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.

Lysosomal storage disorders are a group of multisystem monogenic conditions caused mostly by enzyme deficiencies which disrupt lysosomal functioning. Those which result in neuronal dysfunction are considered 'neuronopathic'. These neurodegenerative conditions, while individually rare, are collectively not uncommon, and are attractive targets for gene and cell-based therapies. In this review we describe the current landscape of such therapies in this group of disorders, where the more severe phenotypes manifest in children. We describe the conditions, the principles of cell therapy and gene therapy, and compare AAV and lentiviral approaches. This is a rapidly evolving area of medicine, and we highlight progress made, and the challenges that are ahead in bringing these therapies to all patients. Throughout, we offer real-world insight into delivering these therapies and suggest a way forward for the future; utilising combined therapies to bridge the obligate delays and increasing collaborative working practices in therapeutic development between clinicians, academics and industry.

Wolman disease (WD) is a lethal disorder defined by the deficiency of the lysosomal acid lipase enzyme. Patients present with intestinal failure, malnutrition, and hepatosplenomegaly. Enzyme replacement therapy (ERT) with dietary substrate reduction (DSR) significantly improves survival. We sought to determine the outcomes of two siblings with WD treated after the onset of symptoms (sibling 1) and presymptomatic (sibling 2). A chart review was conducted on two siblings with WD treated with ERT and DSR at 4 months of age (sibling 1) and immediately after birth (sibling 2) to determine clinical outcomes based on survival, laboratory results, growth, dietary records, and gut biopsies. Sibling 1 presented with hepatosplenomegaly and liver dysfunction and developed hemophagocytic lymphohistiocytosis despite treatment. She received a bone marrow transplant at 8 months of age but died at 13 months. Sibling 2 is alive at 16 months of age with height, weight, and MUAC above the 95th centile, fully orally fed, with no gastrointestinal symptoms, normal liver function, and normal oxysterols. Sibling 2 duodenal biopsies show normal villus architecture with no foamy macrophage infiltration. Initiation of treatment prior to the onset of symptoms can prevent clinical manifestations and increase survival. The divergent trajectory in these siblings raises the question of WD’s candidacy for newborn screening.