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 acid lipase deficiency (LALD) varies from a severe infantile-onset form (Wolman disease) to a late-onset form known as cholesteryl ester storage disease (CESD), both of which are autosomal recessive disorders caused by biallelic LIPA pathogenic variants. We evaluated seventy-three patients enlisted for liver transplant (LT) at Instituto da Criança (HCFMUSP-Brazil) who were subjected to LAL activity measurement and LIPA Sanger sequencing analysis, resulting in a positive LALD diagnosis for only one of these individuals. This LALD patient presented recurrent diarrhea, failure to thrive, hepatomegaly, and dyslipidemia at the age of 4 months and liver failure by the age of 13 years. The LALD diagnosis confirmation was conducted at 24 years old due to low levels of LAL enzyme activity. The causal homozygous variant LIPA(NM_000235.4):c.266T>C(p.Leu89Pro) was identified, but the patient had already undergone his first LT at 18 years with several rejection episodes. Despite beginning treatment with sebelipase alfa at 26 years old (total of five infusions), this patient died at 28 years from complications after his second liver transplant. LALD is an important differential diagnosis in cases presenting with hepatomegaly, elevated liver enzymes, and dyslipidemia. Detecting low/absent LAL activity and identifying the LIPA causal variant are essential for diagnosis and specific treatment, as well as for appropriate genetic counseling. Early diagnosis, along with sebelipase alfa therapy, may improve the prognosis of affected patients.

Lysosomal acid lipase (LAL) is the sole enzyme known to degrade neutral lipids in the lysosome. Mutations in the LAL-encoding LIPA gene lead to rare lysosomal lipid storage disorders with complete or partial absence of LAL activity. This review discusses the consequences of defective LAL-mediated lipid hydrolysis on cellular lipid homeostasis, epidemiology, and clinical presentation. Early detection of LAL deficiency (LAL-D) is essential for disease management and survival. LAL-D must be considered in patients with dyslipidemia and elevated aminotransferase concentrations of unknown etiology. Enzyme replacement therapy, sometimes in combination with hematopoietic stem cell transplantation (HSCT), is currently the only therapy for LAL-D. New technologies based on mRNA and viral vector gene transfer are recent efforts to provide other effective therapeutic strategies.

Late-onset liposomal acid lipase deficiency (LAL deficiency), previously known as Cholesteryl ester storage disease (CESD) is a rare genetic lysosomal storage disorder caused by deficiency of lysosomal acid lipase (LAL) due to mutations in the LIPA gene. LAL deficiency is a systemic disease that leads to the accumulation of fat and inflammation in the liver, premature atherosclerosis and gastrointestinal disease. Most of the patients require liver transplantation due to decompensated cirrhosis. Enzyme replacement therapy has been approved and is available in many countries. Here we describe a 16-year-old patient who was diagnosed to have late-onset LAL deficiency when he presented to us with ESLD. Subsequently, he underwent a living-donor liver transplant (LDLT) successfully. We discuss the ethical dilemmas in considering LDLT for LAL deficiency.

Lysosomal acid lipase deficiency (LAL-D) is an underdiagnosed autosomal recessive disease with onset between the first years of life and adulthood. Early diagnosis is crucial for effective therapy and long-term survival. The objective of this article is to recognize warning signs among the clinical and laboratory characteristics of LAL-D in pediatric patients through a scope review.

Electronic searches in the Embase, PubMed, Livivo, LILACS, Web of Science, Scopus, Google Scholar, Open Gray, and ProQuest Dissertations and Theses databases. The dataset included observational studies with clinical and laboratory characteristics of infants, children and adolescents diagnosed with lysosomal acid lipase deficiency by enzyme activity testing or analysis of mutations in the lysosomal acid lipase gene (LIPA). The reference selection process was performed in two stages. The references were selected by two authors, and the data were extracted in June 2020.

The initial search returned 1593 studies, and the final selection included 108 studies from 30 countries encompassing 206 patients, including individuals with Wolman disease and cholesteryl ester storage disease (CESD). The most prevalent manifestations in both spectra of the disease were hepatomegaly, splenomegaly, anemia, dyslipidemia, and elevated transaminases.

Vomiting, diarrhea, jaundice, and splenomegaly may be correlated, and may serve as a starting point for investigating LAL-D. Familial lymphohistiocytosis should be part of the differential diagnosis with LAL-D, and all patients undergoing upper gastrointestinal endoscopy should be submitted to intestinal biopsy.

Wolman disease (WD), the rapidly progressive phenotype of lysosomal acid lipase (LAL) deficiency, presents in neonates with failure to thrive and hepatosplenomegaly, and leads to multi-organ failure and death before 12 months of age. In clinical trials, enzyme replacement therapy (ERT) with sebelipase alfa led to improved survival, growth and biological parameters in WD patients followed up to 5 years. Long-term follow-up and health-related quality of life (HRQoL) evaluation are lacking.

We performed a nationwide, retrospective study of sebelipase alfa in WD patients. Five patients with abolished LAL activity and bi-allelic LIPA mutations were included with a median follow-up of 7 years (1-10). ERT was initiated at a median age of 1 month (0-4). Infusion tolerance was excellent on the long-term with only one patient requiring systematic pre-medication. Cholestyramine, fat-soluble vitamin supplements and a specific diet (high in medium-chain triglycerides and low in long-chain fatty acids) were prescribed. Liver function tests, plasma lipid profiles, fat-soluble vitamin levels and growth parameters improved. Three patients transiently exhibited a neuromyopathic phenotype (footdrop gait, waddling walk or muscle fatigue) but electromyography and muscle strength testing were normal. At last follow-up, all patients were alive with normal growth parameters and a satisfactory HRQoL, no patient had special education needs, and one patient required parenteral nutrition since an acute gastroenteritis.

Early ERT initiation allowed 100% survival with positive outcomes. Very long-term follow-up and hematopoietic stem cell transplantation while on ERT should be evaluated to strengthen the benefits of sebelipase alfa.

Lysosomal acid lipase deficiency (LALD) is an autosomal recessive inborn error of lipid metabolism characterized by impaired lysosomal hydrolysis and consequent accumulation of cholesteryl esters and triglycerides. The phenotypic spectrum is diverse, ranging from severe, neonatal onset failure to thrive, hepatomegaly, hepatic fibrosis, malabsorption and adrenal insufficiency to childhood-onset hyperlipidemia, hepatomegaly, and hepatic fibrosis. Sebelipase alfa enzyme replacement has been approved by the Food and Drug Administration for use in LALD after demonstrating dramatic improvement in transaminitis and dyslipidemia with initiation of enzyme replacement therapy.

A chart review was performed on 2 patients with childhood-onset, symptomatic LALD with persistent dyslipidemia despite appropriate enzyme replacement therapy to identify biological pathways and risk factors for incomplete response to therapy.

Two patients with attenuated, symptomatic LALD had resolution of transaminitis on enzyme replacement therapy without concomitant effect on dyslipidemia despite dose escalation and no evidence of antibody response to enzyme.

Enzyme replacement therapy does not universally resolve all complications of LALD. Persistent dyslipidemia remains a clinically significant issue, likely related to the complex metabolic pathways implicated in LALD pathogenesis. We discuss the possible mechanistic basis for this unexpected finding and the implications for curative LALD therapy.

Lysosomal acid lipase deficiency is a poorly diagnosed genetic disorder, leading to accumulation of cholesterol esters and triglycerides in the liver, with progression to chronic liver disease, dyslipidemia, and cardiovascular complications. Lack of awareness on diagnosis of this condition may hamper specific treatment, which consists on enzymatic replacement. It may prevent the progression of liver disease and its complications. We describe the case of a 53-year-old Brazilian man who was referred to our center due to the diagnosis of liver cirrhosis of unknown etiology. He was asymptomatic and had normal body mass index. He had dyslipidemia, and family history of myocardial infarction and stroke. Abdominal imaging tests showed liver cirrhosis features and the presence of intrahepatic calcifications. Initial investigation of the etiology of the liver disease was not elucidated, but liver biopsy showed microgoticular steatosis and cholesterol esters deposits in Kuppfer cells. The dosage of serum lysosomal acid lipase was undetectable and we found the presence of a rare homozygous mutation in the gene associated with the lysosomal acid lipase deficiency, (allele c.386A > G homozygous p.H129R).

BACKGROUND Lysosomal acid lipase deficiency is a rare genetic metabolic lipid storage disease, with a high morbidity, and mortality, in children and adults. It is characterized by a mutation in the LIPA gene that causes an alteration of lipid metabolism, resulting in deposits of cholesterol esters and triglycerides in organs such as the liver, blood vessels, and gastrointestinal tract. Lysosomal acid lipase deficiency is predominantly caused by the mutation c.894G>A, seen in approximately 50-70% of patients. Our objective is to report the first pediatric case of lysosomal acid lipase deficiency in a pediatric patient in Colombia. CASE REPORT The patient is a 14-year-old boy with isolated hepatomegaly since 6 years of age without a family history of dyslipidemia. In the pediatric control, laboratory exams revealed dyslipidemia, and a hepatic biopsy was performed, revealing severe fibrosis with septation and grade 3 microvesicular steatosis (>75%). He was referred to our center and was suspected to have lysosomal acid lipase deficiency. Enzymatic activity was measured, showing absent activity. Confirmatory diagnosis with genetic sequencing showed a pathological homozygous mutation of c.894G>A. CONCLUSIONS Lysosomal acid lipase deficiency can manifest as early- or late-onset, with variable and severe signs and symptoms. The late-onset form has a broad spectrum of manifestations with mild symptoms, leading to under-diagnosis, which increases the actual disease burden. Early diagnosis is essential to initiate enzyme replacement therapy, since the natural disease course can be changed. More studies should be conducted in Latin America to evaluate the prevalence of the disease.

Lysosomal acid lipase deficiency (LAL-D) results in progressive microvesicular hepatosteatosis, fibrosis, cirrhosis, dyslipidemia, and vascular disease. Interventions available prior to enzyme replacement therapy development, including lipid lowering medications, splenectomy, hematopoietic stem cell and liver transplantation were unsuccessful at preventing multi-systemic disease progression, and were associated with significant morbidity and mortality. We report two sisters, diagnosed in infancy, who succumbed to LAL-D with accelerated disease progression following splenectomy and liver transplantation. The index patient died one year after hematopoietic stem cell transplant and liver transplantation. Her younger sister survived five years post liver-transplantation, complicated by intermittent, acute rejection. Typical LAL-D hepatopathology, including progressive, microvesicular steatosis, foamy macrophage aggregates, vacuolated Kupffer cells, advanced fibrosis and micronodular cirrhosis recurred in the liver allograft. She died before a second liver transplant could occur for decompensated liver failure. Neither patient received sebelipase alfa enzyme replacement therapy, human, recombinant, lysosomal acid lipase enzyme, FDA approved in 2015. Here are reviewed 18 LAL-D post-liver transplantation cases described in the literature. Multi-systemic LAL-D progression occurred in 11 patients (61%) and death in six (33%). These reports demonstrate that liver transplantation may be necessary for LAL-D-associated liver failure, but is not sufficient to prevent disease progression, or liver disease recurrence, since the pathophysiology is predominantly mediated by deficient enzyme activity in bone marrow-derived monocyte-macrophages. Enzyme replacement therapy addresses systemic disease and hepatopathology, potentially improving liver-transplantation outcomes. This is the first systematic review of liver transplantation for LAL-D, and the first account of liver allograft LAL-D-associated hepatopathology recurrence.

Lysosomal acid lipase deficiency (LALD) is an ultra-rare disease caused by a congenital disorder of the lipid metabolism, characterized by the deposition of cholesterol esters and triglycerides in the organism. In patients with no enzyme function, the disease develops during the perinatal period and is invariably associated with death during the first year of life. In all other cases, the phenotype is heterogeneous, although most patients develop chronic liver diseases and may also develop an early cardiovascular disease. Treatment for LALD has classically included the use of supportive measures that do not prevent the progression of the disease. In 2015, regulatory agencies approved the use of a human recombinant LAL for the treatment of LALD. This long-term enzyme replacement therapy has been associated with significant improvements in the hepatic and lipid profiles of patients with LALD, increasing survival rates in infants with a rapidly progressive disease. Both the severity of LALD and the availability of a specific treatment highlight the need to identify these patients in clinical settings, although its low prevalence and the existing clinical overlap with other more frequent pathologies limit its diagnosis. In this paper we set out practical recommendations to identify and monitor patients with LALD, including a diagnostic algorithm, along with an updated treatment.