Inborn errors presenting with neurological regression

A toddler who was speaking in two-word phrases and running stops talking and begins to stumble, and a school-age boy whose teacher notices falling grades and new seizures turns out to have inflammatory white-matter disease on his scan. In both rooms the unifying question is the same: is this loss of milestones a progressive metabolic disorder, and is there a therapy whose window is closing right now. The fellowship task is to convert that bedside worry into a structured, time-aware workup that does not forfeit a treatable cause to a comforting but wrong label such as cerebral palsy or autism. [5] [8]

Overview & Definition

The clinician's first act is to confirm what kind of developmental problem this is, because the word "regression" is used loosely and the distinction changes everything. Developmental delay means milestones are not being met on time. A plateau means the child has stopped gaining new skills but has not lost old ones. Neurological regression - the entity this page owns - means the child has lost previously acquired skills. Only regression carries the weight of a presumed progressive process, and only regression mandates the search for a neurodegenerative cause at speed. [8]

An inborn error of metabolism is a monogenic disorder in which a deficient enzyme, transporter, cofactor, or structural protein disrupts a biochemical pathway, and the accumulating substrate or the energy deficit injures the cell. When the affected pathway runs through the central nervous system, the injury declares itself as neurological regression - a slide from a higher to a lower level of function. The slide may be rapid, over days to weeks, as in acute decompensation of a late-onset small-molecule disorder; or insidious, over months to years, as in a leukodystrophy or a lysosomal storage disorder. Reading the tempo is part of reading the disease. [5] [13]

What makes the IEM group worth knowing as a cause of regression is that a meaningful subset is treatable, and that treatment works best - or only - when it is begun before the brain injury becomes irreversible. The systematic work of van Karnebeek, Stockler, Saudubray and others reframed the field around this idea: among the IEM that cause intellectual disability and regression, a defined fraction respond to a disease-modifying intervention, and missing them is the cardinal avoidable error in paediatric neurology. [1] [2] [3]

References13Show ledgerHide ledger

1. [1]van Karnebeek CD, Stockler S. Treatable inborn errors of metabolism causing intellectual disability: a systematic literature review. Mol Genet Metab, 2012.PMID 22212131
2. [2]van Karnebeek CD, Shevell M, Zschocke J, Moeschler JB, Stockler S. The metabolic evaluation of the child with an intellectual developmental disorder: diagnostic algorithm for identification of treatable causes and new digital resource. Mol Genet Metab, 2014.PMID 24518794
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