Lysosomal acid lipase deficiency (LAL-D) is an umbrella term for disorders (ie, Wolman disease and cholesteryl ester storage disease [CESD]) driven by an inability of the body to produce enough active LAL enzyme. This can result in significant morbidity and early mortality, even if the initial presentation is heterogeneous.
As recently as the last decade, there was no treatment for this condition, meaning that the best that physicians could do was to offer supportive care, which could result in significant healthcare resource utilization with very little results. Many patients died in childhood. However, this changed when enzyme replacement therapy (ERT), specifically, sebelipase alfa, was introduced. This groundbreaking therapy allows for long-term, exogenous replacement of the LAL enzyme.
Epidemiological studies tell us little about LAL-D for two main reasons: first, it is an extraordinarily rare disease, particularly in Asia; and second, misdiagnosis is likely a common occurrence. Heterogeneity in clinical presentation means that physicians often mistake the disorder for similar diseases, such as Gaucher disease, Niemann-Pick disease type B/C, or nonalcoholic fatty liver disease. There are many cases of patients who are diagnosed with LAL-D incidentally or when asymptomatic.
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Modes of LAL-D Research
Many studies on LAL-D therapeutics are carried out on mouse models. Scientists have found a way to completely eliminate LAL activity in a group of mice; these mice tend to have a life expectancy of approximately 1 year. LAL-D mice are ideal for studies because they mimic the metabolic processes that the human body undergoes when facing a lack in LAL, such as the accumulation of triglycerides and cholesteryl esters, as well as multiorgan inflammation.
“LAL-D mice are an indispensable model to investigate the consequences of LAL-D,” Korbelius and colleagues wrote in Trends in Molecular Medicine.
Read more about LAL-D etiology
It should be noted that the physiology of LAL-D mice appears to be more in line with CESD than Wolman disease. For example, they have a longer-than-expected life expectancy despite being completely deficient in the LAL enzyme. In addition, the liver phenotype of these mouse models appears to be more similar to CESD in that a notable increase in cholesteryl esters is present in their livers.
However, studies using LAL-D mouse models appear to have limits. For example, findings regarding the therapeutic role of the overexpression of LAL in the liver remain controversial. Another challenge with mouse models is that LAL as a secreted lysosomal enzyme appears to be taken up only by some enzyme-deficient cells, which may lead to the correction of LAL-D in certain mice.
In addition, there is a paucity of data regarding the role of LAL in atherosclerosis. The difficulty lies in the fact that the mice in these models die within days of being fed a diet high in fat/cholesterol. Scientists have attempted to introduce recombinant human LAL into mice, which appears to reduce signs of atherosclerosis. However, more research needs to be conducted for the matter to be confirmed.
Despite the potential problems and inaccuracies with using mouse models to learn about LAL-D, they do provide a valuable resource that is helping push LAL-D therapeutic research forward. In vitro studies also have a role to play in LAL-D therapeutic research, albeit a smaller one. For example, scientists can inhibit LAL by lalistat-1 and -2 for the purpose of assessing enzyme function in vitro and to diagnose the disorder in dried blood spot (DBS) assays.
Challenges With Screening
Whenever LAL-D is discussed in the medical literature, the topic of screening inevitably arises. Korbelius and colleagues wrote, “Rapid, cost-effective, and minimally invasive dried-blood spot testing is today’s gold standard for the diagnosis of LAL-D.” In the International Journal of Molecular Sciences, Mashima and Takada wrote that “newborn screening for LAL-D is increasingly demanded.”
With the introduction of life-extending ERT, clinicians are advocating for newborn screening to be carried out as widely as possible so that appropriate treatment can be offered at the first opportunity. Newborn screening has been around since at least the 1960s, during which neonates were first screened for phenylketonuria. Although newborn screening back then required microbial procedures, newborn screening today can be carried out much more effectively via the quantification of biomarkers using modern instruments.
Read more about LAL-D treatment
Screening is carried out in LAL-D today through DBS assays. A number of pathologies can be picked up using this method; it is generally viewed as being reliable and stable. However, the challenge from a global perspective is that some parts of the world simply cannot afford to offer newborn screening for all, especially where the disease is deemed as too rare.
However, the alternative, that is, not offering newborn screening for LAL-D, would mean that pediatric patients with this condition would likely present with the above-mentioned nonspecific signs and symptoms, setting off a diagnostic scramble to make clinical sense of it all, a process that would undoubtedly consume significant healthcare resources. Any delay in diagnosis and treatment can be fatal. So is the alternative better? This is the debate that clinical decision-makers should have.
References
Korbelius M, Kuentzel KB, Bradić I, Vujić N, Kratky D. Recent insights into lysosomal acid lipase deficiency. Trends Mol Med. 2023;29(6):425-438. doi:10.1016/j.molmed.2023.03.001
Mashima R, Takada S. Lysosomal acid lipase deficiency: genetics, screening, and preclinical study. Int J Mol Sci. 2022;23(24):15549. doi:10.3390/ijms232415549
