Novel Missense LCAT Gene Mutation Associated with an Atypical Phenotype of Familial LCAT Deficiency in Two Portuguese Brothers

Abstract

Familial lecithin-cholesterol acyltransferase deficiency (FLD) is a rare recessive disorder of cholesterol metabolism, caused by loss-of-function mutations in the human LCAT gene, leading to alterations in the lipid/lipoprotein profile, with extremely low HDL levels.

The classical FLD phenotype is characterized by diffuse corneal opacification, haemolytic anaemia and proteinuric chronic kidney disease (CKD); an incomplete form, only affecting the corneas, has been reported in a few families worldwide.

We describe an intermediate phenotype of LCAT deficiency, with CKD preceding the development of corneal clouding, in two Portuguese brothers apparently homozygous for a novel missense LCAT gene mutation. The atypical phenotype, the diagnosis of membranous nephropathy in the proband’s native kidney biopsy, the late-onset and delayed recognition of the corneal opacification, the co-segregation with Gilbert syndrome and the late recurrence of the primary disease in kidney allograft all contributed to obscure the diagnosis of an LCAT deficiency syndrome for many years.

A major teaching point is that on standard light microscopy examination the kidney biopsies of patients with LCAT deficiency with residual enzyme activity may not show significant vacuolization and may be misdiagnosed as membranous nephropathy. The cases of these two patients also illustrate the importance of performing detailed physical examination in young adults presenting with proteinuric CKD, as the most important clue to the diagnosis of FLD is in the eyes.

Appendices

Take Home Message

LCAT deficiency diagnosis may be misleading, particularly in atypical phenotypes, highlighting the importance of a detailed physical examination in patients presenting with proteinuric CKD, as the most important clue to the diagnosis of FLD is in the eyes.

Details of the Contributions of Individual Authors

Dr. Inês Castro Ferreira:

provided clinical data and drafted the manuscript;

Dr. Rute Carmo:

performed the kidney biopsy and drafted the manuscript;

Dr. Sérgio Estrela Silva:

performed the ophthalmological examinations and provided clinical data and the relevant photographs;

Dr. Otília Corrêa:

performed the lipid and lipoprotein analyses;

Dr. Susana Fernandes:

performed the LCAT genetic analysis and provided the electropherogram;

Dr. Susana Sampaio:

performed histopathological evaluation of kidney allograft biopsies and provided the relevant illustrations/photographs;

Dr. Pedro Rodrigues Pereira:

performed histopathological evaluation of kidney allograft biopsies and provided the relevant illustrations/photographs;

Dr. Augusta Praça:

provided clinical data;

Prof. Dr. João Paulo Oliveira:

provided clinical data and drafted the manuscript and is the guarantor for the chapter.

Corresponding Author

I. Castro-Ferreira.

E-mail: inescastroferreira@sapo.pt.

Details of Funding

None.

Compliance with Ethics Guidelines

Conflict of Interest

Inês Castro Ferreira, Rute Carmo, Sérgio Estrela Silva, Otília Corrêa, Susana Fernandes, Susana Sampaio, Pedro Rodrigues Pereira, Augusta Praça and João Paulo Oliveira declare that they have no conflict of interest.

Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.

Ethical Standards

There are no identifiable patient’s personal data on this manuscript.

The publication of this manuscript was approved by the Committee on Ethics for Health of the Centro Hospitalar São João/Faculdade de Medicina da Universidade do Porto.