New Classification and Management of Abetalipoproteinemia and Related Disorders

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