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

Review

J Atheroscler Thromb, 2021; 28: 1009-1019. http://doi.org/10.5551/jat.RV17056

Current Diagnosis and Management of Abetalipoproteinemia
Manabu Takahashi 1, Hiroaki Okazaki 2, Ken Ohashi 3, Masatsune Ogura 4, Shun Ishibashi 5, Sachiko Okazaki 6,
Satoshi Hirayama 7, Mika Hori 8, Kota Matsuki 9, Shinji Yokoyama 10 and Mariko Harada-Shiba 11
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†
1

Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan3
Department of General Internal Medicine, National Cancer Center Hospital, Tokyo, Japan
4
Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
5
Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University,
Tochigi, Japan
6
Division for Health Service Promotion, The University of Tokyo, Tokyo, Japan
7
Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
8
Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
9
Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Japan10
Institute for Biological Functions, Chubu University, Aichi, Japan
11
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,
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,1009

Takahashi et al .

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).

Abetalipoproteinemia (ABL) is a rare autosomal recessive disorder caused by biallelic pathogenic mutationsin the MTTP gene. Deficiency of microsomal triglyceride transfer protein (MTTP) abrogates the assembly of
apolipoprotein (apo) B-containing lipoprotein in the intestine and liver, resulting in malabsorption of fat and fatsoluble vitamins and severe hypolipidemia. Patients with ABL typically manifest steatorrhea, vomiting, andfailure to thrive in infancy. The deficiency of fat-soluble vitamins progressively develops into a variety ofsymptoms later in life, including hematological (acanthocytosis, anemia, bleeding tendency, etc.), neuromuscular(spinocerebellar ataxia, peripheral neuropathy, myopathy, etc.), and ophthalmological symptoms (e.g., retinitis
pigmentosa). If left untreated, the disease can be debilitating and even lethal by the third decade of life due to thedevelopment of severe complications, such as blindness, neuromyopathy, and respiratory failure. High dose
vitamin supplementation is the mainstay for treatment and may prevent, delay, or alleviate the complications andimprove the prognosis, enabling some patients to live to the eighth decade of life. However, it cannot fully
prevent or restore impaired function. Novel therapeutic modalities that improve quality of life and prognosis areawaited. The aim of this review is to 1) summarize the pathogenesis, clinical signs and symptoms, diagnosis, andmanagement of ABL, and 2) propose diagnostic criteria that define eligibility to receive financial support fromthe Japanese government for patients with ABL as a rare and intractable disease. In addition, our diagnostic
criteria and the entry criterion of low-density lipoprotein cholesterol (LDL-C) ＜ 15 mg/dL and apoB ＜ 15 mg/
dL can be useful in universal or opportunistic screening for the disease. Registry research on ABL is currently
ongoing to better understand the disease burden and unmet needs of this life-threatening disease with few
therapeutic options.
Key words: Abetalipoproteinemia, MTTP, Fat-soluble vitamin, Chylomicron, VLDL, Hypolipidemia

1. Introduction
Abetalipoproteinemia (ABL; OMIM 200100) is
a rare inherited disease characterized by the absence ofplasma apolipoprotein (apo) B-containing lipoproteinsand fat-soluble vitamins in the plasma. In 1950,
Bassen and Kornzweig first described the syndrome,
which is characterized by acanthocytes (“star-shaped”
erythrocytes with irregular cytoplasmic projections,
i.e., acantha, “thorn” in Greek), retinitis pigmentosa,
and ataxia 1). In 1960, the absence of beta-lipoproteinin the plasma of the syndrome was reported 2). Later,in 1992, the activity of microsomal triglyceridetransfer protein (MTTP) was found to be absent in
the intestinal mucosa of ABL patients 3). In 1993,
mutations in the MTTP gene, which encodes the large
subunit of MTTP, were identified in ABL patients(Fig. 1) 4, 5). In this review, we summarize thepathogenesis, clinical signs and symptoms, diagnosis,
and management of ABL. We also propose diagnostic
criteria for ABL, which have been used to determine
the eligibility to receive financial aid from the Japanese

Address for correspondence: Hiroaki Okazaki, Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo 113–8655, Japan
E-mail: hokazaki-tky@umin.ac.jp
Received: March 23, 2021
Accepted for publication: March 25, 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.

1010

Diagnosis and Management of Abetalipoproteinemia

A.
Fatty liverTG

Hypolipoproteinemia
Hematological symptoms:
acanthocytosis, anemia,
bleeding tendency, etc.

MTTP
VLDL Ļ

Liver
apoB100

Ophthalmological symptoms:
retinitis pigmentosa etc.

LDL Ļ

Small
intestine

TG

MTTP

Deficiency of fat-soluble
vitamins (E,A,D,K)

Neuromuscular symptoms:
spinocerebellar ataxia,
peripheral neuropathy,
myopathy, etc.

Chylomicron Ļ

apoB48Fat malabsorption

B.

Gastrointestinal symptoms:
steatorrhea, vomiting,
failure to thrive

C.

ABL

non-ABLD.

ABL

non-ABL

Fig. 1. Overview of abetalipoproteinemia(A) MTTP is a prerequisite for the assembly and secretion of VLDL and CM by the liver and small intestine, respectively. Homozygous
MTTP deficiency causes fat malabsorption, steatorrhea, vomiting, failure to thrive, hypolipoproteinemia, fatty liver, as well as symptoms
related to deficiencies of fat-soluble vitamins. (B, C) Endoscopic examination and histological analysis of the duodenal mucosa of an ABL
patient and a non-ABL control. Accumulation of intracellular lipids in epithelial cells (C) results in a snowy appearance (B), called snow-white
duodenum, a gelee blanche, or white hoar frosting. (D) Acanthocytes of an ABL patient (Patient 1 in Ref 29). Figures 1B, 1C, and 1D are
reproduced with permission from Ishibashi S and Ohashi K (The Lipid, 2014; 25: 200-203).

government for patients with ABL as a rare andintractable disease. The financial aid is provided by
The Program for Designated Intractable Diseases
under the Japanese Public Healthcare system. Pediatric
ABL patients can be supported separately under The
program of Medical Aid for Chronic PediatricDiseases of Specified Categories.
2. Genetic and Molecular Basis
ABL is an autosomal recessive disorder caused bybiallelic mutations in the MTTP gene. The estimatedfrequency of ABL is as rare as less than 1 in 1,000,000 6).
Approximately 100 cases and at least 74 different
MTTP mutations have been reported, including five(c.61＋1G ＞ C, c.1237-1G ＞ A, c.1389del, p.I564T,
p.N780Y) in four Japanese patients (Fig. 2) 7-35). About
one-third of patients were the progeny ofconsanguineous marriages 7). The male-to-female sex
ratio is reportedly 1:1 7) or 3:2 2), although both males

and females should theoretically be equally affected.
Genetic and clinical features of Japanese ABL patientsare listed in Table 1. As the number of patients islimited, it is difficult to clarify the characteristics ofJapanese cases of ABL.
MTTP is localized in the lumen of theendoplasmic reticulum of hepatocytes and intestinal
epithelial cells. By transferring triglyceride (TG) andcholesterol ester to apoB, MTTP is essential for theformation of very low-density lipoproteins (VLDLs)
and chylomicrons (CMs). A lack of MTTP abrogatesthe secretion of apoB-containing lipoproteins, which
results in malabsorption of dietary fat and fat-soluble
vitamins as well as accumulation of intracellular lipids
in hepatocytes and intestinal epithelial cells. MTTP isa heterodimer of a large 97 kDa subunit containing
894 amino acids (encoded by MTTP) and a 55 kDa
protein disulfide isomerase (PDI) subunit (encoded by
P4HB) 36). The MTTP gene consists of 18 codingexons. Crystal structure analysis reveals three structural1011

Takahashi et al .

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Fig. 2. Mutations in the MTTP geneAt least 74 MTTP mutations have been reported. The type of mutation may influence the severity of the disease 29). The exon-intron structureof the MTTP gene encoded by exons 1a to 18 has been described 52). Gray boxes represent exons. Lines represent the position of each mutationand polymorphism. Adapted from Zamel R, et al. 41), Narcisi TM et al. 27), and Suzuki T et al. 52)

domains in the large subunit of MTTP: an N-terminal
β-barrel domain (amino acids 22-297), which interacts
with the N-terminus of apoB; a central α-helicaldomain (298-603), which interacts with apoB as wellas PDI; and a C-terminal domain (604-894) 7, 37-39).
The interaction between the α-helical domain and
PDI is required for lipid-transfer activity, and the
C-terminal domain mediates lipid-binding and lipidtransfer activity (Fig. 2) 37).
3. Clinical Manifestations
Gastrointestinal Symptoms (Fat Malabsorption
and Failure to Thrive):
Symptoms of ABL typically develop in infancy
after breastfeeding, including vomiting, steatorrhea
due to fat malabsorption, and failure to thrive 2).
Patients often avoid dietary fat to relieve thesegastrointestinal symptoms 2). Endoscopic examinationof the intestinal mucosa may reveal a snowy
appearance, which is also called snow-white
duodenum 40), a gelee blanche, or white hoar frosting(Fig. 1B and 1C) 7, 8).
Symptoms Related to Vitamin Deficiencies:
Chronic lipid malabsorption leads to a deficiency
of fat-soluble vitamins (vitamins E, A, D, K). These
vitamins require apoB-containing lipoproteins fortheir absorption and transport to peripheral tissues
1012

almost totally (for vitamin E and β-carotene) or
partially (for vitamins A, D, and K) 7). The resulting
deficiency of these fat-soluble vitamins, particularly
vitamin E and β-carotene, causes a variety ofsymptoms and complications, as described below.
・Neuromuscular symptoms develop mainly asa result of vitamin E deficiency, which is often
associated with demyelination of spinocerebellaraxons 2, 41, 42). Typical symptoms include spinocerebellar
ataxia, peripheral neuropathy, and myopathy 2).
Myopathy may result from both neural degeneration
and an intrinsic myositis 7), which may be caused by
pigment deposition due to the loss of vitamin E’s antioxidant activity 2, 7). The first symptom is often
diminution of deep tendon reflexes as early as in thefirst few years or the first decade of life 7), followed byprogressive abnormalities such as loss of vibratory
sense, position sense, proprioception, a positive
Romberg sign, spinocerebellar ataxia, dysmetria,
dysarthria, wide-based spastic gait, hypesthesia,
myopathy, muscular weakness, pes cavus, pesequinovarus, kyphoscoliosis, and lordosis. When left
untreated, these symptoms gradually worsen andseverely affect the quality of life, eventually rendering
patients wheelchair-bound or bedridden. Without
early treatment with vitamin E, patients may notsurvive past the third decade 2, 41, 43). Mental retardation
has been reported in some cases, although the evidence
for causality is lacking 2, 17, 26). There might be otherDiagnosis and Management of Abetalipoproteinemia

Table 1. Genetic and clinical features of Japanese patients with abetalipoproteinemia
Authors

Age

GenderMutation(MTTP)TypeTG

LDL-C HDL-C cLDL-C apoB

No
(Uniparental
disomy)

33

0

N.D.

28

5

0

＜ 0.1

Ho

Yes

42

0.2

N.D.

36

6.0

0.9

＜ 0.1

c.2338A＞ T(p.N780Y)

Ho

Yes

34

2.6

N.D.

23

10.5

0.6

＜ 0.1

c.61+1G＞ C
c.1691T＞ C(p.I564T)

C. het

N.D.

46-92

10-100

N.D.

N.D.

-

＜ 7.0

0.43

29

M

c.1237-1G＞ A

Ho

Ohashi K et al. 29)

32

F

c.1389del

29)

27

M

15mo

M

Ohashi K et al.

Sakamoto O et al. 30)

Biochemical parameters (mg/dL)
TC

28)

Yang XP et al.

Consanguinity

Authors

Vitamin E

Clinical features
Gastrointestinal

Neuromuscular

Ophthalmological

28)

Frequent diarrhea, fat malabsorption
with malnutrition, and short stature(from childhood); lipid-laden
enterocytes by intestinal biopsy (29years old).

Cerebellar and posterior spinal
column dysfunction, decreased deep
tendon reflexes, impaired vibratory
sense and proprioception, dysmetria,
ataxia, spastic gait, and positive
Chaddock sign (29 years old).

Suspected loss of night vision (3years old); descreased vision in dim
light, visual field defects, andpigmentary retinal degeneration (29years old).

Ohashi K et al. 29)

Intolerance for fat-rich meals; snowwhite duodenum and lipid-laden
enterocytes by biopsy (32 years old).

Absent ankle and knee jerks, positive Fine mottling in the retina (32 years Acanthocytosis (32 years
Romberg’s sign (32 years old).
old).
old).

Ohashi K et al. 29)

Mild fatty liver, no history ofsteatorrhea

NormalNormalAcanthocytosis

Sakamoto O et al. 30)

Hepatomegaly and fatty liver, nosteatorrhea.

NormalNormalNo acanthocytosis

Yang XP et al.

HematologicalAcanthocytosis＊

Age (years or months (mo)) at molecular diagnosis; M = Males; F = Females; Ho = homozygous; C. het = compound heterozygous; TC, totalcholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; cLDL-C, calculated LDLC; N.D., Not described.

rare mutations due to consanguinity that could cause
mental retardation 2, 17).
・Cardiomyopathy, supposedly due to vitamin
E deficiency, may develop and can be lethal 7, 41, 43).
・Ophthalmological symptoms develop most
likely as a consequence of deficiency of vitamin A and
E. Retinitis pigmentosa is typically present byadolescence. Alterations in visual acuity, loss of nightvision and color vision may appear as the firstophthalmological symptoms, followed by a gradualloss of vision, progressive scotoma, typically annularscotomas with macular sparing 2), and narrowing of
the visual field, which ultimately lead to complete lossof vision. In some cases, ptosis, ophthalmoplegia,
anisocoria, nystagmus, strabismus, and corneal ulcers
may develop 2, 7, 41, 42).

・Hematological abnormalities include
acanthocytosis (Fig. 1D), low erythrocyte sedimentation
rate (ESR), anemia, hemolysis, reticulocytosis,
hyperbilirubinemia, and elevation of prothrombin
time international normalized ratio (PT-INR) 41).
Acanthocytes are often observed, in more than 50% of
the erythrocyte population, likely due to abnormalcomposition and distribution of lipids in the bilayer
leaflets of the cell membrane 2, 44). Low ESR is due toimpaired rouleaux formation 7). Anemia may beobserved due to malabsorption of iron, folate, vitamin
B12, and other nutrients secondary to fat
malabsorption 2, 41). Loss of vitamin E’s anti-oxidant
activity may cause autohemolysis, by acceleratinghydroperoxidation of fatty acids 2). Decreases in thelevels of vitamin K-dependent coagulation factors (Ⅱ,1013

Takahashi et al .

Ⅶ, Ⅸ, Ⅹ) may result in bleeding tendency withelevated PT-INR 2, 41).
・Abnormal bone metabolism and skeletal
deformities may be observed due to Vitamin D
deficiency, as documented in some cases 41, 45, 46).
・Hypothyroidism may be observed in ABL
patients, although the causality remains uncertain 39).
・Fatty liver may develop due to impaired
secretion of VLDL. Steatohepatitis and liver cirrhosis
may develop, requiring liver transplantation in somecases 9, 47).Causality needs to be carefully assessed as
supplementation of medium-chain triglycerides(MCTs) may cause liver cirrhosis 2).
4. Diagnosis
ABL is typically suspected in infants who havesteatorrhea, vomiting, and failure to thrive. However,the severity of the disease varies depending on the typeof mutation in MTTP, and the diagnosis of ABL may
be delayed until adulthood 2, 29). ABL patients may befound opportunistically at health examinations inadulthood because of extremely low plasma cholesterollevels 29). For early diagnosis and treatment of ABL,
simple diagnostic criteria are warranted. Clinicians
across multiple disciplines, including pediatricians,
primary care physicians, neurologists, ophthalmologists
and gastroenterologists, should consult lipidologists
regarding further diagnostic tests when they suspect
ABL.
Typical Levels of Plasma Lipids and Lipoproteins:
Plasma levels of total cholesterol (TC) in ABL
patients are typically less than half normal, ranging
from 20 to 50 mg/dL, with most of TC derived fromhigh-density lipoprotein (HDL). Plasma levels of
HDL are typically decreased by ~50%. The decreasein HDL may result in part from absence ofphospholipid transfer from VLDL to HDL during thelipolysis of VLDL-TG. Catabolism of HDL,
particularly apoE-containing HDL, may be increased,
contributing to the apparently normal delivery ofcholesterol to peripheral tissues in the absence of
apoB-containing lipoproteins in ABL patients 7).
Plasma TG levels in ABL are typically less than 10 mg/
dL 7) and do not increase after a dietary fat load 2, 7, 48).
Although the levels of TC and TG are variable in ABL
patients, plasma levels of low-density lipoprotein(LDL) and apoB are consistently absent or extremely
low. We searched PubMed for all previously reported
cases and found that ABL patients have LDL-C ＜ 15
mg/dL and/or apoB ＜ 15 mg/dL (typically apoB ＜ 5
mg/dL) 7, 9, 28, 29), except for three cases of the mildmoderate phenotype 34). Therefore, patients who have1014

such levels of hypolipidemia should be suspected ofhaving ABL.
Diagnostic Criteria:
A definitive diagnosis of ABL requires genetic
testing of MTTP. Clinical diagnosis of ABL based on
diagnostic criteria would help identify suspected cases
for early diagnosis and treatment. Based on lipid levelsof ABL and the clinical manifestations describedabove, we propose diagnostic criteria for ABL (Table2). Our criteria have been used to define the eligibilityof ABL patients to receive financial support from theJapanese government as a rare and intractable disease.
The entry criterion (LDL-C ＜ 15 mg/dL and/or apoB
＜ 15 mg/dL) of the criteria will also be useful for
identifying suspected cases at health checkups oropportunistic blood testing (i.e., universal or
opportunistic screening) for further referral tolipidology specialty clinics.
Differential Diagnosis:
Hypocholesterolemia in combination with fat
malabsorption may result from the following diseases.
・ Fa m i l i a l h y p o b e t a l i p o p r o t e i n e m i a1(FHBL1; OMIM 615558) is caused by mutationsin APOB (mostly nonsense or frameshift) with anautosomal dominant mode of inheritance. The
homozygous type of FHBL1 (Ho-FHBL1) presentswith similar biochemical and clinical characteristics to
ABL. Ho-FHBL1 can be differentiated from ABL
only by family history. As FHBL1 is an autosomal
dominant disorder, obligate heterozygote parents of
Ho-FHBL1 patients have ＜ 50% of normal plasma
levels of LDL-C and apoB. On the other hand,obligate heterozygote parents of ABL patients havenormal plasma lipid levels. The estimated frequency of
Ho-FHBL1 is as rare as less than 1 in 1,000,000, andthat of heterozygote FHBL1 is 1 in 1,000 to 3,000 42, 49).
・Chylomicron retention disease (CMRD;
OMIM 246700), also referred to as Anderson disease,
is a rare autosomal recessive disorder caused bybiallelic mutations in the SAR1B gene encoding Sar1b(secretion-associated and Ras-related GTPase 1B). The
deficiency of Sar1b, which is a prerequisite for thesecretion of CMs, causes severe hypocholesterolemia
as well as steatorrhea, vomiting, and failure to thrive 50).
As VLDL secretion is preserved, CMRD can bedifferentiated from ABL and FHBL1 by plasma lipid
levels: In CMRD, plasma levels of total cholesterol,
LDL-C, and HDL-cholesterol (HDL-C) are morethan 50% decreased, whereas the plasma TG level isnormal.

Diagnosis and Management of Abetalipoproteinemia

Table 2. Diagnostic criteria for ABL in Japan
A. Entry criterion
・Plasma LDL-C level ＜ 15 mg/dL AND/OR plasma apoB level ＜ 15 mg/dL.
B. Clinical manifestations
1. Gastrointestinal: fat-malabsorption related symptoms (steatorrhea, chronic diarrhea, vomiting, failure to thrive, etc.).
2. Neuromuscular: ataxia, spastic paralysis, hypoesthesia due to peripheral neuropathy, diminution of deep tendon reflexes, etc.
3. Ophthalmological: retinitis pigmentosa, loss of night vision, constriction of visual field, decreased visual acuity, etc.
C. Laboratory findings
1. Acanthocytosis
D. Differential diagnosis
Familial hypobetalipoproteinemia 1 (FHBL1)(OMIM 615558), chylomicron retention disease (Anderson disease) (OMIM 246700),
hyperthyroidism.
＊
ABL and homozygous FHBL (Ho-FHBL) can not be distinguished only from the clinical manifestations and laboratory findings of aproband. Family history is helpful. As FHBL1 is an autosomal dominant disorder, obligate heterozygote parents of Ho-FHBL1 patients
have ＜ 50% of normal LDL-C and apoB plasma levels. On the other hand, obligate heterozygote parents of ABL patients have normal
plasma lipid levels. Plasma levels of lipids, apoB, and fat-soluble vitamin of other family members may be helpful.
E. Genetic test
Pathogenic mutations in the MTTP gene
<Diagnosis>
Definite ABL:
Entry criterion (A) is associated with at least one item of B or C AND exclusion of differential diagnosis (D) AND genetic diagnosis (E).
Probable ABL:
Entry criterion (A) is associated with at least two items of B or C AND exclusion of differential diagnosis (D).

5. Assessment, Treatment, and Management
The current strategy and recommendations forthe treatment and management of ABL, which areadapted and modified from reviews by Hegele et al.
and others, are summarized below 2, 6, 7, 39, 41, 42).
Assessment:
The recommended assessments for ABL patients
include 2, 6, 7, 39, 41, 42):・Evaluation of growth at every visit.
・Annual blood analysis including lipid profiles(TC, TG, LDL-C, HDL-C, apoB, apoA-I), liverfunction tests (aspartate aminotransferase (AST),
alanine aminotransferase (ALT), gamma glutamyltransferase (GGT), total and direct bilirubin, alkaline
phosphatase, albumin), fat-soluble vitamins (Vitamin
A (retinol), β-carotene, 25-OH vitamin D, vitamin E,
vitamin K), other micronutrients (vitamin B12, iron,folate), complete blood count, PT-INR, reticulocyte
count, ESR, calcium, phosphate, uric acid, andthyroid stimulating hormone (TSH).
・Ophthalmological and neurological evaluation
every 6-12 months.
・Hepatic ultrasonography, bone mineraldensity measurements, echocardiography every 3
years.

Treatment and Management:
For the treatment of ABL patients, the standardof care includes 2, 6, 7, 39, 41, 42):・Restriction of fat intake is necessary to
prevent steatorrhea. Total fat intake should be
restricted to less than 30% of the total energy intake,or less than 15 to 20 g per day, or even less than 5 g
per day in children 2, 6, 7, 39, 42). Increased fat in the stool
may induce oxalate urolithiasis by binding dietarycalcium and increasing dietary oxalate absorption.
This might be prevented by providing sufficientdietary calcium, fluid intake, and reducing dietary
oxalate 2).
・Adequate calorie intake is essential to avoid
growth retardation. It should be noted that fat
malabsorption may lead to malabsorption ofcarbohydrates proteins, and other nutrients 7). A fatrestricted diet may mitigate such secondary
malabsorption.
・ Me diu m-cha in trig lyce ride (MCT )administration can help correct malnutrition,
particularly in infants, though not absolutely
necessary. MCTs are absorbed and then transported in
the circulation not by CMs but by albumin. Since
hepatic fibrosis is a potential adverse effect of MCTs,
liver enzymes should be monitored in infants who areadministered MCTs, and long-term administration isbetter avoided 2, 7).
1015

Takahashi et al .

・Oral essential fatty acid supplementation.
The daily requirement for essential fatty acids, e.g., up
to 1 teaspoon per day of oil rich in polyunsaturated
fatty acids (e.g., soybean or olive oil) is
recommended 7, 39, 42).
・High dose oral vitamin E supplementation(100-300 IU/kg/day 6, 7, 39, 42); 1,000-2,000 mg/day(infant), 5,000-10,000 mg/day (older children andadults) 2) ; 2,400-12,000 IU/day 41) ; 1IU = 1mg
tocopheryl acetate) delays or prevents progression ofneurological complications 2, 6). Even with such highdose vitamin E supplementation, serum vitamin E
levels increase to at most 30% of the lower limit of
normal serum levels of vitamin E 7, 41). However, serum
vitamin E levels may not correlate with tissue vitamin
E levels 7, 39, 41). Better methods of monitoring tissue
vitamin E concentrations are awaited. Vitamin E may
be administered via alternative routes (intravenous,
intramuscular, etc.). However, oral supplementation isfavored due to: 1) feasibility for life-longsupplementation, 2) no apparent inferiority inincreasing tissue vitamin E levels compared to othermethods, 3) no apparent toxicity (Other routes ofsupplementation may induce fatty liver and othercomplications 42)). It should be noted that absorptionof large doses of vitamin E may induce or exacerbate
vitamin K deficiency 6, 7, 41)
・High dose oral vitamin A supplementation(100-400 IU/kg/day 39, 41, 42) ) and vitamin E
supplementation can prevent or arrest
ophthalmological complications 2, 6, 7, 39).
・Supplementation of vitamin D (800-1,200
IU/day 39, 42)) should be considered in cases of vitamin
D deficiency.
・Supplementation of vitamin K (5-35 mg/
week 39, 41, 42)) should be considered in cases of vitamin
K deficiency with hypothrombinemia and prolonged
PT-INR. Supplementation of vitamin K will
normalize its blood levels 2, 41).
・Supplementation of iron, folate, or vitamin
B12 may be necessary in the case of anemia 2, 6, 41, 42).
・Multidisciplinary care for neurologicalcomplications involving neurologists, physiatrists,
physical therapists, occupational therapists, and speechtherapists 39).
Particular caution should be taken to avoid
vitamin A toxicity 2, 39, 41), which can be seen even in
those who have a normal plasma vitamin A
concentration 39). To avoid toxicity, it is recommended
that the target vitamin A concentration goal should be
set at the lower limit of normal levels 41), and the doseof vitamin A supplementation should be titrated bymonitoring blood concentrations of vitamin A and
1016

β-carotene 39, 41, 42). Women who are pregnant orplanning to conceive should receive 50% of the doseof vitamin A supplementation to avoid vitamin A
toxicity with careful monitoring of the bloodconcentrations of vitamin A and β-carotene 39, 42).
Supplementation of vitamin A should be continued in
pregnancy as its deficiency could induce lethal
complications in pregnant women 39, 41).
6. Burden of Disease and Unmet Needs
If left untreated, ABL patients start manifesting
systemic complications related to fat-soluble vitamin
deficiencies as early as in the first decade of life,
gradually developing into lethal conditions in thethird decade 7, 41). Early diagnosis and adequate
supplementation of vitamin E, A, and other fatsoluble vitamins may prevent, delay, or alleviate thecomplications and improve the prognosis, enablingsome patients to live to the eighth decade of life 7, 39).
Successful pregnancies in ABL patients have beenreported 2, 7, 41). This review and our simple diagnostic
criteria aim to contribute to the early diagnosis andtreatment of ABL by facilitating cooperation among
various medical specialists.
However, the growth potential of patients may
not be fully restored by dietary therapy 39, 42). Highdose vitamin therapy is insufficient for most patients,and even ineffective for some, to recover from vitamin
deficiencies and their complications 42). Deficiency ofother lipids or nutrients, such as essential fatty acids,
could also contribute to the pathogenesis of ABL.
Therefore, a good understanding of its pathogenesis
and keeping abreast of novel therapeutic developments
are necessary. Gene therapies that correct MTTP
deficiency in the liver and small intestine may bepromising therapeutic candidates 51).
More studies are needed to unravel thepathogenesis, genotype-phenotype relationship,burden of disease, and unmet needs. Considering thepaucity of patients, a nation-wide registry for a longenough period to evaluate the prognosis would help
clarify these issues. To this end, a registry study forrare and intractable lipid disorders including ABL (thePROLIPID study) is ongoing in Japan.
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).

Diagnosis and Management of Abetalipoproteinemia

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
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 nothing
to disclose. Masahiro Koseki has received clinicalresearch funding from Kowa Company, Ltd., Rohto
Pharmaceutical Co., Ltd. Takanari Gotoda has
nothing to disclose. Shingo Koyama has nothing todisclose. 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 Bayer Yakuhin, Ltd., MSD Ltd.,

Takeda Pharmaceutical Company Ltd., andscholarship 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 todisclose. Daisaku Masuda has received clinical researchfunding from MSD 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 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
Pharmaceutical Co., Ltd., AstraZeneca K.K., DaiichiSankyo 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 researchfunding from Taisho 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., DaiichiSankyo Co., Ltd., Teijin Pharma, Ltd., Shionogi Co.,
Ltd., Bayer Yakuhin, Ltd. Jun Wada has nothing todisclose. Ken Ohashi has nothing to disclose.
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