Baylor Research Institute

Gold, R., J. T. Phillips, E. Havrdova, A. Bar-Or, L. Kappos, N. Kim, T. Thullen, P. Valencia, L. Oliva, M. Novas, J. Li, M. T. Sweetser, N. Kurukulasuriya, V. Viglietta and R. J. Fox (2015). “Delayed-Release Dimethyl Fumarate and Pregnancy: Preclinical Studies and Pregnancy Outcomes from Clinical Trials and Postmarketing Experience.” Neurol Ther 4(2): 93-104.

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INTRODUCTION: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) is an oral agent for the treatment of relapsing forms of multiple sclerosis (MS). No formal studies of DMF were conducted in pregnant women, although pregnancies have occurred during clinical trials and in the postmarketing setting. METHODS: Preclinical developmental and reproductive toxicology studies were performed with DMF in rats and rabbits. As of March 26, 2014, the DMF clinical development program included a total of 4132 subjects consisting of 2898 patients with MS, 320 psoriasis patients, 101 rheumatoid arthritis patients, and 813 healthy volunteers. Subjects were required to use reliable contraception and immediately discontinue treatment in the event of pregnancy. RESULTS: Animal studies showed no evidence of impaired fertility or teratogenicity with DMF. Overall as of June 30, 2014, 63 pregnancies were reported in clinical trials. Outcomes are known for 39 of 42 subjects receiving DMF and include 26 live births (67%), three spontaneous abortions (8%), and 10 elective terminations (26%); follow-up is ongoing in 2 cases and one patient was lost to follow-up. The incidence of spontaneous abortion in subjects exposed to DMF was consistent with the expected rate of early pregnancy loss in the general population (12-22%). A total of 135 pregnancies were reported in the postmarketing setting (spontaneous and solicited reports). Outcomes are known for 30 cases and include 10 live births, 13 spontaneous abortions, and 5 elective terminations; follow-up is ongoing in 103 cases and 2 patients have been lost to follow-up. CONCLUSION: Although data are limited and all known exposures have occurred in the first trimester, no increased risk of fetal abnormalities or adverse pregnancy outcomes associated with gestational exposure to DMF has been observed. FUNDING: Biogen, Inc.

Theodore Phillips, J., A. A. Erwin, S. Agrella, M. Kremenchutzky, J. F. Kramer, M. J. Darkes, J. Kendter, H. Abourjaily, J. Rana and R. J. Fox (2015). “Consensus Management of Gastrointestinal Events Associated with Delayed-Release Dimethyl Fumarate: A Delphi Study.” Neurol Ther 4(2): 137-146.

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INTRODUCTION: Delayed-release dimethyl fumarate (DMF, also known as gastro-resistant DMF) is indicated for the treatment of patients with relapsing multiple sclerosis. Gastrointestinal (GI) adverse events (AEs) occur with DMF therapy. METHODS: We used a Delphi process to reach consensus among North American clinicians on effective real-world management strategies for GI AEs associated with DMF. Clinicians were asked to complete two rounds of questionnaires developed by a steering committee; consensus in round 2 was attained if >/=70% of respondents agreed on a particular strategy. RESULTS: Consensus was reached on several strategies to manage GI AEs, including administering DMF with food, slow titration, dose reduction, and use of symptomatic therapies. CONCLUSION: These consensus strategies provide clinicians with information on real-world approaches used to address the tolerability of DMF in patients with multiple sclerosis. FUNDING: Biogen.

Chujo, D., T. S. Nguyen, E. Foucat, D. Blankenship, J. Banchereau, G. T. Nepom, D. Chaussabel and H. Ueno (2015). “Adult-onset type 1 diabetes patients display decreased IGRP-specific Tr1 cells in blood.” Clinical Immunology 161(2): 270-277.

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The breakdown of immune tolerance against islet antigens causes type 1 diabetes (T1D). The antigens associated with adult-onset T1D (AT1D) remain largely undefined. It is possible that AT1D patients display a unique type of CD4(+) T cells specific for a certain islet antigen. Here we analyzed the cytokine production profiles of CD4(+) helper T (Th) cells that are specific for three islet antigens; GAD65, preproinsulin, and IGRP in patients with AT1D, juvenile-onset T1D (JT1D), and age-, gender- and human leukocyte antigen (HLA)-matched control adults. While IGRP-specific Th cells in AT1D patients were dominantly Th1 cells, IGRP-specific Th cells in control adults and JT1D patients were dominantly Th2 and T regulatory type 1 (Tr1) cells. Notably, the frequency of IGRP-specific Tr1 cells was significantly lower in AT1D patients than in control adults and JT1D patients. In conclusion, our study suggests that IGRP-specific Th cells play a unique pathogenic role in AT1D.

Schiffmann, R. (2015). “A genetic form of achlorhydria and gastritis.” American Journal of Clinical Nutrition 102(6): 1615-1615.

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The recent review article on the connection between achlorhydria and iron deficiency anemia concludes that gastritis-induced achlorhydria can be an independent cause of iron deficiency anemia. I would like to attract your attention to a little-known autosomal recessive genetic disease, mucolipidosis type IV (MLIV), in which all patients have constitutive achlorhydria. MLIV is caused by mutation of the MCOLN1 gene that encodes the endosomal/lysosomal transient receptor potential channel protein mucolipin 1 (TRPML1). The exact mechanism by which this nonselective cation channel deficiency prevents hydrochloric acid secretion is incompletely understood. Parietal cells in MLIV are present in seemingly normal numbers, are full of large vacuoles, yet produce normal amounts of intrinsic factor. All patients tested thus far were achlorhydric with up to 10-fold elevations in blood gastrin, which is useful for disease screening (5). Mucosal atrophy was present in biopsy samples, with increasing chronic inflammation with age. Fifty percent of patients with MLIV have iron deficiency anemia, which can be corrected with oral iron preparations. Because the achlorhydria is congenital, it is likely that it leads over time to both gastritis and iron deficiency but that the presence of gastritis is not necessary for abnormal absorption of food iron. To our knowledge, MLIV is the only single-gene disorder associated with a selective defect of gastric hydrochloric acid secretion.

Roe, C. R. and H. Brunengraber (2015). “Anaplerotic treatment of long-chain fat oxidation disorders with triheptanoin: Review of 15 years experience.” Mol Genet Metab 116(4): 260-268.

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BACKGROUND: The treatment of long-chain mitochondrial beta-oxidation disorders (LC-FOD) with a low fat-high carbohydrate diet, a diet rich in medium-even-chain triglycerides (MCT), or a combination of both has been associated with high morbidity and mortality for decades. The pathological tableau appears to be caused by energy deficiency resulting from reduced availability of citric acid cycle (CAC) intermediates required for optimal oxidation of acetyl-CoA. This hypothesis was investigated by diet therapy with carnitine and anaplerotic triheptanoin (TH). METHODS: Fifty-two documented LC-FOD patients were studied in this investigation (age range: birth to 51years). Safety monitoring included serial quantitative measurements of routine blood chemistries, blood levels of carnitine and acylcarnitines, and urinary organic acids. RESULTS: The average frequency of serious clinical complications were reduced from ~60% with conventional diet therapy to 10% with TH and carnitine treatment and mortality decreased from ~65% with conventional diet therapy to 3.8%. Carnitine supplementation was uncomplicated. CONCLUSION: The energy deficiency in LC-FOD patients was corrected safely and more effectively with the triheptanoin diet and carnitine supplement than with conventional diet therapy. Safe intervention in neonates and infants will permit earlier intervention following pre-natal diagnosis or diagnosis by expanded newborn screening.