先天性大脳白質形成不全症

We present a family of five siblings who came to our attention with a clinical and radiological diagnosis of familial hypomyelinating leukodystrophy. Despite brain white matter abnormalities being present in all siblings, the clinical phenotype was variable: the three brothers presented with a clear-cut late-onset spastic paraplegia, whereas the two sisters displayed only mild pyramidal signs. Molecular analysis revealed a single relevant variant shared by all affected siblings, namely the likely pathogenic variant c.659C>T (p.Ser220Phe) in the GJA1 gene. Variants in this gene are generally associated with oculodentodigital dysplasia (ODDD), an autosomal dominant condition characterized by distinctive facial features and anomalies of the eyes, teeth, and digits. Neurological features are reported in about 30% of cases. In this family, ODDD manifested as a predominantly neurological phenotype. Although a clear explanation for this uncommon presentation is lacking, shared genetic modifiers, the effect of the specific variant, and a possible patient-population bias may have contributed. This case highlights the wide phenotypic spectrum of CX43-related disorders and suggests the importance of testing the GJA1 gene in individuals with atypical presentations, including predominant or isolated neurological phenotypes such as late-onset spastic paraplegia. MRI findings may also provide a useful diagnostic clue when ODDD is suspected.

BACKGROUND AND PURPOSE: VPS11-related Hypomyelinating Leukodystrophy (VPS11-HLD), also named HLD12, is an ultrarare lysosomal-autophagic disorder characterized by severe, early-onset neurodevelopmental disability and diffuse hypomyelination. The neuroimaging spectrum of VPS11-HLD had not been systematically studied. We aimed to characterize the MRI phenotype of VPS11-HLD and identify reproducible imaging features that may aid in distinguishing it from other hypomyelinating leukodystrophies. MATERIALS AND METHODS: Patients with VPS11-HLD from two tertiary centers were retrospectively identified between 2019 and 2025. Clinical and genetic data were retrieved from medical records. Brain MRIs were independently reviewed by two pediatric neuroradiologists, and inter-rater agreement was assessed. Imaging features and biometric measurements were compared with those of 21 individuals with other genetically confirmed HLDs using Mann-Whitney U and Fisher's exact tests. A systematic literature review was conducted to identify previously reported cases and provide clinical and neuroimaging data. RESULTS: Six patients (four unrelated boys and two sisters; age range 8 months to 10 years) diagnosed with a homozygous VPS11 c.2536T>G (p.Cys846Gly) variant were identified. The first MRI, obtained at a median age of 9 months (IQR 7.5,13.75), demonstrated the following findings in all patients: 1) a distinct cerebellar signature characterized by focal absence of the cerebellar cortex in the middle-anterior hemispheric portions; 2) diffuse hypomyelination; 3) a periventricular leukomalacia (PVL)-like pattern; 4) short corpus callosum with marked thinning of the posterior portion, 5) hypoplasia of the anterior commissure and 6) mild pontine volume reduction. Inter-rater agreement for MRI feature assessment was high. In a comparative analysis with 21 patients with other HLDs, the cerebellar signature was observed exclusively in VPS11-HLD (6/6 vs. 0/21, respectively, p < .001). CONCLUSION: VPS11-HLD demonstrates a reproducible MRI pattern combining a novel, peculiar cerebellar anomaly, hypomyelination with PVL-like pattern, and extremely thin and short corpus callosum.In the context of an ultra-rare disorder, this pattern may represent a candidate neuroradiologic phenotype that could support diagnostic stratification, guide targeted genetic evaluation, and provide insight into the role of autophagy-lysosome dysfunction in myelin and cerebellar development.

BACKGROUND: POLR3A encodes the largest subunit of RNA polymerase III (Pol III), which, together with POLR3B, forms the catalytic core essential for transcribing small non-coding RNAs, including tRNAs and 5 S rRNA. Although biallelic POLR3A variants are well-known causes of hypomyelinating leukodystrophy, a recent study has expanded the phenotypic spectrum to include peripheral neuropathy associated with heterozygous de novo variants. METHODS AND RESULTS: We present an additional case supporting an association between POLR3A dysfunction and Charcot-Marie-Tooth (CMT) disease. The patient was diagnosed with chronic sensorimotor polyneuropathy with conduction velocities in the intermediate range. Whole exome sequencing (WES) identified a heterozygous de novo missense variant, c.2560G > C (p.Gly854Arg), in POLR3A (NM_007055.4). CONCLUSION: This report presents the second description of POLR3A-related CMT and supports the role of RNA polymerase III dysfunction in peripheral neuropathy. Integration of WES and structural analysis showed that the p.Gly854Arg variant affects the bridge helix of POLR3A, a conserved element essential for transcriptional function. Notably, Gly854 appears to be a functional hotspot within the bridge helix-cleft interface, as distinct amino acid substitutions at this position have been independently associated with peripheral neuropathy. These findings expand the molecular and geographical spectrum of POLR3A-related neuropathy.

Pelizaeus-Merzbacher-like disease type 1 (PMLD1), also known as hypomyelinating dystrophy 2, is a typical slowly progressive hypomyelinating leukodystrophy (HLD) that manifests in the neonatal period or early infancy. In humans, PMLD1 is inherited as an autosomal recessive trait, with genetic variants identified in the gap junction protein gamma 2 (GJC2) gene. Six juvenile-age Toy Poodle dogs exhibited coarse, vertical head and trunk tremors from immediately after birth. Conventional magnetic resonance imaging revealed uniform signal hyperintensities throughout the subcortical white matter in all dogs. All dogs were euthanized. Subsequent histopathological examination revealed vacuolar changes and demyelination in the cerebral and cerebellar white matter, leading to a diagnosis of HLD. Genetic analysis of five affected dogs identified a shared homozygous 14-base pair deletion in the GJC2 gene, XM_038556433.1:c.920_933del. To the best of our knowledge, this is the first report of a pathogenic GJC2 variant in dogs or any other domestic animal species. The results will enable genetic testing and provide a spontaneous large animal model for the homologous human disease.

PURPOSE: Canavan disease (CD) is a leukodystrophy marked by deficiency in the aspartoacylase enzyme and accumulation of N-acetyl aspartate (NAA) in the white matter. MRI and MRS are crucial diagnostic tools for CD. MRS shows a distinctive, significant elevation of the NAA peak, which is typically not quantified and thus not objectively assessed as a diagnostic criterion. This study aimed to establish quantitative cutoff values for the elevated NAA peak on proton MR spectroscopy (1H-MRS) in patients with CD and hence, incorporate MRS into the diagnostic algorithm. METHODS: A cross-sectional retrospective diagnostic study involving 18 confirmed CD cases and 10 healthy individuals was conducted to assess metabolic profiles and determine a diagnostic cutoff for NAA in CD. 1H MRS (TE: 135 ms) was utilized, and data were post-processed using specialized software to quantify the ratios of the three primary metabolites: NAA, Cho, and Cr. RESULTS: The analysis of the CD cases demonstrated substantial elevation in NAA levels compared to the standard control group with the NAA/Cr and NAA/Cho ratios significantly increased in CD patients compared to controls (p < 0.001 for both). Diagnostic cut-off values of 2.75 for NAA/Cr and 7.18 for NAA/Cho yielded an optimism-corrected AUC = 0.96 (95% CI 0.95-1.00) after bootstrap validation. CONCLUSION: This study represents one of the larger single-center cohorts evaluating quantitative MRS metabolite ratios in Canavan disease and proposes preliminary diagnostic thresholds for improved diagnostic objectivity.