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Pisciotta_2017_Atherosclerosis_265_124

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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 - Pisciotta_2017_Atherosclerosis_265_124
Author(s) : Pisciotta L , Tozzi G , Travaglini L , Taurisano R , 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
Ref : Atherosclerosis , 265 :124 , 2017
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.
PubMedSearch : Pisciotta_2017_Atherosclerosis_265_124
PubMedID: 28881270
Gene_locus related to this paper: human-LIPA

Related information

Mutation IVS3+3A>C_human-LIPA    W140X_human-LIPA    R218X_human-LIPA    G342R_human-LIPA    T288I_human-LIPA    L294S_human-LIPA    H295Y_human-LIPA    S275_Q298del_human-LIPA    D345N_human-LIPA
Gene_locus human-LIPA
Disease Wolman disease WD, Cholesterol Ester Storage Disease, CESD

Citations formats

Pisciotta L, Tozzi G, Travaglini L, Taurisano R, 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

Pisciotta L, Tozzi G, Travaglini L, Taurisano R, 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)
Atherosclerosis 265 :124