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Gordon Holmes syndrome and Huntington-like disease: Two types of RNF216-related disorders


 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.