Practical Recommendations for the Diagnosis and Management of Lysosomal Acid Lipase Deficiency with a Focus on Wolman Disease

Abstract

Lysosomal acid lipase deficiency (LAL-D) is an ultra-rare lysosomal storage disease with two distinct phenotypes, an infantile-onset form (formerly Wolman disease) and a later-onset form (formerly cholesteryl ester storage disease). The objective of this narrative review is to examine the most important aspects of the diagnosis and treatment of LAL-D and to provide practical expert recommendations. The infantile-onset form occurs in the first weeks of life and is characterized by malnourishment and failure to thrive due to gastrointestinal impairment (vomiting, diarrhea, malabsorption), as well as systemic inflammation, hepatosplenomegaly, and adrenal calcifications. Mortality is close to 100% before one year of life in the absence of specific treatment. The later-onset form can be diagnosed in childhood or adulthood and is characterized by chronic liver injury and/or lipid profile alterations. When LAL-D is suspected, enzyme activity should be determined to confirm the diagnosis, with analysis from a dried blood spot sample being the quickest and most reliable method. In infantile-onset LAL-D, the initiation of enzyme replacement therapy (sebelipase α) and careful nutritional management with a low-lipid diet is very urgent, as prognosis is directly linked to the early initiation of specific treatment. In recent years, our knowledge of the management of LAL-D has increased considerably, with improvements regarding the initial enzyme replacement therapy dose and careful nutritional treatment with a low-lipid diet to decrease lipid deposition and systemic inflammation, leading to better outcomes. In this narrative review we offer a quick guide for the initial management of infantile-onset LAL-D.

Keywords: LAL-D; LIPA gene; Wolman disease; cholesteryl ester storage disease; diet; enzyme replacement therapy; infantile-onset lysosomal acid lipase deficiency; lysosomal acid lipase; lysosomal acid lipase deficiency; sebelipase.

Figure 1

Abdominal X-ray showing adrenal gland calcifications in a patient with infantile-onset lysosomal acid lipase deficiency (LAL-D). Image courtesy of Dr. de las Heras.

Figure 2

Blood film examination showing lymphocytes with cytoplasmatic lipid vacuoles in a patient with infantile-onset lysosomal acid lipase deficiency (LAL-D). Image courtesy of Dr. de las Heras.

Figure 3

Algorithm for the diagnosis of infantile-onset lysosomal acid lipase deficiency (LAL-D). ASMD: acid sphingomyelinase deficiency; LAL: lysosomal acid lipase; LAL-D: lysosomal acid lipase deficiency; HDL: high-density lipoprotein; LDL: low-density lipoprotein; HLH: hemophagocytic lymphohistiocytosis.

Figure 4

Algorithm for the diagnosis of later-onset lysosomal acid lipase deficiency (LAL-D). ALT: alanine aminotransaminase; ASMD: acid sphingomyelinase deficiency; HBV: hepatitis B virus; HCV: hepatitis C virus; HDL: high-density lipoprotein; LAL: lysosomal acid lipase; LAL-D: lysosomal acid lipase deficiency; LDL: low-density lipoprotein; NGS: next-generation sequencing; ULN: upper limit of normal.