Case ReportExperimental Therapeutics for Challenging Clinical Care of aPatient with an Extremely Rare Homozygous APOC2 Mutation

Masako Ueda ,1 Anna Wolska,2 Frances M. Burke,3 Maria Escobar,1 Laura Walters,1

Dusanka Lalic,1 Robert A. Hegele,4 Alan T. Remaley ,2 Daniel J. Rader,1,3,5

and Richard L. Dunbar 1,6,7

1Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA2Lipoprotein Metabolism Laboratory, NHLBI, National Institutes of Health, Bethesda, MD, USA3Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania Health System,Philadelphia, PA, USA4Department of Medicine, and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University,London, Ontario, Canada5Translational Medicine and Human Genetics, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA6Department of Medicine, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA7Amarin Pharmaceuticals, Bedminster, NJ, USA

Correspondence should be addressed to Masako Ueda; uedam19@gmail.com

Received 9 October 2019; Accepted 24 December 2019; Published 30 March 2020

Academic Editor: Eli Hershkovitz

Copyright © 2020Masako Ueda et al. )is is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Amongmany causes of hypertriglyceridemia (HTG), familial chylomicronemia syndrome (FCS) is a rare monogenicdisorder that manifests as severe HTG and acute pancreatitis. Among the known causal genes for FCS, mutations in APOC2 onlyaccount for 90% post-sessionsand appeared to reduce pancreatitis episodes. Experimental ANGPTL3 and APOC3 inhibitors each lowered TG by >50%.Conclusions. Our case demonstrates the importance of delineating and defining the underlying etiology of a rare disorder tooptimize therapy and to minimize unfavorable outcomes.

1. Introduction

Hypertriglyceridemia (HTG) has numerous etiologies. It isoften polygenic and multifactorial [1]. However, familialchylomicronemia syndrome (FCS) or type I hyper-lipoproteinemia with severe HTG (OMIM: 238600) is a rareand often underdiagnosed monogenic disorder, with an esti-mated prevalence of 1/1,000,000. )ere are five known causalgenes for FCS: lipoprotein lipase (LPL), apolipoprotein (apo)

C-II (APOC2), apoA-V (APOA5), lipase maturation factor 1(LMF1), and glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1). Each geneproduct supports proper LPL synthesis or its function, namely,TG hydrolysis [2].

Abdominal pain of varying intensity due to acutepancreatitis is often the first manifestation of FCS, typicallypresenting in childhood or adolescence. Unfortunately, it isoften disregarded as a childhood illness or can prompt an

HindawiCase Reports in EndocrinologyVolume 2020, Article ID 1865489, 6 pageshttps://doi.org/10.1155/2020/1865489

mailto:uedam19@gmail.comhttps://orcid.org/0000-0002-4429-8924https://orcid.org/0000-0003-2473-5549https://orcid.org/0000-0002-7059-4794https://creativecommons.org/licenses/by/4.0/https://creativecommons.org/licenses/by/4.0/https://doi.org/10.1155/2020/1865489

unnecessary exploratory procedure. )erefore, arriving atthe correct diagnosis is often delayed. Pancreatitis is themost serious, potentially fatal, consequence of FCS. Otherreversible clinical features include dermatological eruptivexanthomas, ophthalmological lipemia retinalis, and hep-atosplenomegaly; however, not all features are present inevery patient.

Fasting chylomicronemic plasma appears milky andviscous with TG> 1,000mg/dL (11.3mmol/L). )ree pre-treatment lipid findings may help distinguish FCS (Table 1)from polygenic or multifactorial chylomicronemia (type Vhyperlipoproteinemia) [3]: (1) TG/total cholesterol (TC)ratio >5 (mg/dL)/(mg/dL) or >2.2 (mmol/L)/(mmol/L), (2)TG/apoB ratio >8.8 (mg/dL)/(mg/dL) or ≥10 (mmol/L)/(g/L), and (3) low apoB

Unfortunately, his unstable medical status with recurrentbouts of pancreatitis precluded him from participating inanother therapy at that time. He had 7 hospital admissionsduring one year, of which 6 occurred within a 6-month period.Five hospitalizations were for acute pancreatitis, and two werefor related complications: anorexia, anemia, and surgical in-tervention to relieve an intestinal obstruction caused by chronicpancreatitis. By this time, themajority of pancreas was replacedby multiloculated, fluid-filled cysts, compromising both exo-crine and endocrine function and worsening his DM.

During the latter half of 2016, we prescribed TPE sessionsto curtail pancreatitis episodes. Reportedly, his sister andbrother often relied successfully on TPE to limit their recurrentpancreatitis. Initially, we prescribed TPE of 1 plasma volume(PV) exchange with FFP every few weeks. However, the patientreceived albumin replacements for the first three sessions as pertheir facility protocol. On albumin TPE, TG fell 70–85% to2,000mg/dL within 2 weeksof each session (Figure 2(b)). On FFP replacement, as originallyplanned, TG initially fell >95% to 1,000mg/dL; >11.3mmol/L

TG/TC ratio:>5 (mg/dL)/(mg/dL); >2 (mmol/L)/

(mmol/L)TG/ApoB ratio:

≥8.8 (mg/dL)/(mg/dL); ≥10 (mmol/L)/(g/L)

ApoB:

Kidney disease

DMKidney disease

HTGPancreatitis

DM

Died in 70’sDM

CVD

DM

DMHTN

HTGPancreatitis

DM

DM

DM

DMKidney disease

HTN

DMHTN HTGHTG

Died in 40’sBreast ca

DM

Died at age 75 Died at age 39 Died in 70’sCancer

HTGPancreatitis

DMAPOC2,

c.215G > Cp.R72T

Other family members are all living in overseas

ApoC-II heterozygote, likely

ApoC-II heterozygote in one parent

ApoC-II status indeterminate

ApoC-II status indeterminate

ApoC-II status indeterminate

ApoCII-status indeterminateApoC-II status indeterminate

ApoC-II status indeterminate

HTN

Homozygous, clinicalHeterozygous, clinical

ApoC-II deficiency

Figure 1: Patient’s family pedigree. )e patient is originally from Sudan, and many family members live overseas. Consanguinity is presenton both sides. )e patient’s paternal and maternal grandparents are distantly related. )e patient’s sister and one brother have similarmedical history with HTG and pancreatitis, as well as DM. His maternal uncles have HTG, and his maternal grandfather was known to havehad HTG.

First and only dose

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2015: response to experimental ANGPTL3 inhibitor mmol/L mg/dL

(a)

Figure 2: Continued.

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Lastly, apoC-II mimetic peptides effectively lowered TGin preclinical animal models of apoC-II deficiency [20]. Infact, adding one of these peptides normalized LPL activity inan ex vivo assay of our patient [11]. Ultimately, an apoC-IImimetic may become the most specific therapeutic optionfor apoC-II deficiency.

6. Conclusion

Our patient’s case clearly illustrates the importance ofcarefully delineating the cause of a rare condition to manageappropriately and to minimize unfavorable outcomes. Moreimportantly, all healthcare providers should be especially

mmol/L mg/dL

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1000

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0 30 60 90 120Day a�er first of two doses of experimental APOC3 inhibitor

2017: response to experimental APOC3 inhibitor

mmol/L mg/dL

(c)

Figure 2: Fasting TG response to chronological therapeutic attempts. (a))e line represents our patient’s TG response to a single dose of anexperimental ANGPTL3 inhibitor. Within 10 days post-dose, TG fell >50%, remaining –50% to –35% below baseline for about 90 daysafterwards. Overall, this effect lasted for about 120 days. (b) )e line represents the patient’s fasting TG in response to therapeutic plasmaexchange (TPE) using two types of replacement infusions: albumin and fresh frozen plasma (FFP).)e asterisks (∗) indicate times when TGdata are unavailable.)e vertical bars indicate 7 hospital admissions: admissions 1, 2, 4, 5, and 7 (brown) for pancreatitis, admission 3 (gray)for anorexia, weakness, and anemia, admission 6 (gray) for the management of duodenal obstruction for pancreatic cysts, receiving totalparental nutrition before converting to jejunostomy feeding followed by slowly resuming oral intake after discharge. 5% albumin re-placement only briefly lowered TG to about 500 to 1000mg/dL after exchanging 1.0 plasma volume (PV). After switching, three sessionswith FFP replacement were more effective in TG-lowering, with a sharp drop of TG to

vigilant when caring for a patient with an unfamiliardisorder.

Conflicts of Interest

Masako Ueda, Maria Escobar, Laura Walters, and DusankaLalic have nothing to disclose. Anna Wolska reports she hasa patent for apoC-II mimetic peptides (PCT/US2018/014532, 107102123) with royalties paid. Frances M. Burkereports personal fees from Akcea )erapeutics, outside thesubmitted work. Robert A. Hegele reports personal fees fromAcasti, Akcea/Ionis, Amgen, HLS )erapeutics, and Sanofiduring the conduct of the study. Alan T. Remaley reports hehas a patent for apoC-II mimetic peptides (PCT/US2018/014532, 107102123) with royalties paid and a patent for 18A-CII mimetic peptide (#8,936,787) issued. Daniel J. Raderreports personal fees from Alnylam, Novartis, Pfizer, Ionis,and Akcea and grants from Regeneron, outside the sub-mitted work. Richard L. Dunbar reports grants fromRegeneron, grants and personal fees from Akcea, grantsfromArizona Pharmaceuticals, grants fromUniQure, grantsfrom Astra-Zeneca, grants and others from Amarin, andothers from ICON Clinical Services, outside the submittedwork.

References

[1] R. A. Hegele, H. N. Ginsberg, M. J. Chapman et al., “)epolygenic nature of hypertriglyceridaemia: implications fordefinition, diagnosis, and management,” 7e Lancet Diabetes& Endocrinology, vol. 2, no. 8, pp. 655–666, 2014.

[2] A. J. Brahm and R. A. Hegele, “Chylomicronaemia-currentdiagnosis and future therapies,” Nature Reviews Endocrinol-ogy, vol. 11, no. 6, pp. 352–362, 2015.

[3] T. Gotoda, K. Shirai, T. Ohta et al., “Diagnosis and man-agement of type I and type V hyperlipoproteinemia,” Journalof Atherosclerosis and 7rombosis, vol. 19, no. 1, pp. 1–12,2012.

[4] J. de Graaf, P. Couture, and A. Sniderman, “A diagnosticalgorithm for the atherogenic apolipoprotein B dyslipopro-teinemias,” Nature Clinical Practice Endocrinology & Meta-bolism, vol. 4, no. 11, pp. 608–618, 2008.

[5] P. Moulin, R. Dufour, M. Averna et al., “Identification anddiagnosis of patients with familial chylomicronaemia syn-drome (FCS): expert panel recommendations and proposal ofan FCS score,” Atherosclerosis, vol. 275, pp. 265–272, 2018.

[6] J. S. Dron, J. Wang, H. Cao et al., “Severe hypertriglyceridemiais primarily polygenic,” Journal of Clinical Lipidology, vol. 13,no. 1, pp. 80–88, 2019.

[7] P. Moulin, R. Dufour, M. Averna et al., “Characterisation ofpatients with familial chylomicronaemia syndrome (FCS) andmultifactorial chylomicronaemia syndrome (MCS): estab-lishment of an FCS clinical diagnostic score,” Data in Brief,vol. 21, pp. 1334–1336, 2018.

[8] C. T. Johansen, J. B. Dubé, M. N. Loyzer et al., “LipidSeq: anext-generation clinical resequencing panel for monogenicdyslipidemias,” Journal of Lipid Research, vol. 55, no. 4,pp. 765–772, 2014.

[9] R. A. Hegele, A. J. Berberich, M. R. Ban et al., “Clinical andbiochemical features of different molecular etiologies of fa-milial chylomicronemia,” Journal of Clinical Lipidology,vol. 12, no. 4, pp. 920–927, 2018.

[10] C. Stefanutti, S. Di Giacomo, A. Vivenzio et al., “)erapeuticplasma exchange in patients with severe hypertriglyceridemia:a multicenter study,” Artificial Organs, vol. 33, no. 12,pp. 1096–1102, 2009.

[11] M. Ueda, R. L. Dunbar, A. Wolska et al., “A novel APOC2missense mutation causing apolipoprotein C-II deficiencywith severe triglyceridemia and pancreatitis,” 7e Journal ofClinical Endocrinology & Metabolism, vol. 102, no. 5,pp. 1454–1457, 2017.

[12] A. Wolska, R. L. Dunbar, L. A. Freeman et al., “Apolipo-protein C-II: new findings related to genetics, biochemistry,and role in triglyceride metabolism,” Atherosclerosis, vol. 267,pp. 49–60, 2017.

[13] R. Inokuchi, A. Matsumoto, R. Azihara et al., “Hyper-triglyceridemia as a possible cause of coma: a case report,”Journal of Medical Case Reports, vol. 6, no. 1, p. 412, 2012.

[14] R. L. Dunbar and D. J. Rader, “Demystifying triglycerides: apractical approach for the clinician,” Cleveland Clinic Journalof Medicine, vol. 72, no. 8, pp. 661–666, 2005.

[15] R. L. Dunbar, S. J. Nicholls, K. C. Maki et al., “Effects ofomega-3 carboxylic acids on lipoprotein particles and othercardiovascular risk markers in high-risk statin-treated pa-tients with residual hypertriglyceridemia: a randomized,controlled, double-blind trial,” Lipids in Health and Disease,vol. 14, no. 1, p. 98, 2015.

[16] D. L. Bhatt, P. G. Steg, M. Miller et al., “Cardiovascular riskreduction with icosapent ethyl for hypertriglyceridemia,”NewEngland Journal of Medicine, vol. 380, no. 1, pp. 11–22, 2019.

[17] A. D. Pradhan, N. P. Paynter, B. M. Everett et al., “Rationaleand design of the pemafibrate to reduce cardiovascularoutcomes by reducing triglycerides in patients with diabetes(PROMINENT) study,” American Heart Journal, vol. 206,pp. 80–93, 2018.

[18] R. L. Dunbar and H. Goel, “Niacin alternatives for dyslipi-demia: fool’s gold or gold mine? Part I: alternative niacinregimens,”Current Atherosclerosis Reports, vol. 18, no. 2, p. 11,2016.

[19] S. Tuteja, D. Duffy, R. L. Dunbar et al., “Pharmacokineticinteractions of the microsomal triglyceride transfer proteininhibitor, lomitapide, with drugs commonly used in themanagement of hypercholesterolemia,” Pharmacotherapy:7e Journal of Human Pharmacology and Drug 7erapy,vol. 34, no. 3, pp. 227–239, 2014.

[20] M. J. A. Amar, T. Sakurai, A. Sakurai-Ikuta et al., “A novelapolipoprotein C-II mimetic peptide that activates lipoproteinlipase and decreases serum triglycerides in apolipoproteinE-knockout mice,” Journal of Pharmacology and Experimental7erapeutics, vol. 352, no. 2, pp. 227–235, 2015.

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