Citations

Background Propionic acidemia (PA) is a rare inborn error of metabolism that typically presents in infancy; however, late-onset variants may manifest with atypical features, including cardiac involvement. Dilated cardiomyopathy (DCM) is an uncommon but serious complication. Case summary A 15-year-old with no prior medical history but a significant maternal family history of cardiomyopathy of unknown etiology from an Amish background presented with altered mental status, increased work of breathing, and progressive edema in the context of preceding viral illness. Evaluation revealed severe biventricular dysfunction, chamber dilation, and findings consistent with chronic DCM. Despite supportive management, her course was complicated by ventricular arrhythmias and clinical deterioration. Metabolic workup demonstrated elevated propionylcarnitine and increased urinary 2-methylcitric acid, confirming late-onset variant PA. She was treated with intravenous carnitine and a specialized metabolic formula; however, cardiac function remained severely impaired. In accordance with family wishes, she was discharged home on hospice care. Conclusion Late-onset PA can present as isolated cardiomyopathy in adolescence. Early consideration of metabolic etiologies is essential in unexplained DCM, particularly in high-risk populations.

Abstract Highly conserved transport protein particle (TRAPP) complexes regulate subcellular trafficking pathways. Accurate protein trafficking has been increasingly recognized to be critically important for normal development, particularly in the nervous system. Variants in most TRAPP complex subunits have been found to lead to neurodevelopmental disorders with diverse but overlapping phenotypes. We expand on limited prior reports on TRAPPC6B with detailed clinical and neuroradiologic assessments, and studies on mechanisms of disease, and new types of variants. We describe 29 additional patients from 18 independent families with biallelic variants in TRAPPC6B. We identified seven homozygous nonsense (n = 12 patients) and eight canonical splice-site variants (n = 17 patients). In addition, we identified one patient with compound heterozygous splice-site/missense variants with a milder phenotype and one patient with homozygous missense variants. Patients displayed non-progressive microcephaly, global developmental delay/intellectual disability, epilepsy and absent expressive language. Movement disorders including stereotypies, spasticity and dystonia were also observed. Brain imaging revealed reductions in cortex, cerebellum and corpus callosum size with frequent white matter hyperintensity. Volumetric measurements indicated globally diminished volume rather than specific regional losses. We identified a reduced rate of trafficking into the Golgi apparatus and Golgi fragmentation in patient-derived fibroblasts that was rescued by wild-type TRAPPC6B. Molecular studies revealed a weakened interaction between mutant TRAPPC6B (c.454C>T, p.Q152*) and its TRAPP binding partner TRAPPC3. Patient-derived fibroblasts from the TRAPPC6B (c.454C>T, p.Q152*) variant displayed reduced levels of TRAPPC6B as well as other TRAPP II complex-specific members (TRAPPC9 and TRAPPC10). Interestingly, the levels of the TRAPPC6B homologue TRAPPC6A were found to be elevated. Moreover, co-immunoprecipitation experiments showed that TRAPPC6A co-precipitates equally with TRAPP II and TRAPP III, while TRAPPC6B co-precipitates significantly more with TRAPP II, suggesting enrichment of the protein in the TRAPP II complex. This implies that variants in TRAPPC6B may preferentially affect TRAPP II functions compared to TRAPP III functions. Finally, we assessed phenotypes in a Drosophila TRAPPC6B-deficiency model. Neuronal TRAPPC6B knockdown impaired locomotion and led to wing posture defects, supporting a role for TRAPPC6B in neuromotor function. Our findings confirm the association of damaging biallelic TRAPPC6B variants with microcephaly, intellectual disability, language impairments, and epilepsy. A subset of patients also exhibited dystonia and/or spasticity with impaired ambulation. These features overlap with disorders arising from pathogenic variants in other TRAPP subunits, particularly components of the TRAPP II complex. These findings suggest that TRAPPC6B is essential for brain development and function, and TRAPP II complex activity may be particularly relevant for mediating this function.

Abstract Intestinal permeability may correlate with adverse outcomes during hematopoietic stem cell transplantation (HSCT), but longitudinal quantification with traditional oral mannitol and lactulose is not feasible in HSCT recipients because of mucositis and diarrhea. A modified lactulose:rhamnose (LR) assay is validated in children with environmental enteritis. Our study objective was to quantify peri-HSCT intestinal permeability changes using the modified LR assay. The LR assay was administered before transplant, at day +7 and +30 to 80 pediatric and young adult patients who received allogeneic HSCT. Lactulose and rhamnose were detected using urine mass spectrometry and expressed as an L:R ratio. Metagenomic shotgun sequencing of stool for microbiome analyses and enzyme-linked immunosorbent assay analyses of plasma lipopolysaccharide binding protein (LBP), ST2, REG3α, claudin1, occludin, and intestinal alkaline phosphatase were performed at the same timepoints. L:R ratios were increased at day +7 but returned to baseline at day +30 in most patients (P = .014). Conditioning regimen intensity did not affect the trajectory of L:R (P = .39). Baseline L:R ratios did not vary with diagnosis. L:R correlated with LBP levels (r2 = 0.208; P = .0014). High L:R ratios were associated with lower microbiome diversity (P = .035), loss of anaerobic organisms (P = .020), and higher plasma LBP (P = .0014). No adverse gastrointestinal effects occurred because of LR. Intestinal permeability as measured through L:R ratios after allogeneic HSCT correlates with intestinal dysbiosis and elevated plasma LBP. The LR assay is well-tolerated and may identify transplant recipients who are more likely to experience adverse outcomes.

Abstract Electroconvulsive therapy (ECT) is a highly therapeutic and cost-effective treatment for severe and/or treatment-resistant major depression. However, because of the varied clinical practices, there is a great deal of heterogeneity in how ECT is delivered and documented. This represents both an opportunity to study how differences in implementation influence clinical outcomes and a challenge for carrying out coordinated quality improvement and research efforts across multiple ECT centers. The National Network of Depression Centers, a consortium of 26+ US academic medical centers of excellence providing care for patients with mood disorders, formed a task group with the goals of promoting best clinical practices for the delivery of ECT and to facilitate large-scale, multisite quality improvement and research to advance more effective and safe use of this treatment modality. The National Network of Depression Centers Task Group on ECT set out to define best practices for harmonizing the clinical documentation of ECT across treatment centers to promote clinical interoperability and facilitate a nationwide collaboration that would enable multisite quality improvement and longitudinal research in real-world settings. This article reports on the work of this effort. It focuses on the use of ECT for major depressive disorder, which accounts for the majority of ECT referrals in most countries. However, most of the recommendations on clinical documentation proposed herein will be applicable to the use of ECT for any of its indications.

4519 Background: Tandem HDC with carbo/etoposide (CE) is curative for a portion of relapsed GCT pts. However, outcomes of refractory or high-risk relapsed pts remain poor. We tested a new HDC regimen of GemDMC, based on DNA damage repair inhibition. We combined BEV with HDC given their potential synergy and the high vascularity of GCT metastases. Methods: Eligibility: Intermediate (int)/high-risk (Beyer Model), creatinine ≤1.8 mg/dL and adequate organ function. HDC included BEV (5 mg/kg) preceding GemDMC (HDC #1) and ifosfamide/CE (ICE) (HDC #2). Following accrual of 42 pts, we amended the trial omitting BEV. The trial was powered to distinguish a target 50% 2-yr RFS from an expected 25% in this population. Results: We enrolled 69 male pts in cohorts 1 (BEV, N=42) and 2 (no BEV, N=27) (Table). Pts were heavily pretreated and most had refractory tumors. Main AE: mucositis and renal (4 HDC-related deaths in cohort 1, 1 in cohort 2). Tumor markers normalized in 90% pts with active tumors at HDC. After HDC, 19 pts were in CR and 28 in PRm- (of these, 22 had residual lesions resected with no viable tumor found in 20/22, 2 xRT, 4 monitored). Median f/u = 39 (2-105) mo. The 2-yr RFS rates in cohorts 1 and 2 = 52% and 78%, respectively. Their respective 2-yr OS rates = 55% and 81%. Conclusions: Sequential HDC with GemDMC–ICE shows encouraging outcomes in heavily pretreated and refractory GCT, exceeding the anticipated results. Addition of BEV increases toxicity but not tumor control. Clinical trial information: NCT00936936. [Table: see text]

Abstract Background: Chemotherapy-related amenorrhea (CRA) impacts quality of life and reproductive options, and may play a role in treatment decision-making for young breast cancer patients. Although age, increasing doses of alkylating agents, and tamoxifen are known to increase the risk of chemotherapy-related amenorrhea (CRA), it is difficult to predict which women will develop CRA in order to inform fertility preservation and treatment decisions. We sought to investigate whether single nucleotide polymorphisms (SNPs) that have been associated with a younger age at natural menopause and ovarian reserve in non-oncologic populations were predictive of CRA in two large German clinical trials that administered gonadotoxic chemotherapy. Methods: A total of 1322 premenopausal participants under age 50 who enrolled in SUCCESS B (a phase 3 trial of FEC-docetaxel-trastuzumab +/- gemcitabine for high risk early stage breast cancer) or SUCCESS C (a phase 3 trial of FEC-docetaxel-cyclophosphamide vs. docetaxel-cyclophosphamide that also tested the efficacy of a weight loss intervention in early stage breast cancer patients) were eligible for this study. We excluded patients who were receiving ovarian suppression. On these trials, menstrual status was self-reported as amenorrheic or not every three months after chemotherapy. Bloods were stored and patients provided consent for DNA analysis. We genotyped nine candidate SNPs in six genes (rs2002555 and rs11170547 in AMHR2, rs6166 in FSHR, rs10852344 <60kb from TNFRSF17/RUNDC2A/ GSPT1, rs12461110 in NLRP11, rs1801133 in MTHFR, rs2066470 in MTHRF, rs3810682 in BMP15, and rs615942 in COASY), and examined their association with CRA at 12-month and 24-month time points using logistic regression adjusted for age, BMI, and tamoxifen. Results: Of the 554 eligible women with SNP data and menstrual data at 12 months, 70% reported CRA; of the 458 eligible women with SNP data and menstrual data at 24 months, 69% reported CRA. The two SNPs in AMHR2 showed suggestive associations with CRA at 12 and 24 months. [Final results pending]. Conclusions: Genetic variation in AMHR2 may be associated with CRA. Additional research will be needed to validate these findings in other breast cancer survivors and to identify additional SNPs that may be associated with CRA. Together with other clinical factors, genetic variation may improve our ability to predict who will experience CRA, and may inform reproductive and treatment decision-making in cancer patients. Citation Format: Ruddy KJ, Rack B, Schwitulla J, Lambrechts D, Haeberle L, Schramm A, Trapp E, Scholz C, Beutler AS, Ginsburg E, Couch F, Partridge AH, Wang L, Weinshilboum RM, Janni W, Vachon C, Fasching P. Genetic predictors of chemotherapy-related amenorrhea. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-10-07.