Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants

Livia Pisciotta; Giulia Tozzi; Lorena Travaglini; Tiziano Lucchi; Giuseppe Indolfi; Francesco Papadia; Maja Di Rocco; Lorenzo D'Antiga; Patricia Crock; Komal Vora; Scott Nightingale; Helen Michelakakis; Anastasia Garoufi; Lilia Lykopoulou; Stefano Bertolini; Sebastiano Calandra

doi:10.1016/j.atherosclerosis.2017.08.021

Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants

Livia Pisciotta, Giulia Tozzi, Lorena Travaglini, Tiziano Lucchi, Giuseppe Indolfi, Francesco Papadia, Maja Di Rocco, Lorenzo D'Antiga, Patricia Crock, Komal Vora, Scott Nightingale, Helen Michelakakis, Anastasia Garoufi, Lilia Lykopoulou, Stefano Bertolini, Sebastiano Calandra

Istituto "Giannina Gaslini"

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	124-132
Number of pages	9
Journal	Atherosclerosis
Volume	265
DOIs	https://doi.org/10.1016/j.atherosclerosis.2017.08.021
Publication status	Published - Oct 2017

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10.1016/j.atherosclerosis.2017.08.021

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Pisciotta, L., Tozzi, G., Travaglini, L., Lucchi, T., Indolfi, G., Papadia, F., Di Rocco, M., D'Antiga, L., Crock, P., Vora, K., Nightingale, S., Michelakakis, H., Garoufi, A., Lykopoulou, L., Bertolini, S., & Calandra, S. (2017). Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants. Atherosclerosis, 265, 124-132. https://doi.org/10.1016/j.atherosclerosis.2017.08.021

Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants. / Pisciotta, Livia; Tozzi, Giulia; Travaglini, Lorena et al.

In: Atherosclerosis, Vol. 265, 10.2017, p. 124-132.

Research output: Contribution to journal › Article › peer-review

Pisciotta, L, Tozzi, G, Travaglini, L, Lucchi, T, Indolfi, G, Papadia, F, Di Rocco, M, D'Antiga, L, Crock, P, Vora, K, Nightingale, S, Michelakakis, H, Garoufi, A, Lykopoulou, L, Bertolini, S & Calandra, S 2017, 'Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants', Atherosclerosis, vol. 265, pp. 124-132. https://doi.org/10.1016/j.atherosclerosis.2017.08.021

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title = "Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants",

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.",

keywords = "Journal Article",

author = "Livia Pisciotta and Giulia Tozzi and Lorena Travaglini and Tiziano Lucchi and Giuseppe Indolfi and Francesco Papadia and {Di Rocco}, Maja and Lorenzo D'Antiga and Patricia Crock and Komal Vora and Scott Nightingale and Helen Michelakakis and Anastasia Garoufi and Lilia Lykopoulou and Stefano Bertolini and Sebastiano Calandra",

note = "Copyright {\textcopyright} 2017. Published by Elsevier B.V.",

year = "2017",

month = oct,

doi = "10.1016/j.atherosclerosis.2017.08.021",

language = "English",

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TY - JOUR

T1 - Molecular and clinical characterization of a series of patients with childhood-onset lysosomal acid lipase deficiency. Retrospective investigations, follow-up and detection of two novel LIPA pathogenic variants

AU - Pisciotta, Livia

AU - Tozzi, Giulia

AU - Travaglini, Lorena

AU - Lucchi, Tiziano

AU - Indolfi, Giuseppe

AU - Papadia, Francesco

AU - Di Rocco, Maja

AU - D'Antiga, Lorenzo

AU - Crock, Patricia

AU - Vora, Komal

AU - Nightingale, Scott

AU - Michelakakis, Helen

AU - Garoufi, Anastasia

AU - Lykopoulou, Lilia

AU - Bertolini, Stefano

AU - Calandra, Sebastiano

PY - 2017/10

Y1 - 2017/10

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.atherosclerosis.2017.08.021

DO - 10.1016/j.atherosclerosis.2017.08.021

M3 - Article

C2 - 28881270

VL - 265

SP - 124

EP - 132

JO - Atherosclerosis

JF - Atherosclerosis

SN - 0021-9150

ER -