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Guidance for the diagnosis and treatment of hypolipidemia disorders

Open AccessPublished:September 28, 2022DOI:https://doi.org/10.1016/j.jacl.2022.08.009

      Highlights

      • A classification and genetic basis for hypolipidemia disorders is provided.
      • We suggest guidance for the diagnosis and treatment of these disorders.
      • We discuss challenges encountered by patients with hypolipidemia disorders.
      • Topics for future research are highlighted.

      Abstract

      The Abetalipoproteinemia and Related Disorders Foundation was established in 2019 to provide guidance and support for the life-long management of inherited hypocholesterolemia disorders. Our mission is “to improve the lives of individuals and families affected by abetalipoproteinemia and related disorders”. This review explains the molecular mechanisms behind the monogenic hypobetalipoproteinemia disorders and details their specific pathophysiology, clinical presentation and management throughout the lifespan. In this review, we focus on abetalipoproteinemia, homozygous hypobetalipoproteinemia and chylomicron retention disease; rare genetic conditions that manifest early in life and cause severe complications without appropriate treatment. Absent to low plasma lipid levels, in particular cholesterol and triglyceride, along with malabsorption of fat and fat-soluble vitamins are characteristic features of these diseases. We summarize the genetic basis of these disorders, provide guidance in their diagnosis and suggest treatment regimens including high dose fat-soluble vitamins as therapeutics. A section on preconception counseling and other special considerations pertaining to pregnancy is included. This information may be useful for patients, caregivers, physicians and insurance agencies involved in the management and support of affected individuals.

      Keywords

      Abbreviations:

      ABL (abetalipoproteinemia), ABLRDF (Abetalipoproteinemia and Related Disorders Foundation), ALA (alpha-linoleic acid), ANGPTL3 (angiopoietin like 3), ApoB (apolipoprotein B), CK (creatine kinase), CVD (cardiovascular disease), DHA (docosahexaenoic acid), EFA (essential fatty acids), EPA (eicosapentaenoic acid), ERG (electroretinogram), FHBL (familial hypobetalipoproteinemia), HDL (high density lipoproteins), HDL-C (HDL-cholesterol), INR (international normalized ratio), LA (linoleic acid), LCT (long chain triglyceride), LDL (low density lipoproteins), LDL-C (LDL-cholesterol), MAG (monoacylglycerols), MCT (medium chain triglycerides), MTP (microsomal triglyceride transfer protein), PCSK9 (proprotein convertase subtilisin/kexin type 9), SAR1B (secretion associated Ras related GTPase 1B), TG (triglyceride), VLDL (very low density lipoproteins.)

      Background

      The Abetalipoproteinemia and Related Disorders Foundation (ABLRDF), a non-profit international organization, consists of patients with abetalipoproteinemia (ABL), familial hypobetalipoproteinemia (FHBL) and related hypobetalipoproteinemia disorders, as well as their caregivers, researchers and medical professionals. Early diagnosis and intervention are essential to minimize the deleterious effects of hypobetalipoproteinemia disorders. Nevertheless, it is not uncommon for patients to experience a delay of weeks to years before achieving a diagnosis, despite seeking medical care for adverse symptoms. The Foundation aims to increase awareness of ABL and other hypobetalipoproteinemia disorders in the medical community and provide clinical guidance that is relevant throughout the lifespan. We aspire to lead efforts for comprehensive affordable care including access to specialized professionals, medical assessments that incorporate preconception counseling and genetic testing as well as treatments. Another goal incorporates fundraising to support research developing means to deliver and maintain the efficacy of fat-soluble vitamins and other therapeutic molecules.
      To ascertain priorities within the Foundation, we conducted limited, qualitative surveys with patients and held multiple conference calls among the founding members. These efforts identified several challenges faced by patients and caregivers (Table 1). It became evident that access to necessary fat-soluble vitamins is compromised by cost and inadequate insurance coverage. Out of pocket expenses ranging up to $800 a month in the United States were reported. Consequently, patients adhere to different vitamin regimens based on their affordability. To address this problem, the medical advisory panel drafted template letters of medical necessity for treating physicians to provide to third party payers when advocating for fat-soluble vitamin coverage on behalf of their patients. In addition, it became apparent that physician awareness of monogenic hypobetalipoproteinemia disorders is suboptimal leading to a delay in diagnosis, substandard treatment and the development of avoidable morbidities. This inattention is perhaps due to the very low prevalence of these diseases and the paucity of published recommendations for their management throughout the lifespan including the peripartum period. These findings illustrate the inconsistencies associated with real-world management of ABL and related hypobetalipoproteinemia disorders. To mitigate these deficiencies, we assembled an international panel of experts to analyze recent literature, summarize known knowledge and propose clinical treatment guidance. Two groups of experts summarized data separately and produced initial written descriptions. Subsequently, these drafts were combined and further expanded with the input from additional leaders in the field who agreed to join our panel. All the panel members then critically read, held several discussion meetings, and critiqued the final manuscript. The objective of this article is to provide: (a) information concerning the molecular basis of these conditions; (b) comprehensive and necessary clinical information to various stakeholders involved in the care of these serious monogenic hypobetalipoproteinemia disorders; and (c) guidance for their diagnosis, assessment and treatment. This review builds on our previous classification proposed for these disorders and recommendations provided for their optimal management
      • Bredefeld C
      • Peretti N
      • Hussain MM
      • Medical Advisory P.
      New classification and management of abetalipoproteinemia and related disorders.
      .
      Table 1Challenges encountered by patients with ABL and related disorders.
      Patient burden of disease
      • High daily vitamin pill burden needed to achieve dosage requirements
      • Cost of fat-soluble vitamins and their insufficient insurance coverage
      • Chronic vitamin treatments and regular physical examinations
      • Disabilities leading to unemployment and reliance on social assistance
      Knowledge gaps in the healthcare system
      • Limited awareness of the condition and delay in diagnosis and treatment by the medical community
      • Lack of recognition by health insurance organizations and regulatory agencies that ABL and related disorders require high dose vitamin treatments
      • Gaps in clinical knowledge of disease evolution with age
      Limited resources for patients and caregivers
      • Paucity of clinical guidance that address management over the lifespan
      • Limited availability of dietary guidance
      • Inadequate preconception and pregnancy medical counseling
      • Absence of a directory of physicians with expertise in disease management
      • Patient awareness of available resources
      The guidance proposed herein is intended to support patients and clinicians in the management of hypobetalipoproteinemia disorders. In the absence of randomized, placebo controlled clinical trials or meta-analysis, our recommendations are based on isolated published reports and the experience of the ABLRDF medical advisory panel. Additional research is needed to substantiate clinical practice guidelines and is beyond the scope of this review.
      We anticipate this document will heighten attention to these under-recognized conditions, including the urgency for improved access to affordable necessary fat-soluble vitamin treatment and medical care.

      Summary of lipoprotein metabolism

      Lipoproteins are lipid-protein emulsion particles that transport lipids in blood circulation. They are also critical for the absorption, transport and delivery of fat-soluble vitamins to peripheral tissues. Lipids and proteins in these particles are held together via hydrophobic interactions
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      . Apolipoprotein B (apoB)-containing lipoprotein particles are mainly assembled in enterocytes and hepatocytes. Enterocytes assemble and secrete very large lipoproteins, chylomicrons, to transport dietary fat and fat-soluble vitamins, whereas hepatocytes produce very low density lipoproteins (VLDL) to deliver endogenous lipids to extrahepatic tissues. Assembly of these particles is dependent on two proteins
      • Hussain MM
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      Microsomal triglyceride transfer protein and its role in apolipoprotein B-lipoprotein assembly.
      ,
      • Hussain MM.
      A proposed model for the assembly of chylomicrons.
      : apoB, a structural protein that acts as a scaffold for lipoprotein integrity, and microsomal triglyceride transfer protein (MTP), a chaperone that transfers lipids and facilitates the assembly of apoB-containing lipoproteins (Fig. 1). In humans, there is one APOB gene. In the liver, it is transcribed and translated into apoB100, a single polypeptide of about 4560 amino acids. In the intestine, apoB mRNA undergoes post-transcriptional C-to-U RNA editing with introduction of a TAA stop codon. It is subsequently translated into apoB48, an isoform representing N-terminal 48% of apoB100
      • Davidson NO.
      Apolipoprotein B mRNA editing: a key controlling element targeting fats to proper tissue.
      . ApoB-containing lipoprotein assembly begins in the endoplasmic reticulum (ER). After their assembly, these particles are first transported to the Golgi complex for further maturation and modification and subsequently to the plasma membrane for secretion via exocytosis. Intracellular trafficking of lipoproteins to different organelles is critically dependent on several proteins including secretion associated Ras related GTPase IB (SAR1B). In the circulation, intestine and liver derived lipoproteins undergo lipolysis by endothelial cell-bound lipoprotein lipase. Several proteins inhibit lipoprotein lipase activity, including apoC-III and angiopoietin like proteins (ANGPTLs) 3 and 4. Lipolysis of lipoproteins by lipoprotein lipase yields chylomicron remnants, intermediate density lipoproteins and low-density lipoproteins (LDL). LDL is removed from the circulation by LDL receptors, whereas, remnants and intermediate density lipoproteins are cleared via LDL receptor-related protein 1 (LRP1), proteoglycans and other receptors
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      Clearance of chylomicron remnants by the low density lipoprotein receptor-related protein/α2-macroglobulin receptor.
      . LDL receptors recognize apoB100 on LDL, internalize the particles, and deliver them to lysosomes for degradation. Subsequently, intact LDL receptors are sent back to the cell-surface for another round of lipoprotein internalization. To prevent excessive accumulation of cholesterol, LDL receptors are degraded after several rounds of recycling. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a plasma protein, binds to LDL receptors and undergoes endocytosis along with the receptor. In the intracellular compartments, the presence of PCSK9 prevents recycling of LDL receptors to the cell surface and augments their lysosomal degradation
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      Fig 1
      Fig. 1Schematic diagram highlighting the role of proteins deficient in chylomicron (CM) assembly and secretion by enterocytes in monogenic hypobetalipoproteinemia disorders. Dietary triglycerides (TG) are hydrolyzed in the intestinal lumen. This process requires bile acids secreted from the liver and pancreatic lipase secreted from the pancreas. Hydrolysis yields free fatty acids (FFA) and monoacylglycerols (MAG) which are taken up by enterocytes via specific transporters for the synthesis of TGs by enzymes, such as diacylglycerol acyltransferase (DGAT), present in the endoplasmic reticulum (ER). During translation, apolipoprotein B48 (B48) interacts with ER membrane. Microsomal triglyceride transfer protein (MTP) transfers lipids onto B48 and assists in the assembly of CM. CM containing TG, cholesterol esters (CEs) and fat soluble vitamins (VITs), such as retinyl esters (REs, VIT A), and VIT E (tocopherols) are transported to Golgi via specialized transport vesicles. This transport process is critically dependent on secretion associated Ras related GTPase 1B (SAR1B). Modified from
      • Iqbal J
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      Intestinal lipid absorption.
      .

      Description and classification of familial hypobetalipoproteinemia disorders

      Primary monogenic FHBL disorders are intricately related to the lipoprotein metabolism summarized above. We have previously proposed a simplified nomenclature based on mechanisms that explain low plasma lipids
      • Bredefeld C
      • Peretti N
      • Hussain MM
      • Medical Advisory P.
      New classification and management of abetalipoproteinemia and related disorders.
      . The Class 1 FHBL disorders are due to secretion defects (FHBL-SD), whereas Class II FHBL disorders relate to enhanced catabolism (FHBL-EC). Members in these classes are further defined by the loss-of-function variants in different genes. Class I disorders have significant effects on growth and development in infancy and require early intervention and lifelong monitoring. Class II disorders do not exhibit any pathologic symptoms or signs; in fact, these variants confer cardiovascular benefit and monitoring is not required. We anticipate that other uncharacterized mechanisms also contribute to FHBL. As such, this classification has flexibility for expansion. Following the discovery of additional causative genes, pathogenic variants and molecular mechanisms, new members can be incorporated within these classes. For example, a LDLR variant with truncations in 3´-untranslated region of the LDLR mRNA has been associated with low plasma lipids
      • Bjornsson E
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      • Halldorsson GH
      • Sigurdsson A
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      Lifelong reduction in LDL (Low-Density Lipoprotein) cholesterol due to a gain-of-function mutation in LDLR.
      . Following confirmatory studies, this variant may be added as a new member under FHBL Class II. New classes may also be added to the nomenclature if a novel mechanism of hypobetalipoproteinemia is discovered. For instance, a single report described subjects with hypolipidemia possessing mutations in the LIMA1 gene leading to defects in intestinal cholesterol absorption
      • Zhang YY
      • Fu ZY
      • Wei J
      • Qi W
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      • Luo J
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      A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption.
      . An additional class of FHBL for defects in cholesterol absorption may be added following further evidence.
      The Class I disorders arise due to secretion defects (SD) in apoB-containing lipoproteins and include FHBL-SD1 (ABL), FHBL-SD2 (FHBL), and FHBL-SD3 (chylomicron retention disease). FHBL-SD1 is an autosomal recessive disorder due to bi-allelic loss-of-function variants in the MTTP gene
      • Wetterau JR
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      • Hermier M
      • et al.
      Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia.
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      Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinemia.
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      • et al.
      A novel abetalipoproteinemia genotype. Identification of a missense mutation in the 97-kDa subunit of the microsomal triglyceride transfer protein that prevents complex formation with protein disulfide isomerase.
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      • Read J
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      • Harrison GB
      • et al.
      Mutations of the microsomal triglyceride-transfer-protein gene in abetalipoproteinemia.
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      • Gordon D
      • et al.
      A 30-amino acid truncation of the microsomal triglyceride transfer protein large subunit disrupts its interaction with protein disulfide-isomerase and causes abetalipoproteinemia.
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      • Barbaro M
      • Mannila MN
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      • Tosi M
      • et al.
      Novel mutations in microsomal triglyceride transfer protein including maternal uniparental disomy in two patients with abetalipoproteinemia.
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      • Bonnet V
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      • Rabes JP
      • et al.
      Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia.
      • Sani MN
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      • Mahjoob F
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      • Rezaei N.
      Identification of a novel mutation of MTP gene in a patient with abetalipoproteinemia.
      • Di Filippo M
      • Moulin P
      • Roy P
      • Samson-Bouma ME
      • Collardeau-Frachon S
      • Chebel-Dumont S
      • et al.
      Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia.
      • Khatun I
      • Walsh MT
      • Hussain MM.
      Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia.
      • Miller SA
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      • Leonis MA
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      Novel missense MTTP gene mutations causing abetalipoproteinemia.
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      Novel abetalipoproteinemia missense mutation highlights the importance of the N-terminal beta-barrel in microsomal triglyceride transfer protein function.
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      Structure-function analyses of microsomal triglyceride transfer protein missense mutations in abetalipoproteinemia and hypobetalipoproteinemia subjects.
      • Ohashi K
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      • et al.
      Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia.
      • Takahashi M
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      • Ishibashi S
      Normal plasma apoB48 despite the virtual absence of apoB100 in a compound heterozygote with novel mutations in the MTTP gene.
      . This gene codes for MTP, which as mentioned above is required for the assembly of apoB-containing lipoproteins both in the intestine and the liver. Autosomal semi-dominant mutations in the APOB gene disable apoB protein from forming lipoproteins and cause FHBL-SD2 with bi-allelic or mono-allelic forms (formerly referred to as “homozygous” or “heterozygous” forms, respectively)
      • Tarugi P
      • Averna M.
      Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum.
      . As mentioned previously, the APOB gene codes for two tissue-specific isoforms, namely apoB100 and apoB48 in the liver and intestine, respectively. Most pathogenic variants in FHBL result from the synthesis of various truncated forms of the liver-derived apoB100 isoform. However, rare missense pathogenic variants in APOB have been reported that produce apoB peptides smaller than apoB48
      • Burnett JR
      • Zhong S
      • Jiang ZG
      • Hooper AJ
      • Fisher EA
      • McLeod RS
      • et al.
      Missense mutations in APOB within the betaalpha1 domain of human APOB-100 result in impaired secretion of ApoB and ApoB-containing lipoproteins in familial hypobetalipoproteinemia.
      ,
      • Burnett JR
      • Shan J
      • Miskie BA
      • Whitfield AJ
      • Yuan J
      • Tran K
      • et al.
      A novel nontruncating APOB gene mutation, R463W, causes familial hypobetalipoproteinemia.
      . The severity of the disease is generally inversely proportional to length of the variant apoB peptide synthesized; the shorter the peptide, the more severe the phenotype. Patients with FHBL-SD1 and bi-allelic FHBL-SD2 have absent to very low levels of plasma lipids and apoB-containing lipoproteins
      • Lee J
      • Hegele RA.
      Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.
      ,
      • Welty FK.
      Hypobetalipoproteinemia and abetalipoproteinemia.
      . FHBL-SD3 is an autosomal recessive disease due to bi-allelic loss-of-function variants in the SAR1B gene, which encodes SAR1B protein. Loss-of-function variants on both alleles of the SAR1B gene profoundly affect secretion of chylomicrons by enterocytes, while one copy of the pathogenic allele is not associated with an abnormal clinical phenotype
      • Levy E
      • Poinsot P
      • Spahis S
      Chylomicron retention disease: genetics, biochemistry, and clinical spectrum.
      .
      The Class II disorders arise due to enhanced catabolism (EC) of lipoproteins and include FHBL-EC1 (familial combined hypolipidemia) and FHBL-EC2. FHBL-EC1 is an autosomal semi-dominant disorder arising due to loss-of-function variants in the ANGPTL3 gene
      • Levy E
      • Beaulieu JF
      • Spahis S.
      From congenital disorders of fat malabsorption to understanding intra-enterocyte mechanisms behind chylomicron assembly and secretion.
      • Musunuru K
      • Pirruccello JP
      • Do R
      • Peloso GM
      • Guiducci C
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      • et al.
      Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.
      • Martin-Campos JM
      • Roig R
      • Mayoral C
      • Martinez S
      • Marti G
      • Arroyo JA
      • et al.
      Identification of a novel mutation in the ANGPTL3 gene in two families diagnosed of familial hypobetalipoproteinemia without APOB mutation.
      . Variant ANGPTL3 proteins do not inhibit lipoprotein lipase resulting in enhanced lipolysis of chylomicrons and VLDL and subsequent faster removal of remnant lipoproteins from plasma. FHBL-EC2 is an autosomal semi-dominant disorder due to loss-of-function variants in the PCSK9 gene, which prevent LDL receptor lysosomal destruction and promote their increased recycling to the liver cell surface. This in turn results in enhanced removal of lipoproteins from circulation leading to reduced plasma LDL-cholesterol (LDL-C) levels
      • Tarugi P
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      Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum.
      ,
      • Wu NQ
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      PCSK9 gene mutations and low-density lipoprotein cholesterol.
      .

      Diagnosis and assessment of Class 1 disorders

      Familial hypobetalipoproteinemia due to lipoprotein assembly and secretion defect 1 (FHBL-SD1), commonly known as abetalipoproteinemia (ABL, OMIM: 200100)

      FHBL-SD1 is an autosomal recessive inherited disorder of fat malabsorption due to impaired formation of apoB-containing lipoproteins. In 1950, Bassen and Kornzweig reported red blood cell acanthocytosis, atypical retinitis pigmentosa and ataxia in a patient
      • Bassen FA
      • Kornzweig AL.
      Malformation of the erythrocytes in a case of atypical retinitis pigmentosa.
      . Jampel and Falls observed low serum cholesterol in affected patients in 1958
      • Jampel RS
      • Falls HF.
      Atypical retinitis pigmentosa, acanthrocytosis, and heredodegenerative neuromuscular disease.
      . Salt et al. reported absence of beta-lipoproteins in the serum in 1960 and the syndrome was called “abetalipoproteinemia”
      • Salt HB
      • Wolff OH
      • Lloyd JK
      • Fosbrooke AS
      • Cameron AH
      • Hubble DV
      On having no beta-lipoprotein. A syndrome comprising a-beta-lipoproteinaemia, acanthocytosis, and steatorrhoea.
      . Ultimately, the first causative variants in the MTTP gene were described by Wetterau et al. in 1992
      • Wetterau JR
      • Aggerbeck LP
      • Bouma M-E
      • Eisenberg C
      • Munck A
      • Hermier M
      • et al.
      Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia.
      . Bi-allelic rare pathogenic variants in the MTTP gene are causative for the near complete absence of plasma lipids and fat-soluble vitamin deficiency (Table 2). The diagnostic criteria of FHBL-SD1 include: (a) extremely low levels of plasma lipids including cholesterol and TG, (b) absence of apoB-containing lipoproteins including chylomicrons, VLDL, remnants and LDL, (c) low levels of fat-soluble vitamins E, A, K, D and carotenoids, (d) presence of acanthocytosis and (e) bi-allelic pathogenic variants in the MTTP gene (either the identical variant on both chromosomes in true homozygosity or two different variants in compound heterozygosity). There is no difference in clinical severity whether both variant alleles are identical or different. Although phenotypic variability exists in FHBL-SD1, the reasons for this are not yet fully understood. Heterozygous parents with a single variant are referred to as “carriers”. Differential diagnostic considerations include: other FHBL disorders, including FHBL-SD2 and -SD3, pancreatic insufficiency including cystic fibrosis, biliary atresia, intolerance to milk proteins, inflammatory bowel disease, intestinal lymphangiectasia, mechanical defects of the small bowel, gluten-sensitive enteropathy, Friedreich ataxia, Refsum disease, spinocerebellar ataxia, acanthocytosis, and ataxia with isolated vitamin E deficiency. Definitive diagnosis is confirmed by sequencing the MTTP gene.
      Table 2Key findings in hypobetalipoproteinemia disorders.
      DiseaseGeneLipids and Lipoproteins

      (mmol/L)
      The lipid and lipoprotein values are representative means/medians from several studies previously published. Plus-minus values are mean ± SD. To convert cholesterol from mmol/L to mg/dL, multiply by 38.67. To convert TG from mmol/L to mg/dL, multiply by 88.57.
      RefNotable

      Features
      Symptoms
      Class I: Familial hypobetalipoproteinemia due to lipoprotein assembly and secretion defects
      Bi-allelic

      FHBL-SD1

      (ABL)
      MTTP
      Median [95% interval of confidence].
      TC: 0.87 [0.82-1.02]

      Below detection threshold.
      LDL-C: <0.04 [0.03-0.13]

      HDL-C: 0.71 [0.66-0.83]

      TG: 0.09 [0.10-0.20]

      (
      • Di Filippo M
      • Moulin P
      • Roy P
      • Samson-Bouma ME
      • Collardeau-Frachon S
      • Chebel-Dumont S
      • et al.
      Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia.
      )
      AcanthocytosisFat malabsorption, steatosis, failure to thrive in infancy, early neurologic and ophthalmologic abnormalities
      Bi-allelic

      FHBL-SD2

      (FHBL)
      APOB
      Median [95% interval of confidence].
      TC: 0.88 [0.83-1.37]

      LDL-C: 0.06 [0.04-0.18]

      HDL-C: 0.77 [0.68-1.23]

      TG: 0.23 [0.22-0.53]

      (
      • Di Filippo M
      • Moulin P
      • Roy P
      • Samson-Bouma ME
      • Collardeau-Frachon S
      • Chebel-Dumont S
      • et al.
      Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia.
      )
      AcanthocytosisFat malabsorption, steatosis, failure to thrive in infancy, early neurologic and ophthalmologic abnormalities

      Mono-allelic

      FHBL-SD2

      (FHBL)
      APOBTC: 2.75 ± 0.62

      LDL-C: 1.05 ± 0.43

      HDL-C: 1.45 ± 0.52

      Median [25°-75° percentiles].
      TG: 0.48 [0.34-0.70]
      (
      • Di Costanzo A
      • Di Leo E
      • Noto D
      • Cefalu AB
      • Minicocci I
      • Polito L
      • et al.
      Clinical and biochemical characteristics of individuals with low cholesterol syndromes: A comparison between familial hypobetalipoproteinemia and familial combined hypolipidemia.
      )
      Usually asymptomatic, possible risk of liver steatosis and fibrosis, Reduced risk for CVD
      Bi-allelic

      FHBL-SD3

      (CRD)

      SAR1BTC: 1.49 ± 0.56

      LDL-C: 0.69 ± 0.38

      HDL-C: 0.46 ± 0.08

      TG in CRD is the same as in controls (0.73 mmol/L).
      TG: 0.73

      (
      • Peretti N
      • Sassolas A
      • Roy CC
      • Deslandres C
      • Charcosset M
      • Castagnetti J
      • et al.
      Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      )
      ↑ CK (up to 10x upper reference limit)

      Absent chylomicrons
      Fat malabsorption, steatosis, failure to thrive in infancy, neurologic and ophthalmologic abnormalities
      Class II: Familial hypobetalipoproteinemia due to enhanced lipoprotein catabolism
      Bi-allelic

      FHBL-EC1

      (FCHL)
      ANGPTL3TC: 2.37 ± 0.40

      LDL-C: 1.46 ± 0.27

      HDL-C: 0.67 ± 0.18

      Median [25°-75° percentiles].
      TG: 0.54 [0.43-0.58]
      (
      • Di Costanzo A
      • Di Leo E
      • Noto D
      • Cefalu AB
      • Minicocci I
      • Polito L
      • et al.
      Clinical and biochemical characteristics of individuals with low cholesterol syndromes: A comparison between familial hypobetalipoproteinemia and familial combined hypolipidemia.
      )
      Reduced risk for CVD

      Mono-allelic

      FHBL-EC1

      (FCHL)
      ANGPTL3TC: 4.62 ± 1.08

      LDL-C: 2.75 ± 0.87

      HDL-C: 1.34 ± 0.34

      Median [25°-75° percentiles].
      TG: 0.97 [0.69-1.60]

      (
      • Di Costanzo A
      • Di Leo E
      • Noto D
      • Cefalu AB
      • Minicocci I
      • Polito L
      • et al.
      Clinical and biochemical characteristics of individuals with low cholesterol syndromes: A comparison between familial hypobetalipoproteinemia and familial combined hypolipidemia.
      )
      Reduced risk for CVD

      Mono-allelic

      FHBL-EC2
      PCSK9
      Mean ± SD values from nonsense mutations in PCSK9142X or 679X.
      TC: 4.47 ± 1.14

      LDL-C: 2.59 ± 1.11

      HDL-C: 1.42 ± 0.41

      TG: 1.06 ± 0.43
      (
      • Cohen JC
      • Boerwinkle E
      • Mosley TH
      • Hobbs HH.
      Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
      )
      Reduced risk for CVD

      CVD=cardiovascular disease, CK=creatine kinase, LDL-C=low density lipoprotein cholesterol, HDL=high density lipoprotein, TC=total cholesterol, TG=triglyceride.
      § The lipid and lipoprotein values are representative means/medians from several studies previously published. Plus-minus values are mean ± SD. To convert cholesterol from mmol/L to mg/dL, multiply by 38.67. To convert TG from mmol/L to mg/dL, multiply by 88.57.
      low asterisk Below detection threshold.
      Median [95% interval of confidence].
      †† Median [25°-75° percentiles].
      TG in CRD is the same as in controls (0.73 mmol/L).
      ¶¶ Mean ± SD values from nonsense mutations in PCSK9142X or 679X.
      The incidence of FHBL-SD1 is reported as less than 1 in 1,000,000
      • Burnett JR
      • Bell DA
      • Hooper AJ
      • Hegele RA.
      Clinical utility gene card for: Abetalipoproteinaemia–Update 2014.
      ,
      • Zamel R
      • Khan R
      • Pollex RL
      • Hegele RA.
      Abetalipoproteinemia: two case reports and literature review.
      . In specific founder populations, however, the incidence is significantly higher. For instance, among Ashkenazi Jews, a nonsense variant in the MTTP gene found in healthy controls had a carrier frequency of 1:131, which would predict a prevalence of affected individuals with FHBL-SD1 at ∼1 in 70,000
      • Benayoun L
      • Granot E
      • Rizel L
      • lon-Shalev S
      • Behar DM
      • Ben-Yosef T
      Abetalipoproteinemia in Israel: evidence for a founder mutation in the Ashkenazi Jewish population and a contiguous gene deletion in an Arab patient.
      . Symptoms of FHBL-SD1 are the result of fat malabsorption in the short-term and fat-soluble vitamin deficiencies, in particular vitamin E deficiency, over the long-term. Vitamin E deficiency predominantly influences the ophthalmologic and nervous system Fig. 2. Gastrointestinal symptoms dominate the clinical picture in infancy and improve within a few days or weeks with a low-fat diet
      • Tarugi P
      • Averna M.
      Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum.
      . Due to the rarity of the condition, a diagnosis of FHBL-SD1 may be overlooked at this stage. As the individual matures, but remains untreated, the clinical impact of fat-soluble vitamin deficiency becomes clinically manifest. A description of specific symptoms that may be present to varying degrees of severity and are summarized in Table 2. The clinical phenotype in adults may differ among probands. The factors contributing to different phenotypes have been poorly characterized and may include genetic and non-genetic influences.
      Fig 2
      Fig. 2Different organ systems and associated symptoms in FHBL-SD1.

      Gastrointestinal

      Infants with FHBL-SD1 experience steatorrhea, vomiting, diarrhea, abdominal pain and distension. These symptoms are aggravated by a diet high in fat, including breast milk. This is a consistent feature of FHBL-SD1 and leads to a rapid failure to thrive in infancy. Endoscopic intestinal biopsy and electron microscopic examination reveal white mucosa and fat droplets in enterocytes, respectively
      • Berriot-Varoqueaux N
      • Aggerbeck LP
      • Samson-Bouma M
      • Wetterau JR.
      The role of the microsomal triglygeride transfer protein in abetalipoproteinemia.
      . The steatorrhea may subside later as affected individuals learn to restrict fat in their diet. Interestingly, Ohashi et al. report adult cases of FHBL-SD1 spared from severe diarrhea and failure to thrive likely due to regional variations in fat intake
      • Ohashi K
      • Ishibashi S
      • Osuga J
      • Tozawa R
      • Harada K
      • Yahagi N
      • et al.
      Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia.
      . Other manifestations include hepatomegaly with fat infiltration and elevated liver enzymes
      • Lee J
      • Hegele RA.
      Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.
      . Hepatic steatosis, steatohepatitis and cirrhosis may develop due to impaired VLDL secretion, although the factors influencing severity and progression of liver disease are poorly understood. Liver transplantation has been reported in a few patients with cirrhosis and liver failure
      • Takahashi M
      • Okazaki H
      • Ohashi K
      • Ogura M
      • Ishibashi S
      • Okazaki S
      • et al.
      Current Diagnosis and Management of Abetalipoproteinemia.
      ,
      • Black DD
      • Hay RV
      • Rohwer-Nutter PL
      • Ellinas H
      • Stephens JK
      • Sherman H
      • et al.
      Intestinal and hepatic apolipoprotein B gene expression in abetalipoproteinemia.
      . Nevertheless, cirrhosis has been reported in only a very small number of cases
      • Black DD
      • Hay RV
      • Rohwer-Nutter PL
      • Ellinas H
      • Stephens JK
      • Sherman H
      • et al.
      Intestinal and hepatic apolipoprotein B gene expression in abetalipoproteinemia.
      • Illingworth DR
      • Connor WE
      • Miller RG.
      Abetalipoproteinemia. Report of two cases and review of therapy.
      • Suarez L
      • Valbuena ML
      • Moreno A
      • Santonja C
      • Gonzalez-Palacios F
      • Camarero C
      • et al.
      Abetalipoproteinemia associated with hepatic and atypical neurological disorders.
      . Hepatic steatosis has also been reported in individuals carrying a single MTTP variant
      • Haas ME
      • Pirruccello JP
      • Friedman SN
      • Wang M
      • Emdin CA
      • Ajmera VH
      • et al.
      Machine learning enables new insights into genetic contributions to liver fat accumulation.
      ,
      • Di Filippo M
      • Varret M
      • Boehm V
      • Rabes JP
      • Ferkdadji L
      • Abramowitz L
      • et al.
      Postprandial lipid absorption in seven heterozygous carriers of deleterious variants of MTTP in two abetalipoproteinemic families.
      .

      Neurologic

      Patients present with neurological disorders, predominantly as a consequence of vitamin E deficiency
      • Zamel R
      • Khan R
      • Pollex RL
      • Hegele RA.
      Abetalipoproteinemia: two case reports and literature review.
      ,
      • Kudo A
      • Tanaka N
      • Oogaki S
      • Niimura T
      • Kanehisa T.
      Hypobetalipoproteinemia with abnormal prebetalipoprotein.
      ,
      • Muller DP
      • Lloyd JK
      • Bird AC.
      Long-term management of abetalipoproteinaemia. Possible role for vitamin E.
      . The onset of neurologic involvement in FHBL-SD1 typically begins in the first or second decade of life due to progressive axonopathy of the posterior columns, spinocerebellar tracts and peripheral nerves. Reduction and eventual loss of deep tendon reflexes are often the first neurological signs, followed by proprioceptive abnormalities and cerebellar symptoms, including dysmetria, ataxia, and wide-based gait
      • Berriot-Varoqueaux N
      • Aggerbeck LP
      • Samson-Bouma M
      • Wetterau JR.
      The role of the microsomal triglygeride transfer protein in abetalipoproteinemia.
      . Lack of voluntary muscle coordination can cause dysarthria and abnormalities in ocular movements
      • Kudo A
      • Tanaka N
      • Oogaki S
      • Niimura T
      • Kanehisa T.
      Hypobetalipoproteinemia with abnormal prebetalipoprotein.
      • Muller DP
      • Lloyd JK
      • Bird AC.
      Long-term management of abetalipoproteinaemia. Possible role for vitamin E.
      • Sobrevilla LA
      • Goodman ML
      • Kane CA
      Demyelinating central nervous system disease, macular atrophy and acanthocytosis (Bassen-Kornzweig Syndrome).
      • Segal S
      • Sharma S
      Ophthaproblem. Vitamin A and vitamin E.
      . Tremors and paresthesias may also occur. In some untreated cases, the neurological manifestations may progress to immobility
      • Zhang YY
      • Fu ZY
      • Wei J
      • Qi W
      • Baituola G
      • Luo J
      • et al.
      A LIMA1 variant promotes low plasma LDL cholesterol and decreases intestinal cholesterol absorption.
      . Electrophysiological abnormalities may be observed as early as 7 months of age. Sensory nerve fibers frequently show abnormal conduction velocities or amplitudes and H-reflexes are often abnormal
      • Brin MF
      • Pedley TA
      • Lovelace RE
      • Emerson RG
      • Gouras P
      • MacKay C
      • et al.
      Electrophysiologic features of abetalipoproteinemia: functional consequences of vitamin E deficiency.
      .

      Musculoskeletal

      Muscle inflammation and weakness have been described. Histologic abnormalities to the myocardium including interstitial fibrosis and enlarged muscle fibers have been described in a patient with heart failure
      • Kott E
      • Delpre G
      • Kadish U
      • Dziatelovsky M
      • Sandbank U.
      Abetalipoproteinemia (Bassen-Kornzweig syndrome). Muscle involvement.
      ,
      • Dische MR
      • RS Porro
      The cardiac lesions in Bassen-Kornzweig syndrome. Report of a case, with autopsy findings.
      . Respiratory failure was described in another patient with severe neuropathy
      • Wang J
      • Hegele RA.
      Microsomal triglyceride transfer protein (MTP) gene mutations in Canadian subjects with abetalipoproteinemia.
      . Skeletal abnormalities including spine curvature disorders and abnormally high foot arches are observed
      • Valk JK
      Van der.
      . Vitamin D deficiency is not a consistent finding; however, defects in normal bone growth have been reported
      • Forsyth CC
      • Lloyd JK
      • Fosbrooke AS.
      A-Beta-Lipoproteinaemia.
      .

      Ophthalmologic

      The cardinal ocular manifestation of FHBL-SD1 is pigmentary retinal degeneration which is likely secondary to vitamin E and vitamin A deficiencies. Symptoms of retinitis pigmentosa typically begin in childhood and although the course can be varied and gradual, most untreated individuals are legally blind by 40 years. Typically, patients will experience loss of night vision first followed by a loss of color vision and peripheral vision
      • Segal S
      • Sharma S
      Ophthaproblem. Vitamin A and vitamin E.
      . Less common symptoms include paralysis of the eye muscles and inability to align both eyes simultaneously, including a posterior internuclear ophthalmoplegia, which can affect depth perception
      • Zamel R
      • Khan R
      • Pollex RL
      • Hegele RA.
      Abetalipoproteinemia: two case reports and literature review.
      ,
      • Brin MF.
      Handbook of Clinical Neurology.
      . Unfortunately, retinal changes can occur despite early initiation of vitamin treatment. On long term follow-up, fundoscopic pigmentary changes and subnormal mixed cone-rod electroretinogram (ERG) amplitudes were observed
      • Chowers I
      • Banin E
      • Merin S
      • Cooper M
      • Granot E
      Long-term assessment of combined vitamin A and E treatment for the prevention of retinal degeneration in abetalipoproteinaemia and hypobetalipoproteinaemia patients.
      . A small group of adults who started vitamin A and E treatment even after electrophysiological functions were altered demonstrated stable ERG and electro-oculography over 2-6 years
      • Bishara S
      • Merin S
      • Cooper M
      • Azizi E
      • Delpre G
      • Deckelbaum RJ.
      Combined vitamin A and E therapy prevents retinal electrophysiological deterioration in abetalipoproteinaemia.
      .

      Hematologic

      A characteristic hematologic manifestation of FHBL-SD1 is acanthocytosis that can involve up to 50% or more of circulating erythrocytes
      • Sobrevilla LA
      • Goodman ML
      • Kane CA
      Demyelinating central nervous system disease, macular atrophy and acanthocytosis (Bassen-Kornzweig Syndrome).
      ,
      • Collins JC
      • Scheinberg IH
      • Giblin DR
      • Sternlieb I.
      Hepatic peroxisomal abnormalities in abetalipoproteinemia.
      ,
      • Calzada C
      • Vericel E
      • Colas R
      • Guillot N
      • El KG
      • Drai J
      • et al.
      Inhibitory effects of in vivo oxidized high-density lipoproteins on platelet aggregation: evidence from patients with abetalipoproteinemia.
      . Alterations in the lipid composition and fluidity of red cell membranes are responsible for this defect
      • Sobrevilla LA
      • Goodman ML
      • Kane CA
      Demyelinating central nervous system disease, macular atrophy and acanthocytosis (Bassen-Kornzweig Syndrome).
      . Vitamin K, which is involved in the coagulation cascade, may be deficient. Consistent with this, patients with FHBL-SD1 may have a prolonged international normalized ratio (INR)
      • Aviram M
      • Deckelbaum RJ
      • Brook JG
      Platelet function in a case with abetalipoproteinemia.
      ,
      • Surya II
      • Mommersteeg M
      • Gorter G
      • Erkelens DW
      • Akkerman JW
      Abnormal platelet functions in a patient with abetalipoproteinemia.
      . Bleeding tendencies including gastrointestinal bleeding have been reported
      • Zamel R
      • Khan R
      • Pollex RL
      • Hegele RA.
      Abetalipoproteinemia: two case reports and literature review.
      . A relationship between vitamin E deficiency and hemolysis has been reported
      • Farrell PM
      • Bieri JG
      • Fratantoni JF
      • Wood RE
      • di Sant'Agnese PA
      The occurrence and effects of human vitamin E deficiency. A study in patients with cystic fibrosis.
      ,
      • Cornblath M
      • Gordon HH
      • Nitowsky HM.
      Studies of tocopherol deficiency in infants and children. II. Plasma tocopherol and erythrocyte hemolysis in hydrogen peroxide.
      .

      Blood metabolites

      The lipid profile of patients with bi-allelic FHBL-SD1 reveal nearly absent LDL-C, TG and apoB, with most of the cholesterol circulating in high density lipoproteins (HDL)
      • Di Filippo M
      • Moulin P
      • Roy P
      • Samson-Bouma ME
      • Collardeau-Frachon S
      • Chebel-Dumont S
      • et al.
      Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia.
      . Lipid soluble vitamins are very low, especially vitamin E (<1/100th of normal) and A. Essential fatty acids (EFAs), linoleic acid (LA) and alpha-linolenic acid (ALA), are also dramatically decreased. Hypothyroidism may occur, although its causality remains unexplained
      • Takahashi M
      • Okazaki H
      • Ohashi K
      • Ogura M
      • Ishibashi S
      • Okazaki S
      • et al.
      Current Diagnosis and Management of Abetalipoproteinemia.
      .

      Familial hypobetalipoproteinemia due to lipoprotein assembly and secretion defect 2 (FHBL-SD2), commonly known as familial hypobetalipoproteinemia (FHBL, OMIM: 615558)

      Bi-allelic FHBL-SD2 is caused by pathogenic variants in the APOB gene resulting in the synthesis of truncated apoB peptides. Some mutations affect the synthesis of both apoB100 and apoB48, whereas others only affect synthesis of apoB100. Low plasma lipids result due to the inability of the smaller peptides to assemble normal lipoproteins. In the case of larger truncated apoB peptides that can assemble lipoproteins, these lipoproteins are cleared rapidly contributing to hypolipidemia. FHBL-SD2 is an autosomal semi-dominant disease, which means that individuals with one variant allele (i.e. monogenic or “heterozygotes”) have a detectable phenotype that is intermediate between individuals with two normal alleles and those with bi-allelic pathogenic variants. The clinical and biochemical presentation of FHBL-SD2 (homozygous or compound heterozygous pathogenic variants of APOB) is virtually indistinguishable from FHBL-SD1 (Table 2). Parents of affected individuals possess lipid profile alterations consistent with the heterozygous FHBL-SD2 phenotype, i.e. their lipid levels are intermediate between normal and homozygous FHBL-SD2 individuals. If available, this information may help discern between FHBL-SD1 (MTTP pathogenic variants) and homozygous FHBL-SD2 (APOB pathogenic variants)
      • Granot E
      • Deckelbaum RJ.
      Hypocholesterolemia in childhood.
      . Early detection and treatment are needed in FHBL-SD2 to prevent the profound multi-organ dysfunction similar to that outlined for FHBL-SD1. In order to definitively distinguish between FHBL-SD1 and homozygous FHBL-SD2, molecular testing by sequencing the MTTP and APOB genes is required
      • Lee J
      • Hegele RA.
      Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.
      ,
      • Ohashi K
      • Ishibashi S
      • Yamamoto M
      • Osuga J
      • Yazaki Y
      • Yukawa S
      • et al.
      A truncated species of apolipoprotein B (B-38.7) in a patient with homozygous hypobetalipoproteinemia associated with diabetes mellitus.
      . Definitive diagnosis of homozygous and heterozygous FHBL-SD2 is further confirmed by sequencing the APOB gene: bi-allelic (i.e. true homozygous or compound heterozygous) pathogenic variants indicate the more severe form encompassed by the term “homozygous FHBL” whereas those with a single variant allele are called “heterozygous FHBL”.
      Mono-allelic FHBL-SD2 is relatively common, with a prevalence of 1 in 700 to 3000 based on observed and estimated reports
      • Tarugi P
      • Averna M
      • Di Leo E
      • Cefalu AB
      • Noto D
      • Magnolo L
      • et al.
      Molecular diagnosis of hypobetalipoproteinemia: an ENID review.
      . Peloso et al. report an observed prevalence of APOB protein–truncating variants in 0.092% of controls
      • Peloso GM
      • Nomura A
      • Khera AV
      • Chaffin M
      • Won HH
      • Ardissino D
      • et al.
      Rare protein-truncating variants in APOB, lower low-density lipoprotein cholesterol, and protection against coronary heart disease.
      . In contrast to homozygotes, heterozygous FHBL-SD1 are often asymptomatic. Affected individuals have no concerns related to fat-soluble vitamin deficiencies including vitamin E, despite some having very low levels of apoB. Patients have low, but not absent LDL-C. Low LDL-C is defined as <5th percentile for age and sex, as derived from National Health and Nutrition Examination Survey data
      • Hartz J
      • Hegele RA
      • Wilson DP
      Low LDL cholesterol-Friend or foe?.
      . Due to the decreased hepatic secretion of apoB and TG, an increased incidence of hepatic steatosis and mild elevation in plasma liver enzymes has been reported
      • Haas ME
      • Pirruccello JP
      • Friedman SN
      • Wang M
      • Emdin CA
      • Ajmera VH
      • et al.
      Machine learning enables new insights into genetic contributions to liver fat accumulation.
      ,
      • Lonardo A
      • Tarugi P
      • Ballarini G
      • Bagni A.
      Familial heterozygous hypobetalipoproteinemia, extrahepatic primary malignancy, and hepatocellular carcinoma.
      . Furthermore, the clinical expression may depend on the size of the truncated apoB species. Kindreds with short truncated apoB isoforms developing steatosis
      • Tarugi P
      • Lonardo A
      • Gabelli C
      • Sala F
      • Ballarini G
      • Cortella I
      • et al.
      Phenotypic expression of familial hypobetalipoproteinemia in three kindreds with mutations of apolipoprotein B gene.
      and cryptogenic cirrhosis have been reported
      • Bonnefont-Rousselot D
      • Condat B
      • Sassolas A
      • Chebel S
      • Bittar R
      • Federspiel MC
      • et al.
      Cryptogenic cirrhosis in a patient with familial hypocholesterolemia due to a new truncated form of apolipoprotein B.
      . Some of the clinical and serologic evaluations listed in (Table 3) may also be appropriate for individuals with a more severe presentation of heterozygous FHBL-SD2
      • Tarugi P
      • Averna M
      • Di Leo E
      • Cefalu AB
      • Noto D
      • Magnolo L
      • et al.
      Molecular diagnosis of hypobetalipoproteinemia: an ENID review.
      ,
      • Lonardo A
      • Tarugi P
      • Ballarini G
      • Bagni A.
      Familial heterozygous hypobetalipoproteinemia, extrahepatic primary malignancy, and hepatocellular carcinoma.
      ,
      • Ballestri S
      • Lonardo A
      • Losi L
      • Pellegrini E
      • Bertolotti M
      • Loria P
      Do diabetes and obesity promote hepatic fibrosis in familial heterozygous hypobetalipoproteinemia?.
      . Interestingly, these individuals appear to be protected from cardiovascular disease (CVD)
      • Peloso GM
      • Nomura A
      • Khera AV
      • Chaffin M
      • Won HH
      • Ardissino D
      • et al.
      Rare protein-truncating variants in APOB, lower low-density lipoprotein cholesterol, and protection against coronary heart disease.
      .
      Table 3Treatment and dietary guidance for Class 1 disorders.
      Physical and biochemical tests are suggested components of the annual assessment and are not comprehensive.
      Annual assessment
      Growth parametersHeight and weight comparison with normal growth charts (as appropriate for age)
      NeurologicExamination with emphasis on cranial nerves, motor and sensory/proprioception, cerebellar, deep tendon reflexes
      OphthalmologicFundoscopy
      GastrointestinalAbdominal distension, hepatomegaly, jaundice
      Lipid panel, apoB, apoA-I do not require repetitive assessment following diagnosis. Plasma vitamin E levels may be measured at time of diagnosis; however, should not be serially monitored as they are not reflective of physiologic homeostasis. Erythrocyte and/or adipose tissue vitamin E level should be measured if possible. (See section 7.2).
      Plasma laboratory tests
      Lipid panel, apoB, apoA-I, albumin, liver enzymes, bilirubin, gamma-glutamyl transferase, 25-hydroxy vitamin D, vitamin A, vitamin E, INR, vitamin B12, folate, CBC, reticulocyte count, ferritin, calcium, phosphorus, creatinine, thyroid stimulating hormone
      Testing is recommended at time of diagnosis or early in the course of the disease and will establish a baseline. Additional testing as clinically indicated to assess for disease stability and/or progression.
      Additional Testing
      Electromyography
      Electroretinography and electro-oculogram
      Ultrasonography of liver; FibroScan/Fibrosis-4 (FIB 4) index
      Bone mineral density testing (DXA)
      Echocardiogram
      Dietary guidance
      Fat caloriesLess than 10-15% (<15 g/day) of total daily caloric requirement
      In infants limit to 5-10% of total calories
      Amount of dietary fat intake may be increased as tolerated in older children and adults
      Essential fatty acidsEnsure 2-4% daily caloric intake of EFAs (alpha-linolenic acid/linoleic acid)
      Long chain fatty acidsNot recommended apart from EFAs. Supplementation with DHA and EPA may be considered while monitoring total daily fat intake
      Medium chain triglyceridesMay prevent or treat malnutrition in infants. Individual assessment of potential benefit is needed. MCT (caprylic and capric acids) provides 8.3 calories/g (14.25 g = 1 tablespoon = 15 ml = 115 kcal). Lauric acid is not recommended.
      Vitamin treatment guidance
      Intramuscular injections of 50 mg alpha-tocopherol can be administered once or twice weekly if needed125.
      Vitamin E
      100-300 IU/kg/day (50 IU/kg/day for FHBL-SD3 if diagnosed by age 1)
      Vitamin A100-400 IU/kg/day
      Vitamin D800-1200 IU/day
      Vitamin K5-35 mg/week
      1 Physical and biochemical tests are suggested components of the annual assessment and are not comprehensive.
      2 Lipid panel, apoB, apoA-I do not require repetitive assessment following diagnosis. Plasma vitamin E levels may be measured at time of diagnosis; however, should not be serially monitored as they are not reflective of physiologic homeostasis. Erythrocyte and/or adipose tissue vitamin E level should be measured if possible. (See section 7.2).
      3 Testing is recommended at time of diagnosis or early in the course of the disease and will establish a baseline. Additional testing as clinically indicated to assess for disease stability and/or progression.
      4 Intramuscular injections of 50 mg alpha-tocopherol can be administered once or twice weekly if needed
      • Grant CA
      • EL Berson
      Treatable forms of retinitis pigmentosa associated with systemic neurological disorders.
      .

      Blood metabolites

      ApoB-containing lipoproteins are virtually absent in the plasma of individuals with homozygous FHBL-SD2
      • Di Filippo M
      • Moulin P
      • Roy P
      • Samson-Bouma ME
      • Collardeau-Frachon S
      • Chebel-Dumont S
      • et al.
      Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia.
      . Lipid soluble vitamins are very low, particularly vitamin E and A. EFAs are also dramatically decreased, especially ALA. ApoB100 and LDL-C levels in heterozygous FHBL-SD2 plasma are ∼24% of those in normal individuals, although the range is wide
      • Hartz J
      • Hegele RA
      • Wilson DP
      Low LDL cholesterol-Friend or foe?.
      ,
      • Levy E
      • Roy CC
      • Thibault L
      • Bonin A
      • Brochu P
      • Seidman EG.
      Variable expression of familial heterozygous hypobetalipoproteinemia: Transient malabsorption during infancy.
      . Variations in lipoprotein profiles between different families have also been reported
      • Granot E
      • Deckelbaum RJ.
      Familial hypobetalipoproteinemia–differences in lipoprotein structure and composition.
      .

      Familial hypobetalipoproteinemia due to lipoprotein assembly and secretion defect 3 (FHBL-SD3), commonly known as chylomicron retention disease (CRD, OMIM: 246700)

      FHBL-SD3 is an extremely rare disease with a few small cohorts described
      • Peretti N
      • Sassolas A
      • Roy CC
      • Deslandres C
      • Charcosset M
      • Castagnetti J
      • et al.
      Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      • Anderson CM
      • Townley RR
      • Freeman JP
      Unusual causes of steatorrhea in infancy and childhood.
      • Bouma ME
      • Beucler I
      • Aggerbeck LP
      • Infante R
      • Schmitz J.
      Hypobetalipoproteinemia with accumulation of an apoprotein B-like protein in intestinal cells: Immunoenzymatic and biochemical characterization of seven cases of Anderson's disease.
      • Dannoura AH
      • Berriot-Varoqueaux N
      • Amati P
      • Abadie V
      • Verthier N
      • Schmitz J
      • et al.
      Anderson's disease: exclusion of apolipoprotein and intracellular lipid transport genes.
      • Gauthier S
      • Sniderman A
      Action tremor as a manifestation of chylomicron retention disease.
      • Lacaille F
      • Bratos M
      • Bouma ME
      • Jos J
      • Schmitz J
      • Rey J
      [Anderson's disease. Clinical and morphologic study of 7 cases].
      • Nemeth A
      • Myrdal U
      • Veress B
      • Rudling M
      • Berglund L
      • Angelin B
      Studies on lipoprotein metabolism in a family with jejunal chylomicron retention.
      • Patel S
      • Pessah M
      • Beucler I
      • Navarro J
      • Infante R
      Chylomicron retention disease: Exclusion of apolipoprotein B gene defects and detection of mRNA editing in an affected family.
      • Pessah M
      • Benlian P
      • Beucler I
      • Loux N
      • Schmitz J
      • Junien C
      • et al.
      Anderson's disease: Genetic exclusion of the apolipoprotein-B gene in two families.
      • Polonovski C
      • Navarro J
      • Fontaine JL
      • de Gouyon F
      • Saudubray JM
      • Cathelineau L.
      [Anderson's disease].
      • Rey J
      • Jos J
      • Rey F
      • Leporrier M
      • Dechaux M
      • Ramon J
      • et al.
      [Idiopathic disorder of intestinal fat transport (Anderson's disease). A further case].
      • Roy CC
      • Levy E
      • Green PHR
      • Sniderman A
      • Letarte J
      • Buts J-P
      • et al.
      Malabsorption, hypocholesterolemia, and fat-filled enterocytes with increased intestinal apoprotein B: Chylomicron retention disease.
      • Scott BB
      • Miller JP
      • Losowsky MS
      Hypobetalipoproteinaemia–a variant of the Bassen-Kornzweig syndrome.
      • Strich D
      • Goldstein R
      • Phillips A
      • Shemer R
      • Goldberg Y
      • Razin A
      • et al.
      Anderson's disease: no linkage to the apo B locus.
      • Charcosset M
      • Sassolas A
      • Peretti N
      • Roy CC
      • Deslandres C
      • Sinnett D
      • et al.
      Anderson or chylomicron retention disease: molecular impact of five mutations in the SAR1B gene on the structure and the functionality of Sar1b protein.
      . It is due to bi-allelic pathogenic variants in the SAR1B gene causing a defect in chylomicron secretion by the intestine. Chylomicrons are assembled in enterocytes, but are not secreted. Heterozygotes for a single pathogenic variant are typically clinically unaffected carriers.

      Gastrointestinal

      As with FHBL-SD1 and homozygous FHBL-SD2, gastrointestinal symptoms are observed at the beginning of life. Diarrhea and malabsorption begin in infants shortly after birth. Other digestive symptoms, such as vomiting or abdominal distension are often present. This malabsorption induces a rapid alteration of the nutritional status with stunting and growth delay in toddlers. Symptoms improve within a few days or weeks with a low-fat diet
      • Roy CC
      • Levy E
      • Green PHR
      • Sniderman A
      • Letarte J
      • Buts J-P
      • et al.
      Malabsorption, hypocholesterolemia, and fat-filled enterocytes with increased intestinal apoprotein B: Chylomicron retention disease.
      . Endoscopy reveals white mucosa and lipid laden enterocytes on histology. Although less commonly seen compared to FHBL-SD1 and homozygous FHBL-SD2, hepatomegaly and steatosis is reported to occur in about 20% of FHBL-SD3 patients. No cases of cirrhosis in FHBL-SD3 have been reported to date
      • Bonnefont-Rousselot D
      • Condat B
      • Sassolas A
      • Chebel S
      • Bittar R
      • Federspiel MC
      • et al.
      Cryptogenic cirrhosis in a patient with familial hypocholesterolemia due to a new truncated form of apolipoprotein B.
      ,
      • Nemeth A
      • Myrdal U
      • Veress B
      • Rudling M
      • Berglund L
      • Angelin B
      Studies on lipoprotein metabolism in a family with jejunal chylomicron retention.
      ,
      • Roy CC
      • Levy E
      • Green PHR
      • Sniderman A
      • Letarte J
      • Buts J-P
      • et al.
      Malabsorption, hypocholesterolemia, and fat-filled enterocytes with increased intestinal apoprotein B: Chylomicron retention disease.
      ,
      • Braegger CP
      • Belli DC
      • Mentha G
      • Steinmann B.
      Persistence of the intestinal defect in abetalipoproteinaemia after liver transplantation.
      ,
      • Partin JS
      • Partin JC
      • Schubert WK
      • McAdams AJ.
      Liver ultrastructure in abetalipoproteinemia: Evolution of micronodular cirrhosis.
      .

      Neurologic

      Neurological aberrations, including proprioceptive abnormalities and areflexia, appear only in older children and adolescents, and differentiate this disorder from FHBL-SD1 and homozygous FHBL-SD2. The mean age for the development of neurological abnormalities in FHBL-SD3 is 12 years. Vitamin E status is considered to play a pivotal role in neurological degenerative complications
      • Kayden HJ.
      The neurologic syndrome of vitamin E deficiency: a significant cause of ataxia.
      ,
      • Sokol RJ.
      Vitamin E and neurologic deficits.
      . In the largest pediatric cohort, patients with the most severe symptoms also had the lowest vitamin E levels at diagnosis
      • Peretti N
      • Sassolas A
      • Roy CC
      • Deslandres C
      • Charcosset M
      • Castagnetti J
      • et al.
      Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      . Severe degenerative symptoms, such as ataxia and sensory neuropathy, have been reported only in a few FHBL-SD3 adults
      • Gauthier S
      • Sniderman A
      Action tremor as a manifestation of chylomicron retention disease.
      ,
      • Roy CC
      • Levy E
      • Green PHR
      • Sniderman A
      • Letarte J
      • Buts J-P
      • et al.
      Malabsorption, hypocholesterolemia, and fat-filled enterocytes with increased intestinal apoprotein B: Chylomicron retention disease.
      ,
      • Scott BB
      • Miller JP
      • Losowsky MS
      Hypobetalipoproteinaemia–a variant of the Bassen-Kornzweig syndrome.
      ,
      • Aguglia U
      • Annesi G
      • Pasquinelli G
      • Spadafora P
      • Gambardella A
      • Annesi F
      • et al.
      Vitamin E deficiency due to chylomicron retention disease in Marinesco-Sjogren syndrome.
      .

      Musculoskeletal

      Muscular pain and cramps are possible, but rarely reported by patients. Poor mineralization and delayed bone maturation have been observed potentially as a consequence of malabsorption, malnutrition and vitamin D deficiency
      • Peretti N
      • Sassolas A
      • Roy CC
      • Deslandres C
      • Charcosset M
      • Castagnetti J
      • et al.
      Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      .

      Ophthalmologic

      Minimal visual abnormalities have been reported in older children with FHBL-SD3, such as nystagmus, mild deficits in the perception of the blue-yellow axis and delayed dark adaptation
      • Roy CC
      • Levy E
      • Green PHR
      • Sniderman A
      • Letarte J
      • Buts J-P
      • et al.
      Malabsorption, hypocholesterolemia, and fat-filled enterocytes with increased intestinal apoprotein B: Chylomicron retention disease.
      .

      Blood metabolites

      A decrease (∼50%) in total cholesterol, LDL-C and HDL-C in the presence of normal TG is a characteristic diagnostic feature of FHBL-SD3
      • Papadogeorgou P
      • Roma E
      • Sassolas A
      • Orfanou I
      • Malliarou A
      • Sakka S
      • et al.
      Chylomicron retention disease: report of two cases from a Greek Island.
      • Desaldeleer C
      • Henno S
      • Bruneau B
      • Dabadie A.
      Chylomicron retention disease.
      • Magnolo L
      • Najah M
      • Fancello T
      • Di Leo E
      • Pinotti E
      • Brini I
      • et al.
      Novel mutations in SAR1B and MTTP genes in Tunisian children with chylomicron retention disease and abetalipoproteinemia.
      • Ben Ameur S
      • Aloulou H
      • Jlidi N
      • Kamoun F
      • Chabchoub I
      • Di Filippo M
      • et al.
      Chylomicron retention disease: a rare cause of chronic diarrhea.
      • Blanco-Vaca F
      • Martin-Campos JM
      • Beteta-Vicente A
      • Canyelles M
      • Martinez S
      • Roig R
      • et al.
      Molecular analysis of APOB, SAR1B, ANGPTL3, and MTTP in patients with primary hypocholesterolemia in a clinical laboratory setting: evidence supporting polygenicity in mutation-negative patients.
      . In comparison, both FHBL-SD1 and homozygous FHBL-SD2 are associated with a very low plasma TG concentration and undetectable LDL-C (Table 2). Lipid soluble vitamins including vitamin E and A as well as EFAs are dramatically reduced. Unlike the other FHBL disorders; creatine kinase (CK) is selectively elevated in FHBL-SD3. The CK increase is 5-10 times the upper reference limit in some patients and may support the diagnosis
      • Peretti N
      • Sassolas A
      • Roy CC
      • Deslandres C
      • Charcosset M
      • Castagnetti J
      • et al.
      Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      . The CK concentration, however, does not correlate well with the severity of the muscular impairment. Finally, acanthocytosis is rare and often transient in FHBL-SD3
      • Peretti N
      • Sassolas A
      • Roy CC
      • Deslandres C
      • Charcosset M
      • Castagnetti J
      • et al.
      Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers.
      .

      Diagnosis and assessment of class II disorders

      Familial hypobetalipoproteinemia due to enhanced lipoprotein catabolism (FHBL-EC1), commonly known as familial combined hypolipidemia (FCHL, OMIM: 605019)

      Hypolipidemia in these individuals is due to enhanced catabolism of lipoproteins resulting from loss-of-function variants in ANGPTL3 gene. Those with FHBL-EC1 do not have defects in fat and fat-soluble vitamin absorption and transport. Therefore, symptoms associated with fat-soluble vitamin or EFA deficiency are not present
      • Di Costanzo A
      • Di Leo E
      • Noto D
      • Cefalu AB
      • Minicocci I
      • Polito L
      • et al.
      Clinical and biochemical characteristics of individuals with low cholesterol syndromes: A comparison between familial hypobetalipoproteinemia and familial combined hypolipidemia.
      .This condition is due to increased hepatic clearance of circulating lipoproteins as a result of increased lipolysis of VLDL. Furthermore, loss-of-function of the ANGPTL3 gene seems beneficial
      • Minicocci I
      • Cantisani V
      • Poggiogalle E
      • Favari E
      • Zimetti F
      • Montali A
      • et al.
      Functional and morphological vascular changes in subjects with familial combined hypolipidemia: an exploratory analysis.
      ,
      • Stitziel NO
      • Khera AV
      • Wang X
      • Bierhals AJ
      • Vourakis AC
      • Sperry AE
      • et al.
      ANGPTL3 deficiency and protection against coronary artery disease.
      . The lower plasma concentrations of cholesterol and TG likely reduce the risk of developing atherosclerotic CVD
      • Minicocci I
      • Montali A
      • Robciuc MR
      • Quagliarini F
      • Censi V
      • Labbadia G
      • et al.
      Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization.
      . Despite the presence of low HDL-C concentrations, FHBL-EC1 patients are protected from developing premature atherosclerosis likely due to the concomitant reduction in atherogenic VLDL and LDL. This protective effect has led to the development of a biologic targeting ANGPTL3
      • Raal FJ
      • Rosenson RS
      • Reeskamp LF
      • Hovingh GK
      • Kastelein JJP
      • Rubba P
      • et al.
      Evinacumab for homozygous familial hypercholesterolemia.
      .

      Blood metabolites

      Compared to normal individuals, reduction of all plasma lipoproteins and apolipoproteins is seen for both homozygous and heterozygous FHBL-EC1. Bi-allelic ANGPTL3 pathogenic variants have been shown to have significant reductions in LDL-C, TG, HDL-C, apoB, and apoA-I compared to individuals with two normal alleles
      • Musunuru K
      • Pirruccello JP
      • Do R
      • Peloso GM
      • Guiducci C
      • Sougnez C
      • et al.
      Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.
      ,
      • Minicocci I
      • Santini S
      • Cantisani V
      • Stitziel N
      • Kathiresan S
      • Arroyo JA
      • et al.
      Clinical characteristics and plasma lipids in subjects with familial combined hypolipidemia: a pooled analysis.
      . Heterozygous individuals show less reduction in plasma LDL compared to homozygous FHBL-EC1
      • Musunuru K
      • Pirruccello JP
      • Do R
      • Peloso GM
      • Guiducci C
      • Sougnez C
      • et al.
      Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.
      . Thus, there is a gene dosage effect (Table 2).

      Familial hypobetalipoproteinemia due to enhanced lipoprotein catabolism 2 (FHBL-EC2)

      Similar to FHBL-EC1, FHBL-EC2 is also not associated with intestinal malabsorption, fat-soluble vitamin or EFA deficiency. This phenotype results from loss-of-function variants in the PCSK9 gene, which results in increased clearance of LDL particles by LDL receptors. Patients have low, but detectable LDL-cholesterol without any deleterious systemic involvement. In fact, loss-of-function in PCSK9 confers substantial protection against coronary atherosclerosis
      • Cohen JC
      • Boerwinkle E
      • Mosley TH
      • Hobbs HH.
      Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
      . Extremely rare individuals with bi-allelic loss-of-function variants in PCSK9 have very depressed levels of LDL-C and apoB containing lipoproteins, but also have no adverse effects
      • Horton JD
      • Cohen JC
      • Hobbs HH.
      Molecular biology of PCSK9: its role in LDL metabolism.
      ,
      • Cohen JC
      • Boerwinkle E
      • Mosley TH
      • Hobbs HH.
      Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
      ,
      • Rosenson RS
      • Hegele RA
      • Koenig W.
      Cholesterol-Lowering Agents.
      • Zhao Z
      • Tuakli-Wosornu Y
      • Lagace TA
      • Kinch L
      • Grishin NV
      • Horton JD
      • et al.
      Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote.
      • Hooper AJ
      • Marais AD
      • Tanyanyiwa DM
      • Burnett JR.
      The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population.
      . Based on these observations, therapies inhibiting PCSK9 are available to lower LDL-C levels
      • Sabatine MS
      • Giugliano RP
      • Keech AC
      • Honarpour N
      • Wiviott SD
      • Murphy SA
      • et al.
      Evolocumab and clinical outcomes in patients with cardiovascular disease.
      • Schwartz GG
      • Steg PG
      • Szarek M
      • Bhatt DL
      • Bittner VA
      • Diaz R
      • et al.
      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
      • Raal FJ
      • Stein EA
      • Dufour R
      • Turner T
      • Civeira F
      • Burgess L
      • et al.
      PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.
      .

      Blood metabolites

      Depending on the type and number of sequence variations, LDL-C concentrations in patients with FHBL-EC2 are 21-40% lower than normal levels (Table 2)
      • Cohen JC
      • Boerwinkle E
      • Mosley TH
      • Hobbs HH.
      Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
      .

      Treatment of FHBL Class 1 patients with defects in lipoprotein assembly and secretion

      As previously mentioned, randomized clinical trial evidence is not available to direct the treatment of FHBL Class 1 patients. The following treatment summary, derived from the research and clinical expertise of the ABLRDF medical expert panel, is intended to minimize risk and improve the well-being of patients. Table 3 shows a framework for clinical assessment, treatment and dietary guidance. The mainstay of treatment for Class 1 disorders consists of three major components: (a) restriction of dietary fat consumption to minimize the steatosis of enterocytes and restore their normal function; (b) consumption of therapeutic doses of fat-soluble vitamins, especially large doses of vitamin E, and; (c) adequate intake of EFAs and micronutrients. All recommendations are best applied with the assistance of a registered dietitian or a specialized provider knowledgeable about FHBL disorders. An emphasis on maintenance of care and adequate follow up is a consequential component of the treatment plan. The gradual progressive nature of FHBL Class 1 disorders requires careful and chronic clinical assessments. Clinical status should direct the frequency of diagnostic testing and intensity of intervention. As such, patient engagement with the healthcare system is essential to maximize outcomes.

      Dietary recommendations

      A very-low fat diet is required in order to alleviate gastrointestinal symptoms and to address failure to thrive in infancy. Breast milk and traditional infant formulas contain a high content of long chain triglycerides (LCT) and are not recommended. A medium chain triglyceride (MCT) commercial formula or skimmed and fortified breast milk (if MCT formula is not available) is preferred. MCT oil, including caprylic acid (8 carbon atoms) and capric acid (10 carbon atoms), bypass the chylomicron fat metabolism pathway and has been successful in several disease states that also require a very-low fat intake including familial chylomicronemia syndrome and cystic fibrosis
      • Williams L
      • Rhodes KS
      • Karmally W
      • Welstead LA
      • Alexander L
      • Sutton L
      • et al.
      Familial chylomicronemia syndrome: Bringing to life dietary recommendations throughout the life span.
      ,
      • Gracey M
      • Burke V
      • Anderson CM
      Medium chain triglycerides in paediatric practice.
      . The infant formula Monogen (Nutricia) is favored as it contains 90% of its fat content as MCT. The remaining 10% of the fat composition includes arachidonic acid, monounsaturated fatty acids and polyunsaturated fatty acids (including LA, ALA and docosahexaenoic acid (DHA)).
      Transitioning from formula to skim milk and low-fat solid foods is advised according to developmental stage. Infants should be restricted to 5-10% of calories from fat while ensuring adequate caloric intake. The amount of dietary fat can be increased with age, as tolerated, but should not exceed 10-15% of total daily caloric intake. Distribution of fat intake throughout the day may minimize symptoms and aid in overall nutrient absorption. Dietary fat intake should be tailored within this framework based on age and caloric needs. Nutrient dense foods as a source of vitamins and minerals should be incorporated within a very-low fat diet. Meal plans that incorporate vegetables, whole grains, proteins, legumes, fruit, and fat-free milk products are encouraged. Psychosocial support may be required with heightened attention for the development of disordered eating patterns. Dietitian consultation is essential for the proper implementation of these recommendations.
      Incorporation of EFAs, LA and ALA, to prevent EFA deficiency should be considered. Whole grains, chia seeds, ground flaxseeds as well as 1-2 teaspoons of oils rich in polyunsaturated fatty acids (i.e. flaxseed, soybean oil) are examples of food sources rich in EFAs. Infants whose diet is based on Monogen do not require additional EFA.
      The use of prescription grade eicosapentaenoic acid (EPA) and DHA, has been inconsistently recommended in the literature. In alignment with the experience of ABLRDF panel members, controlled quantities (1-3 g/day) of these fatty acids can increase their plasma concentrations. The fat content of EFAs, DHA and EPA supplements should be carefully monitored to avoid exceeding the total daily fat threshold. Additionally, intake of omega-3 polyunsaturated fatty acids varies significantly worldwide, necessitating the need to devise separate dietary recommendations for different countries
      • Takahashi M
      • Okazaki H
      • Ohashi K
      • Ogura M
      • Ishibashi S
      • Okazaki S
      • et al.
      Current Diagnosis and Management of Abetalipoproteinemia.
      .
      Our panel recommends that the use of MCT oil in FHBL Class I be tailored to the individual
      • Williams L
      • Rhodes KS
      • Karmally W
      • Welstead LA
      • Alexander L
      • Sutton L
      • et al.
      Familial chylomicronemia syndrome: Bringing to life dietary recommendations throughout the life span.
      • Gracey M
      • Burke V
      • Anderson CM
      Medium chain triglycerides in paediatric practice.
      • McCray S
      • Parrish CR.
      Nutritional management of chyle leaks: an update.
      . MCT oil may be used to increase overall caloric intake particularly in infancy and possibly in pregnancy. It may also improve satiety and help adjust the macronutrient composition of the diet, preventing excessive reliance on carbohydrates in older patients. Importantly, only medical grade MCT oil available via prescription should be used and not over the counter formulations (i.e. coconut oil) that may contain lauric acid (12 carbon atoms), which possesses metabolic properties similar to long chain fatty acids
      • Marriott BM
      Institute of Medicine (U.S.). Committee on Military Nutrition Research
      Food Components To Enhance Performance: An Evaluation Of Potential Performance-Enhancing Food Components For Operational Rations.
      . Gradual introduction of small amounts of MCT oil for low temperature cooking or for supplementation at meals has been utilized in other disease states requiring a very low fat diet
      • Williams L
      • Rhodes KS
      • Karmally W
      • Welstead LA
      • Alexander L
      • Sutton L
      • et al.
      Familial chylomicronemia syndrome: Bringing to life dietary recommendations throughout the life span.
      . Large doses of MCT oil are neither necessary nor recommended.

      Fat-soluble vitamins

      Treatment with high dose fat-soluble vitamins is critical for the prevention of complications. In particular, vitamin E has no carrier protein in plasma and is highly dependent on lipoproteins for intestinal absorption and transport. Over four decades ago, Dr. Herbert Kayden and others recognized that high daily dosages of vitamin E can prevent retinal and neurological adverse effects
      • Bishara S
      • Merin S
      • Cooper M
      • Azizi E
      • Delpre G
      • Deckelbaum RJ.
      Combined vitamin A and E therapy prevents retinal electrophysiological deterioration in abetalipoproteinaemia.
      ,
      • Kayden HJ
      • Traber MG.
      Clinical, nutritional and biochemical consequences of apolipoprotein B deficiency.
      ,
      • Muller DP
      • JK Lloyd
      Effect of large oral doses of vitamin E on the neurological sequelae of patients with abetalipoproteinemia.
      . An exceptionally high dose of vitamin E (100-300 IU/kg/day), compared to the recommended dietary allowance for age of 5-30 IU/day in healthy individuals, is required to halt the progression and potentially reverse the neurologic and ophthalmologic sequelae mentioned previously. Similarly, high dose vitamin A (100-400 IU/kg/day), approximately five times the recommended dietary allowance for age, is required
      • Bishara S
      • Merin S
      • Cooper M
      • Azizi E
      • Delpre G
      • Deckelbaum RJ.
      Combined vitamin A and E therapy prevents retinal electrophysiological deterioration in abetalipoproteinaemia.
      ,
      • Granot E
      • Deckelbaum RJ.
      Hypocholesterolemia in childhood.
      . Lower doses of vitamin E and vitamin A may be needed for FHBL-SD3 if diagnosed by age 1 (Table 3). Vitamin K levels are less compromised than that of other fat-soluble vitamins in FHBL; however, relatively high oral doses (5-35 mg/week) may be needed. Almost all patients with a Class 1 disorder have shown clinical stabilization with oral vitamin treatment; therefore, parenteral treatment is not generally recommended
      • Lee J
      • Hegele RA.
      Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.
      .
      Dosing of vitamin A, D and K can be tailored to plasma vitamin A/β-carotene, 25-hydroxy vitamin D and INR reference intervals, respectively. There are no reliable and easy to perform assays to monitor vitamin E absorption and efficacy. It is widely accepted that neither serum nor plasma vitamin E levels accurately portray vitamin E status. If available, one approach has been to measure erythrocyte tocopherol concentrations. Kayden et al. have reported that the spectrophotometric determination of total tocopherol in erythrocytes is a reproducible method in patients with ABL
      • Kayden HJ
      • Chow CK
      • Bjornson LK.
      Spectrophotometric method for determination of tocopherol in red blood cells.
      . In another study, erythrocyte vitamin E levels significantly increased following four months of oral vitamin E treatment (50 IU/kg/d), in FHBL-SD1 and FHBL-SD3 patients, but plasma vitamin E remained very low
      • Cuerq C
      • Henin E
      • Restier L
      • Blond E
      • Drai J
      • Marcais C
      • et al.
      Efficacy of two vitamin E formulations in patients with abetalipoproteinemia and chylomicron retention disease.
      . Additionally, vitamin E levels in subcutaneous adipose tissue aspirates may be a better representative of whole body status and should be evaluated whenever possible
      • Kayden HJ
      • Hatam LJ
      • Traber MG.
      The measurement of nanograms of tocopherol from needle aspiration biopsies of adipose tissue: normal and abetalipoproteinemic subjects.
      . Data derived from larger cohorts is needed to better assess vitamin E absorption, distribution and remission of symptoms with treatment.
      Vitamin E is available in both water and fat-soluble formulations. Limited evidence for the preferred use of one over the other is available based on laboratory testing. Cuerq and colleagues found initial increased bioavailability of tocofersolan (a water-soluble derivative of RRR-alpha-tocopherol) compared with alpha-tocopherol acetate (form of fat-soluble vitamin E) in patients with CRD, but not in ABL. At four months, no differences in concentration were observed for patients with either CRD or ABL
      • Cuerq C
      • Henin E
      • Restier L
      • Blond E
      • Drai J
      • Marcais C
      • et al.
      Efficacy of two vitamin E formulations in patients with abetalipoproteinemia and chylomicron retention disease.
      . In keeping with available evidence, our panel does not advocate for the use of a specific vitamin formulation.
      Further complicating the management of vitamin E in Class I disorders is the substantial pill burden. Together with the other required fat soluble vitamins, the number of daily pills needed to satisfy weight based dose ranges in adulthood is onerous. Because vitamin E deficiency strongly influences patient outcomes and until more efficient treatment methods are available, care to reach dose requirements is critical. Findings from the ophthalmologic and neurologic examination should be used to gauge treatment efficacy and prompt clinical decision making including vitamin dosage adjustments.
      In all, the ABLRDF medical advisory panel attests that treatment with fat-soluble vitamins is a medical necessity for Class 1 disorders and advocates for third-party payer coverage. It is the experience of the medical advisory panel that patients without adequate insurance coverage succumb to irreversible progressive morbidities.

      Considerations in pregnancy

      Although not systematically evaluated, some men and women with FHBL-SD1 have been shown to be fertile and have completed successful pregnancy and delivery. There is, however, a need for more comprehensive studies to determine fertility in all patients. A multidisciplinary approach to family planning in FHBL Class 1 disorders is favored, including genetic counseling
      • Haney EM
      • Huffman LH
      • Bougatsos C
      • Freeman M
      • Steiner RD
      • HD Nelson
      Screening and treatment for lipid disorders in children and adolescents: systematic evidence review for the US Preventive Services Task Force.
      . This will help inform the probability of disease occurrence in the offspring and expand the discussion regarding pregnancy management, including reproductive options. The significance of this counseling is further supported by the availability of effective interventions that may change management should issues arise with respect to conception, pregnancy complication or symptoms in the newborn.
      The menstrual pattern is normal in FHBL-SD1. FHBL-SD1 women show normal mid-cycle increases in estrogen, prolactin, as well as luteinizing and follicle stimulating hormones. However, distinctly subnormal increases in luteal phase concentrations of progesterone have been reported
      • Illingworth DR
      • Corbin DK
      • Kemp ED
      • EJ Keenan
      Hormone changes during the menstrual cycle in abetalipoproteinemia: reduced luteal phase progesterone in a patient with homozygous hypobetalipoproteinemia.
      ,
      • Triantafillidis JK
      • Kottaras G
      • Peros G
      • Merikas E
      • Gikas A
      • Condilis N
      • et al.
      Endocrine function in abetalipoproteinemia: a study of a female patient of Greek origin.
      . This may be secondary to the absence of LDL
      • Illingworth DR
      • Corbin DK
      • Kemp ED
      • EJ Keenan
      Hormone changes during the menstrual cycle in abetalipoproteinemia: reduced luteal phase progesterone in a patient with homozygous hypobetalipoproteinemia.
      ,
      • Triantafillidis JK
      • Kottaras G
      • Peros G
      • Merikas E
      • Gikas A
      • Condilis N
      • et al.
      Endocrine function in abetalipoproteinemia: a study of a female patient of Greek origin.
      . Insufficient placental biosynthesis of progesterone in patients with FHBL-SD1 has also been reported
      • Illingworth DR
      • Corbin DK
      • Kemp ED
      • EJ Keenan
      Hormone changes during the menstrual cycle in abetalipoproteinemia: reduced luteal phase progesterone in a patient with homozygous hypobetalipoproteinemia.
      . For individuals with a Class 1 disorder, we recommend monitoring of progesterone levels throughout pregnancy and consider the use of exogenous progesterone.
      The expertise of a lipidologist in conjunction with a registered dietitian is recommended to reconcile a very low fat diet while supporting the increased caloric demands throughout the course of pregnancy. If required, MCT oil may serve as a readily absorbed source of calories. As previously mentioned, careful introduction of MCTs into the diet is required to avoid gastrointestinal discomfort owing to its high osmolarity. If needed, doses of 4-6 tablespoons (385-765 calories) over the course of the day have been shown to be tolerated in other disease states
      • McCray S
      • Parrish CR.
      Nutritional management of chyle leaks: an update.
      . MCT oil is not a source of EFA. Maternal serum DHA concentration has been correlated to neurocognitive and anti-inflammatory benefits during pregnancy
      • Rogers LK
      • Valentine CJ
      • Keim SA
      DHA supplementation: current implications in pregnancy and childhood.
      . It is the experience of the ABLRDF panel that supplementation with DHA (1-3 g/day) can improve plasma concentrations in some FHBL Class 1 disorders. Nevertheless, dosing strategies shown to influence neurodevelopment in the context of FHBL Class 1 disorders are not available. Consistent with the US Preventive Services Task Force recommendation to prevent neural tube defects in pregnancy, a daily supplement of 400-800 µg folic acid is also advised
      • Marra MV
      • Bailey RL.
      Position of the academy of nutrition and dietetics: micronutrient supplementation.
      .
      Special considerations surrounding the high doses of fat-soluble vitamins in these disorders are warranted. Postpartum hemorrhage due to vitamin K deficiency has been demonstrated as a significant cause for maternal morbidity in FHBL-SD1
      ACOG practice bulletin - clinical management guidelines for obstetrician-gynecologists - Number 13, February 2000.
      . Vitamin K deficiency in the fetus may lead to neonatal bleeding and intracranial hemorrhage
      • Gaudet LM
      • MacKenzie J
      • GN Smith
      Fat-soluble vitamin deficiency in pregnancy: a case report and review of abetalipoproteinemia.
      . An effort to normalize vitamin K levels and INR prior to conception with close surveillance throughout pregnancy is recommended. In addition, vitamin D deficiency in the mother may contribute to fetal hypocalcemia, impaired bone mineralization and enamel defects
      • Almaghamsi A
      • Almalki MH
      • Buhary BM.
      Hypocalcemia in pregnancy: a clinical review update.
      . Maternal low vitamin A levels have been associated with bilateral ocular colobomata in the infant
      • Gaudet LM
      • MacKenzie J
      • GN Smith
      Fat-soluble vitamin deficiency in pregnancy: a case report and review of abetalipoproteinemia.
      . Nevertheless, because excess vitamin A can cause toxicity in normal individuals, previous reports have recommended setting a vitamin A goal at the lower limit of normal levels with consideration to reduce the dose by 50% in pregnancy
      • Zamel R
      • Khan R
      • Pollex RL
      • Hegele RA.
      Abetalipoproteinemia: two case reports and literature review.
      ,
      • Takahashi M
      • Okazaki H
      • Ohashi K
      • Ogura M
      • Ishibashi S
      • Okazaki S
      • et al.
      Current Diagnosis and Management of Abetalipoproteinemia.
      ,
      • Burnett JR
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      • et al.
      Abetalipoproteinemia.
      . Vitamin E supplements should be continued during pregnancy as its deficiency has been shown to increase miscarriages
      • Shamim AA
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      • Kabir A
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      • et al.
      First-trimester plasma tocopherols are associated with risk of miscarriage in rural Bangladesh.
      .

      Future work

      This manuscript addresses monogenic hypobetalipoproteinemia disorders and their inherent diagnostic and management challenges. Continued work in this area and, in particular surrounding the matters outlined in (Table 1) remains a priority of ABLRDF. Other unresolved issues that require exploration were identified (Table 4). Advances in the preclinical and clinical understanding of pathophysiology will clarify optimal treatment modalities for hypobetalipoproteinemia disorders and likely other conditions of fat malabsorption. Additionally, given the complexity of the problem, strategies to better implement system-based practices that provide social support are warranted. Finally, there is a need for an international registry and collaboration surrounding these rare diseases.
      Table 4Questions and topics requiring further investigation.
      Disease characterization
      • Development of a universal registry for FHBL Class 1 patients and other hypobetalipoproteinemia disorders cataloging demographic, clinical and biochemical data
      • Focus on the peripartum period to increase knowledge and improve clinical recommendations
      • Determine long term health outcomes in patients adhering to suggested vitamin and dietary interventions
      • Preclinical proof of concept research followed by clinical studies demonstrating the clinical efficacy of EFA, DHA and EPA
      • Reasons for elevated CK levels in FHBL-SD3 patients
      • Development and natural history of hepatic steatosis in heterozygous FHBL-SD2 patients
      Mechanisms of disease and treatment
      • How are fat-soluble vitamins absorbed in patients after oral ingestion of megadoses? Identification and upregulation of these mechanisms may help enhance fat-soluble vitamin absorption
      • Role of intestinal HDL in fat-soluble vitamin absorption
      • Evaluating new formulations and routes of vitamin delivery to improve systemic delivery and efficacy
      Treatment standardization
      • Identification of clinically feasible and accurate markers of vitamin E status
      • Standardization of vitamin E measurement and treatment targets
      Quality of life
      • Integration of social services and other supportive measures aimed to improve health-related quality of life (e.g. very low fat meal recipes)

      Conclusions

      Early diagnosis, appropriate dietary interventions and sufficient fat-soluble vitamin intake aligned with rigorous follow-up by a multidisciplinary team can lead to successful management of Class I FHBL and other hypobetalipoproteinemia disorders. In this respect, heightened physician awareness and experience managing these disorders is essential. Adequate insurance coverage for fat-soluble vitamins, MCT formulations and regular physical assessments remain an unmet need in this vulnerable population. The ABLRDF medical advisory panel strongly advocates that fat-soluble vitamins be regarded as medical therapies, and not as dietary supplements, proven to prevent progressive morbidities. Additionally, there is a need for preclinical, clinical and health system research to better understand and document symptoms, pathophysiology and clinical outcomes following therapeutic interventions. It is anticipated that increased knowledge of these understudied disorders and improved access to proper medical care will greatly improve the lives of patients and their families.

      Disclosures

      DB: Consultant: Intercept Pharmaceuticals; MB: Employment: AbbVie; IG: Scientific advisory boards: Ionis and Arrowhead; RAH: Consultant: Acasti, Aegerion, Akcea/Ionis, Amgen, Arrowhead, Boston Heart, HLS Therapeutics, Novartis, Pfizer, Regeneron, Sanofi and Ultragenyx; HO: Scholarship grants: Minophagen Pharmaceutical Co., Ltd., Kowa Company, Ltd., and Tosoh Corporation; DR: Scientific advisory boards: Alnylam, Novartis, Pfizer, and Verve. All other authors report no disclosures.

      Authors’ contribution

      CB, MMH, MDF, NP wrote the original draft of the manuscript. Each author made significant intellectual contributions to the manuscript and participated in the editing and revising process. All authors read and approved the final manuscript.

      Acknowledgement

      The authors are grateful to Mr. Paul Biderman, our patient liaison, for his valuable contributions to this publication. Mr. Biderman has served as a trusted resource to patients and their families. He has conveyed patient concerns and opinions to the advisory panel which in turn have served as guiding principles for ABLRDF. Mr. Biderman is an inspiration to the medical and research community as we advance our understanding of these rare diseases.

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