New Classification and Management of Abetalipoproteinemia and Related Disorders

Abstract

The Abetalipoproteinemia and Related Disorders Foundation (ABLRDF) is a nonprofit organization founded in 2019 that is comprised of patients with abetalipoproteinemia (ABL), familial hypobetalipoproteinemia (FHBL) and related hypobetalipoproteinemia disorders as well as their caregivers, researchers, and medical professionals. The real-world experience of individuals within the ABLRDF provides a closer examination of the unique struggles in managing these complex disorders while affording an opportunity to elevate the standard of medical care. The mission is to improve the lives of all people affected by these disorders. The goals are to increase awareness of ABL and other FHBL disorders, provide a standard for lifelong medical care, and facilitate access to specialized professionals, medical evaluations, and indicated treatments. The foundation conducted surveys using Facebook and completed several conference calls with members. These interactions identified several pressing issues confronting patients and caregivers, including a paucity of guidelines for management throughout the lifespan, particularly in pregnancy. Additionally, compromised access to necessary fat-soluble vitamins owing to cost and inadequate insurance coverage in the United States was highlighted. Consequently, patients within ABLRDF are adhering to varying vitamin regimens. The objective of this article was to provide various stakeholders involved in the care of these serious hypobetalipoproteinemia conditions a standardized approach to their diagnosis, assessment, and treatment. ABLRDF will serve as an international medical advisory resource and advocate for improved access to affordable care. Individuals with ABL and FHBL disorders have absent to very low levels of lipids and apolipoprotein (apo) B-containing lipoproteins.1Lee J. Hegele R.A. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.J Inherit Metab Dis. 2014; 37: 333-339Crossref PubMed Scopus (96) Google Scholar The nomenclature used to classify these various FHBL disorders is inconsistently applied within the literature. We propose a new simplified classification for the various FHBL disorders and summarize their genetic defects (Table 1). We classify these monogenic disorders into 2 classes based on molecular mechanisms. Class I disorders arise from defects in lipoprotein assembly and secretion, have significant effects on growth and development in infancy, and require early intervention and lifelong monitoring. Class II disorders are due to enhanced catabolism of lipoproteins. These individuals do not exhibit symptoms. In fact, these mutations can be beneficial and do not require any monitoring. Likely, there are other FHBL individuals with unidentified genes and mechanisms. To be discovered, genes and mutations can be added to this classification after their genetic and mechanistic characterizations.Table 1Genetic Defects in Monogenic Hypobetalipoproteinemia DisordersNew NamesCommon NamesGene DefectProtein FunctionMode of TransmissionClass I: Lipoprotein assembly and secretion defects (SD)FHBL-SD1Abetalipoproteinemia (ABL)Microsomal triglyceride transfer protein (MTTP)Facilitates the assembly of apoB-containing lipoproteinsAutosomal recessiveFHBL-SD2Familial hypobetalipoproteinemia (FHBL)Apolipoprotein B (APOB)Structural protein for the assembly of apoB-containing lipoproteinAutosomal dominantFHBL-SD3Chylomicron retention disease (CRD)Secretion associated RAS related GTPase1B (SAR1B)Transport of chylomicrons from the endoplasmic reticulum to GolgiAutosomal recessiveClass II: Enhanced lipoprotein catabolism (EC)FHBL-EC1Familial combined hypolipidemia (FCHL)Angiopoietin like protein 3 (ANGPTL3)Inhibits lipoprotein lipase activityAutosomal dominantFHBL-EC2Proprotein convertase subtilisin/kexin type 9 (PCSK9)Increases LDL receptor degradationAutosomal dominant Open table in a new tab Lipoprotein particles are mainly assembled in enterocytes and hepatocytes. Enterocytes assemble and secrete chylomicrons to transport dietary fat and fat-soluble vitamins. Hepatocytes produce very low-density lipoproteins (LDLs). Assembly of these particles is dependent on 2 proteins2Hussain M.M. Shi J. Dreizen P. Microsomal triglyceride transfer protein and its role in apolipoprotein B-lipoprotein assembly.J Lipid Res. 2003; 44: 22-32Abstract Full Text Full Text PDF PubMed Scopus (415) Google Scholar; apoB, a structural protein, and microsomal triglyceride transfer protein (MTP; gene MTTP) that helps to assemble apoB-containing lipoproteins. Loss-of-function mutations in the MTTP gene cause FHBL-SD1 (Table 1) commonly known as ABL.1Lee J. Hegele R.A. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.J Inherit Metab Dis. 2014; 37: 333-339Crossref PubMed Scopus (96) Google Scholar,3Di Filippo M. Moulin P. Roy P. et al.Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia.J Hepatol. 2014; 61: 891-902Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar,4Walsh M.T. Di L.E. Okur I. et al.Structure-function analyses of microsomal triglyceride transfer protein missense mutations in abetalipoproteinemia and hypobetalipoproteinemia subjects.Biochim Biophys Acta. 2016; 1861: 1623-1633Crossref PubMed Scopus (13) Google Scholar Mutations in the APOB gene that disable apoB protein from forming a lipoprotein result in FHBL-SD2 (Table 1), with homozygous and heterozygous forms.5Tarugi P. Averna M. Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum.Adv Clin Chem. 2011; (54: et al-107)Crossref PubMed Scopus (77) Google Scholar ApoB-containing lipoprotein assembly begins in the endoplasmic reticulum. These particles are transported to the Golgi complex and plasma membrane for secretion via exocytosis. Intracellular trafficking of lipoprotein-transporting vesicles is dependent on several proteins. A defect in one protein, Sar1b, affects secretion of chylomicrons by enterocytes and results in FHBL-SD3 (Table 1).6Peretti N. Sassolas A. Roy C.C. 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.Orphanet J Rare Dis. 2010; 5: 24Crossref PubMed Scopus (82) Google Scholar In the circulation, lipoproteins undergo lipolysis by endothelial cell-bound lipoprotein lipase. Several proteins inhibit lipoprotein lipase activity, one of which is angiopoietin like protein 3 (ANGPTL3). Loss of function mutations in the ANGPTL3 gene increase lipoprotein lipase activity, enhance catabolism of apoB-containing lipoproteins and cause FHBL-EC1 (Table 1).7Musunuru K. Pirruccello J.P. Do R. et al.Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.N Engl J Med. 2010; 363: 2220-2227Crossref PubMed Scopus (443) Google Scholar Under normal conditions, lipolysis of apoB-containing lipoproteins generates chylomicron remnants, intermediate density lipoproteins and LDL. LDL are removed from the circulation by LDL receptors, whereas remnants are cleared via LDL receptors and other receptors.8Brown M.S. Goldstein J.L. A receptor-mediated pathway for cholesterol homeostasis.Science. 1986; 232: 34-47Crossref PubMed Scopus (4206) Google Scholar,9Hussain M.M. Kancha R.K. Zhou Z. et al.Chylomicron assembly and catabolism: role of apolipoproteins and receptors.Biochim Biophys Acta. 1996; 1300: 151-170Crossref PubMed Scopus (140) Google Scholar LDL receptors bind to LDL and remnant lipoproteins, internalize them, and deliver these lipoproteins to lysosomes for catabolism. Subsequently, these receptors are recycled to the cell surface for another round of lipoprotein internalization. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a plasma protein, binds to LDL receptors and prevents the recycling of these receptors to the cell surface by enhancing their lysosomal degradation. Loss-of-function PCSK9 mutations prevent such receptor destruction and increase recycling of LDL receptors to the hepatocyte surface. As a result, the LDL receptors are able to clear more lipoproteins resulting in FHBL-EC2 (Table 1).5Tarugi P. Averna M. Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum.Adv Clin Chem. 2011; (54: et al-107)Crossref PubMed Scopus (77) Google Scholar The complete absence of plasma apoB-containing lipopoproteins is responsible for fat malabsorption and fat-soluble vitamin deficiency in FHBL owing to lipoprotein assembly defect 1 (FHBL-SD1). The symptoms of FHBL-SD1 are a direct consequence of fat-soluble vitamin deficiencies (vitamins A, E, D, and K) and impact a wide range of organ systems. Classically, gastrointestinal symptoms dominate the clinical picture in infancy, including steatorrhea, diarrhea, and abdominal distension. Symptoms improve within a few days or weeks on a low-fat diet.5Tarugi P. Averna M. Hypobetalipoproteinemia: genetics, biochemistry, and clinical spectrum.Adv Clin Chem. 2011; (54: et al-107)Crossref PubMed Scopus (77) Google Scholar,10Gaudet L.M. MacKenzie J. Smith G.N. Fat-soluble vitamin deficiency in pregnancy: a case report and review of abetalipoproteinemia.J Obstet Gynaecol Can. 2006; 28: 716-719Abstract Full Text PDF PubMed Scopus (12) Google Scholar Nevertheless, owing to the rarity of the condition, FHBL-SD1 may not be diagnosed at this stage. Gluten intolerance is not present and as such an important distinction from celiac disease. A clinical diagnosis of FHBL-SD1 can also be suspected when severe hypocholesterolemia and acanthocytosis are present. Parents of affected individuals are asymptomatic carriers and have normal lipid profiles. As an individual matures and, if untreated, the clinical impact of fat-soluble vitamin deficiency progresses. Neurologic involvement from vitamin E deficiency typically begins in the first or second decades of life owing to progressive axonopathy, leading to spinocerebellar degeneration, ataxia and dysmetria.1Lee J. Hegele R.A. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.J Inherit Metab Dis. 2014; 37: 333-339Crossref PubMed Scopus (96) Google Scholar Vitamin A deficiency is responsible for pigmentary retinal degeneration in FHBL-SD1. Visual disturbances typically begin in childhood and although the course can be varied and gradual, most untreated individuals are legally blind by age 40.11Segal S. Sharma S. Ophthaproblem. Vitamin A and vitamin E.Can Fam Physician. 2005; 1079: 85-86Google Scholar Bleeding diathesis including gastrointestinal bleeding from vitamin K deficiency have been reported.12Aviram M. Deckelbaum R.J. Brook J.G. Platelet function in a case with abetalipoproteinemia.Atherosclerosis. 1985; 57: 313-323Abstract Full Text PDF PubMed Scopus (11) Google Scholar Ultimately, the clinical phenotype in adults may vary according to the proband. For example, neuropathic symptoms may be the main clinical finding in some individuals, whereas cardiomyopathy may predominate in others. LDL cholesterol (LDL-C) (<0.1 mmol/L), triglycerides (TG) (<0.2 mmol/L), and apoB (<0.1 g/L). Acanthocytosis may encompass 50% of circulating red blood cells.1Lee J. Hegele R.A. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.J Inherit Metab Dis. 2014; 37: 333-339Crossref PubMed Scopus (96) Google Scholar The clinical and biochemical presentation of FHBL owing to lipoprotein assembly defect 2 (FHBL-SD2) (homozygous or compound heterozygous mutations of APOB) is virtually indistinguishable from FHBL-SD1. One variance is that heterozygous parents of FHBL-SD2 show lower lipid levels compared with normal individuals. Similar to FHBL-SD1, early detection and treatment are needed in homozygous FHBL-SD2 to prevent profound multiorgan dysfunction. A definite discernment between FHBL-SD1 and homozygous FHBL-SD2 requires sequencing of the MTTP and APOB genes.1Lee J. Hegele R.A. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.J Inherit Metab Dis. 2014; 37: 333-339Crossref PubMed Scopus (96) Google Scholar Heterozygous FHBL-SD2 is relatively common.13Tarugi P. Averna M. Di Leo E. et al.Molecular diagnosis of hypobetalipoproteinemia: an ENID review.Atherosclerosis. 2007; 195: e19-27Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar The clinical expression may depend on the size of the truncated APOB gene with carriers of small truncated APOB invariably developing steatosis to cryptogenic cirrhosis.14Bonnefont-Rousselot D. Condat B. Sassolas A. et al.Cryptogenic cirrhosis in a patient with familial hypocholesterolemia due to a new truncated form of apolipoprotein B.Eur J Gastroenterol Hepatol. 2009; 21: 104-108Crossref PubMed Scopus (20) Google Scholar Heterozygous FHBL-SD2 patients have low, but not absent, LDL-C levels.15Hartz J. Hegele R.A. Wilson D.P. Low LDL cholesterol-friend or foe?.J Clin Lipidol. 2019; 13: 367-373Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Some of the clinical and serologic evaluations listed in Table 2 may be appropriate for heterozygous FHBL-SD2.13Tarugi P. Averna M. Di Leo E. et al.Molecular diagnosis of hypobetalipoproteinemia: an ENID review.Atherosclerosis. 2007; 195: e19-27Abstract Full Text Full Text PDF PubMed Scopus (130) Google ScholarTable 2Suggested Evaluation and Treatment for Class 1 Monogenic Hypobetalipoproteinemia DisordersInfants and children <10 years of ageAnnual physical examination Growth parameters: height/weight compared with a growth curve Assess for expected development for age Neurologic: deep tendon reflexes, proprioceptive, cerebellar, cranial nerve, motor and sensory function testing Gastrointestinal: abdominal distension, hepatomegaly, jaundiceDietary recommendations Consumption of long chain fatty acids is not recommended Monitor for adequate caloric intake while restricting total fat to <10%–15% (5–15 g/d) of total daily caloric requirement 1–2 teaspoons of oils rich in polyunsaturated fatty acidsaExamples of polyunsaturated fatty acids include flaxseed, safflower, olive and soybean oil. to ensure adequate intake of essential fatty acids Medium chain triglycerides are not routinely recommended; however, in infants may prevent or treat malnutritionVitamin supplementationbDosing of vitamins D and K can be tailored to 25-hydroxy vitamin D and INR, respectively. Serum levels of vitamin E can be monitored, but subcutaneous adipose tissue aspirates are a more sensitive measurement. If oral therapy does not achieve physiologic levels, intramuscular injections of 50 mg alpha-tocopherol can be administered once or twice weekly.20 Vitamin E 100–300 IU/kg/d (50 IU/kg/d in FHBL-SD3 if diagnosed by age 1) Vitamin A 100–400 IU/kg/d (15,000 IU/day in FHBL-SD3) Vitamin D 800–1200 IU/d Vitamin K 5–35 mg/wkBaseline and annual laboratory testing: lipid panel,cThe lipid panel typically remains stable and may not be required on an annual basis.1 apoB, apoA1, albumin, liver function tests, 25-OH vitamin D, plasma vitamin A, plasma or RBC vitamin E, INR, CBC, reticulocyte count, vitamin B12, folate, calcium, phosphorus, uric acidChildren >10 years into adulthood The following are in addition to what is stated above for children <10 years of age •Liver ultrasound examination, FibroScandFibroscan is a specialized ultrasound machine that measures hepatic steatosis and fibrosis. The FIB-4 Index is a noninvasive scoring system of liver scarring used to assess need for biopsy./Fibrosis-4 (FIB 4) index and echocardiogram every 3 years •Bone mineral density via DXA annually through puberty and every 3 years thereafter •Fundoscopic examination every 6–12 months (frequency of examination may be less for FHBL-SD3) •Electromyography when clinically indicated; may be considered early in the course of disease and every 1–3 years to assess peripheral nervous system involvement •Additional treatment considerations •Vigilant monitoring for dietary and vitamin supplementation adherence as well as for complications remains the clinical focus over the life span •Monitor for food and drug interactions associated with high-dose vitamin supplementation •Formal consultation with a dietician familiar with lipid disordersThese recommendations are modified from.1Lee J. Hegele R.A. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.J Inherit Metab Dis. 2014; 37: 333-339Crossref PubMed Scopus (96) Google ScholarAdditional treatment considerations•Vigilant monitoring for dietary and vitamin supplementation adherence as well as for complications remains the clinical focus over the life span•Monitor for food and drug interactions associated with high dose vitamin supplementation•Formal consultation with a dietician familiar with lipid disordersThe following are in addition to what is stated above for children <10 years of age•Liver Sonogram, 4Walsh M.T. Di L.E. Okur I. et al.Structure-function analyses of microsomal triglyceride transfer protein missense mutations in abetalipoproteinemia and hypobetalipoproteinemia subjects.Biochim Biophys Acta. 2016; 1861: 1623-1633Crossref PubMed Scopus (13) Google ScholarFibroScan/Fibrosis-4 (FIB 4) index and echocardiogram every 3 years•Bone mineral density via DXA annually through puberty and every 3 years thereafter•Fundoscopic exam every 6-12 months (frequency of exam may be less for FHBL-SD3)•Electromyography when clinically indicated. May be considered early in the course of disease and every 1-3 years to assess peripheral nervous system involvementCBC, complete blood count; DXA, dual-energy x-ray absorptiometry; FIB-4, Fibrosis-4; INR, international normalized ratio; RBC, red blood cells.a Examples of polyunsaturated fatty acids include flaxseed, safflower, olive and soybean oil.b Dosing of vitamins D and K can be tailored to 25-hydroxy vitamin D and INR, respectively. Serum levels of vitamin E can be monitored, but subcutaneous adipose tissue aspirates are a more sensitive measurement. If oral therapy does not achieve physiologic levels, intramuscular injections of 50 mg alpha-tocopherol can be administered once or twice weekly.20Grant C.A. Berson E.L. Treatable forms of retinitis pigmentosa associated with systemic neurological disorders.Int Ophthalmol Clin. 2001; 41: 103-110Crossref PubMed Scopus (26) Google Scholarc The lipid panel typically remains stable and may not be required on an annual basis.1Lee J. Hegele R.A. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.J Inherit Metab Dis. 2014; 37: 333-339Crossref PubMed Scopus (96) Google Scholard Fibroscan is a specialized ultrasound machine that measures hepatic steatosis and fibrosis. The FIB-4 Index is a noninvasive scoring system of liver scarring used to assess need for biopsy. Open table in a new tab CBC, complete blood count; DXA, dual-energy x-ray absorptiometry; FIB-4, Fibrosis-4; INR, international normalized ratio; RBC, red blood cells. Virtual absence of apoB-containing lipoproteins in homozygous FHBL-SD2.13Tarugi P. Averna M. Di Leo E. et al.Molecular diagnosis of hypobetalipoproteinemia: an ENID review.Atherosclerosis. 2007; 195: e19-27Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar ApoB-100 levels in heterozygous FHBL-SD2 plasma are approximately 24% of normal with an LDL-C of <1.3 mmol/L (ie, <5th percentile for age and sex).15Hartz J. Hegele R.A. Wilson D.P. Low LDL cholesterol-friend or foe?.J Clin Lipidol. 2019; 13: 367-373Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar FHBL owing to lipoprotein assembly defect 3 (FHBL-SD3) is an extremely rare disease with only about 60 cases and a few small cohorts described.6Peretti N. Sassolas A. Roy C.C. 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.Orphanet J Rare Dis. 2010; 5: 24Crossref PubMed Scopus (82) Google Scholar,16Bouma M.E. Beucler I. Aggerbeck L.P. et al.Hypobetalipoproteinemia with accumulation of an apoprotein B-like protein in intestinal cells: immunoenzymatic and biochemical characterization of seven cases of Anderson's disease.J Clin Invest. 1986; 78: 398-410Crossref PubMed Scopus (54) Google Scholar, 17Nemeth A. Myrdal U. Veress B. et al.Studies on lipoprotein metabolism in a family with jejunal chylomicron retention.Eur J Clin Invest. 1995; 25: 271-280Crossref PubMed Scopus (23) Google Scholar, 18Roy C.C. Levy E. Green P.H.R. et al.Malabsorption, hypocholesterolemia, and fat-filled enterocytes with increased intestinal apoprotein B: chylomicron retention disease.Gastroenterology. 1987; 92: 390-399Crossref PubMed Scopus (96) Google Scholar As with FHBL-SD1 and FHBL-SD2, digestive symptoms are most prominent at the beginning of life. Diarrhea and malabsorption begin shortly after birth, often associated with vomiting and abdominal distension. Malabsorption rapidly results in growth retardation in toddlers, but is remedied in a few days or weeks by a low-fat diet. Hepatomegaly is reported in about 20% of FHBL-SD3 patients.18Roy C.C. Levy E. Green P.H.R. et al.Malabsorption, hypocholesterolemia, and fat-filled enterocytes with increased intestinal apoprotein B: chylomicron retention disease.Gastroenterology. 1987; 92: 390-399Crossref PubMed Scopus (96) Google Scholar Neurologic symptoms, including proprioceptive abnormalities and areflexia, appear only in older children with a mean age of 12 years, and as such differentiates itself from FHBL-SD1 and FHBL-SD2. In the largest pediatric cohort, patients with the most severe symptoms also had the lowest vitamin E levels at diagnosis.6Peretti N. Sassolas A. Roy C.C. 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.Orphanet J Rare Dis. 2010; 5: 24Crossref PubMed Scopus (82) Google Scholar A 50% decrease in total cholesterol, LDL-C, and high-density lipoprotein cholesterol with normal TG levels. Creatine kinase is elevated 5–10 times the upper limit of normal. Acanthocytosis is rare.6Peretti N. Sassolas A. Roy C.C. 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.Orphanet J Rare Dis. 2010; 5: 24Crossref PubMed Scopus (82) Google Scholar FHBL owing to enhanced lipoprotein catabolism (FHBL-EC1) is not associated with intestinal malabsorption; therefore, specific clinical complications are absent. Despite the presence of low high-density lipoprotein cholesterol levels, FHBL-EC1 patients are protected from developing premature atherosclerosis, likely owing to the concomitant reduction in atherogenic very LDLs and LDL. This protective effect has prompted the pharmaceutical industry to develop new therapies targeting ANGPTL3. Reduction in all plasma lipoproteins and apolipoproteins in both homozygous and heterozygous ANGPTL3 mutation carriers. Homozygous patients show reduced LDL-C by 67.2%, TG by 71.2%, high-density lipoprotein by 39.9%, ApoB by 48.4%, and ApoA1 by 95.1% compared with noncarriers.7Musunuru K. Pirruccello J.P. Do R. et al.Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.N Engl J Med. 2010; 363: 2220-2227Crossref PubMed Scopus (443) Google Scholar FHBL owing to enhanced lipoprotein catabolism 2 (FHBL-EC2) is also not associated with intestinal malabsorption. Patients have low but detectable LDL-C without any deleterious systemic involvement. Loss of function PCSK9 mutations confer substantial protection against coronary atherosclerosis.19Cohen J.C. Boerwinkle E. Mosley T.H. et al.Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.N Engl J Med. 2006; 354: 1264-1272Crossref PubMed Scopus (2213) Google Scholar Based on this observation, therapeutics inhibiting PCSK9 are available to lower LDL-C levels. Depending on the type and number of sequence variations, LDL-C levels in patients with FHBL-EC2 are approximately 21%–40% lower than normal levels.19Cohen J.C. Boerwinkle E. Mosley T.H. et al.Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.N Engl J Med. 2006; 354: 1264-1272Crossref PubMed Scopus (2213) Google Scholar,20Grant C.A. Berson E.L. Treatable forms of retinitis pigmentosa associated with systemic neurological disorders.Int Ophthalmol Clin. 2001; 41: 103-110Crossref PubMed Scopus (26) Google Scholar It is paramount that FHBL-SD1, homozygous FHBL-SD2, and FHBL-SD3 be treated early in life to slow and prevent the progression of consequences from fat-soluble vitamin deficiencies. Thus, there is a need for early diagnosis by physicians, approval of treatment modalities by insurance companies and adherence to prescribed vitamin recommendations by the patients with the help of caregivers. Table 2 summarizes a proposed framework for the management of class I monogenic FHBL disorders. Given that FHBL-EC1 and FHBL-EC2 do not impose clinical harm, treatment is not recommended for these class II disorders. Women with FHBL-SD1 have a normal menstrual pattern with midcycle increases in luteinizing and follicle-stimulating hormones, prolactin, and estrogen, but a distinctly subnormal increase in the luteal phase concentrations of progesterone. Progesterone is responsible for the thickening of the uterine lining necessary for successful embryo implantation. Reports suggest that, in patients with FHBL-SD1 and homozygous FHBL-SD2, the absence of LDL leads to an impairment in reaching required levels of progesterone.21Illingworth D.R. Corbin D.K. Kemp E.D. et al.Hormone changes during the menstrual cycle in abetalipoproteinemia: reduced luteal phase progesterone in a patient with homozygous hypobetalipoproteinemia.Proc Natl Acad Sci U S A. 1982; 79: 6685-6689Crossref PubMed Scopus (38) Google Scholar,22Triantafillidis J.K. Kottaras G. Peros G. et al.Endocrine function in abetalipoproteinemia: a study of a female patient of Greek origin.Ann Ital Chir. 2004; 75: 683-690PubMed Google Scholar Insufficient placental biosynthesis of progesterone in patients with FHBL-SD1 has also been reported.10Gaudet L.M. MacKenzie J. Smith G.N. Fat-soluble vitamin deficiency in pregnancy: a case report and review of abetalipoproteinemia.J Obstet Gynaecol Can. 2006; 28: 716-719Abstract Full Text PDF PubMed Scopus (12) Google Scholar It is important to consider that achieving conception in FHBL class I disorders may require the use of exogenous progesterone. Fat-soluble vitamins are important in normal fetal development. The correct amount of vitamin A is critical for the growth and cell differentiation in the developing fetus.10Gaudet L.M. MacKenzie J. Smith G.N. Fat-soluble vitamin deficiency in pregnancy: a case report and review of abetalipoproteinemia.J Obstet Gynaecol Can. 2006; 28: 716-719Abstract Full Text PDF PubMed Scopus (12) Google Scholar Low vitamin A has been implicated in congenital decreases in visual acuity and iris coloboma, prematurity, and intrauterine growth retardation.10Gaudet L.M. MacKenzie J. Smith G.N. Fat-soluble vitamin deficiency in pregnancy: a case report and review of abetalipoproteinemia.J Obstet Gynaecol Can. 2006; 28: 716-719Abstract Full Text PDF PubMed Scopus (12) Google Scholar Alternatively, excess vitamin A consumption during pregnancy is known to cause birth defects, including fetal neural tube defects, urinary tract malformations, and craniofacial and cardiac abnormalities.10Gaudet L.M. MacKenzie J. Smith G.N. Fat-soluble vitamin deficiency in pregnancy: a case report and review of abetalipoproteinemia.J Obstet Gynaecol Can. 2006; 28: 716-719Abstract Full Text PDF PubMed Scopus (12) Google Scholar Although it is unlikely that pregnant women with FHBL-SD1 or a homozygous FHBL-SD2 disorder will easily achieve excess plasma vitamin A, vitamin toxicity has been reported in FHBL-SD1.23Bishara S. Merin S. Cooper M. et al.Combined vitamin A and E therapy prevents retinal electrophysiological deterioration in abetalipoproteinaemia.Br J Ophthalmol. 1982; 66: 767-770Crossref PubMed Scopus (61) Google Scholar Postpartum hemorrhage owing to vitamin K deficiency is a significant cause for maternal morbidity in FHBL-SD1.24ACOG Practice BulletinClinical Management Guidelines for Obstetrician-Gynecologists - Number 13, February 2000.Obstet Gynecol. 2000; 95: 1-7PubMed Google Scholar Neonatal bleeding and intracranial hemorrhage are potential risks of vitamin K deficiency in the fetus.10Gaudet L.M. MacKenzie J. Smith G.N. Fat-soluble vitamin deficiency in pregnancy: a case report and review of abetalipoproteinemia.J Obstet Gynaecol Can. 2006; 28: 716-719Abstract Full Text PDF PubMed Scopus (12) Google Scholar In addition, significant vitamin D deficiency in the mother may contribute to fetal hypocalcemia, impaired bone mineralization and enamel defects. Last, breast milk is deficient in essential fatty acids and supplementation may be indicated.25Wang C.S. Illingworth D.R. Lipid composition and lipolytic activities in milk from a patient with homozygous familial hypobetalipoproteinemia.Am J Clin Nutr. 1987; 45: 730-736Crossref PubMed Scopus (11) Google Scholar Our survey within ABLRDF reveal that both men and women with FHBL-SD1 have children. Therefore, preconception counseling regarding the management of fat-soluble vitamins as described elsewhere in this article is emphasized. An attempt to normalize vitamin levels and the international normalized ratio before conception with close surveillance throughout pregnancy is recommended. Individuals diagnosed with a monogenic hypobetalipoproteinemia disorder should also consider genetic counseling when family planning to understand the probability of disease occurrence in the offspring and discuss management, including reproductive options. Genetic testing is encouraged because effective interventions exist that may change treatment recommendations should the newborn develop symptoms. Early diagnosis alongside appropriate fat-soluble vitamin supplementation and follow-up are critical to the successful management of class I FHBL disorders. Adequate insurance coverage for fat-soluble vitamins and physical assessments remain an unmet clinical need, especially in the United States. The ABLRDF medical advisory panel strongly recommends coverage for these medically necessary therapies to avoid progressive morbidities. In addition, lifelong monitoring for the symptoms described in this article and appropriate interventions is recommended.