Exome sequencing reveals mutated SLC19A3 in patients with an early-infantile, lethal encephalopathy

Authors

Sietske H. Kevelam, Amsterdam UMC - Free University Amsterdam
Marianna Bugiani, Amsterdam UMC - Free University Amsterdam
Gajja S. Salomons, Amsterdam UMC - Free University Amsterdam
Annette Feigenbaum, Hospital for Sick Children University of Toronto
Susan Blaser, Hospital for Sick Children University of Toronto
Chitra Prasad, Children's Health Research Institute, London, ONFollow
Johannes Häberle, Kinderspital Zürich
Ivo Barić, University of Zagreb School of Medicine
Ingrid M.C. Bakker, Amsterdam UMC - Free University Amsterdam
Nienke L. Postma, Amsterdam UMC - Free University Amsterdam
Warsha A. Kanhai, Amsterdam UMC - Free University Amsterdam
Nicole I. Wolf, Amsterdam UMC - Free University Amsterdam
Truus E.M. Abbink, Amsterdam UMC - Free University Amsterdam
Quinten Waisfisz, Amsterdam UMC - Free University Amsterdam
Peter Heutink, Amsterdam UMC - Free University Amsterdam
Marjo S. Van Der Knaap, Amsterdam UMC - Free University Amsterdam

Document Type

Article

Publication Date

1-1-2013

Journal

Brain

Volume

136

Issue

5

First Page

1534

Last Page

1543

URL with Digital Object Identifier

10.1093/brain/awt054

Abstract

To accomplish a diagnosis in patients with a rare unclassified disorder is difficult. In this study, we used magnetic resonance imaging pattern recognition analysis to identify patients with the same novel heritable disorder. Whole-exome sequencing was performed to discover the mutated gene. We identified seven patients sharing a previously undescribed magnetic resonance imaging pattern, characterized by initial swelling with T2 hyperintensity of the basal nuclei, thalami, cerebral white matter and cortex, pons and midbrain, followed by rarefaction or cystic degeneration of the white matter and, eventually, by progressive cerebral, cerebellar and brainstem atrophy. All patients developed a severe encephalopathy with rapid deterioration of neurological functions a few weeks after birth, followed by respiratory failure and death. Lactate was elevated in body fluids and on magnetic resonance spectroscopy in most patients. Whole-exome sequencing in a single patient revealed two predicted pathogenic, heterozygous missense mutations in the SLC19A3 gene, encoding the second thiamine transporter. Additional predicted pathogenic mutations and deletions were detected by Sanger sequencing in all six other patients. Pathology of brain tissue of two patients demonstrated severe cerebral atrophy and microscopic brain lesions similar to Leigh's syndrome. Although the localization of SLC19A3 expression in brain was similar in the two investigated patients compared to age-matched control subjects, the intensity of the immunoreactivity was increased. Previously published patients with SLC19A3 mutations have a milder clinical phenotype, no laboratory evidence of mitochondrial dysfunction and more limited lesions on magnetic resonance imaging. In some, cerebral atrophy has been reported. The identification of this new, severe, lethal phenotype characterized by subtotal brain degeneration broadens the phenotypic spectrum of SLC19A3 mutations. Recognition of the associated magnetic resonance imaging pattern allows a fast diagnosis in affected infants. © 2013 The Author).