Research Spotlight

Poffenberger, C.N., Inati, S., Tayebi, N., Stubblefield, B.K., Ryan, E., Schiffmann, R., Sidransky, E. and Lopez, G. (2020). “EEG abnormalities in patients with chronic neuronopathic Gaucher disease: A retrospective review.” Mol Genet Metab Oct 20;S1096-7192(20)30210-9. [Epub ahead of print].

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The clinical phenotype of Gaucher disease type 3 (GD3), a neuronopathic lysosomal storage disorder, encompasses a wide array of neurological manifestations including neuro-ophthalmological findings, developmental delay, and seizures including progressive myoclonic epilepsy. Electroencephalography (EEG) is a widely available tool used to identify abnormalities in cerebral function, as well as epileptiform abnormalities indicating an increased risk of seizures. We characterized the EEG findings in GD3, reviewing 67 patients with 293 EEGs collected over nearly 50 years. Over 93% of patients had some form of EEG abnormality, most consisting of background slowing (90%), followed by interictal epileptiform discharges (IEDs) (54%), and photoparoxysmal responses (25%). The seven patients without background slowing were all under age 14 (mean 6.7 years). There was a history of seizures in 37% of this cohort; only 30% of these had IEDs on EEG. Conversely, only 56% of patients with IEDs had a history of seizures. These observed EEG abnormalities document an important aspect of the natural history of GD3 and could potentially assist in identifying neurological involvement in a patient with subtle clinical findings. Additionally, this comprehensive description of longitudinal EEG data provides essential baseline data for understanding central nervous system involvement in neuronopathic GD.

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.

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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.

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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.

Ather, N. and Roberts, W.C. (2020). “Location of the Cannula of the Left Ventricular Assist Device in Explanted Hearts After Orthotopic Heart Transplantation.” Am J Cardiol 134: 91-98.

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Many patients having orthotopic heart transplantation (OHT) have previously had a left ventricular assist device (LVAD). Such a scenario allows the study of the position of the LVAD cannula in the explanted heart. We studied the explanted hearts in 105 patients who had had a LVAD inserted earlier and later underwent OHT at Baylor University Medical Center from January 2005 to September 2019, and compared the patients in whom the margins of the LVAD cannula contacted the mural endocardium with those in whom it did not. The margins of the orifice of the LVAD cannula contacted the left ventricular (LV) mural endocardium in 38 (36%) patients (considered potentially hazardous insertion) whereas in 67 (64%) patients there was no contact (considered “ideal” insertion). Comparison of the patients with ideal cannular insertion to those with potentially hazardous insertion disclosed insignificant differences in age at LVAD insertion or OHT; gender; interval between the LVAD insertion and OHT; body mass index; underlying cardiac disease; whether or not the heart floated in a container of formaldehyde, and the type of LVAD inserted. The margins of the LVAD cannula contacted the LV mural endocardium significantly more in patients with smaller mean heart weights than those with larger mean heart weights. In conclusion, of the 105 patients studied, the cannula of the LVAD resided in the LV cavity at an angle that allowed the margins of the orifice of the cannula to contact the mural endocardium in 38 (36%), a situation that at least potentially could cause partial obstruction of its orifice. Nevertheless, comparison of the 38 patients with nonideal cannular insertion to the 67 with ideal cannular insertion disclosed only 1 significant difference between the 2 groups.

Rahimi, R.S., Safadi, R., Thabut, D., Bhamidimarri, K.R., Pyrsopoulos, N., Potthoff, A., Bukofzer, S. and Bajaj, J.S. (2020). “Efficacy and Safety of Ornithine Phenylacetate for Treating Overt Hepatic Encephalopathy in a Randomized Trial.” Clin Gastroenterol Hepatol Oct 15;S1542-3565(20)31432-4. [Epub ahead of print].

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BACKGROUND & AIMS: Hepatic encephalopathy (HE) is associated with increased morbidity, mortality, and healthcare resource use. In this phase 2b study, we evaluated the efficacy and safety of ornithine phenylacetate (OP), an ammonia scavenger, in hospitalized patients with cirrhosis, increased levels of ammonia at screening, and acute or overt HE. METHODS: We conducted a double-blind study of 231 patients with cirrhosis and HE at multiple sites in North America, Europe, Israel, and Australia from January 7, 2014, through December 29, 2016. Patients were randomly assigned to groups that received placebo or OP (10, 15, or 20 g/day, based on severity of liver disease), plus each institution’s standard of care (for example, lactulose to achieve 2-3 bowel movements with or without rifaximin, in accordance with guidelines). The primary endpoint was time to confirmed clinical response, defined as reduction to HE staging tool (HEST) stage 2 from baseline HEST stage 3/4 or improvement to HEST stage 0/1 from baseline stage 2, in the intent to treat population (all patients with increased levels of ammonia at screening, determined by a local laboratory). RESULTS: Median times to clinical improvement, based on ammonia measurements at local laboratories, did not differ significantly between the groups given OP vs the placebo group (P=.129). Analyses of central laboratory confirmed increases in levels of ammonia at baseline (n=201) revealed a clinical improvement in HE at a median of 21 hours sooner in groups given OP vs placebo. The percentages of patients with any specific adverse event did not differ significantly between groups. Serious adverse events occurred in 25% of patients in the OP group and 29% in the placebo group (P=.552). CONCLUSIONS: In a randomized controlled trial of patients with cirrhosis and HE, we found no significant difference in time to clinical improvement between patients given OP vs placebo. However, OP appears to be safe and should undergo further testing for treatment of hyperammonemia in hospitalized patients receiving treatment for the underlying precipitant of acute or overt HE.