In medicine, there are 2 main criteria for obtaining public funding: demand and promise. The first is easy to understand. For example, if there is a need for a hospital to be built in a town in which there are no hospitals, the ensuing lobbying by various stakeholders will usually loosen governmental purse strings.

The second is the promise that a particular study may one day identify a cure for one of the world’s most vexing diseases, such as cancer or depression. However, in the field of rare disease, neither demand nor promise often holds much value in persuading decision-makers to release the needed amounts of public funding.

We know that one of the best ways to improve the prognosis of patients with rare diseases such as lysosomal acid lipase deficiency (LAL-D) is early detection and treatment. However, because the percentage of patients affected by this very rare disease is exceedingly small, clinicians face an uphill task in receiving adequate levels of funding for their work.

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Nevertheless, clinicians continue their work with quiet resolve. The maxim remains the same: early detection usually equates with better prognosis.

In the UK, Kwok and colleagues decided to carry out an investigation to detect the number of LAL-D cases they could identify at tertiary referral centers. 

The team noted that LAL-D is often unrecognized or misdiagnosed in the UK. Nevertheless, the availability of enzyme replacement therapy (ERT) has significantly improved the therapeutic landscape of LAL-D and serves as an incentive to accurately identify patients with this disease so they can be started on the therapy sooner rather than later.

Read more about LAL-D therapies

The research team studied LAL-D screening in 3 cohorts of patients: 

  • Patients from hospital lipid and diabetic clinics who were identified using currently available criteria set by Reiner and colleagues
  • Patients from the same clinics who had histological features in their liver biopsies consistent with LAL-D or diagnoses of nonalcoholic steatohepatitis or nonalcoholic fatty liver disease 
  • Patients found to have reduced LAL activity. 

A total of 1730 patients were included in this study. The mean LAL activity in the cohort was 0.4 nmol/punch/hour. The research team obtained a single blood sample from participants, which was then transferred to a dried blood spot (DBS) filter paper for further processing. Genetic testing was offered to patients with reduced LAL activity. 

The results were conclusive: none of the patients identified in this manner were diagnosed with LAL-D. This was consistent with other studies in which potentially vulnerable patients were identified and tested for LAL-D, with the result being that no patients were identified as having the disease.

“There were limitations to our study. We acknowledge that to screen for a rare condition like LAL-D, a much larger number of participants would be required,” the authors of the study wrote. “However, given the ease of diagnostic testing using a DBS and the potential availability of ERT, testing for LAL-D is probably still recommended in atypical cases albeit not as firstline.”

An Alternative Approach 

Kwok et al’s study highlights a fact well-recognized in the medical community: LAL-D is an exceedingly rare disease, meaning that even vulnerable patients have a low chance of being diagnosed with this condition. 

In the International Journal of Molecular Sciences, Mashima and Takada explored the various ways we currently screen for LAL-D. One of the best methods is high-risk screening, which was employed by Kwok and colleagues. 

“High-risk screening is used to identify affected individuals in a relatively small population according to a range of criteria, such as age, ethnicity, or specific disease (eg, familial hypercholesterolemia),” Mashima and Takada wrote. 

The advantage of this approach is that it increases the chance of identifying a patient with LAL-D without the trouble of screening a whole population. Nevertheless, because LAL-D is so rare, such an approach very often yields no results. 

Another means of screening for LAL-D is to pay attention to liver enzymes such as alanine transaminase (ALT) and aspartate aminotransferase (AST), which are surrogate markers for LAL-D. In addition, abnormally high levels of cholesterol can also be a sign of LAL-D. 

Read more about LAL-D etiology

Clinical researchers have also conducted studies to identify LIPA variants in dyslipidemia, given that lipidemia and LAL-D are closely related. A study demonstrated that a patient population with familial hypercholesterolemia but no pathogenic mutations in LDLR, ApoB, or Pask9 consisted of patients affected by LAL-D. 

Although there are many challenges associated with the screening of patients with LAL-D, we can at least draw comfort that ERT is a therapeutic option should a patient receive this devastating diagnosis. Studies using LIPA-deficient mice treated with various levels of the LAL enzyme demonstrated an increase in their lifespan between 52 to 92 days. At a dose of 10 mg/kg, these mice demonstrated normalized organ sizes, as well as normalized liver, spleen, and intestine histology. 

However, we must not give up on the prospect of LAL-D screening, given that it would almost certainly save lives. We must first be able to estimate the prevalence of this disease in order to understand the areas and populations most vulnerable to this condition. 

“The prevalence of LAL-D may vary depending on the ethnicity and disease population,” Mashima and Takada wrote. “To implement screening for LAL-affected individuals, an estimation of the prevalence is required.” 


Kwok S, Soran H, Barr M. Detection of lysosomal acid lipase deficiency in tertiary referral centers. Research Square. Published online February 11, 2022. doi:10.21203/

Mashima R, Takada S. Lysosomal acid lipase deficiency: genetics, screening, and preclinical studyInt J Mol Sci. 2022;23(24):15549. Published December 8, 2022. doi:10.3390/ijms232415549

Sjouke B, Defesche JC, de Randamie JSE, Wiegman A, Fouchier SW, Hovingh GK. Sequencing for LIPA mutations in patients with a clinical diagnosis of familial hypercholesterolemiaAtherosclerosis. 2016;251:263-265. doi:10.1016/j.atherosclerosis.2016.07.008