Neurodegenerative and leukodystrophy disorders — formative SAQs

Question 1 (10 marks)

A previously well seven-year-old boy is referred for declining school performance over two months, difficulty following the ball at sport, and intermittent vomiting. An unenhanced brain MRI shows symmetric parieto-occipital white-matter change. On examination he has increased skin pigmentation and a subtle visual-field deficit. His mother asks whether the scan means a brain tumour. [1] [2]

(a) Give the most likely diagnosis, the single addition to the scan that settles the management decision, and the tool used to stage it. (4 marks) [2]

(b) Name two bedside or biochemical features that support the diagnosis, and explain why adrenal assessment is essential here. (3 marks) [2]

(c) Outline the immediate management, naming the definitive therapy and the principle that governs its timing. (3 marks) [3]

Model answer

The most likely diagnosis is cerebral X-linked adrenoleukodystrophy. The single addition that settles the management decision is gadolinium contrast, because the enhancing leading edge of the inflammatory phase confirms active cerebral disease - a feature that is missed on the unenhanced scan. The tool used to stage the disease and guide the transplant decision is the Loes score, a standardised severity scale for the magnetic-resonance-imaging burden, considered alongside the neurological examination. [2]

Two features that support the diagnosis are the symmetric parieto-occipital, splenium-based white-matter change and the increased skin pigmentation indicating adrenal insufficiency, with the biochemical confirmation provided by plasma very-long-chain fatty acids. Adrenal assessment is essential because adrenal insufficiency accompanies a substantial fraction of cerebral adrenoleukodystrophy, can be the first presentation, and untreated Addisonian crisis is fatal - so a synacthen test is performed and hydrocortisone replacement commenced if deficient, independent of the neurological treatment decision. [2]

The definitive therapy is allogeneic haematopoietic stem cell transplant, which halts the inflammatory demyelination by replacing the microglial lineage with donor cells. The governing principle is that transplant works only when the Loes score is still low and the neurological examination preserved - the window halts the disease before the injury becomes irreversible, which is why the case is referred urgently to a transplant service rather than watched. [3]

Question 2 (10 marks)

A two-year-old girl has lost the ability to walk and most of her single words over six months, with a progressive stiff and unsteady gait and optic atrophy. Her brain MRI shows symmetric confluent periventricular white-matter change with a tigrid pattern. Separately, a one-year-old boy deteriorates abruptly three days into a febrile viral illness, and his MRI shows white matter that is rarefied and cavitating. [1] [5]

(a) Give the most likely diagnosis for the girl, the confirmatory biochemistry, and the principle that governs the timing of her definitive therapy. (4 marks) [1]

(b) Give the most likely diagnosis for the boy and the single most important immediate management act, explaining why. (3 marks) [5]

(c) State the unifying principle that governs the treatment of the leukodystrophies as a group, and name how presymptomatic detection is now achieved for the treatable subset. (3 marks) [4]

Model answer

The girl has metachromatic leukodystrophy. The clinical picture of progressive spastic ataxia and optic atrophy with symmetric confluent white-matter change and a tigrid (leopard) pattern points to a lysosomal leukodystrophy caused by arylsulfatase A deficiency, and the confirmatory biochemistry is a low leucocyte arylsulfatase A activity with increased urinary sulfatides, confirmed by molecular testing of ARSA to exclude a pseudodeficiency allele. The principle that governs the timing of definitive therapy is that lentiviral haematopoietic stem cell gene therapy works when given presymptomatically or very early in the disease, whereas the same therapy has limited benefit once symptoms are established - so the window is measured in months and the diagnosis must be made at speed. [1]

The boy has vanishing white matter disease, caused by eukaryotic initiation factor 2B mutations, in which astrocyte fragility makes the white matter rarefy and cavitate and the child deteriorates in steps provoked by stress. The single most important immediate management act is to remove the trigger - treat the fever, manage the infection, and avoid unnecessary stress and procedures - because the deterioration is driven by the stress response and there is, as yet, no curative therapy. [5]

The unifying principle is that the treatable leukodystrophies - cerebral adrenoleukodystrophy, metachromatic leukodystrophy, and Krabbe disease - are treated before symptoms begin, because disease-modifying therapy works only in the presymptomatic window. Presymptomatic detection is now achieved through newborn-bloodspot screening for X-linked adrenoleukodystrophy and, in some jurisdictions, Krabbe disease, combined with magnetic-resonance-imaging surveillance of at-risk and screen-positive children so that therapy is given before the demyelination or inflammation begins. [4]