Lipa Gene Mutation in PED-LIPIGEN (Pediatric FH Subjects)

NCT03984149 | Unknown DMC

• 1 other identifier: LIPIGEN-002
• Study Type: observational
• Target: 1,000
• Locations: 1 country
• Sites: 4

Brief Summary

Familial Hypercholesterolemia (FH) is a monogenic autosomal dominant disease also known as Autosomal Dominant Hypercholesterolemia - ADH) that leads to dramatically increased levels of Low Density Lipoprotein (LDL) and total cholesterol associated to tendon xanthomas, xanthelasma, corneal arcus, premature atherosclerosis and to an increased risk of coronary artery disease (CAD) and myocardial infarction. FH is mainly caused by mutations in genes encoding for proteins affecting hepatic LDL cholesterol uptake including the LDL receptor (LDLR) gene or the gene encoding the only apolipoprotein of LDL, the apolipoprotein B (APOB), or the gene encoding a protease regulating LDLR levels on the cell membrane Lysosomal Acid Lipase A (LIPA) gene encode for Lysosomal acid lipase (LAL) enzyme responsible for hydrolyzing cholesterol esters and triglycerides that are delivered to lysosomes. Mutations in LIPA that completely inactivate LAL are the molecular cause of Wolman disease, a rapidly lethal disease of infancy while mutations in LIPA that result in residual enzymatic activity of LAL are responsible of a disorder characterized by a less severe phenotype known as cholesterol ester storage disease (CESD). Patients with CESD usually show a phenotype characterized by hepatic disease and mixed hyperlipidemia with elevated levels of LDL-C and triglycerides (TG) and decreased HDL-C levels. A broader phenotypic presentation for loss of function mutations in LIPA suggests that LIPA mutations may be considered in patients with apparently monogenic FH in whom mutations in the known candidate genes are not detectable. The project is aimed to evaluate the prevalence and the mutation rate of LIPA gene in subjects with a clinical diagnosis of FH and already genetically characterized in whom pathogenic mutations in the known candidate genes have not been identified. The analysis will be performed in about 250 FH pediatric subjects and putative causal mutations will be also tested for co-segregation in available families in affected and unaffected members.

Conditions

Lysosomal Acid Lipase Deficiency

Keywords

Atherosclerosis; Familial hypercholesterolemia; LIPA; Lysosomal acid lipase deficiency; Wolman disease

Outcome Measures

Primary Outcomes (1)

• Prevalence of patients with mutations of LIPA gene among clinically diagnosed FH subjects

  Percentage of patients with at least one mutation of LIPA gene among clinically diagnosed FH subjects according to a "Dutch Lipid Clinic Network" score of 6 or above

  2 years from start of the study

Secondary Outcomes (1)

• Frequency of specific mutations of LIPA gene among clinically diagnosed FH subjects

  2 years from start of the study

Study Arms (1)

FH pediatric patients

1000 clinically diagnosed FH pediatric patients (age \<18 years) included in the LIPIGEN (Lipid TransPort Disorders italian Genetic Network) database

Other: Observational study

Interventions

Observational study OTHER

Observational study: There is no intervention.

FH pediatric patients

Eligibility Criteria

• Age: Up to 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

Clinically diagnosed FH pediatric patients (age \<18 years) included in the Lipid TransPort Disorders italian Genetic Network (LIPIGEN) database, already genetically characterized.

You may qualify if:

• Pediatric subjects (\<18 years old) with a clinical diagnosis of FH and without identified pathogenic mutations in the known candidate genes.

You may not qualify if:

• Subjects with a clinical diagnosis of FH with identified pathogenic mutations in the known candidate genes.

Sponsors & Collaborators

• Fondazione SISA (Societa Italiana per lo Studio della Arteriosclerosi): lead

Study Sites (4)

CENTRO PER LO STUDIO DELL'ATEROSCLEROSI - Ospedale Bassini

Cinisello Balsamo, Mi, Italy

RECRUITING

Laboratorio di biochimica delle lipoproteine - DIPARTIMENTO DI SCIENZE BIOMEDICHE

Modena, Italy

RECRUITING

Centro Di Riferimento Regionale Per La Prevenzione, Diagnosi E Cura Delle Malattie Rare Del Metabolismo

Palermo, Italy

RECRUITING

Centro Per L'Arteriosclerosi Dipartimento Di Medicina Interna E Specialità Mediche

Roma, Italy

RECRUITING

Related Publications (13)

• ABRAMOV A, SCHORR S, WOLMAN M. Generalized xanthomatosis with calcified adrenals. AMA J Dis Child. 1956 Mar;91(3):282-6. doi: 10.1001/archpedi.1956.02060020284010. No abstract available.

  PMID: 13301142 BACKGROUND

• Bernstein DL, Hulkova H, Bialer MG, Desnick RJ. Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease. J Hepatol. 2013 Jun;58(6):1230-43. doi: 10.1016/j.jhep.2013.02.014. Epub 2013 Feb 26.

  PMID: 23485521 BACKGROUND

• Bertolini S, Pisciotta L, Rabacchi C, Cefalu AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S. Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

  PMID: 23375686 BACKGROUND

• Burke JA, Schubert WK. Deficient activity of hepatic acid lipase in cholesterol ester storage disease. Science. 1972 Apr 21;176(4032):309-10. doi: 10.1126/science.176.4032.309.

  PMID: 5019788 BACKGROUND

• Futema M, Plagnol V, Li K, Whittall RA, Neil HA, Seed M; Simon Broome Consortium; Bertolini S, Calandra S, Descamps OS, Graham CA, Hegele RA, Karpe F, Durst R, Leitersdorf E, Lench N, Nair DR, Soran H, Van Bockxmeer FM; UK10K Consortium; Humphries SE. Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations. J Med Genet. 2014 Aug;51(8):537-44. doi: 10.1136/jmedgenet-2014-102405. Epub 2014 Jul 1.

  PMID: 24987033 BACKGROUND

• Hamilton J, Jones I, Srivastava R, Galloway P. A new method for the measurement of lysosomal acid lipase in dried blood spots using the inhibitor Lalistat 2. Clin Chim Acta. 2012 Aug 16;413(15-16):1207-10. doi: 10.1016/j.cca.2012.03.019. Epub 2012 Mar 29.

  PMID: 22483793 BACKGROUND

• Hopkins PN, Toth PP, Ballantyne CM, Rader DJ; National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011 Jun;5(3 Suppl):S9-17. doi: 10.1016/j.jacl.2011.03.452. Epub 2011 Apr 3. No abstract available.

  PMID: 21600530 BACKGROUND

• Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Boren J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjaerg-Hansen A; European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013 Dec;34(45):3478-90a. doi: 10.1093/eurheartj/eht273. Epub 2013 Aug 15.

  PMID: 23956253 BACKGROUND

• Patrick AD, Lake BD. Deficiency of an acid lipase in Wolman's disease. Nature. 1969 Jun 14;222(5198):1067-8. doi: 10.1038/2221067a0. No abstract available.

  PMID: 5787090 BACKGROUND

• Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ. 1991 Oct 12;303(6807):893-6. doi: 10.1136/bmj.303.6807.893.

  PMID: 1933004 BACKGROUND

• Stitziel NO, Fouchier SW, Sjouke B, Peloso GM, Moscoso AM, Auer PL, Goel A, Gigante B, Barnes TA, Melander O, Orho-Melander M, Duga S, Sivapalaratnam S, Nikpay M, Martinelli N, Girelli D, Jackson RD, Kooperberg C, Lange LA, Ardissino D, McPherson R, Farrall M, Watkins H, Reilly MP, Rader DJ, de Faire U, Schunkert H, Erdmann J, Samani NJ, Charnas L, Altshuler D, Gabriel S, Kastelein JJ, Defesche JC, Nederveen AJ, Kathiresan S, Hovingh GK; National Heart, Lung, and Blood Institute GO Exome Sequencing Project. Exome sequencing and directed clinical phenotyping diagnose cholesterol ester storage disease presenting as autosomal recessive hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2013 Dec;33(12):2909-14. doi: 10.1161/ATVBAHA.113.302426. Epub 2013 Sep 26.

  PMID: 24072694 BACKGROUND

• Talmud PJ, Futema M, Humphries SE. The genetic architecture of the familial hyperlipidaemia syndromes: rare mutations and common variants in multiple genes. Curr Opin Lipidol. 2014 Aug;25(4):274-81. doi: 10.1097/MOL.0000000000000090.

  PMID: 24977977 BACKGROUND

• Williams RR, Hunt SC, Schumacher MC, Hegele RA, Leppert MF, Ludwig EH, Hopkins PN. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol. 1993 Jul 15;72(2):171-6. doi: 10.1016/0002-9149(93)90155-6.

  PMID: 8328379 BACKGROUND

Related Links

• Familial hypercholesterolaemia (FH) : report of a second World Health Organization (WHO) consultation, Geneva, 4 September 1998

Biospecimen

Retention: SAMPLES WITH DNA

Venous blood samples were taken after 12 hours of fasting. Serum total cholesterol, triglycerides and HDL-cholesterol levels were measured in a centralized laboratory using enzymatic methods. DNA samples, serum, plasma and whole blood were aliquoted and preserved at -80°C.

MeSH Terms

Conditions

Wolman Disease; Atherosclerosis; Hyperlipoproteinemia Type II

Interventions

Observation

Condition Hierarchy (Ancestors)

Cholesterol Ester Storage Disease; Lipidoses; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lysosomal Storage Diseases; Infant, Newborn, Diseases; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases; Hyperlipoproteinemias; Hyperlipidemias; Dyslipidemias

Intervention Hierarchy (Ancestors)

Methods; Investigative Techniques

Study Officials

• Maurizio Averna

  Fondazione SISA

  STUDY DIRECTOR

Central Study Contacts

Alberico L Catapano

CONTACT

alberico.catapano@unimi.it

Alessia Tincani

CONTACT

+39026173276; catapano.centroatero@gmail.com

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: RETROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 21, 2019
• First Posted: June 12, 2019
• Study Start: September 1, 2017
• Primary Completion: July 1, 2023
• Study Completion: July 1, 2023
• Last Updated: July 29, 2022

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: For three years from the end of the study
• Access Criteria: Upon preventive request for a scientific collaboration

Locations

IT (4)