The official journal of the Japan Atherosclerosis Society andthe Asian Pacific Society of Atherosclerosis and Vascular Diseases

Review

J Atheroscler Thromb, 2021; 28: 679-691. http://doi.org/10.5551/jat.RV17051

Current Status of Familial LCAT Deficiency in Japan
Masayuki Kuroda 1, Hideaki Bujo 2, Koutaro Yokote 3, Takeyoshi Murano 4, Takashi Yamaguchi 5,
Masatsune Ogura 6, Katsunori Ikewaki 7, Masahiro Koseki 8, Yasuo Takeuchi 9, Atsuko Nakatsuka 10,
Mika Hori 11, Kota Matsuki 12, Takashi Miida 13, Shinji Yokoyama 14, Jun Wada 10 and Mariko Harada-Shiba 15
on behalf of the Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable
Disease of the Ministry of Health, Labour and Welfare of Japan †1Center for Advanced Medicine, Chiba University Hospital, Chiba University, Chiba, Japan
Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Chiba, Japan3
Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan
4
Clinical Laboratory Program, Faculty of Science, Toho University, Funabashi, Chiba, Japan
5
Center of Diabetes, Endocrinology and Metabolism, Toho University Sakura Medical Center, Chiba, Japan
6
Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
7
Division of Neurology, Anti-Aging, and Vascular Medicine, Department of Internal Medicine, National Defense Medical College,
Saitama, Japan
8
Division of Cardiovascular Medicine, Department of Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
9
Division of Nephrology, Kitasato University School of Medicine, Kanagawa, Japan10
Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine,
Dentistry and Pharmaceutical Sciences, Okayama, Japan
11
Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
12
Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
13
Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
14
Institute for Biological Functions, Chubu University, Aichi, Japan
15
Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
2†

The Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable Disease of the Ministry of
Health, Labour and Welfare of Japan: Mariko Harada-Shiba (Department of Molecular Pathogenesis, National Cerebral andCardiovascular Center Research Institute, Osaka, Japan), Shun Ishibashi (Division of Endocrinology and Metabolism, Department
of Internal Medicine, School of Medicine, Jichi Medical University, Tochigi, Japan), Shinji Yokoyama (Institute for Biological
Functions, Chubu University, Aichi, Japan), Hitoshi Shimano (Department of Internal Medicine (Endocrinology and Metabolism),
Faculty of Medicine University of Tsukuba, Tsukuba, Japan), Koutaro Yokote (Department of Endocrinology, Hematology andGerontology, Chiba University Graduate School of Medicine, Chiba, Japan), Hideaki Bujo (Department of Clinical-Laboratory andExperimental-Research Medicine, Toho University Sakura Medical Center, Chiba, Japan), Shizuya Yamashita (Rinku General
Medical Center, Osaka, Japan), Kazuhisa Tsukamoto (Department of Internal Medicine, Teikyo University, Tokyo, Japan), Toshio
Hayashi (School of Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan), Katsunori Ikewaki (Divisionof Neurology, Anti-Aging, and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Saitama,
Japan), Takanari Gotoda (Department of Metabolic Biochemistry, Faculty of Medicine, Kyorin University, Tokyo, Japan), Kazushige
Dobashi (Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan), Yoshihiro Miyamoto (Open
Innovation Center, National Cerebral and Cardiovascular Center, Osaka, Japan), Misa Takegami (Department of Preventive
Medicine and Epidemiology, National Cerebral and Cardiovascular Center, Osaka, Japan), Yoshiki Sekijima (Department ofMedicine (Neurology & Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan), Yasushi Ishigaki (Division of
Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan), Hiroaki
Okazaki (Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan),Atsushi Nohara (Ishikawa Prefectural Central Hospital, Kanazawa, Japan), Shingo Koyama (Division of Neurology and Clinical
Neuroscience, Department of Internal Medicine III, Yamagata University Faculty of Medicine, Yamagata, Japan), Kyoko Inagaki(Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Nippon Medical School, Tokyo, Japan), Koh
Ono (Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan), Masahiro Koseki(Division of Cardiovascular Medicine, Department of Medicine, Osaka University Graduate School of Medicine, Osaka, Japan),
Hiroyuki Daida (Faculty of Health Science, Juntendo University, Juntendo University Graduate School of Medicine, Tokyo, Japan),
Manabu Takahashi (Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University,
Tochigi, Japan), Kimitoshi Nakamura (Department of Pediatrics, Kumamoto University Graduate School of Medical Sciences,
Kumamoto, Japan), Takashi Miida (Department of Clinical Laboratory Medicine, Juntendo University Graduate School of
Medicine, Tokyo, Japan), Masa-aki Kawashiri (Department of Cardiovascular Medicine, Graduate School of Medical Sciences,679

Kuroda et al .

Kanazawa University, Kanazawa, Japan), Tetsuo Minamino (Department of Cardiorenal and Cerebrovascular Medicine, Faculty of
Medicine, Kagawa University, Kagawa, Japan), Sachiko Okazaki (Division for Health Service Promotion, The University of Tokyo,
Tokyo, Japan), Hayato Tada (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences,
Kanazawa, Japan), Jun Wada (Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University
Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan), Masatsune Ogura (Division of Lipid
Metabolism, Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute,
Osaka, Japan), Hirotoshi Ohmura (Department of Cardiovascular Medicine, School of Medicine, Juntendo University, Tokyo,
Japan), Mika Hori (Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya,Japan), Kota Matsuki (Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki,
Japan), Masashi Yamamoto (Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of
Medicine, Chiba, Japan), Yasuo Takeuchi (Division of Nephrology, Kitasato University School of Medicine, Kanagawa, Japan),
Atsuko Nakatsuka (Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate
School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan), Daisaku Masuda (Department of Cardiology,
Health Care Center, Rinku Innovation Center for Wellness Care and Activities (RICWA), Rinku General Medical Center, Osaka,
Japan), Satoshi Hirayama (Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo,
Japan), Masayuki Kuroda (Center for Advanced Medicine, Chiba University Hospital, Chiba University, Chiba, Japan), Takashi
Yamaguchi (Center of Diabetes, Endocrinology and Metabolism, Toho University Sakura Medical Center, Chiba, Japan), Takeyoshi
Murano (Clinical Laboratory Program, Faculty of Science, Toho University, Chiba, Japan).

Lecithin cholesterol acyltransferase (LCAT) is a lipid-modification enzyme that catalyzes the transfer of theacyl chain from the second position of lecithin to the hydroxyl group of cholesterol (FC) on plasma lipoproteins
to form cholesteryl acylester and lysolecithin. Familial LCAT deficiency is an intractable autosomal recessive
disorder caused by inherited dysfunction of the LCAT enzyme. The disease appears in two different phenotypes
depending on the position of the gene mutation: familial LCAT deficiency (FLD, OMIM 245900) that lacks
esterification activity on both HDL and ApoB-containing lipoproteins, and fish-eye disease (FED, OMIM
136120) that lacks activity only on HDL. Impaired metabolism of cholesterol and phospholipids due to LCAT
dysfunction results in abnormal concentrations, composition and morphology of plasma lipoproteins and further
causes ectopic lipid accumulation and/or abnormal lipid composition in certain tissues/cells, and serious
dysfunction and complications in certain organs. Marked reduction of plasma HDL-cholesterol (HDL-C) andcorneal opacity are common clinical manifestations of FLD and FED. FLD is also accompanied by anemia,
proteinuria and progressive renal failure that eventually requires hemodialysis. Replacement therapy with the
LCAT enzyme should prevent progression of serious complications, particularly renal dysfunction and corneal
opacity. A clinical research project aiming at gene/cell therapy is currently underway.
Key words: Lecithin cholesterol acyltransferase, Low HDL-cholesterol, Abnormal LDL, Corneal opacity,
Proteinuria, Enzyme replacement therapy

Introduction
The enzyme that esterifies cholesterol in humanplasma was discovered in 1962 1). The reaction wasdetermined to be an acyl transfer reaction from
phosphatidylcholine (lecithin) associated with HDL.
The enzyme was named LCAT, and the physiologicalrole proposed for it was creating a gradient ofcholesterol content between the HDL surface and cell
membrane to generate efflux of cell cholesterol 2). At

around the same time, a patient with deficiency of thisenzyme was identified in Norway. A 33-year-old
woman in a hospital in Oslo was suspected of having
chronic nephritis due to proteinuria and exhibited
corneal opacity, anemia, and slight hypoalbuminemia,
though renal function was normal. Renal biopsy
revealed presence of foam cells in the glomerular tufts.
Plasma total cholesterol and triglyceride levels werehigh but most of the cholesterol was found not to beesterified and further biochemical analyses

Address for correspondence: Masayuki Kuroda, Center for Advanced Medicine, Chiba University Hospital, Chiba University, 1–8–1 Inohana, Chuo-ku, Chiba
260–8677, Japan.
E-mail: kurodam@faculty.chiba-u.jp
Received: March 16, 2021
Accepted for publication: March 19, 2021
Copyright©2021 Japan Atherosclerosis Society
This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

680

LCAT Deficiency in Japandemonstrated that the patient was deficient in LCAT
activity. Similar signs and symptoms were also notedin her sister, suggesting a hereditary disorder.
Therefore, the disorder was named familial LCAT
deficiency (FLD, OMIM 245900) by Norum andGjone 1). The classical form of this disease exhibits
plasma LCAT activity of less than 10% of normal
whereas, in partial deficiency the decrease may be 15
to 40%. In FLD, there is lack of esterification activity
on both HDL and ApoB-containing lipoproteins.
Later, a subtype of this disease was found and named
fish-eye disease (FED, OMIM 136120), where
esterification is inactive only on HDL 3). Both FLD
and FED are caused by LCAT gene mutations. The
profile and progression of the accompanying
symptoms vary depending on the extent of LCAT
activity impairment. In this review, the clinical andbiochemical features, genetic backgrounds and current
treatment of this hereditary disease are summarized
and, referring to cases reported in Japan, clinicalpractice guidelines for Japan are proposed.
Background Mechanism
for Clinical Findings of Familial LCAT
Deficiency and Fish-Eye Disease
LCAT is the enzyme that acyl-esterifies
cholesterol in plasma, which reduces unesterified
cholesterol on the HDL surface to generate efflux ofcell cholesterol to HDL. This comprises an importantpart of cholesterol transport from peripheral organs
and cells to the liver for its catabolism. LCAT
dysfunction disrupts this process, resulting in marked
reduction of HDL-C and deformation of HDL
particles due to lack of their major core lipid,cholesteryl acyl-ester. Impaired turnover of cellularcholesterol leads to its accumulation in cells in thecornea, bone marrow, liver, spleen, and glomerularbasement membrane of the kidney 4, 5). It is visible
from the abnormal shape of erythrocytes 4, 5). The
clinical prognosis of LCAT deficiency is largely
dependent on progression of renal dysfunction 4, 5).
Both FLD and FED are commonly screened for by
low plasma HDL-C level and corneal opacity 4, 5).
1) Dyslipidemia
LCAT catalyzes acylesterification of cholesterolon plasma lipoproteins in the steady state, both on α
-lipoproteins (HDL) (α-activity) and β-lipoproteins(LDL and VLDL) (β activity). The reaction requires
the presence of helical apolipoproteins such asapolipoprotein (apo) A-I and E. It takes place on
HDL, where particles are initially assembled as disclike particles from extracellular helical apolipoproteinssuch as apoA-I with cellular phospholipid andcholesterol (nascent HDL or preβ-HDL), to generate
the core and make particles spherical (mature HDL).
This process maintains the efflux of cholesterol from
cells to HDL. The reaction also takes place on apoB
lipoproteins (β-lipoproteins), which should provide
additional efflux of cell cholesterol. Lack of LCAT
activity therefore causes a marked decrease in HDL-C
and “immature” HDL remains in plasma appearing as
rouleaux under electron microscopic observation.
Owing to this abnormal HDL, plasma apoA-I andapoA-II, the first and second major apolipoproteins,also decrease. Thus, among FLD plasma lipoproteins,the percentage of esterified cholesterol in totalcholesterol (CE/TC) is markedly low. There are also
abnormal findings for LDL fractions inultracentrifugation analysis 6) due to lack of the LCAT
reaction, in which three subtypes of particles withdifferent lipid compositions are evident. They are LpX
particles, which are called FC-rich, PL-rich andTG-poor particles, and have a larger size (40 nm-60
nm). A large subtype of LDL rich in TG and PL(Lp8) 7) was identified by gel filtration HPLC analysis
as a specific subtype for FLD. However, the exact
mechanism for generating these abnormal LDL
particles is not fully understood. Moreover, specificchanges in LDL in FED are not clearly defined.
2) Corneal Opacity
FC and phospholipids accumulate excessively inthe cornea due to lack of the LCAT reaction. Corneal
turbidity is observed from early childhood in both
FLD and FED, with patients presenting severe visual
impairment and requiring corneal transplantation.
Corneal opacity is frequently observed not only in
LCAT deficiency but also in other HDL-deficiencies
such as those related to apoA-I and ABCA1 (Tangierdisease) 8). Electron microscopic studies have shownthat corneas from FLD patients are similar to those ofpatients with familial apoA1 deficiency 9-13). In apatient with Tangier disease, very mild corneal
clouding (usually requiring a slit-lamp examination
for detection) has been reported, with less abundant
extracellular corneal stromal deposits and cholesterol/phospholipid accumulation than in FED 14). Since
FED is usually not accompanied by renal dysfunction,
the underlying mechanisms for corneal opacity andrenal dysfunction may differ. Since the largest particle
size capable of diffusing through the central stromal
matrix is about 12 nm 15), it is unlikely that LDL and/or LpX infiltrate into the corneal stroma. On theother hand, small to normal-sized spherical HDL
particles are found only in very small amounts in FLD
and FED and Tangier disease 16-18). As cholesterol is
681

Kuroda et al .

synthesized in the cornea 19) reduced removal is apossible cause of its accumulation.
3) Hemolytic Anemia
Abnormally shaped erythrocytes, called target red
blood cells, appear in LCAT deficiency due to theabnormal lipid composition of the cell membranes,
which sometimes leads to hemolytic anemia, perhaps
due to their fragility 20, 21). The half-life of red blood
cells is approximately half that of healthy people.
4) Splenomegaly
Splenomegaly with sea-blue histiocytosis has
been reported 22, 23) in some FLD patients presenting
abnormal lipid profiles. The histiocytes contained
cytoplasmic vacuoles and membrane-like structures
resembling rose petals, indicating that they werecomposed of phospholipid-containing membranes.
5) Proteinuria and Renal Dysfunction
Proteinuria is detected relatively early in the lifeof patients and frequently develops into progressive
renal failure at 40 to 50 years of age, and eventuallyrequires hemodialysis 24, 25). It has been reported that
proteinuria occurred in FLD patients at 3 years ofage 26). As kidney damage does not generally developin FED, renal biopsy may be useful for differential
diagnosis of the subtypes of LCAT deficiency. Renal
lesions begin with deposition of lipid in theglomerular basement membrane, and later in themesangium and capillary subendothelium. LpX
particles, abnormal lipoprotein particles identified in
the LDL fractions of FLD, have been considered to bea causative factor of renal damage in many studies 5, 27-29).
Recently, large TG-rich LDL (Lp8) 7) has beenreported to be associated with the progression of renal
dysfunction. It has also been reported that oxidized
lecithin in the LDL of patients causes renal
dysfunction 30). In addition, lipoproteins containing
apoE have been shown to be taken up by renal
glomerular mesangial cells, causing excessive lipid
deposition, possibly leading to renal dysfunction 31).
ApoE is a physiological LCAT activator in β-activity
on LDL/VLDL particles 32), and effect of apoE
genotype on clinical manifestations has beenreported 33, 34), although further analyses are required
to draw a definitive conclusion. In mice, LpX is taken
up by glomerular endothelial cells, podocytes, andmesangial cells, it causes dysfunction in glomerular
endothelial cells, and increases secretion of
inflammatory cytokines 35). Recent follow-up studies
of families with an FLD mutation for a median of 12
years showed that eGFR deteriorated amonghomozygous family members at an average annual rate682

of 3.56 mL/min/1.73 m2, whereas deterioration inheterozygous members and family controls was 1.33
and 0.68 mL/min/1.73 m2, respectively 36). A recent
Italian cohort study in which 18 FLD patients (12males and 6 females) were followed up for 12±8.5
years reported that renal events (dialysis, kidneytransplant, or death due to renal complications) occur
at a median age of 46 years 37).
6) Atherosclerosis
Based on the inverse association between
cardiovascular risk and plasma HDL-C levels found in
epidemiological studies and the proposed function of
LCAT in cholesterol transport, it is conceivable thatthe risk of cardiovascular events is increased in genetic
low HDL-C patients. However, studies on FLD
patients have produced inconsistent findings regarding
a correlation between LCAT activity andatherosclerosis 38, 39). Recently, Italian and Dutch
research groups assessed subclinical atherosclerosis
using carotid intima-media thickness in 74 patientswith heterozygous mutations leading to the FLD and
FED phenotypes 40). Carriers of LCAT mutations
leading to FLD exhibited less carotid atherosclerosis,
whereas carriers of those leading to FED showedmarginally more atherosclerosis. Thus, the clinicalsignificance of the function of HDL 41) and other
LCAT-associated lipoproteins 7) in the progression ofatherosclerosis has not been established from thefindings in FLD and FED. Also, no significant
information in this regard has been reported inJapanese FLD and FED patients.
Disease Prevalence and Genetics
FLD and FED are autosomal recessive inherited
diseases caused by mutations of the LCAT gene locatedin the short arm of chromosome 16. In Japan, theprevalence of these diseases is extremely low so theexact rate of mutation is unknown. Fig. 1 shows
previously identified LCAT gene mutations in patients
according to The Human Gene Mutation Database 42),
showing great diversity in the positions of mutations
causing dysfunction of LCAT. An association between
position and extent or nature of dysfunction has notbeen well established. A report by the Ministry of
Health, Labor and Welfare Research Group described
13 types of mutations identified in Japan 43) by 2004.
Since the report, a further 7 mutations of the LCAT
gene have been identified as causative mutations of
FLD or FED in Japan 34, 44-46); 5 of them were novel
mutations and 2 had already been reported in patientsin other countries. Mutations occurring in Japaneseare summarized in Table 1.

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Fig. 1. Previously identified mutations in LCAT gene
The LCAT gene is composed of six exons. Mutations identified so far are depicted according to The Human Gene Mutation Database (HGMD®)(http://www.hgmd.cf.ac.uk/ac/index.php). Numbers of amino acid residues are expressed based on mature LCAT protein after signal peptide(24 amino acid residues) is cleaved. Mutations in red and bule are causative mutations identified in familial LCAT deficiency (FLD) and fisheye disease (FED), respectively. The ＊ symbol indicates a mutation reported in Japan, and the # symbol indicates a mutation identified inJapan as well as other countries. Mutations shown in black are variants of uncertain significance found by such as genome-wide nucleotide
sequencing of clinical samples.

Table 1. Mutations identified in patients in Japan
Exon

Mutation

Codon

Amino acid substitution

Phenotype

1
1
1
1
2
2
2
3
4
4
4
4
5
6
6
6
6
6
6
6

c.86A ＞ Tc.101insC
c.101C ＞ T
c.110C ＞ T
c.160G ＞ A
c.278C ＞ T
c.293G ＞ A
c.367C ＞ T
c.440C ＞ T
c.490C ＞ T
c.491G ＞ A
c.493insGGC
c.607G ＞ C
c.756C ＞ A
c.821C ＞ G
c.862delc.950T ＞ C
c.951G ＞ A
c.1034C ＞ T
c.1102G ＞ A

5
10
10
13
30
69
74
99
123
140
140
141
179
228
250
264
293
293
321
344

Asn ＞ Ile
Pro10fsTer17
Pro ＞ Leu
Thr ＞ Met
Gly ＞ SerPro ＞ Leu
Cys ＞ Tyr
Arg ＞ Cys
Thr ＞ Ile
Arg ＞ Cys
Arg ＞ His
ins Gly
Gly ＞ Arg
Asn ＞ Lys
Pro ＞ Arg
His263fsTer385
Met ＞ Thr
Met ＞ Ile
Thr ＞ Met
Gly ＞ Ser

FLD
FLD
FED
FED
FLD
FLD
FLD
FED
FED
FLD
FLD
FLD
FLD
FLD
FLD
FLD
FLD
FED
FLD
FLD

Mutations identified in Japanese patients are summarized. Note that numbering of amino acidresidues is based on mature LCAT protein in which 24 signal peptide sequence is removed.

683

Kuroda et al .

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Fig. 2. Distribution of HDL-C in patients
Clinical levels of HDL-C available from published data (until Aug. 2019) for homozygous and compound heterozygous patients (n = 86) andheterozygotes (n = 141) have been collected and their distribution is shown in the figure. Note that their assay methods are not taken into consideration in the data distribution.

Clinical Examinations and Diagnostic
Approach to LCAT Deficiency in JapanThe main clinical findings in FLD and FED arecorneal opacity and low HDL-C. They are the key
signs for suspecting these diseases. Proteinuria and/or
anemia are also observed in many cases of FLD, but
not in FED.
1) Lipid Examination
HDL-C values reported in the literature aresummarized for homozygous and compound
heterozygous FLD patients (n = 86) in Fig. 2 (until
Aug. 2019). More than 72% of patients exhibited
HDL-C levels less than 10 mg/dL. However, 3.5 %had levels higher than 20 mg/dL though the assay
methods were not standardized. When a patient has
an HDL-C level less than 25 mg/dL and corneal
opacity, LCAT activity analysis should be considered(proposed by the Committee on Primar y
Dyslipidemia under the Research Program on Rareand Intractable Diseases of the Ministry of Health,Labour and Welfare of Japan in 2020). In assays, since
α-activity represents LCAT activity using synthetic
HDL (specific for HDL) as a substrate 47), measured
levels are largely decreased in all plasma samples frompatients with FLD or FED and may be below the684

detection limit in both. Cholesterol esterification rate
(CER) 48) represents total esterification activity,
including β-activity (specific for β-lipoproteins) and
α-activity. As β-activity is also disrupted in FLD but
not much in FED, measured levels are usually moredecreased in FLD, compared with FED, which isuseful for distinguishing FLD and FED. However,these assays are not routinely available in the clinicallaboratories of regular hospitals in Japan. Therefore,
the CE/TC ratio in plasma is a useful alternative for
distinguishing FLD and FED. CE/TC is always
reduced in FLD but not in FED and partial LCAT
deficiency. ApoA-I and apoA-II are also significantly
reduced due to the reduced HDL levels in FLD and
FED. In the electrophoretic analysis of lipoproteins(agarose or polyacrylamide), LCAT dysfunction resultsin the appearance of abnormal lipoproteins, including
LpX and IDL. Large and triglyceride-rich LDL (Lp8)
is identified through HPLC gel filtration analysis oflipoproteins 7).
2) Ophthalmic Examination
Corneal opacity (Fig. 3A) is recognized in most
LCAT deficiency patients. Grayish white granularspots are observed in corneal layers excluding theepithelium by the slit-lamp test. To assess the extent ofcorneal opacity, a contrast sensitivity test 49) is useful.

LCAT Deficiency in Japanand mesangial region 50).

$%

4) Hematological Examination
Mild hemolytic anemia is present in many casesof FLD. A blood count shows a decreased hemoglobin
level. HbA1c and haptoglobin levels are also decreased.
Red blood cells with an abnormal appearance (called“target cells”, “knizocytes”, “stomatocytes”, or“spherostomatocytes”) are observed in FLD due tocholesterol accumulation in the cell membranes.
5) Gene Analysis
Genetic analysis is useful for the final diagnosis,
combined with the results of the above examinations.
The recessive inheritance format is determinedthrough identification of mutations in the LCAT geneof the FLD or FED patients.
Differential Diagnosis&
Fig. 3. Case with LCAT deficiency manifesting as corneal
opacities and proteinuria (patient from ref. 31)
A) Corneal opacities in right eye (arrows).
B) Light microscopic findings for renal biopsy (Periodic acid
methenamine silver stain). Thickened with bubbly, vacuolated, andhoneycomb appearance. (Bar = 10 µm)
C) Electron microscopic findings for renal biopsy. Electron micrograph shows glomerular epimembranous, intramembranous, andsubendothelial lipid droplets. Electron-lucent deposits with anelectron-dense core can be observed in the glomerular basement
membrane and mesangial matrix. (Bar = 2 µm)

3) Renal Examination
When proteinuria is present in patients withdecreased LCAT activity who present with corneal
opacity, renal biopsy may be considered (Fig. 3B and
3C). Deposition of FC and phospholipids in the
subendothelium of glomerular basement membrane isoften observed. Accumulation of foam cells andthickening of Bowman’s sac and glomerular basement
membrane are also observed. Electron microscopy
reveals an extensive high electron density membrane
structure in the capillary lumen, basement membrane,

1) Hereditary Low HDL-Cholesterolemia (TangierDisease, Familial Hypo-Alpha-Lipoproteinemia
and ApoA-I Deficiency)
Patients with apoA-I deficiency and Tangierdisease have a marked reduction in plasma HDL-C
levels, which are generally lower than those in FLD
and FED. Corneal opacity is also observed in these
diseases 8). The apo A-I level is about 30-50 mg/dL inpatients with FLD or FED, but levels in Tangierdisease are more markedly decreased (less than 10 mg/dL). Thus, the plasma apolipoprotein A-I
concentration is useful for the differential diagnosis ofthese diseases. However, genetic analysis may beneeded for final differentiation of diseases withhereditary low HDL-cholesterolemia.
2) Immune-Mediated LCAT Deficiency
There have been reports of patients exhibiting
marked reduction in plasma HDL-C and renal
dysfunction, similar to those in genetic LCAT
deficiency, but are due to the presence ofautoantibodies against LCAT protein 51, 52). Immunemediated LCAT deficiency is sometimes foundthrough a gradual decrease in HDL-C. Testing for theantibodies and investigation of family history arenecessary for differentiating this disorder from genetic
LCAT deficiency, especially FLD.
3) Liver Disease (Liver Cirrhosis and Fulminant
Hepatitis), Biliary Tract Obstruction, Malnutrition,
or Cachexia
LCAT is an enzyme produced in the liver, so its
biosynthesis is susceptible to hepatic damage. It is thus
necessary to differentiate FLD and FED from685

Kuroda et al .

conditions where there is a secondary decrease in the
enzyme due to serious liver dysfunction 53).
4) Drug-Induced Low HDL-Cholesterolemia(Probucol and Probucol/Fibrates)
Probucol has been found to reduce plasma HDL
by inhibiting ABCA1 activity. In addition, it has beenreported that plasma HDL is reduced to an extreme
degree when probucol is taken with fibrate, even when
fibrate is initiated after discontinuing probucol 54-56).
Patient histories need to be examined for use of these
medications.
Since it is a designated intractable disease,diagnostic criteria for familial LCAT deficiency werepreviously proposed by the research group of the
Ministry of Health, Labor and Welfare of Japan. The
guidelines have been updated based on additionallyaccumulated Japanese clinical and laboratory data by adyslipidemia research group supported by a grantfrom the Ministry of Health, Labor and Welfare(Table 2).
Current Treatment
There is no currently approved effective
treatment for FLD and FED. Effective treatments
would be replacement with normal or recombinant
LCAT enzymes and gene therapy, and they are now
under development. To mitigate renal dysfunction, a
low-fat diet and renoprotective drugs, such as
angiotensin converting enzyme (ACE) inhibitors or
angiotensin II receptor blockers (ARB), are prescribed.
1) DietThere has been a study on the FLD siblings
where the younger brother, who was put on a low
calorie intake (1900 Cal) with fat restriction (25 g/day), did not develop proteinuria while his elder
brother having a total calorie intake of 2500 Cal andfat intake of 65 g/day did 57). Together with those ofother studies 46, 58), these findings indicate thatdevelopment of renal dysfunction can be delayed by a
low-fat diet. A low-fat diet may lead to a decrease inabnormal lipoproteins associated with LCAT
deficiency as well as reduced renal damage, although it
may not be effective in all cases 59).
2) Blood Transfusion Therapy
Fresh blood (whole blood or plasma) transfusion
therapy has been reported to be effective for LCAT
replacement 60, 61). An increase in LCAT activity wasobserved, but it returned to the pre-transfusion levelwithin one week, indicating that it is difficult to
686

Table 2. Diagnostic criteria for Japan proposed by researchgroup of Ministry of Health, Labor and Welfare
A. Required item
1. Blood HDL-C level less than 25 mg/dL
2. Decrease in cholesteryl ester/TC ratio (CE/TC) (60% or less)
B. Symptom
1. Proteinuria, renal dysfunction
2. Corneal opacities
C. Laboratory findings
Blood and biochemical examination findings
1. Anemia (hemoglobin level, less than 11 g/dL)
2. Abnormalities in morphology of red blood cells (called “target
cells”, “knizocytes”, “stomatocytes”, or “spherostomatocytes”)
3. Appearance of abnormal lipoproteins (LpX, IDL, or large
TG rich LDL)
Ophthalmic examination findings
Decreased contrast sensitivity
D. Differential diagnosis
Differentiate from following diseases.
1. Other hereditary low HDL-cholesterolemia (Tangierdisease, apolipoprotein AI deficiency)
2. Secondary LCAT deficiency (pathophysiology showing
decreased protein synthesis such as liver disease (hepatic
cirrhosis, fulminant hepatitis), biliary obstruction,
malnutrition, cachexia, and autoimmune LCAT deficiency
with underlying disease)
3. Secondary low HDL-cholesterolemia (After surgery, hepatopathy(especially cirrhosis, severe hepatitis, including convalescentstage), acute phase of systemic inflammatory disease,debilitating diseases such as cancer. history of oral probucol
within the past 6 months, probucol and fibrate combination(including prescription after discontinuation of probucol))E. Genetic testing
1. Mutation of LCAT geneIn a clinical sample in which two essential items are satisfied, thefollowing determinations are made.
Definite: A disease that meets one or more of B and C and excludes
any disease to be differentiated from in D, and satisfies E
Probable: Disease that meets one or more of B and C andexcludes any disease that should be differentiated from in D

maintain a therapeutic level.
3) Drug Treatment
There is no definitive drug treatment foralleviating decreased or defective LCAT activity in
FLD. Drug therapy, combined with diet, has been
attempted with the purpose of preventing or
mitigating the deterioration in renal function. ACE
inhibitors reportedly reduced proteinuria after one

LCAT Deficiency in Japan

year of treatment 26). Also, combination therapy of
nicotinic acid and fenofibrate lead to a reduction in
LpX and an associated reduction in albuminuria in apatient 62). In addition, high-dose ARB with statin wasreported to stabilize the progression of renal
dysfunction 63). Results for corticosteroid treatment(with ACE inhibitor) suggested that reduced
inflammatory responses lead to a decrease inproteinuria in a patient 64).
4) Recombinant hLCAT Protein (rhLCAT)
Replacement Therapy
A clinical trial on rhLCAT has been conductedin the United States 65). High-dose rhLCAT (9.0 mg/kg) improved anemia and renal function to somedegree with improvement in lipid parameters,
including an increase in HDL-C but there was a
return to the pre-treatment status by 2 weeks afteradministration, and the supply of rhLCAT became
insufficient during the trial. As with other enzyme
replacement therapies, it is necessary to continue
administration. Another clinical trial has been
conducted to evaluate the safety, pharmacokinetics
and pharmacodynamics of rhLCAT in subjects withstable coronary artery disease (NCT02601560) 66). It
was reported that antibodies against rhLCAT appearedin some of the participants on the highest dose ofrhLCAT.
5) Gene Therapy
A gene therapy-mediated continuous supply of
LCAT would improve patient QOL by reducing thefrequency of hospital visits and administration oftherapy. No gene therapy has received regulatory
approval anywhere. In Japan, the first in-human study
on gene therapy/regenerative medicine via autotransplantation of LCAT gene-transduced preadipocytes
has been approved by the Ministry of Health, Laborand Welfare, under the Act on Securement of Safetyof Regenerative Medicine 67). The first patient has been
followed up for more than three years sincetransplantation at Chiba University Hospital. It was
well-tolerated. The second clinical trial was started in2020 for the purpose of obtaining regulatory approvalin Japan.
6) Organ Transplantation
Kidney transplantation to treat renal dysfunction
and corneal transplantation to remedy visual
impairment are performed, but the risk of recurrence
is inevitably high. In recent years, single-donor
sequential kidney and liver transplantation has been
performed in one patient 68). During the 5-year
follow-up period, the function of the transplanted

organs was maintained, but dyslipidemia recurred
within 1 year after liver transplantation.
Future Perspectives
Our current understanding of familial LCAT
deficiency and its complications is summarized in thisreview based on information from the literature,including that from Japan. More than 100 LCAT
mutations have been identified in the world, butmechanisms of development of subsequent
complications remain to be elucidated. A better
understanding of the pathophysiology of this disease
will be necessary to make further progress intreatment. We hope that this review will be helpful forclinicians in performing diagnosis and medical carefor patients suspected of having the disease in Japan.
The diagnosis of the subtypes of this rare genetic
disease, FLD and FED, requires the involvement ofmultiple departments such as lipid metabolism,
nephrology, and ophthalmology. Also, the onset ofsevere renal dysfunction is relatively late (40 to 50
years old). These could be reasons for the delay indiagnosis. Measurement of LCAT activity and genetic
testing for FLD and FED are not covered by National
Health Insurance in Japan, and this also makes it
difficult for physicians to diagnose patients with thedisease.
Currently, LCAT enzyme replacement therapy
by means of transfusion of a recombinant preparationor gene/cell therapy is under development. We hopethat these treatments are put into practice in near
future, and improve patients’ survival and QOL.
Acknowledgments andNotice of Grant Support
This work has been supported by Health, Labourand Welfare Sciences Research Grant for Research on
Rare and Intractable Diseases (H30-nanji-ippan-003).
Conflicts of Interest
Atsushi Nohara has nothing to disclose. Hayato
Tada has nothing to disclose. Masatsune Ogura hasreceived honoraria from Amgen Inc., Astellas Pharma
Inc. Sachiko Okazaki has received scholarship grants
from Minophagen Pharmaceutical Co., Ltd., Kowa
Company, Ltd. Koh Ono has nothing to disclose.
Hitoshi Shimano has nothing to disclose. Hiroyuki
Daida has received honoraria from Amgen Inc.,
Daiichi-Sankyo Co., Ltd., Kowa Co., Ltd., and MSD
K.K., Novartis Pharma K.K., Bayer Yakuhin, Ltd. andreceived clinical research funding from Canon Medical
687

Kuroda et al .

Systems Corporation, Philips Japan, Ltd., Toho
Holdings Co., Ltd., Asahi Kasei Corporation, andInter Reha Co., Ltd. HD has also received scholarshipgrants from Nippon Boehringer Ingelheim Co., Ltd.,
Otsuka Pharmaceutical Co., Ltd., Sanofi K.K., MSD
K.K., Daiichi-Sankyo Co., Ltd., Pfizer Co., Ltd.,
Mitsubishi Tanabe Pharma Corp., Astellas PharmaInc., Takeda Pharmaceutical Co., Ltd., Teijin Pharma,
Ltd., Shionogi & Co., Ltd., Actelion Pharmaceuticals,Ltd., Actelion Ltd., Kowa Co., Ltd., Bayer Yakuhin,Ltd. HD has also courses endowed by companies,
including Philips Japan, Ltd., ResMed, Fukuda
Denshi Co., Ltd., and Paramount Bed Co., Ltd.
Kazushige Dobashi has nothing to disclose. Toshio
Hayashi has nothing to disclose. Mika Hori has
nothing to disclose. Kota Matsuki has nothing todisclose. Tetsuo Minamino has nothing to disclose.
Shinji Yokoyama has nothing to disclose. Mariko
Harada-Shiba has received stock holdings or options
from Liid Pharma, honoraria from Amgen Inc.,
Astellas Pharma Inc., Sanofi, and scholarship grants
from Aegerion Pharmaceuticals, Inc., Recordati Rare
Diseases Japan, and Kaneka Corporation. Katsunori
Ikewaki has nothing to disclose. Yasushi Ishigaki has
nothing to disclose. Shun Ishibashi has received
honoraria from Kowa Co., Ltd., and a scholarshipgrant from Ono Pharmaceutical Co., Ltd. Kyoko
Inagaki has nothing to disclose. Hirotoshi Ohmura
has nothing to disclose. Hiroaki Okazaki has received
scholarship grants from Minophagen PharmaceuticalCo., Ltd., Kowa Company, Ltd. Masa-aki Kawashiri
has nothing to disclose. Masayuki Kuroda has received
clinical research funding from CellGenTech, Inc.
Masahiro Koseki has received clinical research funding
from Kowa Company, Ltd., Rohto PharmaceuticalCo., Ltd. Takanari Gotoda has nothing to disclose.
Shingo Koyama has nothing to disclose. Yoshiki
Sekijima has nothing to disclose. Manabu Takahashi
has nothing to disclose. Yasuo Takeuchi has nothing
to disclose. Misa Takegami has nothing to disclose.
Kazuhisa Tsukamoto has received honoraria from
Ba ye r Ya k u h i n , L t d . , M S D L t d . , Ta k e d a
Pharmaceutical Company Ltd., and scholarship grants
from Mitsubishi Tanabe Pharma Corporation., Bayer
Yakuhin, Ltd., Sanofi K.K. Atsuko Nakatsuka has
nothing to disclose. Kimitoshi Nakamura has nothing
to disclose. Satoshi Hirayama has nothing to disclose.
Hideaki Bujo has nothing to disclose. Daisaku
Masuda has received clinical research funding fromMSD K.K., Ono Pharmaceutical Co., Ltd., Takeda
Pharmaceutical Co., Ltd., Kowa Co., Ltd. Takashi
Miida has nothing to disclose. Yoshihiro Miyamoto
has nothing to disclose. Takeyoshi Murano has
nothing to disclose. Takashi Yamaguchi has nothing to
688

disclose. Shizuya Yamashita has received honoraria
from Kowa Company, Ltd., MSD K.K. Masashi
Yamamoto has nothing to disclose. Koutaro Yokote
has received honoraria from Kowa Company, Ltd.,MSD K.K., Astellas Pharma Inc., Mitsubishi Tanabe
Pharma Corp., Amgen K.K., Takeda Pharmaceutical
Company Limited, Sanofi K.K., Ono PharmaceuticalCo., Ltd., AstraZeneca K.K., Daiichi-Sankyo Co.,
Ltd., Novartis Pharma K.K., Sumitomo Dainippon
Pharma Co., Ltd., Kyowa Kirin Co., Ltd., Pfizer Japan
Inc., Novo Nordisk Pharma Ltd., Nippon Boehringer
Ingelheim Co., Ltd., Eli Lilly Japan K.K., Taisho
Pharmaceutical Co., Ltd., Janssen Pharmaceutical
K.K., and received clinical research funding fromTaisho Pharmaceutical Co., Ltd. KY has also received
scholarship grants from Mitsubishi Tanabe Pharma
Corp., Takeda Pharmaceutical Co., Ltd., MSD K.K.,
Pfizer Japan Inc., Novo Nordisk Pharma Ltd., Taisho
Pharmaceutical Co., Ltd., Kao Corporation, Ono
Pharmaceutical Co., Ltd., Eli Lilly Japan K.K.,
Sumitomo Dainippon Pharma Co., Ltd., Nippon
Boehringer Ingelheim Co., Ltd., Daiichi-Sankyo Co.,
Ltd., Teijin Pharma, Ltd., Shionogi Co., Ltd., Bayer
Yakuhin, Ltd. Jun Wada has nothing to disclose.
References
1) Glomset JA, Parker F, Tjaden M, Williams RH. The
esterification in vitro of free cholesterol in human and rat
plasma. Biochim Biophys Acta, 1962; 58: 398-406
2) Glomset JA, Janssen ET, Kennedy R, Dobbins J. Role ofplasma lecithin: cholesterol acyltransferase in themetabolism of high density lipoproteins. J Lipid Res,
1966; 7: 638-648
3) Carlson LA., Philipson B. Fish-eye disease: a new familial
condition with massive corneal opacities anddyslipoproteinem. Lancet, 1979; 314: 921-924
4) Glomset JA, Assmann G, Gjone E, Norum KR. Lecithincholesterol acyltransferase deficiency and fish eye disease.
In: The Metabolic and Molecular Bases of Inherited
Disease, 7th ed. by Scriver CR, Beaudet AL, Sly WS,
Valle D, Stanbury JB, Wyngaarden JB, Fredrickson DS.,
McGraw-Hill Inc., New York, 1995, 1933-1951
5) Santamarina-Fojo S, Hoeg JM, Assman G, Brewer Jr HB.
Lecithin cholesterol acyltransferase deficiency and fish eyedisease. In: The metabolic and molecular bases ofinherited disease, 8th ed. by Scriver CR, Beaudet AL, Sly
WS, Valle D, Childs B, Kinzler KW, Vogelstein B.,
McGraw-Hill Inc., New York, 2001, 2817-2833
6) Forte T, Nichols A, Glomset J, Norum K. The
ultrastructure of plasma lipoproteins in lecithin:cholesterol acyltransferase deficiency. Scand J Clin Lab
Invest Suppl, 1974; 137: 121-132
7) Kuroda M, Holleboom AG, Stroes ES, Asada S, Aoyagi Y,
Kamata K, Yamashita S, Ishibashi S, Saito Y, Bujo H.
Lipoprotein subfractions highly associated with renal
damage in familial lecithin:cholesterol acyltransferase
deficiency. Arterioscler Thromb Vasc Biol, 2014; 34:

LCAT Deficiency in Japan

1756-1762
8) von Eckardstein A. Differential diagnosis of familial highdensity lipoprotein deficiency syndromes. Atherosclerosis,
2006; 186: 231-239
9) Cogan DG, Kruth HS, Datilis MB, Martin N. Corneal
opacity in LCAT disease. Cornea, 1992; 11: 595-599
10) Philipson BT. Fish eye disease. Birth Defects Orig Artic
Ser, 1982; 18: 441-448
11) Bethell W, McCulloch C, Ghosh M. Lecithin cholesterolacyl transferase deficiency. Light and electron microscopic
finding from two corneas. Can J Ophthalmol, 1975; 10:494-501
12) Viestenz A, Schlotzer-Schrehardt U, Hofmann-Rummelt
C, Seitz B, Kuchle M. Histopathology of corneal changes
in lecithin-cholesterol acyltransferase deficiency. Cornea,
2002; 21: 834-837
13) Koster H, Savoldelli M, Dumon MF, Dubourg L, Clerc
M, Pouliquen Y. A fish-eye disease-like familial condition
with massive corneal clouding and dyslipoproteinemia.
Report of clinical, histologic, electron microscopic, andbiochemical features. Cornea, 1992; 11: 452-464
14) Flores R, Jin X, Chang J, Zhang C, Cogan DG, Schaefer
EJ, Kruth HS. LCAT, ApoD, and ApoA1 Expression andReview of Cholesterol Deposition in the Cornea.
Biomolecules, 2019; 9: 785
15) McCulley JP. The circulation of fluid at the limbus (flowand diffusion at the limbus). Eye, 1989; 3: 114-120
16) Forte T, Norum KR, Glomset JA, Nichols AV. Plasma
lipoproteins in familial lecithin: Cholesterolacyltransferase deficiency: Structure of low and highdensity lipoproteins as revealed by elctron microscopy. J
Clin Investig, 1971; 50: 1141-1148
17) Forte TM, Carlson LA. Electron microscopic structure ofserum lipoproteins from patients with fish eye disease.
Arteriosclerosis, 1984; 4: 130-137
18) Rye KA, Clay MA, Barter PJ. Remodelling of high density
lipoproteins by plasma factors. Atherosclerosis, 1999;
145: 227-238
19) Cenedella RJ, Fleschner CR. Cholesterol biosynthesis by
the cornea. Comparison of rates of sterol synthesis withaccumulation during early development. J Lipid Res,
1989; 30: 1079-1084
20) Godin DV, Gray GR, Frohlich J. Erythrocyte membranealterations in lecithin:cholesterol acyltransferase deficiency.
Scand J Clin Lab Invest Suppl, 1978; 150: 162-167
21) Suda T, Akamatsu A, Nakaya Y, Masuda Y, Desaki J.
Alterations in erythrocyte membrane lipid and its fragility
in a patient with familial lecithin:cholesterol acyltrasferase(LCAT) deficiency. J Med Invest, 2002; 49: 147-155
22) Jacobsen CD, Gjone E, Hovig T. Sea-blue histiocytes infamilial lecithin: cholesterol acyltransferase deficiency.
Scand J Haematol, 1972; 9: 106-113
23) Naghashpour M, Cualing H. Splenomegaly with sea-blue
histiocytosis, dyslipidemia, and nephropathy in a patientwith lecithin-cholesterol acyltransferase deficiency: aclinicopathologic correlation. Metabolism, 2009; 58:
1459-1464
24) Tsuchiya Y, Ubara Y, Hiramatsu R, Suwabe T, Hoshino J,
Sumida K, Hasegawa E, Yamanouchi M, Hayami N,
Marui Y, Sawa N, Hara S, Takaichi K, Oohashi K. A caseof familial lecithin-cholesterol acyltransferase deficiency

on hemodialysis for over 20 years. Clin Nephrol, 2011;
76: 492-498
25) Weber CL, Frohlich J, Wang J, Hegele RA, Chan-Yan C.
Stability of lipids on peritoneal dialysis in a patient withfamilial LCAT deficiency. Nephrol Dial Transplant, 2007;
22: 2084-2088
26) Holleboom AG, Kuivenhoven JA, van Olden CC, Peter J,
Schimmel AW, Levels JH, Valentijn RM, Vos P, Defesche
JC, Kastelein JJ, Hovingh GK, Stroes ES, Hollak CE.
Proteinuria in early childhood due to familial LCAT
deficiency caused by loss of a disulfide bond inlecithin:cholesterol acyl transferase. Atherosclerosis, 2011;
216: 161-165
27) Calabresi L, Pisciotta L, Costantin A, Frigerio I, Eberini I,
Alessandrini P, Arca M, Bon GB, Boscutti G, Busnach G,
Frascà G, Gesualdo L, Gigante M, Lupattelli G, Montali
A, Pizzolitto S, Rabbone I, Rolleri M, Ruotolo G,
Sampietro T, Sessa A, Vaudo G, Cantafora A, Veglia F,
Calandra S, Bertolini S, Franceschini G. The molecularbasis of lecithin:cholesterol acyltransferase deficiency
syndromes: a comprehensive study of molecular andbiochemical findings in 13 unrelated Italian families.
Arterioscler Thromb Vasc Biol, 2005; 25: 1972-1978
28) Ahsan L, Ossoli AF, Freeman L, Vaisman B, Amar MJ,
Shamburek RD, Remaley AT. Role of lecithin: cholesterolacyltransferase in HDL metabolism and atherosclerosis.
The HDL Handbook, 2014; 159-194
29) Borysiewicz LK, Soutar AK, Evans DJ, Thompson GR,
Rees AJ. Renal failure in familial lecithin: cholesterolacyltransferase deficiency. Q J Med, 1982; 51: 411-426
30) Jimi S, Uesugi N, Saku K, Itabe H, Zhang B, Arakawa K,
Takebayashi S. Possible induction of renal dysfunction inpatients with lecithin:cholesterol acyltransferase deficiency
by oxidized phosphatidylcholine in glomeruli. Arterioscler
Thromb Vasc Biol, 1999; 19: 794-801
31) Groene EF, Walli AK, Groene HJ, Miller B, Seidel D. The
role of lipids in nephrosclerosis and glomerulosclerosis.
Atherosclerosis, 1994; 107: 1-13
32) Zhao Y, Thorngate FE, Weisgraber KH, Williams DL,
Parks JS. Apolipoprotein E is the major physiologicalactivator of lecithin-cholesterol acyltransferase (LCAT) on
apolipoprotein B lipoproteins. Biochemistry, 2005; 44:1013-1025
33) Baass A, Wassef H, Tremblay M. Characterization of a
new LCAT mutation causing familial LCAT deficiency(FLD) and the role of APOE as a modifier gene in FLD
phenotype. Atherosclerosis, 2009; 207: 452-457
34) Katayama A, Wada J, Kataoka HU, Yamasaki H,
Teshigawara S, Terami T, Inoue K, Kanzaki M, Murakami
K, Nakatsuka A, Sugiyama H, Koide N, Bujo H, Makino
H. Two novel mutations of lecithin:cholesterolacyltransferase (LCAT) gene and the influence of APOE
genotypes on clinical manifestations. NDT Plus, 2011; 4:
299-30235) Ossoli A, Neufeld EB, Thacker SG, Vaisman B, Pryor M,
Freeman LA, Brantner CA, Baranova I, Francone NO,
Demosky SJ Jr, Vitali C, Locatelli M, Abbate M, Zoja C,
Franceschini G, Calabresi L, Remaley AT. Lipoprotein X
Causes Renal Disease in LCAT Deficiency. PLoS One,2016; 11: e0150083
36) Fountoulakis N, Lioudaki E, Lygerou D, Dermitzaki EK,
689

Kuroda et al .

Papakitsou I, Kounali V, Holleboom AG, Stratigis S,
Belogianni C, Syngelaki P, Stratakis S, Evangeliou A,
Gakiopoulou H, Kuivenhoven JA, Wevers R, Dafnis E,
Stylianou K. The P274S Mutation of Lecithin-Cholesterol
Acyltransferase (LCAT) and Its Clinical Manifestations ina Large Kindred. Am J Kidney Dis, 2019; 74: 510-522
37) Pavanello C, Ossoli A, Arca M, D’Erasmo L, Boscutti G,
Gesualdo L, Lucchi T, Sampietro T, Veglia F, Calabresi L.
Progression of chronic kidney disease in familial LCAT
deficiency: a follow-up of the Italian cohort. J Lipid Res,
2020; 61: 1784-1788
38) Tietjen I, Hovingh GK, Singaraja R, Radomski C,
McEwen J, Chan E, Mattice M, Legendre A, Kastelein JJ,
Hayden MR. Increased risk of coronary artery disease in
Caucasians with extremely low HDL cholesterol due tomutations in ABCA1, APOA1, and LCAT. Biochim
Biophys Acta, 2012; 1821: 416-424
39) Ossoli A, Simonelli S, Vitali C, Franceschini G, Calabresi
L. Role of LCAT in Atherosclerosis. J Atheroscler
Thromb, 2016; 23: 119-127
40) Oldoni F, Baldassarre D, Castelnuovo S, Ossoli A, AmatoM, van Capelleveen J, Hovingh GK, De Groot E,
Bochem A, Simonelli S, Barbieri S, Veglia F, Franceschini
G, Kuivenhoven JA, Holleboom AG, Calabresi L.
Complete and Partial LCAT Deficiency are Differentially
Associated with Atherosclerosis. Circulation, 2018; 138:
1000-1007
41) Toh R. Assessment of HDL Cholesterol Removal
Capacity: Toward Clinical Application. J Atheroscler
Thromb, 2019; 26: 111-120
42) The Human Gene Mutation Database (HGMD®) http://
www.hgmd.cf.ac.uk/ac/index.php
43) Maruyama T, Yamashita S, Matsuzawa Y, Bujo H,
Takahashi K, Saito Y, Ishibashi S, Ohashi K, Shionoiri F,
Gotoda T, Yamada N, Kita T; Research Committee on
Primary Hyperlipidemia of the Ministry of Health andWelfare of Japan. Mutations in Japanese subjects withprimary hyperlipidemia--results from the ResearchCommittee of the Ministry of Health and Welfare ofJapan since 1996--. J Atheroscler Thromb, 2004; 11: 131145
44) Hirashio S, Izumi K, Ueno T, Arakawa T, Naito T,
Taguchi T, Yorioka N. Point mutation (C to T) of the
LCAT gene resulting in A140C substitution. J Atheroscler
Thromb, 2010; 17: 1297-1301
45) Wang XL, Osuga J, Tazoe F, Okada K, Nagashima S,
Takahashi M, Ohshiro T, Bayasgalan T, Yagyu H, Okada
K, Ishibashi S. Molecular analysis of a novel LCAT
mutation (Gly179→Arg) found in a patient withcomplete LCAT deficiency. J Atheroscler Thromb, 2011;
18: 713-719
46) Naito S, Kamata M, Furuya M, Hayashi M, Kuroda M,
Bujo H, Kamata K. Amelioration of circulating
lipoprotein profile and proteinuria in a patient withLCAT deficiency due to a novel mutation (Cys74Tyr) in
the lid region of LCAT under a fat-restricted diet and
ARB treatment. Atherosclerosis, 2013; 228: 193-197
47) Manabe M, Abe T, Nozawa M, Maki A, Hirata M,
Itakura H. New substrate for determination of serum
lecithin:cholesterol acyltransferase. J Lipid Res, 1987; 28:1206-1215
69048) Nagasaki T, Akanuma Y. A new colorimetric method forthe determination of plasma lecithin-cholesterolacyltransferase activity. Clin Chim Acta, 1977; 75: 371375
49) Kanai M, Koh S, Masuda D, Koseki M, Nishida K.
Clinical features and visual function in a patient with
Fish-eye disease: Quantitative measurements and opticalcoherence tomography. Am J Ophthalmol Case Rep,
2018; 10: 137-141
50) Najafian B, Lusco MA, Finn LS, Alpers CE, Fogo AB.
AJKD Atlas of Renal Pathology: Lecithin-Cholesterol
Acyltransferase (LCAT) Deficiency. Am J Kidney Dis,
2017; 70: e5-e651) Takahashi S, Hiromura K, Tsukida M, Ohishi Y,
Hamatani H, Sakurai N, Sakairi T, Ikeuchi H, Kaneko Y,
Maeshima A, Kuroiwa T, Yokoo H, Aoki T, Nagata M,
Nojima Y. Nephrotic syndrome caused by immunemediated acquired LCAT deficiency. J Am Soc Nephrol,
2013; 24: 1305-1312
52) Ishibashi R, Takemoto M, Tsurutani Y, Kuroda M, Ogawa
M, Wakabayashi H, Uesugi N, Nagata M, Imai N,
Hattori A, Sakamoto K, Kitamoto T, Maezawa Y, Narita I,
Hiroi S, Furuta A, Miida T, Yokote K. Immune-mediatedacquired lecithin-cholesterol acyltransferase deficiency: A
case report and literature review. J Clin Lipidol, 2018; 12:888-89753) Jones DP, Sosa FR, Shartsis J, Shah PT, Skromak E, Beher
WT. Serum cholesterol esterifying and cholesteryl esterhydrolyzing activities in liver diseases: relationships tocholesterol, bilirubin, and bile salt concentrations. J Clin
Invest, 1971; 50: 259-265
54) Davignon J, Nestruck AC, Alaupovic P, Bouthillier D.
Severe hypoalphalipoproteinemia induced by a
combination of probucol and clofibrate. Adv Exp Med
Biol, 1986; 201: 111-125
55) Yokoyama S, Yamamoto A, Kurasawa T. A little more
information about aggravation of probucol-induced
HDL-reduction by clofibrate. Atherosclerosis, 1988; 70:
179-18156) Murphy MJ, Duncan A, Vallance BD, Packard CJ, O’Reilly
DS. Iatrogenic profound hypoalphalipoproteinaemia: an
unrecognised cause of very low HDL cholesterol. Postgrad
Med J, 1995; 71: 498-500
57) Takata K, Kajiyama G, Horiuchi I, Watanabe T, Tokumo
H, Hirata Y. A new case of familial lecithin: cholesterolacyltransferase (LCAT) deficiency--paradoxical findings
regarding LCAT mass and activity in 23 members of afamily. Jpn J Med, 1989; 28: 765-771
58) Gjone E. Familial lecithin: cholesterol acyltransferase
deficiency--a clinical survey. Scand J Clin Lab Invest
Suppl, 1974; 137: 73-82
59) Homma S, Murayama N, Kodama T, Yamada N,
Takahashi K, Asano Y, Hosoda S, Murase T, Akanuma Y.
Effects of long-term, low-fat diet on plasma apo E infamilial LCAT deficiency. Nihon Jinzo Gakkai Shi, 1993;
35: 999-1006
60) Norum KR, Gjone E. The effect of plasma transfusion on
the plasma cholesterol esters in patients with familial
plasma lecithin:cholesterol acyltransferase deficiency.
Scand J Clin Lab Invest, 1968; 22: 339-342
61) Murayama N, Asano Y, Kato K, Sakamoto Y, Hosoda S,

LCAT Deficiency in Japan

Yamada N, Kodama T, Murase T, Akanuma Y. Effects ofplasma infusion on plasma lipids, apoproteins and plasma
enzyme activities in familial lecithin: cholesterolacyltransferase deficiency. Eur J Clin Invest, 1984; 14:
122-12962) Yee MS, Pavitt DV, Richmond W, Cook HT, McLean
AG, Valabhji J, Elkeles RS. Changes in lipoprotein profile
and urinary albumin excretion in familial LCAT
deficiency with lipid lowering therapy. Atherosclerosis,
2009; 205: 528-532
63) Aranda P, Valdivielso P, Pisciotta L, Garcia I, Garcã
A-Arias C, Bertolini S, Martã N-Reyes G, Gonzã LezSantos, Calandra S. Therapeutic management of a newcase of LCAT deficiency with a multifactorial long-term
approach based on high doses of angiotensin II receptor
blockers (ARBs). Clin Nephrol, 2008; 69: 213-218
64) Miarka P, Idzior-Waluś B, Kuźniewski M, Waluś-Miarka
M, Klupa T, Sułowicz W. Corticosteroid treatment ofkidney disease in a patient with familial lecithin-cholesterol acyltransferase deficiency. Clin Exp Nephrol,
2011; 15: 424-429
65) Shamburek RD, Bakker-Arkema R, Auerbach BJ, Krause
BR, Homan R, Amar MJ, Freeman LA, Remaley AT.
Familial lecithin:cholesterol acyltransferase deficiency:
First-in-human treatment with enzyme replacement. J
Clin Lipidol, 2016; 10: 356-367
66) https://www.clinicaltrials.gov/ct2/show/NCT02601560
67) Kuroda M, Saito Y, Aso M, Yokote K. A Novel Approachto the Treatment of Plasma Protein Deficiency: Ex VivoManipulated Adipocytes for Sustained Secretion of
Therapeutic Proteins. Chem Pharm Bull (Tokyo), 2018;
66: 217-224
68) Ahmad SB, Miller M, Hanish S, Bartlett ST, Hutson W,
Barth RN, LaMattina JC. Sequential kidney-livertransplantation from the same living donor for lecithincholesterol acyl transferase deficiency. Clin Transplant,
2016; 30: 1370-1374

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