Hypomyelination of Early Myelinating Brain Structures

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Clinical Case A 2-year-old boy presented with gait ataxia, tremor, and delayed motor development, evolving into spastic paraplegia. Following referral to our tertiary center, brain MRI was performed at 4 years of age ([ Fig. 1 ]) which revealed symmetric mild T2-hyperintensities of brainstem, posterior limbs of the internal capsules, perirolandic white matter, and optic radiations. Mild T2-hyperintensity suggests hypomyelination rather than lesion. Strikingly, these structures normally myelinate early. Other white matter structures, which normally myelinate later, were T2-hypointense, indicating more advanced myelination. The thalamus was mildly T2-hyperintense except for the ventrolateral thalamus, a pattern related to partial myelination, normally seen in neonates. This MRI pattern is suggestive of “hypomyelination of early myelinating structures” (HEMS).[ 1 ] Reanalysis of whole-exome sequencing identified a hemizygous deep intronic PLP1 variant (c.453 + 159G > A), confirming the diagnosis. This variant disrupts normal PLP1/DM20 alternative splicing, reducing functional proteolipid protein expression and impairing myelin formation.[ 2 ] Recognition of this distinct MRI pattern is essential to prompt targeted reanalysis of genetic data when initial sequencing is inconclusive. Fig. 1 MRI at the age of 4 years. Axial T2-weighted images showed symmetric mild hyperintensities involving the posterior limbs of the internal capsules ( A ), periventricular ( A, B ) and perirolandic subcortical ( C ) white matter, optic radiations ( A ), pons ( D , E ), and hilum of the dentate nucleus ( E ). The thalamus was mildly T2-hyperintense with hypointensity of the ventrolateral nucleus ( A ). The posterior limb of the internal capsule displayed alternating hyperintense–hypointense–hyperintense stripes ( A ), as commonly seen in hypomyelination of early myelinating structures (HEMS). Ethical Approval Our institutions do not require ethical approval for reporting individual cases, case series, or systematic reviews. Informed Consent Signed informed consent was obtained from patient. Note This work was performed at Unidade Local de Saúde de Santo António, a healthcare institution located in Porto, Portugal. Publication History Received: 30 December 2025 Accepted after revision: 20 February 2026 Article published online: 07 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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