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Experimental Therapeutics for Challenging Clinical Care of a Patient with an Extremely Rare Homozygous APOC2 Mutation.

ABSTRACT: Background:Among many causes of hypertriglyceridemia (HTG), familial chylomicronemia syndrome (FCS) is a rare monogenic disorder that manifests as severe HTG and acute pancreatitis. Among the known causal genes for FCS, mutations in APOC2 only account for <2% of cases. Medical nutrition therapy is critical for FCS because usual triglyceride- (TG-) lowering medications are ineffective. Therapeutic plasma exchange (TPE) with fresh frozen plasma (FFP) is an option to urgently reduce TG and pancreatitis episodes. Several novel biologics are under development to treat HTG and may provide therapeutic options for FCS in the future. Objective:We present the challenging care of a 43-year-old man with FCS with apoC-II deficiency and the results of two types of TPE and of investigational TG-lowering biologic therapies. Results:The patient's lipid profile was consistent with FCS. A novel homozygous variant was identified in APOC2, and its pathogenicity was confirmed. Even on a fat-restricted diet, his care was tremendously complicated with unremitting bouts of pancreatitis. TPE with FFP replacement lowered TG >90% post-sessions and 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 to optimize therapy and to minimize unfavorable outcomes.

SUBMITTER: Ueda M

PROVIDER: S-EPMC7149354 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Experimental Therapeutics for Challenging Clinical Care of a Patient with an Extremely Rare Homozygous <i>APOC2</i> Mutation.

Ueda Masako M Wolska Anna A Burke Frances M FM Escobar Maria M Walters Laura L Lalic Dusanka D Hegele Robert A RA Remaley Alan T AT Rader Daniel J DJ Dunbar Richard L RL

Case reports in endocrinology 20200327

<h4>Background</h4>Among many causes of hypertriglyceridemia (HTG), familial chylomicronemia syndrome (FCS) is a rare monogenic disorder that manifests as severe HTG and acute pancreatitis. Among the known causal genes for FCS, mutations in <i>APOC2</i> only account for <2% of cases. Medical nutrition therapy is critical for FCS because usual triglyceride- (TG-) lowering medications are ineffective. Therapeutic plasma exchange (TPE) with fresh frozen plasma (FFP) is an option to urgently reduce ...[more]

PMID: 32292609

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Project description:ObjectivesPreprotein convertase 1/3 deficiency is a rare autosomal recessive disorder in which patients present with malabsorptive diarrhea and a series of symptoms of endocrine disorders such as polydipsia, reactive hypoglycemia, growth hormone deficiency, hypothyroidism, adrenal insufficiency, and early onset obesity. In its essence, pituitary hormone deficiency is caused by insufficient cleavage of pituitary prohormones. Here, we describe a female child with a rare double-site homozygous mutation in PCSK1 (Proprotein convertase subtilisin/kexin-type 1) gene, and thereby intend to investigate the relationship between these novel mutation sites and changes in protein synthesis and function.MethodsWe tested this patient's blood and urine fecal indicators of infection, blood electrolytes, and relevant endocrine hormone levels in the laboratory. Next Generation Sequencing was applied to screen the patient's DNA. Western Blot was performed to evaluate the mutant protein's expression. The enzymatic activity was measured as the rate of cleavage of a synthetic fluorogenic substrate in a specific solution.ResultsWe found that this patient presented shortly after birth with uncorrectable diarrhea and symptoms of metabolic acidosis with hypothyroidism. Next Generation Sequencing revealed that a rare double-site homozygous missense mutation, c.763G > A (p.G255R) and c.758C > T (p.S253L), were detected in exon 7 of PCSK1 (Proprotein convertase subtilisin/kexin-type 1) gene on chromosome 5 of the patient. Western blotting revealed that there was no significant decrease in protein synthesis levels in the mutant phenotype compared to the wild type. Compared with WT type, the proteins expressed by the mutations showed a significant decrease in the enzyme activity towards the fluorescent substrates. However, neither the single site mutation p.S253L or p.G255R, nor the double-site mutation of both, all showed no significant differences from each other.ConclusionsThese two missense mutations have not been reported before, and it is even rarer to find homozygous variation of two sites in one patient. This study identifies two novel mutations for the first time and further investigates the changes in protein synthesis and enzyme activity, providing a new pathway to continue to explore the pathogenesis of diseases associated with the function of PC1/3.

Dataset Information

Experimental Therapeutics for Challenging Clinical Care of a Patient with an Extremely Rare Homozygous APOC2 Mutation.

Publications

Experimental Therapeutics for Challenging Clinical Care of a Patient with an Extremely Rare Homozygous <i>APOC2</i> Mutation.

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