Livia Pisciotta1, Giulia Tozzi2, Lorena Travaglini2, Roberta Taurisano3, Tiziano Lucchi4, Giuseppe Indolfi5, Francesco Papadia6, Maja Di Rocco7, Lorenzo D'Antiga8, Patricia Crock9, Komal Vora9, Scott Nightingale9, Helen Michelakakis10, Anastasia Garoufi11, Lilia Lykopoulou12, Stefano Bertolini13, Sebastiano Calandra14. 1. Department of Internal Medicine, University of Genoa, Italy. 2. Laboratory of Molecular Medicine, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 3. Metabolism Division, Department of Pediatrics Specialist, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 4. Department of Internal Medicine and Medical Specialities, IRCSS Ca' Granda, Milan, Italy. 5. Paediatric and Liver Unit, Meyer Children's University-Hospital, Florence, Italy. 6. University Pediatric Hospital Giovanni XXIII, O.U. Metabolic and Genetic Diseases, Bari, Italy. 7. IRCCS Institute Giannina Gaslini, Department of Pediatrics, Unit of Rare Diseases, Genoa, Italy. 8. Pediatric Department, Hospital Papa Giovanni XXIII, Bergamo, Italy. 9. John Hunter Children Hospital, Discipline of Paediatrics and Child Health, University of Newcastle, Newcastle, Australia. 10. Department of Enzymology and Cellular Function, Institute of Child Health, Athens, Greece. 11. 2nd Department of Pediatrics, National and Kapodistrian University of Athens, "P. & A. Kyriakou" Children's Hospital, Athens, Greece. 12. 1st Department of Pediatrics, University of Athens, Aghia Sofia Children's Hospital, Athens, Greece. 13. Department of Internal Medicine, University of Genoa, Italy. Electronic address: stefbert@unige.it. 14. Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Italy. Electronic address: sebcal@unimore.it.
Abstract
BACKGROUND AND AIMS: Childhood/Adult-onset Lysosomal Acid Lipase Deficiency (LAL-D) is a recessive disorder due to loss of function variants of LAL, the enzyme which hydrolyses cholesteryl esters, derived from internalized apoB containing lipoproteins. The disease is characterized by multi-organ involvement including the liver, spleen, intestine and cardiovascular system. The aim of this study was the clinical and molecular characterization of 14 (13 unrelated) previously unreported patients with childhood-onset LAL-D. METHODS: Data collected included clinical and laboratory investigations, liver imaging, liver biopsy and LIPA gene analysis. The response to lipid-lowering medications, liver transplantation and enzyme replacement therapy (ERT) was reported for some patients. RESULTS: LAL-D was suspected at 4.4 ± 3.3 years of age for the presence of hepatomegaly, elevated serum transaminases and hypercholesterolemia, and was confirmed by liver biopsy/imaging and LAL assay. The follow up period ranged from 3 to 40 years (mean 7.8 ± 4.0 years in 13 cases). Patients treated with statins with or without ezetimibe showed 28% reduction of plasma LDL-cholesterol without a tangible effect on liver enzymes; some patients receiving ERT showed normalized lipoprotein profile and transaminase levels. The common c.894G > A variant was observed in homozygosity or compound heterozygosity in 10 patients. We found seven previously reported variants: p.(Trp140*), p.(Arg218*), p.(Gly266*), p.(Thr288Ile), p.(Leu294Ser), p.(His295Tyr) and p.(Gly342Arg) and two novel variants: p.(Asp345Asn), affecting the LAL catalytic triad, and c.229+3A > C, affecting splicing. Homozygosity for p.(Thr288Ile) or c.229+3A > C was associated with a severe phenotype. CONCLUSIONS: This study provides additional data on the features of childhood-onset LAL-D and describes two novel pathogenic variants of the LIPA gene.
BACKGROUND AND AIMS: Childhood/Adult-onset Lysosomal Acid Lipase Deficiency (LAL-D) is a recessive disorder due to loss of function variants of LAL, the enzyme which hydrolyses cholesteryl esters, derived from internalized apoB containing lipoproteins. The disease is characterized by multi-organ involvement including the liver, spleen, intestine and cardiovascular system. The aim of this study was the clinical and molecular characterization of 14 (13 unrelated) previously unreported patients with childhood-onset LAL-D. METHODS: Data collected included clinical and laboratory investigations, liver imaging, liver biopsy and LIPA gene analysis. The response to lipid-lowering medications, liver transplantation and enzyme replacement therapy (ERT) was reported for some patients. RESULTS: LAL-D was suspected at 4.4 ± 3.3 years of age for the presence of hepatomegaly, elevated serum transaminases and hypercholesterolemia, and was confirmed by liver biopsy/imaging and LAL assay. The follow up period ranged from 3 to 40 years (mean 7.8 ± 4.0 years in 13 cases). Patients treated with statins with or without ezetimibe showed 28% reduction of plasma LDL-cholesterol without a tangible effect on liver enzymes; some patients receiving ERT showed normalized lipoprotein profile and transaminase levels. The common c.894G > A variant was observed in homozygosity or compound heterozygosity in 10 patients. We found seven previously reported variants: p.(Trp140*), p.(Arg218*), p.(Gly266*), p.(Thr288Ile), p.(Leu294Ser), p.(His295Tyr) and p.(Gly342Arg) and two novel variants: p.(Asp345Asn), affecting the LAL catalytic triad, and c.229+3A > C, affecting splicing. Homozygosity for p.(Thr288Ile) or c.229+3A > C was associated with a severe phenotype. CONCLUSIONS: This study provides additional data on the features of childhood-onset LAL-D and describes two novel pathogenic variants of the LIPA gene.
Authors: Camila da Rosa Witeck; Anne Calbusch Schmitz; Júlia Meller Dias de Oliveira; André Luís Porporatti; Graziela De Luca Canto; Maria Marlene de Souza Pires Journal: J Pediatr (Rio J) Date: 2021-05-06 Impact factor: 2.990