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.

Neuropathological characteristics of the brain in two patients with SLC19A3 mutations related to the biotin-thiamine-responsive basal ganglia disease

“…In 2013, the research team of van den Knaap identified a distinct MRI pattern [6] in seven patients with lethal leukoencephalopathy (out of more than 3000 MRIs). Using WES technology they linked this condition to SLC19A3 mutations.…”

“…Using WES technology they linked this condition to SLC19A3 mutations. The pattern includ- MRIs, atrophy of affected structures" [6]. Acute, postacute, intermediate and end stage of the disease were specified in that study [6].…”

“…Neuropathological characteristics of the brain of patients with SLC19A3 defect were analysed in detail to establish usefulness of diagnostic criteria proposed by van den Knaap et al [6]. Two Polish patients with the SLC19A3 mutations identified out of 113 mitochondrial patients studied in The Children's Memorial Health Institute (CMHI) in the period of 1995-2016 [13] were included.…”

“…Since its discovery, almost a hundred patients have been reported, mainly from Saudi Arabia [2], but also from Japan, Lebanon, Mexico, Sweden and other countries. The natural history of the condition is quite well recognized, pointing to a remarkable clinical heterogeneity, even inside the same family and the wide range of severity and prognoses [6]. Recently this has been comprehensively reviewed [1,2].…”

“…Although in the literature there are numerous magnetic resonance imagining (MRI) series of SLC19A3 defect illustrating both specific changes in detail [6,17] and the response to specific treatment [1,2], only few reports focus on brain pathology in affected patients [15]. Herein, we present our unique autopsy findings ("walnut" appearance of the brain) in a Polish child who died many years ago, and in whom the underlying SLC19A3 homozygous mutation has been recently established by WES (whole-exome sequencing).…”