATHFINDER (ferritin, alkaline phosphatase, platelets) study

et al. 2021

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Aims Lysosomal β‐glucocerebrosidase A (GBA) deficiency causes Gaucher disease (GD), a recessive disorder caused by bi‐allelic mutations in GBA. The prevalence of GD is associated with ethnicity but largely unknown and potentially underestimated in many countries. GD may manifest with organomegaly, bone involvement, and neurological symptoms as well as abnormal laboratory biomarkers. This study attempted to screen for GD in patients using abnormal platelet, alkaline phosphatase (ALP), and ferritin results from laboratory databases. Methods Electronic laboratory databases were interrogated using a 2‐ to 4‐year time interval to identify from clinical biochemistry records patients with a phenotype of reduced platelets (<150 × 109/L) and either elevated ALP (>130 iu/L) or ferritin [>150 (female) or >250 µg/L (male)]. The mean value over the screening window was used to reduce variability in results. A dried blood spot sample was collected for the determination of GBA activity in patients meeting these criteria. If low GBA activity was found, then the concentration of the GD‐specific biomarker glucosyl‐sphingosine (lyso‐GB1) was assayed, and the GBA gene sequenced. Results Samples were obtained from 1058 patients; 232 patients had low GBA activity triggering further analysis. No new cases of GD with homozygosity for pathogenic variants were identified, but 12 patients (1%) were identified to be carriers of a pathogenic variant in GBA. Conclusions Pathology databases hold routine information that can be used to screen for patients with inherited errors of metabolism. However, biochemical screening using mean platelets, ALP, and ferritin has a low yield for unidentified cases of GD.

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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

Cited by 12 publications

References 15 publications

<p>Lysosomal Acid Lipase Deficiency: Therapeutic Options</p>

<p>Lysosomal Acid Lipase Deficiency: Therapeutic Options</p>

Nonalcoholic fatty liver disease in lean subjects: is it all metabolic-associated fatty liver disease?

Screening for patients with Gaucher's disease using routine pathology results: PATHFINDER (ferritin, alkaline phosphatase, platelets) study

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