title: Exome sequencing reveals mutated SLC19A3 in patients with an early-infantile, lethal encephalopathy.
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.
authors.affiliation: Department of Child Neurology, VU Medical Centre, de Boelelaan 1117, 1081 HV Amsterdam, The Netherlands.
authors.forename: Sietske H
authors.initials: SH
authors.lastname: Kevelam
authors.forename: Marianna
authors.initials: M
authors.lastname: Bugiani
authors.forename: Gajja S
authors.initials: GS
authors.lastname: Salomons
authors.forename: Annette
authors.initials: A
authors.lastname: Feigenbaum
authors.forename: Susan
authors.initials: S
authors.lastname: Blaser
authors.forename: Chitra
authors.initials: C
authors.lastname: Prasad
authors.forename: Johannes
authors.initials: J
authors.lastname: Häberle
authors.forename: Ivo
authors.initials: I
authors.lastname: Baric
authors.forename: Ingrid M C
authors.initials: IM
authors.lastname: Bakker
authors.forename: Nienke L
authors.initials: NL
authors.lastname: Postma
authors.forename: Warsha A
authors.initials: WA
authors.lastname: Kanhai
authors.forename: Nicole I
authors.initials: NI
authors.lastname: Wolf
authors.forename: Truus E M
authors.initials: TE
authors.lastname: Abbink
authors.forename: Quinten
authors.initials: Q
authors.lastname: Waisfisz
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
mesh_terms: D001923:Brain Chemistry / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007888:Leigh Disease / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: D026901:Membrane Transport Proteins; C492291:SLC19A3 protein, human