RESUMO
Glycosylation is a critical post/peri-translational modification required for the appropriate development and function of the immune system. As an example, abnormalities in glycosylation can cause antibody deficiency and reduced lymphocyte signaling, although the phenotype can be complex given the diverse roles of glycosylation. Human MGAT2 encodes N-acetylglucosaminyltransferase II, which is a critical enzyme in the processing of oligomannose to complex N-glycans. Complex N-glycans are essential for immune system functionality, but only one individual with MGAT2-CDG has been described to have an abnormal immunologic evaluation. MGAT2-CDG (CDG-IIa) is a congenital disorder of glycosylation (CDG) associated with profound global developmental disability, hypotonia, early onset epilepsy, and other multisystem manifestations. Here, we report a 4-year old female with MGAT2-CDG due to a novel homozygous pathogenic variant in MGAT2, a 4-base pair deletion, c.1006_1009delGACA. In addition to clinical features previously described in MGAT2-CDG, she experienced episodic asystole, persistent hypogammaglobulinemia, and defective ex vivo mitogen and antigen proliferative responses, but intact specific vaccine antibody titers. Her infection history has been mild despite the testing abnormalities. We compare this patient to the 15 previously reported patients in the literature, thus expanding both the genotypic and phenotypic spectrum for MGAT2-CDG.
Assuntos
Arritmias Cardíacas/genética , Defeitos Congênitos da Glicosilação/genética , Doenças do Sistema Imunitário/genética , N-Acetilglucosaminiltransferases/genética , Arritmias Cardíacas/complicações , Arritmias Cardíacas/imunologia , Arritmias Cardíacas/patologia , Pré-Escolar , Defeitos Congênitos da Glicosilação/complicações , Defeitos Congênitos da Glicosilação/imunologia , Defeitos Congênitos da Glicosilação/patologia , Feminino , Glicosilação , Homozigoto , Humanos , Doenças do Sistema Imunitário/complicações , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Mutação/genética , N-Acetilglucosaminiltransferases/imunologia , FenótipoRESUMO
BACKGROUND: Patients with severe long-chain fatty acid oxidation disorders (LC-FAODs) experience serious morbidity and mortality despite traditional dietary management including medium-chain triglyceride (MCT)-supplemented, low-fat diets. Triheptanoin is a triglyceride oil that is broken down to acetyl-coenzyme A (CoA) and propionyl-CoA, which replenishes deficient tricarboxylic acid cycle intermediates. We report the complex medical and nutrition management of triheptanoin therapy initiated emergently for 3 patients with LC-FAOD. METHODS: Triheptanoin (Ultragenyx Pharmaceutical, Inc, Novato, CA, USA) was administered to 3 patients with LC-FAOD on a compassionate-use basis. Triheptanoin was mixed with non-MCT-containing low-fat formula. Patients were closely followed with regular cardiac and laboratory monitoring. RESULTS: Cardiac ejection fraction normalized after triheptanoin initiation. Patients experienced fewer hospitalizations related to metabolic crises while on triheptanoin. Patient 1 has tolerated oral administration without difficulty since birth. Patients 2 and 3 experienced increased diarrhea. Recurrent breakdown of the silicone gastrostomy tube occurred in patient 3, whereas the polyurethane nasogastric tube for patient 2 remained intact. Patient 3 experiences recurrent episodes of elevated creatine kinase levels and muscle weakness associated with illness. Patient 3 had chronically elevated C10-acylcarnitines while on MCT supplementation, which normalized after initiation of triheptanoin and discontinuation of MCT oil. CONCLUSIONS: Triheptanoin can ameliorate acute cardiomyopathy and increase survival in patients with severe LC-FAOD. Substituting triheptanoin for traditional MCT-based treatment improves clinical outcomes. MCT oil might be less effective in carnitine-acylcarnitine translocase deficiency patients compared with other FAODs and needs further investigation.
Assuntos
Erros Inatos do Metabolismo Lipídico , Carnitina , Ácidos Graxos , Humanos , Erros Inatos do Metabolismo Lipídico/tratamento farmacológico , Oxirredução , TriglicerídeosRESUMO
Exome sequencing (ES) has revolutionized molecular diagnosis in children with genetic disease over the past decade. However, exome sequencing in the inpatient setting has traditionally been discouraged, in part due to an increased risk of providers failing to retrieve and act upon results, as many patients are discharged before results return. The development of rapid turn-around-times (TATs) for genomic testing has begun to shift this paradigm. Rapid exome sequencing (rES) is increasingly being used as a diagnostic tool for critically ill infants with likely genetic disease and presents significant challenges to execute. We implemented a program, entitled the Rapid Inpatient Genomic Testing (RIGhT) project, to identify critically ill children for whom a molecular diagnosis is likely to change inpatient management. Two important goals of the RIGhT project were to provide appropriate genetic counseling, and to develop protocols to ensure efficient test coordination- both of which relied heavily on laboratory and clinic-based genetic counselors (GCs). Here, rES was performed on 27 inpatient trios from October 2016 to August 2018; laboratory and clinical GCs encountered significant challenges in the coordination of this testing. The GCs involved retrospectively reviewed these cases and identified three common challenges encountered during pretest counseling and coordination. The aim of this paper is to define these challenges using illustrative case examples that highlight the importance of including GCs to support rES programs.