Genetic leukoencephalopathies (gLEs) are a highly heterogeneous group of rare genetic disorders. The spectrum of gLEs varies among patients of different ages. Distinct from the relatively more abundant studies of gLEs in children, only a few studies that explore the spectrum of adult gLEs have been published, and it should be noted that the majority of these excluded certain gLEs. Thus, to date, no large study has been designed and conducted to characterize the genetic and phenotypic spectra of gLEs in adult patients. We recruited a consecutive series of 309 adult patients clinically suspected of gLEs from Beijing Tiantan Hospital between January 2014 and December 2021. Whole exome sequencing, mitochondrial DNA sequencing, and repeat analysis of NOTCH2NLC, FMR1, DMPK and ZNF9 were performed for patients. We describe the genetic and phenotypic spectra of the set of patients with a genetically confirmed diagnosis and summarize their clinical and radiological characteristics. A total of 201 patients (65%) were genetically diagnosed, while 108 patients (35%) remained undiagnosed. The most frequent diseases were NOTCH3 (25%), NOTCH2NLC (19%), ABCD1 (9%), CSF1R (7%), and HTRA1 (5%)-related leukoencephalopathies. Based on a previously proposed pathological classification, the gLEs in our cohort were divided into leukovasculopathies (35%), leuko-axonopathies (31%), myelin disorders (21%), microgliopathies (7%), and astrocytopathies (6%). Patients with NOTCH3 mutations accounted for 70% of the leukovasculopathies, followed by HTRA1 (13%) and COL4A1/2 (9%). The leuko-axonopathies contained the richest variety of associated genes, of which NOTCH2NLC comprised 62%. Among myelin disorders, demyelinating leukoencephalopathies (61%)—mainly adrenoleukodystrophy and Krabbe disease—accounted for the majority, while hypomyelinating leukoencephalopathies (2%) were rare. CSF1R was the only mutated gene detected in microgliopathy patients. Leukoencephalopathy with vanishing white matter disease due to mutations in EIF2B2-5 accounted for half of the astrocytopathies. We characterized the genetic and phenotypic spectra of adult gLEs in a large Chinese cohort. The most frequently mutated genes were NOTCH3, NOTCH2NLC, ABCD1, CSF1R, and HTRA1.

Background and purpose: Cases of RNF216-related disorders have been reported sporadically. The systemic clinical classification and phenotype-genotype correlations of these disorders have not been fully studied.Methods: We report the case of a patient with a novel homozygous mutation in RNF216 and review the cases of all patients with RNF216 mutations reported in the literature. These patients were classified by clinical phenotypes into those with Gordon Holmes syndrome (GHS) and those with Huntington-like disease (HLD). Clinical and genetic features were compared between the groups.Results: The cases of twenty-one patients from 14 families with RNF216 mutations were identified and collected. Eleven (52.4%) patients presented with GHS, and eight (38.1%) presented with HLD. GHS patients had a younger age of onset (24.2 vs. 36.9 years, P<0.001) and a higher percentage of male patients (81.8% vs. 25.0%, P=0.024) than HLD patients. Five (62.5%) HLD patients had ataxia, but only one (9.1%) GHS patient developed chorea. Male patients had a higher percentage of poor pubertal development than female patients (69.2% vs. 12.5%, P=0.024). White matter lesions and cerebellar atrophy were the most common imaging findings in both groups. The mutations in nine (64.3%) families were inherited in a monogenic recessive pattern, whereas the mutations in five (35.7%) were inherited in an oligogenic pattern by acting with mutations in OTUD4, SRA1 or other unknown genes. All eight mutations found in GHS patients and 57.1% (4/7) of mutations found in HLD patients resulted in amino acid changes or the truncation of the “RING-between-RING” (RBR) domain, which plays a key role in the ubiquitin E3 ligase activity of RNF216.Conclusion: Patients with RNF216 mutations mainly presented with GHS or HLD in a monogenic autosomal-recessive pattern or an oligogenic pattern. The mutations in GHS patients affected the RBR domain and are thought to abrogate ubiquitin E3 ligase activity. The pathogenic mechanism underlying RNF216-related HLD is still unknown.

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