Prevalence of p.G87V and p.Gln298=Variations in LIPA Gene Within Middle Eastern Population Living Around Los Angeles.

Background: The LIPA gene encodes for lysosomal acid lipase (LAL), which catalyzes the hydrolysis of cholesterol esters and triglycerides. Variations in the LIPA gene impair LAL activity, predisposing patients to a rare metabolic disorder called LAL deficiency (LAL-D). The lack of functioning LAL promotes lipid accumulation and subsequent dyslipidemia, which can increase the likelihood of complications in both infants and adults. Although the worldwide prevalence is 1:500,000 births, the frequency in Mizrahi Jewish populations is projected to be as high as 1 in every 4200 births (Valles-Ayoub et al.) based on the LIPA p.G87V variant frequency among 162 individuals. Materials and Methods: This study was conducted to validate the previously reported prevalence of LAL-D in the Mizrahi Jewish population based on the pathogenic LIPA missense variants in exon 4 (c.260G>T; p.G87V) and exon 8 (c.894G>A; p.Gln298=) using a larger cohort of those with Middle Eastern ancestry living around Los Angeles. Among the 1184 individual samples sequenced, 660 self-reported as Mizrahi Jewish, while the remaining 524 came from other Middle Eastern groups labeled as "non-Jewish." Results: Of the 1184 samples, 22 alleles of the exon 4 variant were identified (1.85%), and 2 alleles of the exon 8 variant were identified (0.16%). For the exon 4 variant, 20 of 22 (90.9%) heterozygotes were Mizrahi Jewish, while 2 of 22 (9.09%) heterozygotes were "non-Jewish." For the exon 8 variant, 2 of 2 (100%) heterozygotes were Mizrahi Jewish. This suggests that the prevalence of LAL-D in this population is 1 in 900, which suggests that LAL-D may be 4.6% higher in the Mizrahi Jewish population in previous reports. Conclusion: These findings show increased prevalence of LIPA gene exon 4 variation p.G87V in the Middle East population when compared to the general population, indicating the need for prenatal screening in those of Mizrahi Jewish ancestry.

Deficiencia de lipasa ácida lisosomal, una patología infrecuente.

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.

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.

Large-scale functional LIPA variant characterization to improve birth prevalence estimates of lysosomal acid lipase deficiency.

Lysosomal acid lipase (LAL) deficiency is an autosomal recessive disorder caused by LIPA gene mutations that disrupt LAL activity. We performed in vitro functional testing of 149 LIPA variants to increase the understanding of the variant effects on LAL deficiency and to improve disease prevalence estimates. Chosen variants had been reported in literature or population databases. Functional testing was done by plasmid transient transfection and LAL activity assessment. We assembled a set of 165 published LAL deficient patient genotypes to evaluate this assay's effectiveness to recapitulate genotype/phenotype relationships. Rapidly progressive LAL deficient patients showed negligible enzymatic activity (<1%), whereas patients with childhood/adult LAL deficiency typically have 1-7% average activity. We benchmarked six in silico variant effect prediction algorithms with these functional data. PolyPhen-2 was shown to have a superior area under the receiver operating curve performance. We used functional data along with Genome Aggregation Database (gnomAD) allele frequencies to estimate LAL deficiency birth prevalence, yielding a range of 3.45-5.97 cases per million births in European-ancestry populations. The low estimate only considers functionally assayed variants in gnomAD. The high estimate computes allele frequencies for variants absent in gnomAD, and uses in silico scores for unassayed variants. Prevalence estimates are lower than previously published, underscoring LAL deficiency's rarity.

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.

Opening a window on lysosomal acid lipase deficiency: Biochemical, molecular, and epidemiological insights.

Lysosomal acid lipase deficiency (LAL-D) is a multi-organ autosomal recessive disease caused by mutations in LIPA. We reviewed data from 681 samples (white blood cells [WBC] n = 625, fibroblasts = 30, liver = 4, amniocytes = 13, chorionic villus = 9) received for analysis of lysosomal acid lipase (LAL) activity over a 15-year period. LIPA sequencing was performed in 49 patients with reduced (n = 26) or deficient (n = 23) LAL activity. The Exome Aggregation Consortium and Genome Aggregation Database dataset were used for LAL-D prevalence calculations. LAL WBC activity was reduced in 67 patients (10.72%) and deficient in 37 (5.92%). The average of LAL activity ± margin of error (CI 95%) was 19.32 ± 0.86 pmol/min/mg for reduced activity patients and 5.90 ± 1.42 pmol/min/mg for deficient patients. The average age at diagnosis for LAL-D was 23.6 years with several patients older than age 30. The correlation between the age at diagnosis and LAL activity showed a significant moderate direct correlation (Pearson's r = 0.46, P < 0.005). Homozygous or compound heterozygous mutations were identified in 9 out of 23 patients with deficient results (detection rate 39.1%). The average LAL activity in molecularly confirmed patients was 4.02 ± 2.02 pmol/min/mg protein, while in molecularly negative patients was 13.886 ± 1.49 pmol/min/mg (P < 0.0001). Twenty-two different mutations were identified including two novel variants (c.309C>A and c.856G>C). A carrier frequency of approximately 1 in 350 was inferred. LAL activity in WBC is a validated tool for LAL-D diagnosis. Higher residual enzymatic activity might result in a milder phenotype leading to diagnosis delay. A cut-off below 12 pmol/min/mg protein might be useful to discriminate patients with LIPA mutations.

The global prevalence and genetic spectrum of lysosomal acid lipase deficiency: A rare condition that mimics NAFLD.

BACKGROUND & AIMS: Lysosomal acid lipase deficiency (LAL-D) is an autosomal recessive condition that may present in a mild form (cholesteryl ester storage disease [CESD]), which mimics non-alcoholic fatty liver disease (NAFLD). It has been suggested that CESD may affect 1 in 40,000 and is under-diagnosed in NAFLD clinics. Therefore, we aimed to estimate the prevalence of LAL-D using analysis of genetic variation in LIPA. METHODS: MEDLINE and EMBASE were systematically searched for previously reported disease variants and prevalence estimates. Previous prevalence estimates were meta-analysed. Disease variants in LIPA were annotated with allele frequencies from gnomAD and combined with unreported major functional variants found in humans. Pooled ethnicity-specific prevalences for LAL-D and CESD were calculated using the Hardy-Weinberg equation. RESULTS: Meta-analysis of existing genetic studies estimated the prevalence of LAL-D as 1 per 160,000 (95% CI 1 per 65,025-761,652) using the allele frequency of c.894G>A in LIPA. A total of 98 previously reported disease variants in LIPA were identified, of which 32/98 were present in gnomAD, giving a prevalence of 1 per 307,482 (95% CI 257,672-366,865). Wolman disease was associated with more loss-of-function variants than CESD. When this was combined with 22 previously unreported major functional variants in LIPA identified in humans, the pooled prevalence of LAL-D was 1 per 177,452 (95% CI 149,467-210,683) with a carrier frequency of 1 per 421. The prevalence is lowest in those of East Asian, South Asian, and Finnish ancestry. CONCLUSION: Using 120 disease variants in LIPA, these data can reassure clinicians that LAL-D is an ultra-rare disorder. Given the therapeutic capability of sebelipase alpha, investigation for LAL-D might be included in second-line metabolic screening in NAFLD. LAY SUMMARY: Lysosomal Acid Lipase Deficiency (LAL-D) is a rare genetic condition that can cause severe liver disease, but it is difficult to diagnose and sometimes can look like simple fatty liver. It was not clear how common LAL-D was and whether many cases were being missed. To study this, we searched for all genetic mutations that could cause LAL-D, calculated how common those mutations were, and added them up. This let us estimate that LAL-D affects roughly 1 in 175,000 people. We conclude that LAL-D is a very rare condition, but it is treatable so may be included in a 'second-line' of tests for causes of fatty liver.

Identification of rare diseases by screening a population selected on the basis of routine pathology results-the PATHFINDER project: lysosomal acid lipase/cholesteryl ester storage disease substudy.

AIMS: Lysosomal acid lipase deficiency (LALD) is an autosomal recessive disorder of cholesterol ester storage associated with hepatic disease, cirrhosis and accelerated atherosclerosis. Its prevalence in the general population, patients with dyslipidaemia and raised transaminases is unclear. This study attempted to identify the prevalence of LALD from patients with abnormal results in laboratory databases. METHODS: Electronic laboratory databases were interrogated to identify from clinical biochemistry records patients with a phenotype of low high-density lipoprotein-cholesterol (≤0.85 mmol/L; 33 mg/dL) and with elevated alanine or aspartate transaminases (≥60 IU/L) on one occasion or more over a 3-year time interval. Patients were recalled, and a dried blood spot sample was collected for lysosomal acid lipase determination by a fluorimetric enzyme assay. Histopathology databases of liver biopsies were interrogated for patients with features of 'microvesicular cirrhosis' or 'cryptogenic cirrhosis' in the report. Histological blocks were sampled, and samples were analysed by next-generation sequencing for the presence of mutations in the LAL gene. RESULTS: Samples were obtained from 1825 patients with dyslipidaemia and elevated transaminases. No cases of LALD were identified. Liver biopsies were obtained from six patients. DNA extraction was successful from four patients. Two patients were homozygous for the LAL c.46A>C;p.Thr16Pro unclassified variant in exon 2. CONCLUSIONS: Pathology databases hold routine information that can be used to identify patients with specific patterns of results or those who had biopsies to allow targeted testing for possible causes of disease. Biochemical screening suggests that the gene frequency of LAL deficiency in adults is less than 1 in 100.

Wolman's disease and cholesteryl ester storage disorder: the phenotypic spectrum of lysosomal acid lipase deficiency.

Lysosomal acid lipase deficiency is a rare, autosomal recessive condition caused by mutations in the gene encoding lysosomal acid lipase (LIPA) that result in reduced or absent activity of this essential enzyme. The severity of the resulting disease depends on the nature of the underlying mutation and magnitude of its effect on enzymatic function. Wolman's disease is a severe disorder that presents during infancy, resulting in failure to thrive, hepatomegaly, and hepatic failure, and an average life expectancy of less than 4 months. Cholesteryl ester storage disorder arises later in life and is less severe, although the two diseases share many common features, including dyslipidaemia and transaminitis. The prevalence of these diseases has been estimated at one in 40 000 to 300 000, but many cases are undiagnosed and unreported, and awareness among clinicians is low. Lysosomal acid lipase deficiency-which can be diagnosed using dry blood spot testing-is often misdiagnosed as non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hereditary dyslipidaemia, or cryptogenic cirrhosis. There are no formal guidelines for treatment of these patients, and treatment options are limited. In this Review we appraise the existing literature on Wolman's disease and cholesteryl ester storage disease, and discuss available treatments, including enzyme replacement therapy, oral lipid-lowering therapy, stem-cell transplantation, and liver transplantation.

Cholesteryl ester storage disease: a rare and possibly treatable cause of premature vascular disease and cirrhosis.

Cholesteryl ester storage disease (CESD) is an autosomal recessive lysosomal storage disorder caused by a variety of mutations of the LIPA gene. These cause reduced activity of lysosomal acid lipase, which results in accumulation of cholesteryl esters in lysosomes. If enzyme activity is very low/absent, presentation is in infancy with failure to thrive, malabsorption, hepatosplenomegaly and rapid early death (Wolman disease). With higher but still low enzyme activity, presentation is later in life with hepatic fibrosis, dyslipidaemia and early atherosclerosis.Identification of this rare disorder is difficult as it is essential to assay leucocyte acid phosphatase activity. An assay using specific inhibitors has now been developed that facilitates measurement in dried blood spots. Treatment of CESD has until now been limited to management of the dyslipidaemia, but this does not influence the liver effects. A new enzyme replacement therapy (Sebelipase) has now been developed that could change treatment options for the future.

Association of LIPA gene polymorphisms with obesity-related metabolic complications among severely obese patients.

The lipase A, lysosomal acid, cholesterol esterase enzyme (LIPA) is involved in the hydrolysis of triglycerides (TGs) and cholesteryl esters (CEs) delivered to lysosomes. LIPA deficiency in human causes two distinct phenotypes characterized by intracellular storage of CE and derangements in the control of cholesterol production, namely the Wolman disease (WD) and the CE storage disease (CESD). To test the potential association of LIPA gene polymorphisms with obesity-related metabolic complications, promoter, exons, and intronic flanking regions of the LIPA gene were first sequenced in 25 individuals. From the 14 common polymorphisms identified, 12 tagging single-nucleotide polymorphisms (tSNPs) were genotyped in a cohort of 1,751 obese individuals. After adjustments for the effect of age, sex, diabetes, and medication, the C allele of SNP rs1051338 was associated with lower blood pressure (BP; systolic (SBP) P = 0.004; diastolic (DBP) P = 0.006). Three of the tested SNPs were associated with modifications of the plasma lipid profile. The G/G genotype of rs2071509 was associated with higher high-density lipoprotein cholesterol (HDL-C) levels (P = 0.009) and minor allele of rs1131706 was also associated with higher HDL-C (P = 0.004) and an association between rs3802656 and total cholesterol (total-C)/HDL-C ratio was identified (P = 0.04). These results thus suggest that LIPA polymorphisms contribute to the interindividual variability observed in obesity-related metabolic complications.

Sobre el descubrimiento de los fármacos hipolipemiantes / About the discovery of hypolipidemic drugs

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Valoració dels criteris diagnòstics de la icterícia colestàtica durant el primer any de vida / Valoración de los criterios diagnósticos de la ictericia colestásica durante el primer año de vida / Evaluation of diagnostic criteria for cholestatic jaundice during the first year of life

Fonament. La icterícia és un motiu habitual de consulta en els lactants. És important detectar les colestàtiques per establir precoçment el diagnòstic i millorar el pronòstic. Objectius. Analitzar les diferències clíniques i de les exploracions complementàries dels lactants amb colèstasi segons l’etiologia, per determinar quines haurien de guiar l’especialista per a un diagnòstic precoç. Material i mètodes. Estudi retrospectiu dels nadons ingressats per icterícia colestàtica entre gener de 1997 i desembre de 2001. Resultats. Es recullen setze casos, onze masculins, de disset dies a onze mesos d’edat. Es diagnostiquen: sis hepatitis (H), cinc atrèsies de vies biliars (AVB), dos dèficits d’alfa-1-antitripsina (Dα1AT), un ARC-I (síndrome caracteritzada per presentar artrogriposi, tubulopatia renal, colèstasi i ictiosi), una malaltia de Wolman (W) i una colèstasi extrahepàtica amb cirrosi micronodular (CM). Nou pacients presenten hipocòlia, set colúria, i tres estancament ponderal. Quatre nens amb baix pes en néixer tenen H. Es detecta hepatomegàlia en cinc pacients i esplenomegàlia només en el cas de W. La bilirubina (Br) total, directa i gammaglutamiltranspeptidasa (GGT) en les AVB són més elevades que en les H. L’ecografia abdominal no objectiva bufeta biliar en quatre AVB, una H i a la CM. Es fa gammagrafia i és diagnòstica a les AVB, surt alterada en un Dα1AT i en la CM i és normal en una H. Comentaris. L’hepatitis idiopàtica es relaciona més freqüentment amb baix pes en néixer que l’AVB. Una colèstasi amb Br total > 7 mg/dl i GGT > 300 UI/L suggereix AVB. L’ecografia abdominal és la primera prova d’imatge a fer davant una colèstasi; la gammagrafia es reserva per als casos amb alta sospita d’AVB (AU)

Fundamento. La ictericia es motivo habitual de consulta en los lactantes. Es importante detectar las colestásicas para establecer precozmente el diagnóstico y mejorar el pronóstico. Objetivos. Analizar las diferencias clínicas y de las exploraciones complementarias de los lactantes con colestasis según la etiología, para determinar cuales tendrían que guiar al especialista para un diagnóstico precoz. Material y métodos. Estudio retrospectivo de los lactantes ingresados por ictericia colestásica entre enero de 1997 y diciembre de 2001. Resultados. Se recogen 16 casos, 11 masculinos, de 17 días a 11 meses de edad. Se diagnostican: 6 hepatitis (H), 5 atresias de vías biliares (AVB), 2 déficits de alfa-1-antitripsina, (Dα1AT), un ARC-I (síndrome caracterizado por artrogriposis, tubulopatía renal, colestasis e ictiosis), una enfermedad de Wolman (W) y una colestasis extrahepática con cirrosis micronodular (CM). Presentan hipocolia 9 pacientes, coluria 7 y estancamiento ponderal 3. Hay 4 niños con bajo peso al nacer tienen H. Se detecta hepatomegalia en 5 pacientes y esplenomegalia sólo en W. La bilirrubina (Br) total, directa y gamma-glutamiltranspeptidasa (GGT) en las AVB son más elevadas que en las H. La ecografía abdominal no objetiva vesícula biliar en 4 AVB, una H y en la CM. Se realiza gammagrafía y es diagnóstica en las AVB, está alterada en un Dα1AT y en la CM y es normal en una H. Comentarios. La hepatitis idiopática se relaciona más frecuentemente con bajo peso al nacer que la AVB. Una colestasis con Br total > 7 mg/dl y GGT > 300 UI/L sugiere AVB. La ecografía abdominal es la primera prueba de imagen a realizar ante una colestasis; la gammagrafía se reserva para los casos con alta sospecha de AVB (AU)

Background. Jaundice is a common reason for consultation in infants. Early detection of cholestatic jaundice may result in improved prognosis. Objectives. To analyze the distinct clinical features of the different types of cholestatic jaundice that can assist in an early diagnosis. Material and methods. Retrospective study of infants with cholestatic jaundice admitted between January 1997 and December 2001. Results. Sixteen infants (11 males), aged 17 days to 11 months, were included. Distribution by diagnosis was as follows: Hepatitis, 6 cases; Biliary atresia, 5 cases, alpha 1αantitrypsine deficiency, 2 cases; ARC-1 syndrome (arthrogryposis, renal tubulopathy, cholestasis and ichthyosis), 1 case; Wolman disease, 1 case; extrahepatic cholestasis with micronodular chirrosis, 1 case. Nine patients had hypocholia, 7 patients had choluria, and 3 patients had failure to thrive. The 4 patients with low birth weight had hepatitis. Five patients had hepatomegaly, and splenomegaly was only present in the case with Wolman syndrome. Total and direct bilirubin and gamma-glutamyltranspeptidase (GGT) were higher in biliary atresia than in hepatitis. Abdominal ultrasound failed to identify the gallbladder in 4 cases of biliary atresia, in one case of hepatitis, and in the case of micronodular chirrosis. A scintigraphy was diagnostic in the cases of biliary atresia, was abnormal in the cases of alpha-1-antitrypsine deficiency and micronodular chirrosis, and was normal in one case of hepatitis. Comments. Idiopatic hepatitis is more commonly associated with low birth weight than biliary atresia. A cholestasis with a total bilirrubin of > 7 mg/dl and GGT > 300 IU/L suggests biliary atresia. Abdominal ultrasound is the first imaging study that should be performed; the scintigraphy should be performed in those cases highly suspicious of biliary atresia (AU)

[Lysosomal acid lipase deficiency. Overview of Czech patients]. / Deficit kyselé (lysozomální) lipázy. Prehled ceských pacientu.

Lysosomal lipase deficiency is a hereditary autosomal recessive enzymopathy leading to lysosomal storage of triacylglycerols (TAG) and cholesterol esters (CE). In particular cells with a permanently high receptor-mediated LDL endocytosis are affected (liver, kidneys). There are two basic phenotypes. The fatal infantile phenotype (Wolman's disease) with generalized storage of both types of apolar lipids. This form was diagnosed in this country only once. The opposite is the protracted, oligosymptomatic form encountered in all age groups. It is characterized by the storage of CE (which gave this entity the name of cholesteryl storage disease--CESD). Its main sign is affection of the liver (hepatomegaly, hepatopathy), which in some instances may lead to organ failure, directly or after cirrhotic transformation. Furthermore there is permanent hypercholesterolaemia (high LDL cholesterol) due to increased VLDL synthesis by hepatocytes, low HDL cholesterol and variably raised TAG. This constellation of blood lipids is a risk factor for the development of atherosclerosis. In the course of 25 years in the Czech Republic 13 cases of CESD were diagnosed in 11 families. Ten of these cases were characterized by clinically manifest hepatopathy with hepatomegaly, detected incidentally during medical examinations (at the age of 2-14 years). In three adult patients with permanent hypercholesterolaemia the storage process was subclinical and the diagnosis was established quite incidentally by examination of non-specific secondary and tertiary manifestations of the disease. The diagnosis was established in all cases of CESD at the tissue level (liver biopsy), at the biochemical (acid lipase deficiency) and molecular genetic level (mutation in enzyme locus). In all instances mutation of G934A was found leading to reduction and loss of the eighth exon. This mutation was present in five patients in a homozygous state. Six mutations were heterozygous. In one instance for technical reasons only one allele was analyzed. In three instances a point "missense" mutation was found: T323A (Trp74Arg), T4(75)A (Asp124Glu), A210T (Asp36Gl), in one instance a "nonsense" mutation: C233T (Arg44-stop) and twice a deletion mutation delta C673-5 and delta G1068-8 leading to impairment of the reading frame and to premature stop of the codon.