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]

Question 2 (10 marks)

A six-year-old boy presents with new-onset seizures, behavioural change, and declining school performance over two months. He is found to have mild adrenal insufficiency, and brain MRI shows a contrast-enhancing parieto-occipital white-matter lesion. [4]

(a) Give the most likely diagnosis and the affected pathway. (2 marks) [4]

(b) Justify the urgency of the diagnosis with three features that make this a transplant-pace decision rather than a routine referral. (3 marks) [4]

(c) Describe the confirmatory investigation and the management principle, and contrast the prognosis of early transplant with untreated disease. (5 marks) [4]

Model answer

The most likely diagnosis is the cerebral inflammatory form of X-linked adrenoleukodystrophy, a peroxisomal disorder of very-long-chain fatty-acid metabolism in the lipid-traffic and metal pathway group that affects boys. [4]

Three features make this a transplant-pace decision. First, once the cerebral inflammatory demyelination begins on MRI, the disease progresses rapidly and is usually fatal or profoundly disabling within two years untreated. Second, haematopoietic stem cell transplant, given early in the inflammatory window before neurological injury is fixed, can halt the process. Third, the window for transplant closes as the disease advances, so delay forfeits the only disease-modifying option - which is why recognition is a resuscitation-pace decision, not a routine referral. [4]

The confirmatory investigation is measurement of plasma very-long-chain fatty acids, which is elevated in X-ALD, followed by molecular testing of the ABCD1 gene. Adrenal function is assessed and adrenal replacement therapy is given for adrenal insufficiency regardless of the neurological decision. The management principle is urgent referral to a specialist metabolic and transplant service within days, with transplant considered for the cerebral inflammatory form. The prognosis of early transplant is halting or slowing of the disease process, with preservation of function in carefully selected patients; untreated cerebral X-ALD follows a rapid neurodegenerative course to severe disability or death within two years. The contrast is why every boy with unexplained regression and a white-matter lesion must have very-long-chain fatty acids measured urgently. [4] [1]