Profound Biotinidase Deficiency as a Treatable Cause of Pediatric Diffuse Leukoencephalopathy and Diffusion Restriction

BackgroundBiotinidase deficiency (BTD) is a rare, autosomal-recessive neurometabolic disorder due to biallelic pathogenic variants in the BTD gene. Diffuse leukoencephalopathy with diffusion restriction on neuroimaging is a rare but reversible radiologic pattern associated with BTD.ObjectivesTo describe the clinico-radiologic profile of 3 children with genetically confirmed profound BTD presenting with diffuse leukoencephalopathy and diffusion restriction, and to compare findings with similar cases reported in the literature.MethodsConsecutive children attending the pediatric neurology clinic were evaluated for early-onset seizures, developmental delay, respiratory symptoms, and encephalopathy. Clinical, biochemical, genetic, neurophysiological, and magnetic resonance imaging findings were analysed. Whole exome sequencing confirmed BTD gene variants. A systematic PubMed search and literature review were conducted using specified MeSH terms to identify similar cases.ResultsThree male children from 2 families were evaluated. All cases had early-onset seizures, developmental delay, and profound biotinidase deficiency. Stridor was noted in 2 cases. Genetic analysis identified 2 pathogenic BTD variants: homozygous, frameshift deletion (c.38_44delinsTCC; p.Cys13PhefsTer36), and another homozygous, nonsense variant (c.946C>T; p.Gln316Ter). Neuroimaging revealed diffuse leukoencephalopathy with intense diffusion restriction in all, which reversed completely with biotin supplementation. Seizures and encephalopathy resolved while optic neuropathy progressed despite treatment. Literature review identified 13 additional cases with diffusion restriction, and all of them had an early presentation.ConclusionsProfound BTD may present with diffuse leukoencephalopathy and diffusion restriction, mimicking neuroinflammatory or degenerative conditions. This reversible metabolic disorder should be considered in the differential diagnosis of pediatric white matter disorders. Early diagnosis and biotin supplementation are crucial for neurologic recovery although optic and auditory neuropathy may progress despite treatment.