Considerations for Familial Chylomicronemia Diagnosis in the Era of Next-Generation Sequencing: A Latin American Perspective

Familial chylomicronemia syndrome (FCS) is an autosomal recessive disorder, characterized by alterations in the catabolism of chylomicrons and by increased levels of plasma triglycerides. It has been shown that about 60-90% of FCS patients have biallelic mutations in the LPL gene and the remaining patients have mutations in genes encoding proteins closely related to LPL function. The objective of this manuscript is to illustrate the different clinical scenarios of FCS presentation, and to guide practitioners on the usefulness of genetic tests in each of them. To this end, several published papers about recommendations for the diagnosis of FCS are discussed briefly, in addition to the presentation of several hypothetical cases, highlighting different clinical presentations and possible associated genetic findings. These cases illustrate the multiplicity of potential aspects of family history, clinical manifestations, biochemical parameters, and patterns of genetic variants found in genomic analyses of FCS.

Keywords
Familial chylomicronemia syndrome; genomics; genetic analyses

Authorship

Charles Marques Lourenco

Faculdade de Medicina de São José do Rio Preto, Rio de Janeiro, RJ, Brazil.Faculdade de Medicina de São José do Rio PretoBrazilRio de Janeiro, RJ, BrazilFaculdade de Medicina de São José do Rio Preto, Rio de Janeiro, RJ, Brazil.

http://orcid.org/0000-0002-2296-6098

Pablo Corral

FASTA University, Buenos Aires, Argentina.FASTA UniversityArgentinaBuenos Aires, ArgentinaFASTA University, Buenos Aires, Argentina.

Raul D. Santos

Universidade de São Paulo, São Paulo, SP, Brazil.Universidade de São PauloBrazilSão Paulo, BrazilUniversidade de São Paulo, São Paulo, SP, Brazil.

http://orcid.org/0000-0002-9860-6582

Juan Patricio Nogueira

Universidad Nacional de Formosa, Facultad de Ciencias de la Salud, Formosa, Argentina.Universidad Nacional de FormosaArgentinaFormosa, ArgentinaUniversidad Nacional de Formosa, Facultad de Ciencias de la Salud, Formosa, Argentina.

Carlos O. Mendivil

School of Medicine, Universidad de los Andes, Bogotá, Colombia.Universidad de los AndesColombiaBogotá, ColombiaSchool of Medicine, Universidad de los Andes, Bogotá, Colombia.

http://orcid.org/0000-0001-5546-4206

José L. Santos

Escuela de Medicina, Departamento de Nutrición, Diabetes y Metabolismo. Pontificia Universidad Católica de Chile, Santiago, Chile.Pontificia Universidad Católica de ChileChileSantiago, ChileEscuela de Medicina, Departamento de Nutrición, Diabetes y Metabolismo. Pontificia Universidad Católica de Chile, Santiago, Chile.

Harry Pachajoa

Universidad Icesi, Cali, Colombia.Universidad IcesiColombiaCali, ColombiaUniversidad Icesi, Cali, Colombia.

Virginia Bañares

Centro Nacional de Genética Médica, Departamento de Genética Experimental, Buenos Aires, Argentina.Centro Nacional de Genética MédicaArgentinaBuenos Aires, ArgentinaCentro Nacional de Genética Médica, Departamento de Genética Experimental, Buenos Aires, Argentina.

Maria Belen Mattos-Velez

Hospital de Especialidades Carlos Andrade Marín, Quito, Ecuador.Hospital de Especialidades Carlos Andrade MarínEcuadorQuito, EcuadorHospital de Especialidades Carlos Andrade Marín, Quito, Ecuador.

Corresponding Author:
Charles Lourenço, E-mail: charles.lourenco@estacio.br

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

SCIMAGO INSTITUTIONS RANKINGS

FASTA University, Buenos Aires, Argentina.FASTA UniversityArgentinaBuenos Aires, ArgentinaFASTA University, Buenos Aires, Argentina.

Universidade de São Paulo, São Paulo, SP, Brazil.Universidade de São PauloBrazilSão Paulo, BrazilUniversidade de São Paulo, São Paulo, SP, Brazil.

School of Medicine, Universidad de los Andes, Bogotá, Colombia.Universidad de los AndesColombiaBogotá, ColombiaSchool of Medicine, Universidad de los Andes, Bogotá, Colombia.

Universidad Icesi, Cali, Colombia.Universidad IcesiColombiaCali, ColombiaUniversidad Icesi, Cali, Colombia.

Hospital de Especialidades Carlos Andrade Marín, Quito, Ecuador.Hospital de Especialidades Carlos Andrade MarínEcuadorQuito, EcuadorHospital de Especialidades Carlos Andrade Marín, Quito, Ecuador.

Figures

Figures (7)

Thumbnail

Figure 1.
Crops of small, red-yellow dome-shaped papules of approx. 6 mm with well-defined borders located on the anterior medial thigh [55. Vangara SS, Klingbeil KD, Fertig RM, Radick JL. Severe hypertriglyceridemia presenting as eruptive xanthomatosis. J Family Med Prim Care. 2018;7(1):267-270. doi:10.4103/jfmpc.jfmpc_270_17.
https://doi.org/10.4103/jfmpc.jfmpc_270_... ].

Thumbnail

Figure 2.
Right eye fundus with signs of lipemia retinalis (optic disc and nasal part of retina). Characteristic whitish vessels are visible. It is difficult to distinguish the arteries from the veins [66. Rymarz E, Matysik-Woźniak A, Baltaziak L, Prystupa A, Sak J, Grzybowski A. Lipemia retinalis - an unusual cause of visual acuity deterioration. Med Sci Monit. 2012;18(8):CS72-CS75. doi:10.12659/msm.883257.
https://doi.org/10.12659/msm.883257... ].

Thumbnail

Figure 3.
Lipemic plasma distribution in an EDTA tube (a) immediately after blood sampling (b) after 1 h (c) after 2 h (d) after 3 h [77. Thajer A, Skacel G, de Gier C, Greber-Platzer S. The effect of a fat-restricted diet in four patients with familial chylomicronemia syndrome: A long-term follow-up study. Children (Basel). 2021;8(11):1078. doi:10.3390/children8111078.
https://doi.org/10.3390/children8111078... ].

Thumbnail

Figure 4.
Serum opacity with a chylomicron layer on top after overnight refrigeration at 4 °C [88. Jiang J, Wang Y, Ling Y, Kayoumu A, Liu G, Gao X. A novel APOC2 gene mutation identified in a Chinese patient with severe hypertriglyceridemia and recurrent pancreatitis. Lipids Health Dis. 2016;15:12. doi:10.1186/s12944-015-0171-6.
https://doi.org/10.1186/s12944-015-0171-... ].

Thumbnail

Figure 5.
The figure shows the color change from pink to red of the blood of the neonate following the treatment of familial chylomicronemia syndrome [99. Susheela AT, Vadakapet P, Pillai L, Thampi S. Familial chylomicronemia syndrome: A case report. J Med Case Rep. 2021;15(1):5. doi:10.1186/s13256-020-02609-0.
https://doi.org/10.1186/s13256-020-02609... ].

Thumbnail

Figure 6.
The FCS score. Modified from: [1919. Moulin P, Dufour R, Averna M, et al. Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): Expert panel recommendations and proposal of an "FCS score". Atherosclerosis. 2018;275:265-272. doi:10.1016/j.atherosclerosis.2018.06.814.
https://doi.org/10.1016/j.atherosclerosi... ].

Thumbnail

Figure 7.
European Consensus algorithm for FCS diagnosis. Modified from: [2020. Hegele RA, Borén J, Ginsberg HN, et al. Rare dyslipidaemias, from phenotype to genotype to management: A European Atherosclerosis Society task force consensus statement. Lancet Diabetes Endocrinol. 2020;8(1):50-67. doi:10.1016/S2213-8587(19)30264-5.
https://doi.org/10.1016/S2213-8587(19)30... ].

Figure 1. Crops of small, red-yellow dome-shaped papules of approx. 6 mm with well-defined borders located on the anterior medial thigh [55. Vangara SS, Klingbeil KD, Fertig RM, Radick JL. Severe hypertriglyceridemia presenting as eruptive xanthomatosis. J Family Med Prim Care. 2018;7(1):267-270. doi:10.4103/jfmpc.jfmpc_270_17.
https://doi.org/10.4103/jfmpc.jfmpc_270_... ].

Figure 2. Right eye fundus with signs of lipemia retinalis (optic disc and nasal part of retina). Characteristic whitish vessels are visible. It is difficult to distinguish the arteries from the veins [66. Rymarz E, Matysik-Woźniak A, Baltaziak L, Prystupa A, Sak J, Grzybowski A. Lipemia retinalis - an unusual cause of visual acuity deterioration. Med Sci Monit. 2012;18(8):CS72-CS75. doi:10.12659/msm.883257.
https://doi.org/10.12659/msm.883257... ].

Figure 3. Lipemic plasma distribution in an EDTA tube (a) immediately after blood sampling (b) after 1 h (c) after 2 h (d) after 3 h [77. Thajer A, Skacel G, de Gier C, Greber-Platzer S. The effect of a fat-restricted diet in four patients with familial chylomicronemia syndrome: A long-term follow-up study. Children (Basel). 2021;8(11):1078. doi:10.3390/children8111078.
https://doi.org/10.3390/children8111078... ].

Figure 4. Serum opacity with a chylomicron layer on top after overnight refrigeration at 4 °C [88. Jiang J, Wang Y, Ling Y, Kayoumu A, Liu G, Gao X. A novel APOC2 gene mutation identified in a Chinese patient with severe hypertriglyceridemia and recurrent pancreatitis. Lipids Health Dis. 2016;15:12. doi:10.1186/s12944-015-0171-6.
https://doi.org/10.1186/s12944-015-0171-... ].

Figure 5. The figure shows the color change from pink to red of the blood of the neonate following the treatment of familial chylomicronemia syndrome [99. Susheela AT, Vadakapet P, Pillai L, Thampi S. Familial chylomicronemia syndrome: A case report. J Med Case Rep. 2021;15(1):5. doi:10.1186/s13256-020-02609-0.
https://doi.org/10.1186/s13256-020-02609... ].

Figure 6. The FCS score. Modified from: [1919. Moulin P, Dufour R, Averna M, et al. Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): Expert panel recommendations and proposal of an "FCS score". Atherosclerosis. 2018;275:265-272. doi:10.1016/j.atherosclerosis.2018.06.814.
https://doi.org/10.1016/j.atherosclerosi... ].

Figure 7. European Consensus algorithm for FCS diagnosis. Modified from: [2020. Hegele RA, Borén J, Ginsberg HN, et al. Rare dyslipidaemias, from phenotype to genotype to management: A European Atherosclerosis Society task force consensus statement. Lancet Diabetes Endocrinol. 2020;8(1):50-67. doi:10.1016/S2213-8587(19)30264-5.
https://doi.org/10.1016/S2213-8587(19)30... ].

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Latin American Society Inborn Errors and Neonatal Screening (SLEIMPN); Instituto Genética para Todos (IGPT) Rua Ramiro Barcelos, 2350, CEP: 90035-903, Porto Alegre, RS - Brasil, Tel.: 55-51-3359-6338, Fax: 55-51-3359-8010 - Porto Alegre - RS - Brazil
E-mail: rgiugliani@hcpa.edu.br

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Considerations for Familial Chylomicronemia Diagnosis in the Era of Next-Generation Sequencing: A Latin American Perspective

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[1] Corresponding Author:
Charles Lourenço, E-mail: charles.lourenco@estacio.br