Objective: To describe the neuropathology in a rare case of autosomal recessive HD like syndrome due to homozygous RNF216 mutations. To confirm the hypothesis of defective ubiquitination and to indicate the differences with earlier published cases with a different phenotype.

Background: Two families with autosomal recessive HD like syndrome due to RNF216 mutations were described earlier by our group (1). Two siblings of one family with early-onset disease had homozygous mutations in the context of parental consanguinity, while two siblings of a second family had compound heterozygous mutations. In both families chorea and cognitive deterioration were present and hypogonadotropic hypogonadism was found. All affected patients had extensive white matter lesions. RNF216 mutations were earlier described as a cause of ataxia with dementia and hypogonadotropism (2). The pathology in these latter cases indicated underlying defects of ubiquitination with intranuclear inclusions.

Method: Neuropathological examination of the brain of one of the patients with early-onset disease and homozygous loss-of-function mutation in RNF216.

Results: Similar to the pathological findings in the cases described by Margolin et al (2) atrophy of the cerebellum and inferior olive was prominent. There was substantial loss of Purkinje cells and inferior olive neurons, and additionally also of dentate nucleus neurons. Cerebellar white matter showed increased gliosis. The pontine and mesencephalic tegmentum were rather small. Pyramidal neurons in CA1 and CA2 of the hippocampus showed ubiquitin immunoreactive neuronal intranuclear inclusions. These were also detected in the substantia nigra, the putamen and the caudate nucleus. The latter was also mildly atrophic with loss of large neurons.

Conclusion: This case confirms earlier findings in rare cases of neurodegenerative disorders associated with RNF216 mutations. There is a predominant olivo-cerebellar pathology with ubiquitin-immunoreactive neuronal intranuclear inclusions in the hippocampus, confirming the hypothesis of disordered ubiquitination. In our case with HD-like phenotype additional pathology was detected in the basal ganglia. The nature of the filaments remains to be demonstrated, and proteomics is currently underway.

References: 1.Santens et al. Neurology 2015; 84(17): 1760-6. 2.Margolin et al. N Engl J Med 2013; 368(21): 1992–2003.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/neuropathology-in-a-case-of-hd-like-syndrome-caused-by-mutations-in-rnf216/