Inborn errors presenting with neurological regression — branching viva

Opening branch — the regressing toddler

A two-year-old who was speaking in two-word phrases and running has stopped speaking and begun to stumble over four months. The candidate must first confirm that this is true regression - loss of previously acquired skills - distinguished from delay, plateau, and a static deficit by a meticulous developmental history anchored to earlier milestones. The candidate states that regression mandates a search for a progressive and potentially treatable cause at speed, because the commonest error is reading a static deficit as progressive or, conversely, labelling a treatable IEM as cerebral palsy. [3]

The examiner probes the classification. The candidate groups the regressing IEM by affected pathway - intoxicating small-molecule, energy or mitochondrial, storage or lysosomal, and lipid-traffic and metal - and explains that the pathway predicts the bedside pattern, the first-line test, and whether a disease-modifying therapy exists. The teaching point is that a treatable subset spans every group, which is why the governing principle is to exclude the treatable IEM before labelling a child degenerative. [1] [3]

Second branch — the workup and the genomic question

The examiner asks for the investigation strategy. The candidate gives the tiered approach: a first-line metabolic screen (free-flowing lactate, ammonia on ice, plasma amino acids, acylcarnitines, urine organic acids, homocysteine, creatine kinase) plus brain MRI with spectroscopy; then targeted assays by pattern; then chromosomal microarray as the first-line genetic test; then trio exome or genome sequencing when targeted testing is unrevealing. The candidate states that trio exome is the single highest-yield test for unexplained neuroregression and explains why a normal initial metabolic screen does not exclude an IEM - lactate and organic acids may be normal outside a decompensation, and a disorder not on the newborn-bloodspot panel will not be caught by the panel. [2] [3]

Third branch — the transplant emergency

The case shifts to a six-year-old boy with new seizures, behavioural change, school decline, and mild adrenal insufficiency, whose brain MRI shows a contrast-enhancing parieto-occipital white-matter lesion. The candidate diagnoses the cerebral inflammatory form of X-linked adrenoleukodystrophy, a peroxisomal very-long-chain fatty-acid disorder, and justifies the urgency: once the inflammatory demyelination begins the disease progresses rapidly, haematopoietic stem cell transplant given early can halt it, and the window closes as the disease advances - making recognition a resuscitation-pace decision. The confirmatory test is plasma very-long-chain fatty acids and ABCD1 molecular testing, and the management is urgent referral to a specialist metabolic and transplant service within days, with adrenal replacement therapy for the adrenal insufficiency. [4]

Fourth branch — the treatable energy disorder

The examiner moves to an infant with epilepsy resistant to standard anticonvulsants, a paroxysmal movement disorder, and developmental regression, in whom a lumbar puncture shows a low cerebrospinal-fluid glucose and a low CSF-to-plasma glucose ratio. The candidate diagnoses glucose transporter type 1 deficiency and explains that the defective transport of glucose across the blood-brain barrier starves the brain of its preferred fuel, declaring itself as epilepsy, a movement disorder, and regression. The candidate names the treatment - the ketogenic diet, which provides ketones as an alternative brain fuel - and states that this is a genuinely treatable cause of regression that is missed when the epilepsy is treated without a metabolic workup. [5]

Closing synthesis

The examiner asks for the single unifying principle. The candidate states that every regressing child reduces to four questions: is this true regression, which pathway group, which tier of the workup names it, and is there a treatable subset whose window is closing. The governing rule is that the treatable inborn errors of metabolism must be excluded before a child is labelled degenerative or palliative, and trio exome is the single highest-yield test when targeted testing is unrevealing. [1] [2]