Current Diagnosis and Management of Familial Hypobetalipoproteinemia 1

Abstract

Familial hypobetalipoproteinemia (FHBL) 1 is a rare genetic disorder with an autosomal codominant mode of inheritance and is caused by defects in the apolipoprotein (apo) B (APOB) gene that disable lipoprotein formation. ApoB proteins are required for the formation of very low-density lipoproteins (VLDLs), chylomicrons, and their metabolites. VLDLs transport cholesterol and triglycerides from the liver to the peripheral tissues, whereas chylomicrons transport absorbed lipids and fat-soluble vitamins from the intestine. Homozygous or compound heterozygotes of FHBL1 (HoFHBL1) are extremely rare, and defects in APOB impair VLDL and chylomicron secretion, which result in marked hypolipidemia with malabsorption of fat and fat-soluble vitamins, leading to various complications such as growth disorders, acanthocytosis, retinitis pigmentosa, and neuropathy. Heterozygotes of FHBL1 are relatively common and are generally asymptomatic, except for moderate hypolipidemia and possible hepatic steatosis. If left untreated, HoFHBL1 can cause severe complications and disabilities that are pathologically and phenotypically similar to abetalipoproteinemia (ABL) (an autosomal recessive disorder) caused by mutations in the microsomal triglyceride transfer protein (MTTP) gene. Although HoFHBL1 and ABL cannot be distinguished from the clinical manifestations and laboratory findings of the proband, moderate hypolipidemia in first-degree relatives may help diagnose HoFHBL1. There is currently no specific treatment for HoFHBL1. Palliative therapy including high-dose fat-soluble vitamin supplementation may prevent or delay complications. Registry research on HoFHBL1 is currently ongoing to better understand the disease burden and unmet needs of this life-threatening disease with few therapeutic options.

^†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 (Cardiovascular Center, Osaka Medical and Pharmaceutical University, Osaka, Japan), Hayato Tada (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Ishikawa, 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, Ibaraki, Japan), Koutaro Yokote (Chiba University, Chiba, Japan), Hideaki Bujo (Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Chiba, Japan), Shizuya Yamashita (Department of Cardiology, Rinku General Medical Center, Osaka, Japan), Kazuhisa Tsukamoto (Department of Internal Medicine, Teikyo University, Tokyo, Japan), Katsunori Ikewaki (Division of 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), Tomohiro Fujisaka (Department of Cardiology, Osaka Medical and Pharmaceutical University, Osaka, Japan), Misa Takegami (Department of Preventive Medicine and Epidemiology, National Cerebral and Cardiovascular Center, Osaka, Japan), Yoshiki Sekijima (Department of Medicine (Neurology & Rheumatology), Shinshu University School of Medicine, Nagano, Japan), Yasushi Ishigaki (Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan), Hiroaki Okazaki (Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan), Atsushi Nohara (Ishikawa Prefectural Central Hospital, Ishikawa, 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), Tetsuji Wakabayashi (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 Cardiology, Kaga Medical Center, Ishikawa, 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), Jun Wada (Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan), Masatsune Ogura (Department of Clinical Laboratory Technology, Faculty of Medical Science, Juntendo University, Chiba, Japan), Hiroshi Yoshida (Department of Laboratory Medicine, Jikei University Kashiwa Hospital, Chiba, Japan), Yu Kataoka (Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, 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, Aomori, Japan), Takashi Yamaguchi (Center for Diabetes, Metabolism and Endocrinology, Toho University Medical Center Sakura Hospital, Chiba, Japan), Hirofumi Okada (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Ishikawa, Japan), Masashi Yamamoto (Division of Diabetes, Metabolism and Endocrinology, Matsudo City General Hospital, Chiba, Japan), Yasuo Takeuchi (Division of Nephrology, Kitasato University School of Medicine, Ishikawa, 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), Manabu Minami (Department of Data Science, National Cerebral and Cardiovascular Center, Osaka, Japan), Hisashi Makino (Division of Diabetes and Lipid Metabolism, National Cerebral and Cardiovascular Center, Osaka, Japan), Masaki Matsubara (Department of General Medicine, Nara Medical University, Nara, Japan), Sayaka Funabashi (Department of Cardiovascular Medicine, Kyorin University School of Medicine, Tokyo, Japan), Keiko Goto (Department of Clinical Genetics, Juntendo University, Graduate School of Medicine, Tokyo, Japan), Masa-aki Hoshiga (Department of Cardiology, Osaka Medical and Pharmaceutical University, Osaka, Japan), Shinpei Fujioka (Department of Cardiology, Osaka Medical and Pharmaceutical University, Osaka, Japan), Manabu Takahashi (Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan), Kayoko Sato (Department of Cardiology, Tokyo Women’s Medical University, Tokyo, Japan), Daisuke Shishikura (Department of Cardiology, Osaka Medical and Pharmaceutical University, Osaka, Japan), Yasuaki Takeji (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Ishikawa, Japan).

1.Introduction

Familial hypobetalipoproteinemia 1 (FHBL1; OMIM 615558) is an autosomal codominant disease characterized by decreased levels of plasma apolipoprotein (apo) B-containing lipoproteins. In 1987, Young et al. identified small amounts of truncated apoB (apoB37) caused by a mutation in the APOB gene in the plasma of a patient with hypobetalipoproteinemia¹⁾. Thereafter, various lengths of truncated apoB proteins have been identified in FHBL1 families, and more than 140 genetic variants of APOB have been identified so far^2-6). Patients with heterozygous FHBL1 (HeFHBL1) generally show no symptoms except for moderate hypocholesterolemia, whereas patients with homozygous FHBL1 (HoFHBL1) manifest severe hypocholesterolemia and malabsorption of fat and fat-soluble vitamins, leading to neurological and ocular complications (Fig.1).

Fig.1. Overview of familial hypobetalipoproteinemia 1 (FHBL1)

ApoB is necessary for the assembly and secretion of triglyceride-rich particles such as VLDL and CM. Homozygous or compound heterozygous APOB deficiency (HoFHBL1) causes hypolipoproteinemia, hepatic steatosis, fat malabsorption, steatorrhea, vomiting, failure to thrive, and symptoms related to fat-soluble vitamin deficiency. Adapted from Gill PK et al.⁵⁶⁾

Proteins encoded by the causative genes of familial hypobetalipoproteinemia (FHBL) class I disorders that arise from lipoprotein secretion defects (MTTP for FHBL-SD1, APOB for FHBL-SD2, SAR1B for FHBL-SD3) are shown in bold red. Proteins encoded by the causative genes of FHBL class II disorders that arise from the enhanced catabolism of lipoproteins (ANGPTL3 for FHBL-EC1 and PCSK9 for FHBL-EC2) are shown in bold blue. The symptoms associated with FHBL-SD are indicated by red arrows and boxes.

TG, triglyceride; CM, chylomicron; VLDL, very low-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; MTTP, microsomal triglyceride transfer protein; SAR1B, secretion-associated and Ras-related GTPase 1B; PCSK9, proprotein convertase subtilisin/kexin 9; ANGPTL3, angiopoietin-like protein 3; LPL, lipoprotein lipase; EL, endothelial lipase; LDLR, LDL receptor; LRP, LDL receptor-related protein.

Inherited hypobetalipoproteinemia can be caused by mutations in other genes such as proprotein convertase subtilisin/kexin 9 (PCSK9) and angiopoietin-like protein 3 (ANGPTL3), etc^{7, 8)}. Hypobetalipoproteinemia caused by loss-of-function mutations in ANGPTL3 is referred to as FHBL2 (OMIM 605019).

This review focuses on FHBL1, and summarizes its pathogenesis, clinical characteristics, diagnosis, and management. We also present our diagnostic criteria for HoFHBL1, which have been used to determine eligibility for financial aid from the Japanese government for patients with rare and intractable diseases funded by the Program for Designated Intractable Diseases under the Japanese Public Healthcare System.

2.Genetics and Mechanism

The APOB gene, located on chromosome 2p24, is a 43-kb gene consisting of 29 exons encoding 4563 amino acids⁹⁾. ApoB proteins exist in two forms in the plasma, apoB100 and apoB48, both of which are products of the APOB gene. ApoB100 is synthesized by hepatocytes and secreted within very-low-density lipoproteins (VLDLs). ApoB48 is synthesized by enterocytes and secreted within chylomicrons as a result of a premature stop codon at APOB codon 2153 by tissue-specific mRNA processing, which confers 48% of the total length of apoB100 ¹⁰⁾.

Including variants identified only in heterozygotes, more than 140 APOB variants have been reported so far (Fig.2, Supplementary Table 1)^2-6). Exon 26 is the largest exon with 7572 bases, and many APOB mutations of FHBL1 are concentrated in this region¹¹⁾. Most mutations are frameshift, nonsense, or splice site mutations, typically resulting in truncated apoB proteins. Missense mutations that do not present with truncated apoB have also been reported¹²⁾. It should be noted that c.1468C>T has been previously described as a missense variant (p.Arg490Trp), but was recently described also as a splicing variant with the activation of a cryptic donor splice site (p.Arg490Serfs*12)¹³⁾.

Fig.2. Mutations in the APOB gene

More than 140 APOB mutations have been reported in literature. The APOB gene comprises 29 exons. Blue boxes represent exons. Lines represent the positions of each mutation and polymorphism. Causative mutations are distributed throughout the coding region, most of which are nonsense, frameshift, or splicing variants. Variants that cause homozygous or compound heterozygous FHBL1 are shown in bold. The type of mutation may influence disease severity. Adapted from Rabacchi C et al.²⁾, Peloso GM et al.³⁾, Blanco-Vaca F et al.⁴⁾, Elbitar S et al.⁵⁾, and Cefalu AB et al.⁶⁾

^† c.1468C>T has been previously described as a missense variant (p.Arg490Trp) but was recently described also as a splicing variant with the activation of a cryptic donor splice site (p.Arg490Serfs*12)¹³⁾.

Supplementary Table 1.APOB gene mutations identified in FHBL1 patients

Exon	DNA change (cDNA)	Protein change	Type	Reference
1	c.3G>C	p.Met1Ile	missense	1)##
1	c.73del	p.Ala25Profs*68	frameshift	2)#
1i	c.82+1G>A	N.D.	splice site	3)#
1i	c.82+1G>C	N.D.	splice site	4)##
3	c.133C>T	p.Arg45*	nonsense	1)
3	c.158_163del	p.Thr53_Tyr54del	deletion	5)
3	c.172G>C	p.Ala58Pro	missense	6)
3	c.226_237+1del	N.D.	deletion	7)#
3i	c.237+1G>A	N.D.	splice site	8)
4	c.289T>G	p.Cys97Gly	missense	2)#
5	c.394A>T	p.Lys132*	nonsense	9)
5i	c.537+1G>T	N.D.	splice site	10)##
6	c.614del	p.Thr205Metfs*27	frameshift	2)#
7i	c.818+5G>A	N.D.	splice site	8)
7i	c.819-2A>G	N.D.	splice site	11)#
8	c.904G>A	p.Gly302Ser	missense	6)
8	c.905-1_905dup	p.Thr303Valfs*25	frameshift	12)#
8i	c.904+4A>G	N.D.	splice site	13)
9	c.961C>T	p.Gln321*	nonsense	14)##
9	c.1014_1015del	p.Glu339Alafs*7	frameshift	15)
9	c.1019_1026del	p.Gln340Profs*4	frameshift	3)
9	c.1051C>A	p.Leu351Met	missense	6)
9	c.1108C>G	p.Leu370Val	missense	16)
9	c.1124G>A	p.Ser375Lysfs*93	frameshift	17)
10	c.1183del	p.Leu395Serfs*4	frameshift	18)
10	c.1250del	p.Leu417Argfs*29	frameshift	19)
10	c.1315C>T	p.Arg439*	nonsense	10)##
11	c.1407C>A	p.Tyr469*	nonsense	1)
11	c.1418del	p.Gln473Argfs*15	frameshift	15)
11	c.1468C>T	p.Arg490Trp	missense	20)#
		p.Arg490Serfs*12	splice site	21)
11i	c.1471-1G>A	N.D.	splice site	22)
12	c.1594C>T	p.Arg532Trp	missense	23)#
13	c.1621C>T	p.Gln541*	nonsense	24)#
13	c.1720_1721del	p.Ile574*	nonsense	25)
13i	c.1829+2T>G	N.D.	splice site	9)
13i	c.1830-1G>A	N.D.	splice site	26)
14	c.1902_1903del	p.Arg635Glufs*14	frameshift	27)
14i	c.2068-4T>A	N.D.	splice site	15)##
15	c.2115del	p.Phe705Leufs*30	frameshift	2)##
15	c.2172del	p.Gln725Lysfs*10	frameshift	28)#
17	c.2534del	p.Gln845Argfs*18	frameshift	25)
17	c.2555del	p.Gly852Glufs*11	frameshift	15)
18	c.2726C>A	p.Ser909*	nonsense	1)#
18	c.2781del	p.Ser928Profs*25	frameshift	1)
18	c.2786del	p.Pro929Glnfs*24	frameshift	25)
18	c.2786dup	p.Arg931Glufs*28	frameshift	15)
18	c.2816G>A	p.Gly939Asp	missense	6)
19	c.2876del	p.Asn959Thrfs*15	frameshift	15)
19	c.2889G>A	p.Trp963*	nonsense	15)##
19	c.2890dup	p.Ser964Phefs*49	frameshift	15)
19	c.2914G>A	p.Gly972Ser	missense	6)
19	c.2946del	p.Asn983Thrfs*13	frameshift	9)
19i	c.3000-1G>T	N.D.	splice site	8)
21	c.3133_3139del	p.Thr1045Leufs*3	frameshift	15)##
22	c.3383G>A	p.Arg1101His	missense	14)##
22	c.3427C>T	p.Pro1143Ser	missense	19)
23	c.3600T>A	p.Tyr1200*	nonsense	3)##
23i	c.3696+1G>C	p.Val1205fs*71	splice site	29)##
23i	c.3697-1G>A	p.Val1205fs*15	splice site	29)##
23i	c.3697-1G>C	p.Ala1206Argfs*16	splice site	22)
24	c.3711G>A	p.Trp1237*	nonsense	30)#
24	c.3741T>A	p.Tyr1247*	nonsense	31)
24i	c.3842+1G>A	N.D.	splice site	8)
24i	c.3842+2T>C	N.D.	splice site	32)#
24i	c.3843-2A>G	p.Ser1254Argfs*8	splice site	13)
25	c.3918del	p.Ser1307Profs*4	frameshift	15)
25	c.3997C>T	p.Arg1333*	nonsense	33)##
25	c.4006C>T	p.Gln1336*	nonsense	25)
25	c.4089C>A	p.Tyr1363*	nonsense	34)
25	c.4098dup	p.Tyr1367Valfs*28	frameshift	15)
25	c.4187_4188del	p.Val1396Glyfs*2	frameshift	19)
25	c.4211del	p.Val1404Glyfs*28	frameshift	35)#
25i	c.4217-1G>T	N.D.	splice site	13)
26	c.4283A>G	p.His1428Arg	missense	36)
26	c.4304del	p.Ile1435Thrfs*6	frameshift	26)
26	c.4352del	p.Gly1451Valfs*3	frameshift	37)
26	c.4429C>T	p.Gln1477*	nonsense	38)
26	c.4439_4440del	p.Phe1480Cysfs*7	frameshift	9)
26	c.4473_4474del	p.Arg1491Serfs*7	frameshift	15)
26	c.4503T>G	p.Tyr1501*	nonsense	39)
26	c.4611T>A	p.Tyr1537*	nonsense	18)
26	c.4675_4682del	p.Ala1559Lysfs*3	frameshift	15)
26	c.4709T>A	p.Leu1570*	nonsense	40)##
26	c.4715_4716del	p.Ser1572*	nonsense	2)#
26	c.4800_4801insC	p.Glu1601Argfs*5	frameshift	19)
26	c.4818C>G	p.Tyr1606*	nonsense	2)##
26	c.5238T>A	p.Tyr1746*	nonsense	19)
26	c.5263_5266del	p.Asn1728_Ser1729delinsVal*	deletion	41)##
26	c.5290_5291dup	p.Asp1765Trpfs*31	frameshift	15)
26	c.5344C>T	p.Gln1782*	nonsense	42)#
26	c.5350_5363del	p.Val1784Thrfs*12	frameshift	43)
26	c.5463del	p.His1822Metfs*6	frameshift	33)##
26	c.5564dup	p.Val1856Cysfs*3	frameshift	3)
26	c.5566_5567del	p.Val1856Cysfs*2	frameshift	44)##
26	c.5865del	p.Ser1956Leufs*62	frameshift	15)
26	c.5943G>A	p.Trp1981*	nonsense	9)#
26	c.6031A>G	p.Ile2010Thr	missense	40)##
26	c.6034C>T	p.Arg2012*	nonsense	45)
26	c.6115_6116insAATATCATTGA	p.Ala2039Glufs*4	frameshift	46)##
26	c.6240T>A	p.Tyr2080*	nonsense	47)#
26	c.6253C>T	p.Arg2085*	nonsense	48)
26	c.6544G>T	p.Asp2155Tyr	missense	2)#
26	c.6558del	p.Asp2187Ilefs*8	frameshift	49)
26	c.6630_6631del	p.Leu2212*	nonsense	1)##
26	c.6634del	p.Asp2213Metfs*8	frameshift	50)
26	c.6714insT	p.Asn2239*	nonsense	24)#
26	c.6718A>T	p.Lys2240*	nonsense	51)
26	c.6835C>T	p.Gln2279*	nonsense	52)#
26	c.6943G>T	p.Glu2315*	nonsense	53)
26	c.7151_7155del	p.Val2384Aspfs*6	frameshift	54)
26	c.7161del	p.Asp2388Ilefs*36	frameshift	19)
26	c.7167del	p.Phe2390Leufs*34	frameshift	39)
26	c.7231del	p.Thr2411Hisfs*13	frameshift	39)
26	c.7505C>A	p.Ser2502*	nonsense	15)
26	c.7537C>T	p.Arg2513*	nonsense	55)
26	c.7564C>T	p.Arg2522*	nonsense	56)
26	c.7600C>T	p.Arg2534*	nonsense	25)#
26	c.8216C>T	p.Pro2712Leu	missense	57)##
26	c.8397_8433del	p.Lys2800Hisfs*13	frameshift	58)##
26	c.8502C>G	p.Tyr2834*	nonsense	59)
26	c.8771del	p.Ser2924Leufs*27	frameshift	19)
26	c.9104dup	p.Asn3035Lysfs*11	frameshift	15)##
26	c.9152_9155del	p.Asn3051Metfs*5	frameshift	60)##
26	c.9200del	p.Lys3067Argfs*2	frameshift	61)
26	c.9466dup	p.Thr3156Asnfs*15	frameshift	15)
26	c.9632dup	p.Asn3211Lysfs*14	frameshift	62)
26	c.9673G>T	p.Glu3225*	nonsense	15)
26	c.10238del	p.Thr3413Metfs*2	frameshift	63)
26	c.10312del	p.Met3438*	nonsense	64)
26	c.10386del	p.Tyr3462*	nonsense	18)
26	c.10430_10440del	p.Val3477Alafs*2	frameshift	1)
26	c.10706del	p.Asn3569Thrfs*5	frameshift	65)
26	c.10728dup	p.Phe3577Leufs*36	frameshift	19)
26	c.11040T>G	p.Tyr3680*	nonsense	26)
26	c.11095A>T	p.Arg3699*	nonsense	50)
26	c.11283C>A	p.Cys3761*	nonsense	27)#
26	c.11330C>A	p.Ser3777*	nonsense	66)
26	c.11333C>A	p.Ser3778*	nonsense	67)
26	c.11433dup	p.Glu3812*	nonsense	15)#
26	c.11483del	p.Pro3828Glnfs*13	frameshift	15)
26	c.11536A>T	p.Lys3846*	nonsense	68)
26	c.11549_11550del	p.Phe3850*	nonsense	25)
26	c.11712del	p.Asn3904Lysfs*20	frameshift	41)##
26	c.11728G>T	p.Glu3910*	nonsense	1)
27	c.11905del	p.Glu3969Asnfs*38	frameshift	69)#
27	c.11928del	p.Asn3977Ilefs*30	frameshift	70)#
28	c.12035_12036del	p.Met3984Aspfs*2	frameshift	15)
29	c.12181del	p.Glu4061Argfs*7	frameshift	44)##

N.D., Not described.

^# Reported as causative mutations of homozygous FHBL1.

^## Reported as causative mutations of compound heterozygous FHBL1.

The frequency of apoB truncations in the general population is reported to be approximately 1:3000 ¹⁴⁾, whereas the incidence of homozygous or compound heterozygous FHBL1 (HoFHBL1) is extremely rare and is estimated to be less than one in a million¹⁴⁾. To date, approximately 50 causative mutations of HoFHBL1 have been reported worldwide (Fig.2). In Japan, four HoFHBL1 cases with APOB mutations have been reported since Ohashi identified the first case in 1998 ¹⁵⁾ (Table 1).

Table 1.Genetic and clinical characteristics of Japanese patients with homozygous FHBL1 (HoFHBL1)

No	Age	sex	Gene Type	Mutation (APOB)	Consanguinity	Biochemical parameters (mg/dL)					Clinical features	Authors	Year
						TC	TG	LDL-C	HDL-C	ApoB
1	57	M	Ho	c.5344C>T	N.D.	84.0	56.7	＜5	77.0	3	Acanthocytosis, retinitis pigmentosa, loss of deep tendon reflexes, type 2 diabetes mellitus, anemia, mild hepatic steatosis, cholelithiasis, hepatic hemangioma, bronchiectasis	Ohashi K, et al.15)	1998
2	41	F	Ho	c.11283C>A	N.D.	103	7	13	89	1	Hepatic steatosis	Katsuda S, et al.69)	2009
3	23	M	Ho	c.11928del	Yes	63	13	1	51	0	Severe hepatic steatosis with mild fibrosis	Kawashiri M, et al.70)	2015
4	42	F	Ho	c.5943C>T	N.D.	86	42	29	49	0	Hepatic steatosis	Peloso GM, et al.3)	2019

Year, year of publication; M, male; F, female; Ho, homozygous; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; N.D., not described.

In general, shorter apoB proteins confer lower rates of synthesis and secretion of apoB-containing lipoproteins and higher rates of catabolism of truncated apoB-containing lipoproteins. The shorter the length of the truncated apoBs, the more severe the degree of complications. Truncated apoBs shorter than apoB30 are reportedly not secreted into the blood^{16, 17)}. Truncated apoBs shorter than apoB48 generally impair the production of both VLDLs and chylomicrons, thus leading to severe complications due to a deficiency of fat-soluble vitamins. In contrast, truncated apoBs longer than apoB48 generally present with a milder phenotype, likely due to the preserved secretion of chylomicrons¹⁸⁾.

3.Clinical Characteristics

HeFHBL1 patients are usually asymptomatic, except for the lower plasma levels of low-density lipoprotein cholesterol (LDL-C) and apoB, which are approximately one-third of the normal range. They may have mild liver dysfunction due to hepatic steatosis, and approximately 5-10% of HeFHBL1 patients may develop severe steatotic liver disease and occasionally cirrhosis or hepatic cancer^19-22). Some cases of HeFHBL1 have been reported to exhibit acanthocytosis, fat malabsorption, and mild vitamin deficiency^{14, 23)}. Very rarely, neurological complications have been reported in HeFHBL1, possibly due to mild vitamin E and A deficiencies^{23, 24)}. The lifelong reduction in serum lipids in HeFHBL1 patients may confer protection against atherosclerotic cardiovascular diseases³⁾.

In contrast, the clinical symptoms of individuals with HoFHBL1 are severe and similar to those of abetalipoproteinemia (ABL) caused by homozygous mutations in the microsomal triglyceride transfer protein (MTTP) gene²⁵⁾. The symptoms of typical severe cases are as follows:

Gastrointestinal Symptoms:

Infants with severe HoFHBL1 typically experience vomiting, steatorrhea owing to fat malabsorption, and abdominal distention. Patients often learn to avoid dietary fat, which improves these gastrointestinal symptoms^{14, 23)}. Global caloric deficiency leads to a rapid failure to thrive. Endoscopic examinations revealed white mucosa and fat droplets in enterocytes, called snow-white duodenum, gelee blanche, or white hoar frosting^{14, 26)}. Hepatic steatosis and hepatomegaly with fat infiltration may develop due to impaired VLDL secretion and thereafter progress to steatohepatitis, cirrhosis (in rare cases), and hepatocellular carcinoma (in extremely rare cases)¹⁴⁾.

Symptoms Related to Vitamin Deficiencies:

Fat-soluble vitamins (vitamins E, A, D, and K) require apoB-containing lipoproteins for absorption and transport to peripheral tissues. Chronic fat malabsorption in severe HoFHBL1 leads to fat-soluble vitamins deficiency and its complications, as described below.

・Neuromuscular disorders develop due to progressive axonopathy of the spinocerebellar tracts, posterior columns, and peripheral nerves, predominantly as a result of vitamin E deficiency^{23, 27-30)}. Vitamin E may act as an antioxidant by protecting cells from damaging molecules such as lipid peroxyl radicals and lipid peroxide. However, it is not fully understood how a lack of vitamin E leads to neurological dysfunction³¹⁾. The onset of neurological manifestations usually begins in the first or second decade of life¹⁴⁾. Diminished deep tendon reflexes are often the first neurological signs to appear as early as in the first few years of life. The typical symptoms include spinocerebellar ataxia, peripheral neuropathy, and myopathy²³⁾. Vibratory sense and position sense become progressively impaired, resulting in an ataxic gait. The Romberg sign is frequently positive. Additionally, progressive abnormalities may occur in ocular motility disorders, dysarthria, dysmetria, proprioception, spinocerebellar ataxia, hypesthesia, myopathy, and muscular weakness, thus leading to a wide-based spastic gait, skeletal muscle contractures, pes cavus, pes equinovarus, kyphoscoliosis, and lordosis. If left untreated, patients may become unable to walk on their own by the third decade of life and may progress to immobility. Cardiomyopathy and subsequent arrhythmia, which can be lethal, have been reported in ABL cases^{29, 30, 32-34)}.

・Ophthalmological disorders most likely develop due to deficiencies in vitamins A and E. The most prominent manifestation is pigmentary retinal degeneration. Alterations in visual acuity, a loss of night vision or color vision may appear first followed by expanding scotomas, visual field impairment, and a gradual loss of vision^{14, 23, 27)}. Untreated patients may experience a complete loss of vision.

・Abnormal bone metabolism and skeletal deformities may be caused by vitamin D deficiency^{28, 29, 35, 36)}.

・Hypothyroidism, overt or subclinical, has been reported in individuals with ABL or FHBL1, although the causality remains uncertain^{32, 37, 38)}.

Hematological Abnormalities:

A characteristic hematological manifestation is acanthocytosis, typically detected in more than 50% of the erythrocyte population, possibly arising from alterations in the lipid composition and fluidity of red blood cell membranes^{23, 39)}. Impaired rouleaux formation leads to a low erythrocyte sedimentation rate (ESR)^{14, 23)}. Anemia may be observed due to the deficiency of iron, folate, vitamin B12, and other nutrients secondary to fat malabsorption, albeit often of low-grade¹⁴⁾. Decreased levels of vitamin K-dependent coagulation factors may result in bleeding tendency with a prolonged prothrombin time international normalized ratio (PT-INR)²³⁾. Hemolysis, reticulocytosis, and hyperbilirubinemia have also been reported¹⁴⁾.

Considerations in Pregnancy:

Although some women with HoFHBL1 were reported to have insufficient progesterone concentrations in the luteal phase, most patients with HoFHBL1 are considered to have a preserved gonadal function and therefore can normally be fertile^{23, 27, 28, 40, 41)}.

4.Diagnosis

Disease severity generally depends on the mutation type in APOB. Severe cases are suspected in early childhood due to steatorrhea, vomiting, and growth disorders, whereas milder cases may be discovered in adulthood with hypolipidemia at a general medical check-up. In HoFHBL1, the parents are often consanguineous. The median age at diagnosis is 21 years old⁴²⁾. Although an early diagnosis is critical for obtaining timely and appropriate treatment, severe cases diagnosed in their 50’s without any previous treatment have been reported⁴³⁾.

Diagnostic Criteria:

The diagnostic criteria used in Japan are shown in Table 2. These criteria have been used to define the eligibility of HoFHBL1 patients to receive financial support from the Japanese government for a rare and intractable disease. We searched PubMed for HoFHBL1 cases with genetic diagnosis and found that HoFHBL1 patients had LDL-C ＜15 mg/dL and/or apoB ＜15 mg/dL (typically apoB ＜5 mg/dL), except for two cases with a mild phenotype^{3, 44)}. Gastrointestinal symptoms, neurological symptoms, ocular symptoms, or acanthocytes should be observed when making a clinical diagnosis. Other diseases that cause hypolipidemia should be excluded. Detection of abnormal apoB proteins by electrophoresis or immunoblotting is informative, whereas a definitive diagnosis of HoFHBL1 requires genetic testing of the APOB gene.

Table 2.Diagnostic criteria for Homozygous or compound heterozygous FHBL1 (HoFHBL1) in Japan

A. 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.
B. Laboratory findings
1. Plasma LDL-C level ＜15 mg/dL AND/OR plasma apoB level ＜15 mg/dL
2. Acanthocytosis
C. Differential diagnosis
Abetalipoproteinemia (ABL) (OMIM 200100), chylomicron retention disease (Anderson disease) (OMIM 246700), hyperthyroidism.
＊Homozygous FHBL1 and ABL cannot be distinguished only from the clinical manifestations and laboratory findings of a proband. Family history is helpful. As FHBL1 is an autosomal dominant disorder, obligate heterozygote parents of HoFHBL1 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.
D. Genetic test
Pathogenic mutations in the APOB gene
<Diagnosis categories>
Definite FHBL1:
Laboratory findings (B-1) is associated with at least one item of (A) or (B-2) AND exclusion of differential diagnosis (C) AND genetic diagnosis (D).
Probable FHBL1:
Laboratory findings (B-1) is associated with at least two items of (A) or (B-2) AND exclusion of differential diagnosis (C).

Differential Diagnosis:

・Secondary hypobetalipoproteinemia may be associated with the chronic course or terminal stage of various diseases, including cancer, hyperthyroidism, liver disease, impaired intestinal fat absorption due to chronic pancreatitis, severe malnutrition, and other wasting disorders.

・Hypobetalipoproteinemia caused by PCSK9 loss-of-function mutations exhibits an autosomal dominant mode of inheritance. PCSK9 is a protein that degrades LDL receptors and is mainly secreted from the liver. A loss of the PCSK9 function leads to low LDL-cholesterolemia due to an increased LDL uptake into the liver⁴⁵⁾. It is usually asymptomatic, does not increase the frequency of hepatic steatosis, and is reported to be anti-atherosclerotic^{7, 46)}.

・Familial hypobetalipoproteinemia 2 (FHBL2), also referred to as familial combined hypobetalipoproteinemia, is caused by either homozygous or compound heterozygous mutations in ANGPTL3. ANGPTL3 inhibits lipoprotein lipase (LPL) and endothelial lipase (EL). A loss of the ANGPTL3 function leads to decreased TG, LDL-C, and high-density lipoprotein cholesterol (HDL-C) due to the increased catabolism of VLDL, intermediate-density lipoprotein (IDL), and HDL via increased activities of LPL and EL^47-50). In FHBL2 heterozygotes, the HDL-C levels were not reduced, while the TG and LDL-C levels were moderately reduced. Similar to the loss-of-function mutation of PCSK9, FHBL2 is usually asymptomatic, does not increase the frequency of hepatic steatosis, and is reported to be anti-atherosclerotic^{8, 46, 51)}.

・Abetalipoproteinemia (ABL; OMIM 200100) is a rare autosomal recessive disorder caused by biallelic mutations in MTTP. MTTP deficiency abrogates the assembly of apoB-containing lipoproteins in the small intestine and liver, resulting in biochemical and clinical characteristics similar to those seen in severe HoFHBL1 patients²⁵⁾. However, there are several differences between ABL and HoFHBL1. Compared to HoFHBL1, ABL is generally more severe and is diagnosed at a younger age (median age of diagnosis: 3.8 years). Diarrhea in infancy, growth disorders, a lean phenotype, and ophthalmological disorders are more frequent in ABL than in HoFHBL1⁴²⁾. Although the serum levels of LDL-C and HDL-C are similar, serum TG levels are generally higher in HoFHBL1 than in ABL. A patient’s family history may help differentiate these two disorders: obligate heterozygote parents of FHBL1 patients usually present with lower plasma levels of LDL-C and apoB, whereas obligate heterozygous parents of ABL patients have normal plasma lipid levels. The estimated frequency of ABL is as low as less than one in a million^{52, 53)}.

・Chylomicron retention disease (CMRD; OMIM 246700), also referred to as Anderson disease, is an extremely rare autosomal recessive disease caused by biallelic pathogenic variants in the SAR1B gene encoding SAR1B (Secretion-associated and Ras-related GTPase 1B), which is required for the transport of chylomicrons from the endoplasmic reticulum to the Golgi apparatus. A deficiency of SAR1B proteins disables the synthesis and secretion of chylomicrons from enterocytes, which in turn results in clinical phenotypes similar to those of ABL or severe HoFHBL1, such as severe hypolipidemia, fat-soluble vitamin deficiency, steatorrhea, vomiting, and a failure to thrive⁵⁴⁾. CMRD can be differentiated from ABL and HoFHBL1 by the plasma lipid levels: in CMRD, plasma levels of total cholesterol, LDL-C, and HDL-C typically decrease by more than 50%, whereas plasma TG levels are usually normal because VLDL secretion is maintained⁵⁵⁾.

To better classify these hereditary hypolipidemia disorders based on molecular mechanisms, a new classification was proposed by the Abetalipoproteinemia and Related Disorders Foundation (ABLRDF)^{27, 40)} (Table 3). Class I disorders, which arise from lipoprotein assembly and secretion defects (FHBL-SD), include FHBL-SD1 (ABL), FHBL-SD2 (FHBL1), and FHBL-SD3 (CMRD). Class II disorders, which arise from an enhanced catabolism of lipoproteins (FHBL-EC), include FHBL-EC1 (FHBL2) and FHBL-EC2 (hypobetalipoproteinemia caused by PCSK9 loss-of-function mutations). Class II disorders are generally asymptomatic and anti-atherogenic.

Table 3.New classification of hereditary familial hypobetalipoproteinemia (FHBL) disorders proposed by ABL and related disorders foundation (ABLRDF)

New name	Common name	Gene	Mode of inheritance	Lipid profile	Clinical feature
Class I: Lipoprotein assembly and secretion defects (SD)
FHBL-SD1	Abetalipoproteinemia (ABL)	MTTP	Autosomal recessive	LDL-C ↓ ↓ TG ↓ ↓ HDL-C ↓	Fat malabsorption, steatosis, failure to thrive in infancy, early neurologic and ophthalmologic abnormalities
Bi-allelic FHBL-SD2	Familial hypobetalipoproteinemia 1	APOB	Autosomal codominant	LDL-C ↓ ↓ TG ↓ ↓ HDL-C ↓
Mono-allelic FHBL-SD2				LDL-C ↓ TG → ~ ↓ HDL-C →	Usually asymptomatic, possible risk of hepatic steatosis and fibrosis, reduced risk for CVD
FHBL-SD3	Chylomicron retention disease (CRD), Anderson disease	SAR1B	Autosomal recessive	LDL-C ↓ TG → HDL-C ↓	Fat malabsorption, steatosis, failure to thrive in infancy, neurologic and ophthalmologic abnormalities, CK ↑
Class II: Enhanced lipoprotein catabolism (EC)
Bi-allelic FHBL-EC1	Familial hypobetalipoproteinemia 2, Familial combined hypolipidemia (FCHL)	ANGPTL3	Autosomal codominant	LDL-C ↓ TG ↓ HDL-C ↓	Usually asymptomatic, reduced risk for CVD
Mono-allelic FHBL-EC1				LDL-C → ~ ↓ TG → ~ ↓ HDL-C →
FHBL-EC2		PCSK9	Autosomal codominant	LDL-C ↓ TG → ~ ↓ HDL-C →

TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; CVD, cardiovascular disease; CK, creatinine kinase. Adapted from Bredefeld C, et al.27, 40)

An early diagnosis and therapeutic intervention are essential to prevent the progression of undesired complications in patients with severe congenital hypolipidemia. Genetic testing is required for definitive diagnosis of HoFHBL1 and its related disorders. The genotype–phenotype relationship, often conferred by the length of the truncated apoB, may help predict the severity of the disease. Genetic testing for intractable lipid disorders, including HoFHBL1 and ABL, is now covered by the national health insurance program in Japan.

5.Management

The prognosis varies depending on the type of mutation, timing of diagnosis, treatment details, and environment. In severe cases, activities of daily living (ADL) are significantly impaired owing to neurological symptoms or blindness. Some patients die in their 20s because of severe neurological complications and respiratory failure if they do not receive sufficient treatment, while others survive into their 70s with successful treatment¹⁴⁾. Vitamin supplementation has been reported to improve the symptoms and prognosis. Early therapeutic intervention is essential, as it might be difficult to relieve symptoms if treatment is started in adulthood.

The current strategy and recommendations for the clinical follow-up and treatment of FHBL1 are summarized below, adapted and modified from reviews by Hegele et al. and others^{14, 23, 27, 28, 56)}.

Clinical Follow-Up:

The recommended regular assessments for FHBL1 patients include:

・Measurement of the growth parameters every 6-12 months^{14, 27, 28, 56)}

・Evaluation of progressive signs and symptoms of gastrointestinal problems (including hepatomegaly and diarrhea) every 6-12 months^{14, 27, 28, 56)}.

・Ophthalmological and neurological evaluations every 6-12 months after 10 years of age^{14, 28)}.

・An annual blood analysis including lipid profiles (TC, TG, LDL-C, HDL-C, apoB, apoA-I), liver function tests (aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), total and direct bilirubin, alkaline phosphatase, and albumin), fat-soluble vitamins (vitamin A (retinol), β-carotene, 25-OH vitamin D, vitamin E, and vitamin K), other micronutrients (vitamin B12, iron, and folate), complete blood count, PT-INR, reticulocyte count, ESR, calcium, phosphate, uric acid, and thyroid-stimulating hormone (TSH)^{14, 27, 28, 56)}.

・Hepatic ultrasonography and bone mineral density measurements every 3-5 years after 10 years of age^{14, 27, 28, 56)}.

・Echocardiography every 3 years^{27, 28, 56)}.

Treatment:

For the treatment of HoFHBL1 patients, the standard of care includes:

・Adequate calorie intake is essential to avoid growth retardation^{14, 23, 27, 28, 56)}.

・Medium-chain triglyceride (MCT) administration may help with proper nutritional intake, particularly in infants, although it is not absolutely necessary. The absorption of MCTs can bypass the chylomicron pathway, as MCTs are transported into the circulation by albumin⁵⁷⁾. As MCTs have been reported to cause hepatic fibrosis and cirrhosis^{58, 59)}, liver enzymes should be monitored when administering MCTs, and long-term administration is not generally recommended^{23, 30)}.

・Restriction of fat intake is required to mitigate gastrointestinal symptoms and avoid failure to thrive during infancy. The total fat intake should be restricted to less than 30% of the total caloric requirement, or less than 15 to 20 g/day, or even less than 5 g/day in children^{14, 23, 28, 60, 61)}. In particular, the consumption of long-chain fatty acids should be avoided^{27, 28, 56)}. Secondary malabsorption of carbohydrates, proteins, and other nutrients following fat malabsorption³⁰⁾ may be alleviated by a low-fat diet.

・Oral essential fatty acid (EFA) supplementation. It is necessary to ensure an adequate intake of EFAs while restricting the total fat intake. Daily 1-3 teaspoons of oils rich in polyunsaturated fatty acids (e.g., soybean or olive oil) are examples of food sources rich in EFAs^{27, 61)}.

・High-dose oral vitamin E supplementation may prevent neurological complications^{23, 27, 60)}. A substantially high dose of vitamin E (100-300 IU/kg/day^{14, 28)}; 1,000-2,000 mg/day (infant), 5,000-10,000 mg/day (older children and adults)²³⁾; 2,400-12,000 IU/day^{29, 62)}; 1IU=1 mg tocopheryl acetate) is required to delay or reverse the progression of neurological complications. Even with high-dose vitamin E supplementation, the serum vitamin E levels may only increase by at most 30% of the lower limit of normal serum vitamin E levels. However, the serum vitamin E levels may not reflect the vitamin E levels in the whole body^{29, 30, 61)}, and better methods to monitor tissue vitamin E levels are awaited. Measuring the vitamin E levels in erythrocytes or subcutaneous adipose tissue aspirates has been reported^63-65). As most patients with hereditary hypolipidemia disorders have shown a clinical improvement with oral vitamin administration, parenteral treatment (e.g., intravenous or intramuscular) is considered unnecessary²⁸⁾. It is important to note that high-dose vitamin E supplementation may competitively inhibit the absorption of other fat-soluble vitamins, particularly vitamin K^{29, 30, 52)}.

・High-dose oral vitamin A supplementation (100-400 IU/kg/day^{14, 28)}) with vitamin E may prevent or arrest ophthalmological complications^{14, 23, 60)}. As vitamin A toxicity has been reported even in cases with normal plasma vitamin A levels⁶⁶⁾, the therapeutic goal of vitamin A concentration is recommended to be set at the lower limit of the normal range, and the dose of vitamin A supplementation should be adjusted by monitoring the blood concentrations of vitamin A or β-carotene^{14, 28)}. Particular caution should be taken in women who are pregnant or are planning to become pregnant. Vitamin A supplementation should be continued during pregnancy because it is essential for normal growth and cell differentiation of the developing fetus⁶⁷⁾, and it is recommended that the dose of vitamin A supplementation should be reduced by 50% at the beginning of pregnancy to avoid vitamin A toxicity. Careful monitoring of the blood concentrations of vitamin A or β-carotene throughout pregnancy is recommended²⁸⁾.

・Supplementation of vitamin D (800-1,200 IU/day^{14, 28)}) should be considered in cases of vitamin D deficiency.

・Supplementation of vitamin K (5-35 mg/ week or 5 mg/ day^{14, 28, 29, 62)}) should be considered in cases of vitamin K deficiency. Supplementation with vitamin K may normalize hypothrombinemia and prolonged PT-INR^{23, 29)}.

・Supplementation of iron, folate, or vitamin B12 may be necessary in cases of anemia, albeit generally infrequent in HoFHBL1 patients^{14, 23, 28)}.

・Liver transplantation may be considered in patients with end-stage liver disease¹⁴⁾.

・Multidisciplinary care for each complications should be implemented in coordination with neurologists, ophthalmologists, physical therapists, occupational therapists, speech therapists, and various supportive devices¹⁴⁾.

6.Conclusions

This review addressed the current diagnosis and management of HoFHBL1. Untreated patients may present with severe complications related to fat and fat-soluble vitamin malabsorption in the first or second decade of life, possibly followed by lethal conditions in the third decade. Early diagnosis, appropriate dietary therapy, and supplementation with fat-soluble vitamins can prevent or delay these unfavorable outcomes. Nevertheless, it is not uncommon for HoFHBL1 patients to experience a delay in diagnosis, mainly because of a lack of recognition of this rare disease by medical personnel. It is particularly important to improve awareness of this disease among doctors who may encounter these patients, such as pediatricians, gastroenterologists, ophthalmologists, and neurologists. The appropriate transition of medical care from childhood to adulthood is imperative for lifelong management and treatment involving multidisciplinary collaboration⁶⁸⁾. Additionally, there are unmet needs for the management and treatment of HoFHBL1. First, current dietary therapy or high-dose supplementation of fat-soluble vitamins is not necessarily effective for all patients. Second, mechanism-based therapies to restore the expression of apoB in the small intestine and liver are lacking. Third, the pathogenesis of complications, genotype-phenotype relationships, and other possible complications are still not fully understood. In this regard, a nationwide registry of this rare disease for genetic mutations, symptoms, complications, treatment status, and prognosis is required to help understand the natural history of this disease and to establish personalized management and treatment. In Japan, a registry study for rare and intractable lipid disorders, including HoFHBL1, is ongoing (PROLIPID Study). Increased knowledge and awareness of this rare disease will greatly help HoFHBL1 patients to receive appropriate therapies at the right time.

Acknowledgments and Notice of Grant Support

This work was supported by a Health, Labour, and Welfare Sciences Research Grant for Research on Rare and Intractable Diseases (H30-nanji-ippan-003, 21FC1009).

Conflicts of Interest

Tetsuji Wakabayashi has nothing to disclose. Manabu Takahashi has nothing to disclose. Hiroaki Okazaki received scholarship grants from Minophagen Pharmaceutical Co., Ltd. and Kowa Company, Ltd. Sachiko Okazaki received scholarship grants from Minophagen Pharmaceutical Co., Ltd. and Kowa Company, Ltd. Koutaro Yokote has received honoraria from MSD K.K., Kowa Company, Ltd., Sanofi K.K., Sumitomo Pharma Co., Ltd., Daiichi Sankyo Co, Ltd., Taisho Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corp., Boehringer Ingelheim International GmbH., Novartis Pharma K.K., Novo Nordisk Pharma, Ltd., Bayer Yakuhin, Ltd., and Pfizer Japan Inc. KY also received scholarship grants from Abbott Japan LLC, Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Kowa Company, Ltd., Sumitomo Pharma Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corp., Teijin Pharma, Ltd., Eli Lilly Japan K.K., Boehringer Ingelheim International GmbH., and Mochida Pharmaceutical Co., Ltd. Hayato Tada has nothing to disclose. Masatsune Ogura received honoraria from Amgen Inc. and Kowa Company, Ltd. Yasushi Ishigaki received honoraria from Novo Nordisk Pharma, Ltd., Sumitomo Pharma Co., Ltd., and Kowa Company, Ltd.; clinical research funding from Novo Nordisk Pharma, Ltd. and Daiichi Sankyo Co, Ltd. Shizuya Yamashita received honoraria from Kowa Company, Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Skylight Biotech Inc., and Hayashibara Co., Ltd. Mariko Harada-Shiba received stock holdings or options from Liid Pharma; honoraria from Amgen Inc., Medpace Japan K.K., Novartis Pharma K.K., Protosera Inc., BML Inc., and Kowa Company, Ltd.

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