Baylor Research Institute

Pewzner-Jung, Y., Joseph, T., Blumenreich, S., Vardi, A., Ferreira, N.S., Cho, S.M., Eilam, R., Tsoory, M., Biton, I.E., Brumfeld, V., Haffner-Krausz, R., Brenner, O., Sharabi, N., Addadi, Y., Salame, T.M., Rotkopf, R., Wigoda, N., Yayon, N., Merrill, A.H., Jr., Schiffmann, R. and Futerman, A.H. (2020). “Brain pathology and cerebellar purkinje cell loss in a mouse model of chronic neuronopathic Gaucher disease.” Prog Neurobiol Nov 3;101939. [Epub ahead of print]. 101939.

Full text of this article.

Gaucher disease (GD) is currently the focus of considerable attention due primarily to the association between the gene that causes GD (GBA) and Parkinson’s disease. Mouse models exist for the systemic (type 1) and for the acute neuronopathic forms (type 2) of GD. Here we report the generation of a mouse that phenotypically models chronic neuronopathic type 3 GD. Gba(-/-);Gba(tg) mice, which contain a Gba transgene regulated by doxycycline, accumulate moderate levels of the offending substrate in GD, glucosylceramide, and live for up to 10 months, i.e. significantly longer than mice which model type 2 GD. Gba(-/-);Gba(tg) mice display behavioral abnormalities at ∼4 months, which deteriorate with age, along with significant neuropathology including loss of Purkinje neurons. Gene expression is altered in the brain and in isolated microglia, although the changes in gene expression are less extensive than in mice modeling type 2 disease. Finally, bone deformities are consistent with the Gba(-/-);Gba(tg) mice being a genuine type 3 GD model. Together, the Gba(-/-);Gba(tg) mice share pathological pathways with acute neuronopathic GD mice but also display differences that might help understand the distinct disease course and progression of type 2 and 3 patients.

Hughes, D.A., Aguiar, P., Deegan, P.B., Ezgu, F., Frustaci, A., Lidove, O., Linhart, A., Lubanda, J.C., Moon, J.C., Nicholls, K., Niu, D.M., Nowak, A., Ramaswami, U., Reisin, R., Rozenfeld, P., Schiffmann, R., Svarstad, E., Thomas, M., Torra, R., Vujkovac, B., Warnock, D.G., West, M.L., Johnson, J., Rolfe, M.J. and Feriozzi, S. (2020). “Early indicators of disease progression in Fabry disease that may indicate the need for disease-specific treatment initiation: findings from the opinion-based PREDICT-FD modified Delphi consensus initiative.” BMJ Open 10(10): e035182.

Full text of this article.

OBJECTIVES: The PRoposing Early Disease Indicators for Clinical Tracking in Fabry Disease (PREDICT-FD) initiative aimed to reach consensus among a panel of global experts on early indicators of disease progression that may justify FD-specific treatment initiation. DESIGN AND SETTING: Anonymous feedback from panellists via online questionnaires was analysed using a modified Delphi consensus technique. Questionnaires and data were managed by an independent administrator directed by two non-voting cochairs. First, possible early indicators of renal, cardiac and central/peripheral nervous system (CNS/PNS) damage, and other disease and patient-reported indicators assessable in routine clinical practice were compiled by the cochairs and administrator from panellists’ free-text responses. Second, the panel scored indicators for importance (5-point scale: 1=not important; 5=extremely important); indicators scoring ≥3 among >75% of panellists were then rated for agreement (5-point scale: 1=strongly disagree; 5=strongly agree). Indicators awarded an agreement score ≥4 by >67% of panellists achieved consensus. Finally, any panel-proposed refinements to consensus indicator definitions were adopted if >75% of panellists agreed. RESULTS: A panel of 21 expert clinicians from 15 countries provided information from which 83 possible current indicators of damage (kidney, 15; cardiac, 15; CNS/PNS, 13; other, 16; patient reported, 24) were compiled. Of 45 indicators meeting the importance criteria, consensus was reached for 29 and consolidated as 27 indicators (kidney, 6; cardiac, 10; CNS/PNS, 2; other, 6; patient reported, 3) including: (kidney) elevated albumin:creatinine ratio, histological damage, microalbuminuria; (cardiac) markers of early systolic/diastolic dysfunction, elevated serum cardiac troponin; (CNS/PNS) neuropathic pain, gastrointestinal symptoms suggestive of gastrointestinal neuropathy; (other) pain in extremities/neuropathy, angiokeratoma; (patient-reported) febrile crises, progression of symptoms/signs. Panellists revised and approved proposed chronologies of when the consensus indicators manifest. The panel response rate was >95% at all stages. CONCLUSIONS: PREDICT-FD captured global opinion regarding current clinical indicators that could prompt FD-specific treatment initiation earlier than is currently practised.

Morvaridzadeh, M., Fazelian, S., Agah, S., Khazdouz, M., Rahimlou, M., Agh, F., Potter, E., Heshmati, S. and Heshmati, J. (2020). “Effect of ginger (Zingiber officinale) on inflammatory markers: A systematic review and meta-analysis of randomized controlled trials.” Cytokine 135: 155224.

Full text of this article.

The aim of this systematic review and meta-analysis was to investigate the efficacy of ginger supplementation on circulating levels of C-reactive protein (CRP), high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α), soluble intercellular adhesion molecule (sICAM), and interleukin-6 (IL-6) concentrations in randomized controlled trials (RCTs). The search included PubMed-Medline, EMBASE, Scopus, Web of Science and Cochrane Library databases to identify randomized clinical trials on the effect of ginger supplementation on circulation levels of CRP, hs-CRP, IL-6, sICAM, and TNF-α published up until February 1st, 2020. We did not restrict articles based on language of publication. Standard mean differences and 95% confidence intervals were calculated for net changes in inflammatory mediators using a random-effects model. Sixteen RCTs comprising 1010 participants were found to be eligible for this meta-analysis. There was a significant reduction of circulating CRP (SMD: -5.11, 95% CI: -7.91, -2.30, I(2) = 98.1%), hs-CRP (SMD: -0.88, 95% CI: -1.63, -0.12, I(2) = 90.8%) and TNF-α levels (SMD: -0.85, 95% CI: -1.48, -0.21, I(2) = 89.4%) following ginger supplementation. However, meta-analysis results did not show any significant impact of ginger supplementation on IL-6 (SMD: -0.45, 95% CI: -1.29, 0.38, I(2) = 89.2%), and sICAM levels (SMD: -0.05, 95% CI: -0.36, 0.26, I(2) = 00.0%). This systematic review and meta-analysis of RCTs demonstrates a significant impact of ginger in lowering circulating CRP, hs-CRP and TNF-α levels. Large-scale RCTs are still needed to draw concrete conclusions about the effect of ginger on other inflammatory mediators.

Froehlich-Grobe, K., Betts, A.C., Driver, S.J., Carlton, D.N., Lopez, A.M., Lee, J. and Kramer, M.K. (2020). “Group Lifestyle Balance Adapted for Individuals With Impaired Mobility: Outcomes for 6-Month RCT and Combined Groups at 12 Months.” Am J Prev Med 59(6): 805-817.

Full text of this article.

INTRODUCTION: This study examines the feasibility and effectiveness of an intensive lifestyle intervention adapted for people with impaired mobility. STUDY DESIGN: This was a randomized, wait-list controlled trial. The experimental group immediately received the 12-month weight loss program; the wait-list control group received it after a 6-month delay. Between-group comparisons were conducted for the 6-month RCT study design. Repeated measures were conducted for both groups combined after receiving the 12-month intervention. Data were collected August 2015-February 2017 and analyzed in 2017. SETTING/PARTICIPANTS: A community-based sample received 23, group-based sessions via a mix of telephone and in-person sessions in a hospital-based setting. Participants with impaired mobility (n=66) were middle-aged (49.80 [SD=11.37] years), mostly White (66.7%), female (66.7%), and most commonly had spinal cord injury (47.0%). INTERVENTION: The 12-month intervention delivered 23 group-based sessions that promoted weight loss through reducing caloric intake and increasing physical activity. MAIN OUTCOME MEASURES: Primary outcomes were effectiveness measured as change in weight and time spent in moderate physical activity. Feasibility was assessed in 12-month combined group analyses, measured as retention, attendance, and dietary self-monitoring. RESULTS: The 6-month RCT results showed that the immediate and delayed groups differed significantly (p<0.05) in weight (-1.66 [SD=4.42] kg loss vs 0.05 [SD=4.15] kg gain) and moderate physical activity (52.93 [SD=90.74] minutes/week increase vs -14.22 [SD=96.02] minutes/week decrease), accounting for baseline weight, time with disability, and age of onset. The 12-month results with groups combined demonstrated 74.2% retention and 77.7% core session attendance. Self-monitoring was higher in the delayed group (77.3%), who used a smartphone app, than the immediate group (47.3%), who mostly used paper trackers. Participants achieved significant 12-month weight loss of 3.31 (SD=10.13) kg (d=0.33) in mixed modeling analyses with groups combined yet did not significantly increase moderate physical activity. CONCLUSIONS: Group Lifestyle Balance Adapted for Individuals with Impaired Mobility is a feasible, effective approach to teach healthy lifestyle skills to individuals with mobility impairment, yielding modest weight loss and enhanced self-efficacy.

Pelletier, F., Perrier, S., Cayami, F.K., Mirchi, A., Saikali, S., Tran, L.T., Ulrick, N., Guerrero, K., Rampakakis, E., van Spaendonk, R.M.L., Naidu, S., Pohl, D., Gibson, W.T., Demos, M., Goizet, C., Tejera-Martin, I., Potic, A., Fogel, B.L., Brais, B., Sylvain, M., Sebire, G., Lourenço, C.M., Bonkowsky, J.L., Catsman-Berrevoets, C., Pinto, P.S., Tirupathi, S., Strømme, P., de Grauw, T., Gieruszczak-Bialek, D., Krägeloh-Mann, I., Mierzewska, H., Philippi, H., Rankin, J., Atik, T., Banwell, B., Benko, W.S., Blaschek, A., Bley, A., Boltshauser, E., Bratkovic, D., Brozova, K., Cimas, I., Clough, C., Corenblum, B., Dinopoulos, A., Dolan, G., Faletra, F., Fernandez, R., Fletcher, J., Garcia Garcia, M.E., Gasparini, P., Gburek-Augustat, J., Gonzalez Moron, D., Hamati, A., Harting, I., Hertzberg, C., Hill, A., Hobson, G.M., Innes, A.M., Kauffman, M., Kirwin, S.M., Kluger, G., Kolditz, P., Kotzaeridou, U., La Piana, R., Liston, E., McClintock, W., McEntagart, M., McKenzie, F., Melançon, S., Misbahuddin, A., Suri, M., Monton, F.I., Moutton, S., Murphy, R.P.J., Nickel, M., Onay, H., Orcesi, S., Özkınay, F., Patzer, S., Pedro, H., Pekic, S., Pineda Marfa, M., Pizzino, A., Plecko, B., Poll-The, B.T., Popovic, V., Rating, D., Rioux, M.F., Rodriguez Espinosa, N., Ronan, A., Ostergaard, J.R., Rossignol, E., Sanchez-Carpintero, R., Schossig, A., Senbil, N., Sønderberg Roos, L.K., Stevens, C.A., Synofzik, M., Sztriha, L., Tibussek, D., Timmann, D., Tonduti, D., van de Warrenburg, B.P., Vázquez-López, M., Venkateswaran, S., Wasling, P., Wassmer, E., Webster, R.I., Wiegand, G., Yoon, G., Rotteveel, J., Schiffmann, R., van der Knaap, M., Vanderver, A., Martos-Moreno, G., Polychronakos, C., Wolf, N.I. and Bernard, G. (2020). “Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.” J Clin Endocrinol Metab Oct 1;dgaa700. [Epub ahead of print.].

Full text of this article.

CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015-2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from three predominant centers. PATIENTS: 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-1, prolactin, ACTH, cortisol, TSH, and T4), height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically under-investigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.