Primary and secondary conditions leading to thiamine deficiency have overlapping features in children, presenting with acute episodes of encephalopathy, bilateral symmetric brain lesions, and high excretion of organic acids that are specific of thiamine-dependent mitochondrial enzymes, mainly lactate, alpha-ketoglutarate, and branched chain keto-acids. Undiagnosed and untreated thiamine deficiencies are often fatal or lead to severe sequelae. Herein, we describe the clinical and genetic characterization of 79 patients with inherited thiamine defects causing encephalopathy in childhood, identifying outcome predictors in patients with pathogenic SLC19A3 variants, the most common genetic etiology. We propose diagnostic criteria that will aid clinicians to establish a faster and accurate diagnosis so that early vitamin supplementation is considered. Ann Neurol 2017;82:317-330.
We investigated the genetic, phenotypic, and interferon status of 46
patients from 37 families with neurological disease due to mutations in
ADAR1. The clinicoradiological phenotype encompassed a
spectrum of Aicardi–Goutières syndrome, isolated bilateral
striatal necrosis, spastic paraparesis with normal neuroimaging, a progressive
spastic dystonic motor disorder, and adult-onset psychological difficulties with
intracranial calcification. Homozygous missense mutations were recorded in five
families. We observed a p.Pro193Ala variant in the heterozygous state in 22 of
23 families with compound heterozygous mutations. We also ascertained 11 cases
from nine families with a p.Gly1007Arg dominant-negative mutation, which
occurred de novo in four patients, and was inherited in three families in
association with marked phenotypic variability. In 50 of 52 samples from 34
patients, we identified a marked upregulation of type I interferon-stimulated
gene transcripts in peripheral blood, with a median interferon score of 16.99
(interquartile range [IQR]: 10.64–25.71) compared with
controls (median: 0.93, IQR: 0.57–1.30). Thus, mutations in
ADAR1 are associated with a variety of clinically distinct
neurological phenotypes presenting from early infancy to adulthood, inherited
either as an autosomal recessive or dominant trait. Testing for an interferon
signature in blood represents a useful biomarker in this context.
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