先天性大脳白質形成不全症

BACKGROUND: Leukodystrophies are inherited disorders that primarily affect the central nervous system white matter and often present with nonspecific symptoms, making early diagnosis difficult. Magnetic resonance imaging (MRI) is the key initial imaging test because it reveals characteristic myelin patterns that can guide biochemical and genetic workups. OBJECTIVE: To review clinically useful MRI and MR spectroscopy (MRS) patterns in major leukodystrophies and emphasize their diagnostic relevance using a practical, pattern-recognition approach. METHODS: Narrative review of the literature integrating conventional MRI, including T1/T2 fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI), as well as advanced techniques (MRS), with a pictorial, case-based approach. RESULTS: The pivotal imaging distinction is between hypomyelination-diffuse, persistent T2/FLAIR hyperintensity with relative temporal stability and absent enhancement-and demyelination, characterized by confluent, progressive lesions with disorder-specific topographic predilection. Recognizable signatures include U-fiber sparing and a tigroid pattern in metachromatic leukodystrophy (MLD); parieto-occipital predominance with trizonal enhancement and restricted diffusion in X-linked adrenoleukodystrophy (X-ALD); frontal predominance and the "tadpole sign" in Alexander's disease; optic pathway and thalamic involvement in Krabbe's disease; markedly elevated N-acetylaspartate (NAA) on MRS in Canavan's disease; and tract-selective leukoencephalopathy brainstem/spinal cord involvement with a lactate peak (LBSL). These imaging clues refine differential diagnosis, guide targeted genetic testing, and support longitudinal monitoring. CONCLUSION: The use of MRI-especially when complemented by DWI and MRS-remains central for early recognition and classification of leukodystrophies. A structured, pattern-based approach integrating clinical context with imaging topography can reduce diagnostic delay and support timely management.

CLDN11 has recently been associated with hypomyelinating leukodystrophy caused by de novo stop-loss variants. Here, we present a new case involving a homozygous variant in order to expand the genetic and clinical spectrum of the disease. We performed a comprehensive clinical, neuroradiological, and genetic evaluation in a child presenting with global developmental delay. Brain MRI and MR spectroscopy were obtained, and next-generation sequencing with parental segregation analysis was conducted. The patient presented with developmental delay, hypotonia, limb hypertonia, esotropia, and an absence of early developmental milestones in infancy, followed by partial motor improvement and persistent language and cognitive impairment. Brain MRI revealed diffuse supratentorial hypomyelination with stability over time. Genetic analysis identified a novel homozygous CLDN11 start-loss variant (c.1A>G; p.Met1Val), which is predicted to result in biallelic loss of function. Both parents were found to be heterozygous carriers. This case supports an autosomal recessive mechanism of CLDN11-related disease, which differs from the dominant stop-loss variants reported previously. The phenotype partially overlaps with that of earlier cases, but is characterized by milder motor involvement and more pronounced cognitive impairment. These findings broaden the mutational spectrum and suggest distinct pathogenic mechanisms, with important implications for diagnosis and genetic counselling.

Inherited metabolic disorders (IMDs) comprise a diverse group of rare genetic conditions that frequently present with neurologic manifestations in infancy and childhood. Brain MR imaging remains a critical tool for suggesting the diagnosis or narrowing the differential diagnosis of such entities. IMDs may affect preferentially the white matter, gray matter or both. It may be present as delayed myelination, permanent hypomyelination or manifest as acute or subacute encephalopathies with inflammatory, necrotic or degenerative imaging patterns. This article will focus on imaging phenotype and the principle of selective vulnerability.

BACKGROUND: RNA polymerase I enzyme plays a pivotal role in the biosynthesis of 28S, 18S, and 5.8S ribosomal RNAs, which are crucial components of the protein synthesis machinery. The largest subunit of this enzyme, POLR1A, is encoded by the POLR1A gene. Homozygous variants in POLR1A cause an ultra-rare disorder known as hypomyelinating leukodystrophy type-27 (HLD27) with only four families reported worldwide to date. Here, we describe a fifth family harboring a novel homozygous variant in the POLR1A gene, presenting with atypical features and initially suspected of having complicated hereditary spastic paraplegia (c-HSP). In addition, we conducted a systematic review following the PRISMA 2020 guidelines to identify all reported cases with variants in the POLR1A gene. RESULTS: The proband's clinical features were characterized in detail. Whole-exome sequencing (WES) identified a novel homozygous variant in the proband, NM_015425.6:c.2357C > T POLR1A:p.(Thr786Ile). This variant co-segregated with the disease status within the family. The systematic review identified a total of 27 variants in the POLR1A gene, three of which were linked to HLD27. CONCLUSION: Our findings further expand the genetic and clinical spectrum of POLR1A-related disorders by identifying a novel variant and a distinct clinical manifestation characterized by a c-HSP-like phenotype, without apparent hypomyelination. Nevertheless, hypomyelination may develop as the disease progresses. Additionally, our findings raise the possibility that POLR1A variants may be related to HSP-like phenotypes. These findings underscore the critical importance of WES in the diagnosis of complicated disorders, particularly in patients with atypical or difficult-to-interpret clinical presentations.

Pathogenic variants in DEGS1, encoding a sphingolipid desaturase critical for ceramide biosynthesis, disrupt sphingolipid homeostasis and oligodendrocyte function, leading to abnormal myelination. We report an infant with genetically confirmed DEGS1-related leukodystrophy (homozygous c.337A > C, p.Asn113His) who presented with abnormal eye movements and early-onset developmental arrest. This was accompanied by axial hypotonia, severe feeding difficulties, and refractory epilepsy, including epileptic spasms with modified hypsarrhythmia. Brain MRI demonstrated diffuse abnormal myelination per age, thin corpus callosum, and cerebellar involvement. Notably, susceptibility-weighted imaging suggested cerebellar white matter calcifications, which were confirmed on brain CT, alongside punctate supratentorial calcifications, an atypical finding for DEGS1-related disease. This case expands the neuroimaging phenotype of DEGS1-related leukodystrophy and highlights intracranial calcifications, particularly within the cerebellum, as a potential diagnostic clue in the differential diagnosis of hypomyelinating disorders with conatal onset. Our findings also underscore the severe clinical course associated with DEGS1 deficiency, including profound developmental impairment, early-onset epilepsy, and persistent feeding difficulties.