Lysosomal acid lipase deficiency in pediatric patients: a scoping review

Abstract Objective: 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. Sources: 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. Summary of the findings: 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. Conclusions: 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.

Deficiencia de lipasa ácida lisosomal, una patología infrecuente / Lysosomal acid lipase deficiency, a rare pathology

Resumen El déficit de lipasa ácida lisosomal es una enfermedad genética poco prevalente, con alta morbimortalidad en niños y adultos. Se caracteriza por alteración del metabolismo lipídico que genera depósitos de ésteres de colesterol y triglicéridos en el organismo. La presentación clínica depende de la actividad enzimática. Se debe sospechar en pacientes con alteraciones lipídicas o alteraciones hepáticas después de descartar otros diagnósticos. Actualmente existe la opción de utilizar enzima recombinante, la cual puede mejorar los parámetros lipídicos y hepáticos, así como detener la progresión de la enfermedad. Es imperioso realizar el diagnóstico oportuno para iniciar de forma temprana el tratamiento específico, con el fin de prevenir la morbimortalidad. Se llevó a cabo revisión de la literatura en torno del déficit de lipasa ácida lisosomal, para orientar acerca de su fisiopatología, manifestaciones clínicas, diagnóstico y tratamiento.

Abstract Lysosomal acid lipase deficiency is a genetic disease with a low prevalence and high morbidity and mortality in children and adults. It is characterized by an alteration of lipid metabolism, which generates cholesterol and triglyceride esters deposits in the body. Its clinical presentation depends on enzymatic activity. This condition should be suspected in patients with lipid or liver alterations after ruling out other diagnoses. Currently, there is the option of using a recombinant enzyme, which can improve lipid and liver parameters, as well as disease progression. Establishing a timely diagnosis in order to initiate specific treatment early is imperative for the prevention of morbidity and mortality. The purpose of this work is to perform a review of the literature about lysosomal acid lipase deficiency and to guide about its pathophysiology, clinical manifestations, diagnosis and treatment.

A Novel Homozygous LIPA Mutation in a Korean Child with Lysosomal Acid Lipase Deficiency / 대한소아소화기영양학회지

Patients with lysosomal acid lipase (LAL) deficiency and glycogen storage disease (GSD) demonstrated hepatomegaly and dyslipidemia. In our case, a 6-year-old boy presented with hepatosplenomegaly. At 3 years of age, GSD had been diagnosed by liver biopsy at another hospital. He showed elevated serum liver enzymes and dyslipidemia. Liver biopsy revealed diffuse microvesicular fatty changes in hepatocytes, septal fibrosis and foamy macrophages. Ultrastructural examination demonstrated numerous lysosomes that contained lipid material and intracytoplasmic cholesterol clefts. A dried blood spot test revealed markedly decreased activity of LAL. LIPA gene sequencing identified the presence of a novel homozygous mutation (p.Thr177Ile). The patient's elevated liver enzymes and dyslipidemia improved with enzyme replacement therapy. This is the first report of a Korean child with LAL deficiency, and our findings suggest that this condition should be considered in the differential diagnosis of children with hepatosplenomegaly and dyslipidemia.

A Novel Homozygous LIPA Mutation in a Korean Child with Lysosomal Acid Lipase Deficiency / 대한소아소화기영양학회지

Patients with lysosomal acid lipase (LAL) deficiency and glycogen storage disease (GSD) demonstrated hepatomegaly and dyslipidemia. In our case, a 6-year-old boy presented with hepatosplenomegaly. At 3 years of age, GSD had been diagnosed by liver biopsy at another hospital. He showed elevated serum liver enzymes and dyslipidemia. Liver biopsy revealed diffuse microvesicular fatty changes in hepatocytes, septal fibrosis and foamy macrophages. Ultrastructural examination demonstrated numerous lysosomes that contained lipid material and intracytoplasmic cholesterol clefts. A dried blood spot test revealed markedly decreased activity of LAL. LIPA gene sequencing identified the presence of a novel homozygous mutation (p.Thr177Ile). The patient's elevated liver enzymes and dyslipidemia improved with enzyme replacement therapy. This is the first report of a Korean child with LAL deficiency, and our findings suggest that this condition should be considered in the differential diagnosis of children with hepatosplenomegaly and dyslipidemia.

Guía colombiana para el diagnóstico de la deficiencia de lipasa ácida / Colombian Guidelines for Diagnosis of Lipase Acid Deficiency

Resumen Introducción: la deficiencia de lipasa ácida lisosomal (LAL-D) es una entidad de herencia autosómica recesiva que lleva a la acumulación de esteres de colesterol y triglicéridos en el hígado, bazo y otros órganos. La edad de inicio y la tasa de progresión son muy variables, lo que posiblemente sea explicado por las mutaciones presentes en el gen LIPA. Las manifestaciones clínicas son las mismas que para otras patologías hepáticas, cardiovasculares y metabólicas, lo que hace difícil reconocerla en la práctica clínica. Objetivo: proveer una guía que permita a los clínicos reconocer los principales grupos de riesgo en los cuales se debe sospechar de LAL-D y mejorar su diagnóstico. Metodología: este documento se diseñó como un consenso de expertos en el cual participaron médicos especialistas en gastroenterología, hepatología, endocrinología, genética, patología y pediatría. Se realizó una revisión de la literatura acerca de las manifestaciones clínicas y de las herramientas para el diagnóstico de LAL-D y se siguió la metodología de técnica de grupo nominal. Resultados: se generaron algoritmos diagnósticos por consenso para cada uno de los grupos de riesgo, que facilitaran la sospecha y el diagnóstico de LAL-D. Conclusiones: esta guía propone algoritmos para el diagnóstico de LAL-D con base en el consenso clínico, que buscan optimizar la ruta diagnóstica en los pacientes con dicha patología.

Abstract Introduction: Lysosomal acid lipase deficiency (LAL-D) is an inherited autosomal recessive entity that leads to the accumulation of cholesterol and triglyceride esters in the liver, spleen and other organs. The age of onset and rate of progression vary greatly, possibly explained by mutations of the LIPA gene. Clinical manifestations are the same as those of other hepatic, cardiovascular and metabolic pathologies which makes it difficult to recognize in clinical practice. Objective: The objectives of these guidelines is to help clinicians recognize the major groups at risk for LAL-D and to improve its diagnosis. Methodology: This document was designed as a consensus of experts in gastroenterology, hepatology, endocrinology, genetics, pathology and pediatrics. A review of the literature regarding clinical manifestations and tools for diagnosis of LAL-D was conducted and the nominal group technique was followed. Results: Diagnostic algorithms which facilitate suspicion and diagnosis of LAL-D were generated by consensus for each of the risk groups. Conclusions: This guide proposes algorithms for the diagnosis of LAL-D based on clinical consensus. The algorithms seek to optimize diagnosis for patients with this pathology.