title: Determinants of white matter hyperintensity burden in patients with Fabry disease.
abstract: OBJECTIVE
  Using a semiautomated volumetric MRI assessment method, we aimed to identify determinants of white matter hyperintensity (WMH) burden in patients with Fabry disease (FD).
  
  
  METHODS
  Patients with confirmed FD and brain MRI available for this analysis were eligible for this protocol after written consent. Clinical characteristics were abstracted from medical records. T2 fluid-attenuated inversion recovery MRI were transferred in electronic format and analyzed for WMH volume (WMHV) using a validated, computer-assisted method. WMHV was normalized for head size (nWMHV) and natural log-transformed (lnWMHV) for univariate and multivariate linear regression analyses. Level of significance was set at p < 0.05 for all analyses.
  
  
  RESULTS
  Of 223 patients with FD and WMHV analyzed, 132 (59%) were female. Mean age at MRI was 39.2 ± 14.9 (range 9.6-72.7) years, and 136 (61%) patients received enzyme replacement therapy prior to enrollment. Median nWMHV was 2.7 cm(3) (interquartile range 1.8-4.0). Age (β 0.02, p = 0.008) and history of stroke (β 1.13, p = 0.02) were independently associated with lnWMHV. However, WMH burden-as well as WMHV predictors-varied by decade of life in this cohort of patients with FD (p < 0.0001).
  
  
  CONCLUSIONS
  In this largest-to-date cohort of patients with FD who had volumetric analysis of MRI, age and prior stroke independently predicted the burden of WMH. The 4th decade of life appears to be critical in progression of WMH burden, as novel predictors of WMHV emerged in patients aged 31-40 years. Future studies to elucidate the biology of WMH in FD and its role as potential MRI marker of disease progression are needed.
authors.affiliation: From the J. Philip Kistler Stroke Research Center, Department of Neurology (N.S.R., L.C., A.S.K., K.M.F.), and the Center for Human Genetic Research, Department of Neurology (N.S.R., D.R.A., V.C., K.B.S.), Massachusetts General Hospital, Boston; Neurogenetics Unit (C.M.L.), School of Medicine of Riberirao Preto, University of São Paulo, Brazil; Division of Medical Genetics (D.P.G.), University of Versailles-St Quentin en Yvelines Paris-Saclay University, France; Fundación para el Estudio de las Enfermedades Neurometabólicas (FESEN) (J.M.P.), Buenos Aires, Argentina; and Departments of Neuroradiology (G.A.H.) and Neurology (C.S., N.Ü.), Fabry Center for Interdisciplinary Therapy (FAZIT) (C.S., N.Ü.), University of Würzburg, Germany. nrost@partners.org.
authors.forename: Natalia S
authors.initials: NS
authors.lastname: Rost
authors.affiliation: From the J. Philip Kistler Stroke Research Center, Department of Neurology (N.S.R., L.C., A.S.K., K.M.F.), and the Center for Human Genetic Research, Department of Neurology (N.S.R., D.R.A., V.C., K.B.S.), Massachusetts General Hospital, Boston; Neurogenetics Unit (C.M.L.), School of Medicine of Riberirao Preto, University of São Paulo, Brazil; Division of Medical Genetics (D.P.G.), University of Versailles-St Quentin en Yvelines Paris-Saclay University, France; Fundación para el Estudio de las Enfermedades Neurometabólicas (FESEN) (J.M.P.), Buenos Aires, Argentina; and Departments of Neuroradiology (G.A.H.) and Neurology (C.S., N.Ü.), Fabry Center for Interdisciplinary Therapy (FAZIT) (C.S., N.Ü.), University of Würzburg, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Cloonan
authors.affiliation: From the J. Philip Kistler Stroke Research Center, Department of Neurology (N.S.R., L.C., A.S.K., K.M.F.), and the Center for Human Genetic Research, Department of Neurology (N.S.R., D.R.A., V.C., K.B.S.), Massachusetts General Hospital, Boston; Neurogenetics Unit (C.M.L.), School of Medicine of Riberirao Preto, University of São Paulo, Brazil; Division of Medical Genetics (D.P.G.), University of Versailles-St Quentin en Yvelines Paris-Saclay University, France; Fundación para el Estudio de las Enfermedades Neurometabólicas (FESEN) (J.M.P.), Buenos Aires, Argentina; and Departments of Neuroradiology (G.A.H.) and Neurology (C.S., N.Ü.), Fabry Center for Interdisciplinary Therapy (FAZIT) (C.S., N.Ü.), University of Würzburg, Germany.
authors.forename: Allison S
authors.initials: AS
authors.lastname: Kanakis
authors.affiliation: From the J. Philip Kistler Stroke Research Center, Department of Neurology (N.S.R., L.C., A.S.K., K.M.F.), and the Center for Human Genetic Research, Department of Neurology (N.S.R., D.R.A., V.C., K.B.S.), Massachusetts General Hospital, Boston; Neurogenetics Unit (C.M.L.), School of Medicine of Riberirao Preto, University of São Paulo, Brazil; Division of Medical Genetics (D.P.G.), University of Versailles-St Quentin en Yvelines Paris-Saclay University, France; Fundación para el Estudio de las Enfermedades Neurometabólicas (FESEN) (J.M.P.), Buenos Aires, Argentina; and Departments of Neuroradiology (G.A.H.) and Neurology (C.S., N.Ü.), Fabry Center for Interdisciplinary Therapy (FAZIT) (C.S., N.Ü.), University of Würzburg, Germany.
authors.forename: Kaitlin M
authors.initials: KM
authors.lastname: Fitzpatrick
authors.affiliation: From the J. Philip Kistler Stroke Research Center, Department of Neurology (N.S.R., L.C., A.S.K., K.M.F.), and the Center for Human Genetic Research, Department of Neurology (N.S.R., D.R.A., V.C., K.B.S.), Massachusetts General Hospital, Boston; Neurogenetics Unit (C.M.L.), School of Medicine of Riberirao Preto, University of São Paulo, Brazil; Division of Medical Genetics (D.P.G.), University of Versailles-St Quentin en Yvelines Paris-Saclay University, France; Fundación para el Estudio de las Enfermedades Neurometabólicas (FESEN) (J.M.P.), Buenos Aires, Argentina; and Departments of Neuroradiology (G.A.H.) and Neurology (C.S., N.Ü.), Fabry Center for Interdisciplinary Therapy (FAZIT) (C.S., N.Ü.), University of Würzburg, Germany.
authors.forename: Danielle R
authors.initials: DR
authors.lastname: Azzariti
authors.affiliation: From the J. Philip Kistler Stroke Research Center, Department of Neurology (N.S.R., L.C., A.S.K., K.M.F.), and the Center for Human Genetic Research, Department of Neurology (N.S.R., D.R.A., V.C., K.B.S.), Massachusetts General Hospital, Boston; Neurogenetics Unit (C.M.L.), School of Medicine of Riberirao Preto, University of São Paulo, Brazil; Division of Medical Genetics (D.P.G.), University of Versailles-St Quentin en Yvelines Paris-Saclay University, France; Fundación para el Estudio de las Enfermedades Neurometabólicas (FESEN) (J.M.P.), Buenos Aires, Argentina; and Departments of Neuroradiology (G.A.H.) and Neurology (C.S., N.Ü.), Fabry Center for Interdisciplinary Therapy (FAZIT) (C.S., N.Ü.), University of Würzburg, Germany.
authors.forename: Virginia
authors.initials: V
authors.lastname: Clarke
authors.affiliation: From the J. Philip Kistler Stroke Research Center, Department of Neurology (N.S.R., L.C., A.S.K., K.M.F.), and the Center for Human Genetic Research, Department of Neurology (N.S.R., D.R.A., V.C., K.B.S.), Massachusetts General Hospital, Boston; Neurogenetics Unit (C.M.L.), School of Medicine of Riberirao Preto, University of São Paulo, Brazil; Division of Medical Genetics (D.P.G.), University of Versailles-St Quentin en Yvelines Paris-Saclay University, France; Fundación para el Estudio de las Enfermedades Neurometabólicas (FESEN) (J.M.P.), Buenos Aires, Argentina; and Departments of Neuroradiology (G.A.H.) and Neurology (C.S., N.Ü.), Fabry Center for Interdisciplinary Therapy (FAZIT) (C.S., N.Ü.), University of Würzburg, Germany.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Lourenco
authors.affiliation: From the J. Philip Kistler Stroke Research Center, Department of Neurology (N.S.R., L.C., A.S.K., K.M.F.), and the Center for Human Genetic Research, Department of Neurology (N.S.R., D.R.A., V.C., K.B.S.), Massachusetts General Hospital, Boston; Neurogenetics Unit (C.M.L.), School of Medicine of Riberirao Preto, University of São Paulo, Brazil; Division of Medical Genetics (D.P.G.), University of Versailles-St Quentin en Yvelines Paris-Saclay University, France; Fundación para el Estudio de las Enfermedades Neurometabólicas (FESEN) (J.M.P.), Buenos Aires, Argentina; and Departments of Neuroradiology (G.A.H.) and Neurology (C.S., N.Ü.), Fabry Center for Interdisciplinary Therapy (FAZIT) (C.S., N.Ü.), University of Würzburg, Germany.
authors.forename: Dominique P
authors.initials: DP
authors.lastname: Germain
authors.affiliation: From the J. Philip Kistler Stroke Research Center, Department of Neurology (N.S.R., L.C., A.S.K., K.M.F.), and the Center for Human Genetic Research, Department of Neurology (N.S.R., D.R.A., V.C., K.B.S.), Massachusetts General Hospital, Boston; Neurogenetics Unit (C.M.L.), School of Medicine of Riberirao Preto, University of São Paulo, Brazil; Division of Medical Genetics (D.P.G.), University of Versailles-St Quentin en Yvelines Paris-Saclay University, France; Fundación para el Estudio de las Enfermedades Neurometabólicas (FESEN) (J.M.P.), Buenos Aires, Argentina; and Departments of Neuroradiology (G.A.H.) and Neurology (C.S., N.Ü.), Fabry Center for Interdisciplinary Therapy (FAZIT) (C.S., N.Ü.), University of Würzburg, Germany.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Politei
authors.affiliation: From the J. Philip Kistler Stroke Research Center, Department of Neurology (N.S.R., L.C., A.S.K., K.M.F.), and the Center for Human Genetic Research, Department of Neurology (N.S.R., D.R.A., V.C., K.B.S.), Massachusetts General Hospital, Boston; Neurogenetics Unit (C.M.L.), School of Medicine of Riberirao Preto, University of São Paulo, Brazil; Division of Medical Genetics (D.P.G.), University of Versailles-St Quentin en Yvelines Paris-Saclay University, France; Fundación para el Estudio de las Enfermedades Neurometabólicas (FESEN) (J.M.P.), Buenos Aires, Argentina; and Departments of Neuroradiology (G.A.H.) and Neurology (C.S., N.Ü.), Fabry Center for Interdisciplinary Therapy (FAZIT) (C.S., N.Ü.), University of Würzburg, Germany.
authors.forename: György A
authors.initials: GA
authors.lastname: Homola
authors.affiliation: From the J. Philip Kistler Stroke Research Center, Department of Neurology (N.S.R., L.C., A.S.K., K.M.F.), and the Center for Human Genetic Research, Department of Neurology (N.S.R., D.R.A., V.C., K.B.S.), Massachusetts General Hospital, Boston; Neurogenetics Unit (C.M.L.), School of Medicine of Riberirao Preto, University of São Paulo, Brazil; Division of Medical Genetics (D.P.G.), University of Versailles-St Quentin en Yvelines Paris-Saclay University, France; Fundación para el Estudio de las Enfermedades Neurometabólicas (FESEN) (J.M.P.), Buenos Aires, Argentina; and Departments of Neuroradiology (G.A.H.) and Neurology (C.S., N.Ü.), Fabry Center for Interdisciplinary Therapy (FAZIT) (C.S., N.Ü.), University of Würzburg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommer
authors.affiliation: From the J. Philip Kistler Stroke Research Center, Department of Neurology (N.S.R., L.C., A.S.K., K.M.F.), and the Center for Human Genetic Research, Department of Neurology (N.S.R., D.R.A., V.C., K.B.S.), Massachusetts General Hospital, Boston; Neurogenetics Unit (C.M.L.), School of Medicine of Riberirao Preto, University of São Paulo, Brazil; Division of Medical Genetics (D.P.G.), University of Versailles-St Quentin en Yvelines Paris-Saclay University, France; Fundación para el Estudio de las Enfermedades Neurometabólicas (FESEN) (J.M.P.), Buenos Aires, Argentina; and Departments of Neuroradiology (G.A.H.) and Neurology (C.S., N.Ü.), Fabry Center for Interdisciplinary Therapy (FAZIT) (C.S., N.Ü.), University of Würzburg, Germany.
authors.forename: Nurcan
authors.initials: N
authors.lastname: Üçeyler
authors.affiliation: From the J. Philip Kistler Stroke Research Center, Department of Neurology (N.S.R., L.C., A.S.K., K.M.F.), and the Center for Human Genetic Research, Department of Neurology (N.S.R., D.R.A., V.C., K.B.S.), Massachusetts General Hospital, Boston; Neurogenetics Unit (C.M.L.), School of Medicine of Riberirao Preto, University of São Paulo, Brazil; Division of Medical Genetics (D.P.G.), University of Versailles-St Quentin en Yvelines Paris-Saclay University, France; Fundación para el Estudio de las Enfermedades Neurometabólicas (FESEN) (J.M.P.), Buenos Aires, Argentina; and Departments of Neuroradiology (G.A.H.) and Neurology (C.S., N.Ü.), Fabry Center for Interdisciplinary Therapy (FAZIT) (C.S., N.Ü.), University of Würzburg, Germany.
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Sims
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D001921:Brain / Q000000981:diagnostic imaging*; D002648:Child; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000453:epidemiology; D005260:Female; D006801:Humans; D007090:Image Interpretation, Computer-Assisted / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D010363:Pattern Recognition, Automated / Q000379:methods; D012189:Retrospective Studies; D012720:Severity of Illness Index; D020521:Stroke / Q000453:epidemiology; D066127:White Matter / Q000000981:diagnostic imaging*; D055815:Young Adult