Raphael Schiffmann M.D.

Moreno-Martinez, D., Aguiar, P., Auray-Blais, C., Beck, M., Bichet, D.G., Burlina, A., Cole, D., Elliott, P., Feldt-Rasmussen, U., Feriozzi, S., Fletcher, J., Giugliani, R., Jovanovic, A., Kampmann, C., Langeveld, M., Lidove, O., Linhart, A., Mauer, M., Moon, J.C., Muir, A., Nowak, A., Oliveira, J.P., Ortiz, A., Pintos-Morell, G., Politei, J., Rozenfeld, P., Schiffmann, R., Svarstad, E., Talbot, A.S., Thomas, M., Tøndel, C., Warnock, D., West, M.L. and Hughes, D.A. (2021). “Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.” Mol Genet Metab Feb 20;S1096-7192(21)00035-4. [Epub ahead of print].

Full text of this article.

BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

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., Sébire, 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.S., Vanderver, A., Martos-Moreno, G., Polychronakos, C., Wolf, N.I. and Bernard, G. (2021). “Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.” J Clin Endocrinol Metab 106(2): e660-e674.

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 and 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 3 predominant centers. PATIENTS: A total of 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-I, prolactin, ACTH, cortisol, TSH, and T4), and 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 underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

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].

Full text of this article.

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.

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.