Lysosomal acid lipase deficiency (LAL-D) is part of a group of disorders known as lysosomal storage diseases. The disease tends to have its onset in childhood. Patients usually suffer from progressive liver failure and cardiovascular disease later in life. 

As its name suggests, LAL-D is the result of deficient activity of the enzyme lysosomal acid lipase (LAL). This results in the abnormal accumulation of cholesteryl esters and triglycerides in various organs in the body, including the liver, intestine, adrenal glands, and macrophage-monocyte system cells. 

There are 2 main types of LAL-D. In Wolman disease, a less aggressive form of the disease, patients typically have LAL activity between 1% and 2% of normal. Cholesteryl ester storage disease (CESD) has a heterogeneous clinical presentation; it is typically characterized by accelerated atherosclerosis, high cholesterol, and liver fibrosis. 

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One of the major problems with LAL-D and other lysosomal storage diseases is that their vague presentation means misdiagnosis occurs often. In addition, lysosomal storage diseases can have overlapping symptomatology and considerable clinical variability. Physicians are typically alerted to the possibility of an LAL-D diagnosis if there is a family history of such disease. 

Read more about LAL-D etiology 

“The relatively low number of cases diagnosed with LAL-D in comparison to its genetic prevalence is likely explained by a low degree of suspicion for the diagnosis,” Witeck and colleagues wrote in Jornal de Pediatria. “For this reason, raising pediatrician awareness about this condition is an essential step for identifying individuals with LAL-D, as there are means for diagnosis available after the disease is suspected.” 

The Importance of Family History

To arrive at a correct diagnosis of LAL-D or another lysosomal storage disease, pediatricians first need to take a detailed medical history from the patient’s parents or caregivers. Taking a good medical history is medicine 101; however, time constraints can sometimes push physicians to limit the questions asked, causing them to miss out on vital information. 

When it comes to genetic diseases (of which LAL-D is one), family disease history can be illuminating, helping physicians understand the signs and symptoms that they are to look out for. LAL-D is inherited in an autosomal recessive manner; hence, if any parent has this disease or is a carrier, physicians should immediately be on high alert for the possibility of an LAL-D diagnosis among their offspring. 

A detailed medical history and clinical examination may yield findings that encourage physicians to conduct further investigations. In medicine, physicians are taught to observe a stepwise approach to both diagnosis and care. If medical history and clinical presentation suggests a diagnosis of LAL-D, the next step would be for physicians to order biochemical tests to identify levels of LAL activity and its impact on other biochemical parameters. 

“Finally, if deficient enzyme activity is detected, second-tier confirmatory biomarker tests or Sanger sequencing are performed for the suspected gene,” La Cognata and Cavallaro wrote in Genes. 

This step represents the current gold standard for diagnosing lysosomal storage diseases. However, there are limitations to this diagnostic procedure. For example, physicians need to have an expert grasp of phenotypic overlapping manifestations in order to cut down on unnecessary biochemical tests for each patient. In addition, multiple biochemical enzymatic assays can be prohibitively expensive, as well as time-consuming. 

Recently, the emergence of next-generation sequencing as an alternative to conventional technologies allows a number of genes to be simultaneously interrogated in a single setting. This has the effect of making Sanger sequencing of a single gene more effective. Hence, many medical researchers are advocating for its inclusion in the diagnostic workflow for suspected lysosomal storage diseases. 

Diagnostic Accuracy 

As mentioned earlier, one of the best defenses against misdiagnosis of LAL-D and other lysosomal storage diseases is to ensure that pediatricians remain acutely aware of the possibility of this diagnosis, despite its rarity among the population. Of course, it is not practical for physicians to suspect every disorder under the sun for every patient they see; however, if the diagnostic workflow above yields findings that raise suspicion of a possible diagnosis of LAL-D, pediatricians should conduct the necessary tests to confirm/exclude the diagnosis. 

The primary problem that LAL-D causes is dyslipidemia, which predisposes patients to developing cardiovascular disease. In the early-onset version of this disease, patients typically have elevated triglyceride concentration. In patients with CESD, low-density lipoprotein and very low-density lipoprotein concentrations tend to be high. All this can contribute to pathology in multiple organs, which when untreated can lead to early death. 

Read more about LAL-D diagnosis

“Fatal outcomes of LAL-D can be avoided when there is a high degree of clinical suspicion and this rare hereditary disease is included in the differential diagnosis of hepatomegaly, lipid metabolism disorder and non-alcoholic fatty liver disease with fibrosis or cirrhosis,” Witeck and colleagues wrote. 

The key to winning the battle against this disease is to diagnose it early and initiate treatment immediately. The current mainstay treatment for LAL-D, sebelipase alfa, has been shown to prevent cirrhosis, cardiovascular disease, and death. In other words, physicians have a very real prospect of reducing morbidity and mortality if they follow the diagnostic workflow for this disease and conduct relevant tests that confirm or exclude a diagnosis of this disorder. 


La Cognata V, Cavallaro S. A comprehensive, targeted NGS approach to assessing molecular diagnosis of lysosomal storage diseasesGenes (Basel). 2021;12(11):1750. doi:10.3390/genes12111750

Witeck CDR, Schmitz AC, de Oliveira JMD, Porporatti AL, De Luca Canto G, Pires MMS. Lysosomal acid lipase deficiency in pediatric patients: a scoping reviewJ Pediatr (Rio J). 2022;98(1):4-14. doi:10.1016/j.jped.2021.03.003