LAL-D experimental therapies
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Lysosomal acid lipase deficiency (LAL-D) is a rare metabolic disorder that can present with different phenotype severity. For instance, Wolman disease (WD), the most severe form of LAL-D, is an early-onset and life-limiting illness. On the other hand, the cholesteryl ester storage disease (CESD) is a later-onset condition with a mild phenotype. Therefore, LAL-D treatment is challenging despite the recent advances.

LAL-D is caused by defects in the LIPA gene, which provides instructions for producing the enzyme lysosomal acid lipase (LAL).

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Historically, therapeutic interventions in LAL-D patients had been focused on managing symptoms. Hence, the primary approach consisted of dietary modifications and the administration of lipid-lowering drugs. Patients with advanced disease could also benefit from treatment with invasive methods, such as splenectomy, ligation of esophageal varices, hematopoietic stem cell transplantation (HSCT), and liver transplantation to either target symptoms or manage end-organ failure. More recently, other treatment options have emerged to improve LAL-D clinical management, including enzyme replacement therapy (ERT).

Outcomes of HSCT in Wolman Disease

HSCT had been performed prior to the use of ERT in patients with WD. However, many reports relayed unfavorable outcomes. “HSCT had been historically the only treatment available but has a high procedure-related mortality because of disease progression and disease-associated morbidities,” Potter et al wrote in the Orphanet Journal of Rare Diseases.

Lessons From a Case Study of Wolman Disease

The high treatment-related mortality has been addressed in some case reports. For instance, according to a review article by Pastores et al, 4 children with WD died after HSCT. The younger child (age at transplantation, 19 weeks) developed sinusoidal obstruction syndrome 19 days after the procedure. The child died on day 67 post-procedure with multiorgan (ie, liver, kidney, and lung) failure, coagulopathy, and sepsis. Another child (age at transplantation, 19 months) developed sepsis and liver failure 14 days after the procedure and died months later at 27 months old.

The other children were 2 brothers who died from liver-related complications. One had transplantation at 127 days old and died at the age of 6 years, while the other had transplantation at 8 months of age and died 21 days after the procedure.

In 2016, researchers conducted a multicenter, retrospective study that enrolled 35 WD patients. Ten of the patients received HSCT and 1 of them had also undergone liver transplantation. All patients later died, with a median survival age of 3.7 months when untreated and 8.6 months when treated with HSCT.

According to Potter et al, “untreated WD patients are poor candidates for HSCT as they are severely malnourished, frequently present with fever, with an ongoing inflammatory process and have significant, rapidly progressive liver disease.”

However, there are also a few cases of success. In 2009, 2 WD patients were considered long-term survivors of HSCT. At follow-up, the younger patient, aged 4 years, had age-appropriate neurodevelopmental and adaptive abilities. The older patient, aged 11 years, had normal adaptive functions but showed mild to moderate neurocognitive impairment.

New Perspectives on Multimodal Treatment

Recently, an analysis performed by Potter et al shed new light on the use of HSCT in WD patients, despite the poor outcomes observed when used as a standalone therapy. They proposed a multimodal management system that includes dietary substrate reduction (DSR), ERT, and HSCT.

In the study published in the Orphanet Journal of Rare Diseases, they analyzed the response to HSCT of 5 WD patients previously treated with ERT and DSR. The decision to progress to HSCT followed the attenuation of the initial response to ERT due to the development of anti-drug antibodies (ADA) in 3 patients. According to Pastores et al, ADA usually develops within the first 3 months of exposure to treatment.

Hence, all patients from Potter et al’s study received allogeneic HSCT and 4 of them were still alive at the time of publication. “ERT and DSR improves the [HSCT] process, and [HSCT] likely provides better enzyme delivery to tissues and better long-term disease outcomes than those achievable with ERT alone,” they wrote.

The authors noted an improvement in gastrointestinal symptoms (ie, reduced diarrhea and vomiting) after HSCT, which allowed for a gradual normalization of diet with improved tolerance for fat intake. Histologically, they observed a decrease in cholesterol clefts and foamy macrophages, as well as an improvement in villous structure.

“Multimodal treatment (ERT and DSR followed by [HSCT]) should be considered a new paradigm of treatment for Wolman disease patients where there is an attenuated response to ERT, and for all patients where there is a well-matched donor for [HSCT]. This will improve long term gut function, tolerance of a more normal diet and ultimately quality of life,” they wrote.


Pastores GM, Hughes DA. Lysosomal acid lipase deficiency: therapeutic options. Drug Des Devel Ther. 2020;14:591-601. doi:10.2147/DDDT.S149264

Potter JE, Petts G, Ghosh A, et al. Enzyme replacement therapy and hematopoietic stem cell transplant: a new paradigm of treatment in Wolman disease. Orphanet J Rare Dis. 2021;16(1):235. doi:10.1186/s13023-021-01849-7