Highlights
- •There are 98 disease-causing LIPA variants associated with LAL-D.
- •An additional 22 predicted pathogenic LIPA variants have been identified in humans.
- •LAL-D has an estimated prevalence of 1 per 177,000.
- •Clinicians can be reassured that LAL-D is an ultra-rare mimic of NAFLD.
- •Consider LAL-D testing in a second-line metabolic screen in patients with atypical NAFLD.
Background & Aims
Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive condition that
may present in a mild form (cholesteryl ester storage disease [CESD]), which mimics
non-alcoholic fatty liver disease (NAFLD). It has been suggested that CESD may affect
1 in 40,000 and is under-diagnosed in NAFLD clinics. Therefore, we aimed to estimate
the prevalence of LAL-D using analysis of genetic variation in LIPA.
Methods
MEDLINE and EMBASE were systematically searched for previously reported disease variants
and prevalence estimates. Previous prevalence estimates were meta-analysed. Disease
variants in LIPA were annotated with allele frequencies from gnomAD and combined with unreported major
functional variants found in humans. Pooled ethnicity-specific prevalences for LAL-D
and CESD were calculated using the Hardy-Weinberg equation.
Results
Meta-analysis of existing genetic studies estimated the prevalence of LAL-D as 1 per
160,000 (95% CI 1 per 65,025–761,652) using the allele frequency of c.894G>A in LIPA. A total of 98 previously reported disease variants in LIPA were identified, of which
32/98 were present in gnomAD, giving a prevalence of 1 per 307,482 (95% CI 257,672–366,865).
Wolman disease was associated with more loss-of-function variants than CESD. When
this was combined with 22 previously unreported major functional variants in LIPA identified in humans, the pooled prevalence of LAL-D was 1 per 177,452 (95% CI 149,467–210,683)
with a carrier frequency of 1 per 421. The prevalence is lowest in those of East Asian,
South Asian, and Finnish ancestry.
Conclusion
Using 120 disease variants in LIPA, these data can reassure clinicians that LAL-D is an ultra-rare disorder. Given the
therapeutic capability of sebelipase alpha, investigation for LAL-D might be included
in second-line metabolic screening in NAFLD.
Lay summary
Lysosomal Acid Lipase Deficiency (LAL-D) is a rare genetic condition that can cause
severe liver disease, but it is difficult to diagnose and sometimes can look like
simple fatty liver. It was not clear how common LAL-D was and whether many cases were
being missed. To study this, we searched for all genetic mutations that could cause
LAL-D, calculated how common those mutations were, and added them up. This let us
estimate that LAL-D affects roughly 1 in 175,000 people. We conclude that LAL-D is
a very rare condition, but it is treatable so may be included in a ‘second-line’ of
tests for causes of fatty liver.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: October 10, 2018
Accepted:
September 27,
2018
Received in revised form:
September 13,
2018
Received:
July 22,
2018
Identification
Copyright
© 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
