Inborn errors presenting with neurological regression — formative SAQs

Question 1 (10 marks)

A two-year-old who was speaking in two-word phrases and running has, over four months, stopped speaking and begun to stumble and fall. The parents are frightened. Examination shows normal head circumference, no organomegaly, no dysmorphism, a normal fundus, and a slightly ataxic gait. Initial basic bloods and a full blood count are normal. ^{[1] [3]}

(a) Define neurological regression and distinguish it from developmental delay, plateau, and a static deficit. (3 marks) ^[3]

(b) Outline a tiered investigation strategy for unexplained neurological regression, naming the first-line metabolic screen, the role of brain MRI, and the single highest-yield genetic test when targeted testing is unrevealing. (4 marks) ^{[2] [3]}

(c) State the principle that governs the workup, and name three treatable inborn errors of metabolism that must be excluded before this child is labelled degenerative. (3 marks) ^{[1] [2]}

Model answer

Neurological regression is the loss of previously acquired developmental milestones, and it is distinguished from delay (milestones never met on time), plateau (skills stopped accruing but none lost), and a static deficit (a non-progressive level present from early life, as in unrecognised cerebral palsy). Only regression carries the weight of a presumed progressive process and mandates the search for a neurodegenerative cause at speed. The safeguard against the commonest error - reading a static deficit as progressive - is a meticulous developmental history anchored to specific earlier milestones and ages, confirmed with a witness. ^[3]

The investigation strategy is tiered. The first-line metabolic screen, sent on every child, comprises a free-flowing venous lactate, ammonia on ice, plasma amino acids, acylcarnitine profile, urine organic acids, total homocysteine, and creatine kinase, alongside basic bloods and an infective and autoimmune screen to exclude mimics. Brain MRI, ideally with magnetic resonance spectroscopy, is central because the pattern of basal-ganglia, white-matter, cortical, or atrophic change points to a pathway group. When targeted assays are unrevealing, trio exome or genome sequencing - analysing the child and both parents together - is the single highest-yield test for unexplained neuroregression, identifying a diagnostic variant in a substantial fraction of cases. ^{[2] [3]}

The governing principle is that the treatable inborn errors of metabolism must be excluded before a regressing child is labelled degenerative or palliative, because a defined fraction of the IEM respond to a disease-modifying intervention and treatment works best when begun early. Three treatable IEM that must be excluded are glucose transporter type 1 deficiency (treated with the ketogenic diet), a cofactor-responsive disorder such as biotinidase deficiency (treated with biotin), and a late-onset small-molecule disorder such as homocystinuria or a treatable organic aciduria (treated with diet and cofactors). The diagnostic rate-limiting step is naming the disorder early, so the workup must be deliberate and time-aware. ^{[1] [2]}