Fabry disease: an ultrastructural comparative study of skin in hemizygous and heterozygous patients

Acta Neuropathol (2006) 111: 178185

DOI 10.1007/s00401-005-0026-8ORIGINAL PAPERCarmen Navarro Susana Teijeira Carmen Dominguez

Jose M. Fernandez Eloy Rivas Carmen Fachal

Soraya Barrera Carmen Rodriguez Pilar IranzoFabry disease: an ultrastructural comparative study of skin in hemizygous

and heterozygous patientsReceived: 2 August 2005 / Revised: 21 November 2005 / Accepted: 22 November 2005 / Published online: 7 February 2006

Springer-Verlag 2006Abstract Fabry disease is a rare X-linked lysosomal

storage disorder due to alpha galactosidase A deciency,

better known after the advent of a promising treatment,

a periodical enzyme replacement. As other hereditary

X-linked disorders, females have historically been considered non-aected carriers, although they are, actually, clinically and pathologically aected to a variable

degree. Some women are asymptomatic, but the

majority present milder forms of the disease and later

onset. This wide range of disease expression is supposed

to be related to the levels of enzymatic activity, probably

in accordance with a skewing of X inactivation. Lysosomal deposits of ceramide trihexoside have been

repeatedly documented in a wide range of tissues,

including those found in angiokeratoma, the characteristic cutaneous lesion which allowed the denition of

Fabry disease. The aim of this study was to investigate

whether there was any dierence in the amount of dermal lysosomal storage in males and females, thus

accounting for the dierence in clinical severity of both

groups. For that purpose, with electron microscopy and

quantitative methods, we studied the extent of lysosomal

deposits in dermal broblasts of normal-appearing skin

in six females and nine men, enzymatically and genetically proven as to have Fabry disease, and results were

compared. Our results indicate a statistically signicant

dierence between the two groups regarding both the

percentage of dermal broblasts bearing stored material,

and the storage surface occupied in 100 broblasts per

case. We suggest that periodical ultrastructural examination of normal-appearing skin could be an indicator

of the ecacy of enzyme replacement therapy and could

help to evaluate results.Keywords Dermal ultrastructure Fabry disease

Fibroblast Heterozygous women Lysosomal storageIntroductionC. Navarro (&) S. Teijeira E. Rivas C. Fachal S. Barrera

Department of Pathology and Neuropathology,University Hospital (Meixoeiro), Meixoeiro, s/n,36215 Vigo, SpainE-mail: [email protected].: [phone]Fax: [phone]C. DominguezBiochemistry and Molecular Biology Research Center,

Vall dHebron Hospital, Barcelona, SpainJ. M. FernandezDepartment of Clinical Neurophysiology, University Hospital

(Xeral-Cies), Vigo, SpainC. RodriguezDermatology Service, University Hospital...