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Spinocerebellar ataxia type 48: last but not least

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Abstract

Introduction

Biallelic mutations in STUB1, which encodes the E3 ubiquitin ligase CHIP, were originally described in association with SCAR16, a rare autosomal recessive spinocerebellar ataxia, so far reported in 16 kindreds. In the last 2 years, a new form of spinocerebellar ataxia (SCA48), associated with heterozygous mutations in the same gene, has been described in 12 kindreds with autosomal dominant inheritance.

Methods

We reviewed molecular and clinical findings of both SCAR16 and SCA48 described patients.

Results and conclusion

SCAR16 is characterized by early onset spastic ataxia and a wide disease spectrum, including cognitive dysfunction, hyperkinetic disorders, epilepsy, peripheral neuropathy, and hypogonadism. SCA48 is an adult-onset syndrome characterized by ataxia and cognitive-psychiatric features, variably associated with chorea, parkinsonism, dystonia, and urinary symptoms. SCA48, the last dominant ataxia to be described, could emerge as the most frequent among the SCAs due to conventional mutations. The overlap of several clinical signs between SCAR16 and SCA48 indicates the presence of a continuous clinical spectrum among recessively and dominantly inherited mutations of STUB1. Different kinds of mutations, scattered over the three gene domains, have been found in both disorders. Their pathogenesis and the relationship between SCA48 and SCAR16 remain to be clarified.

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Data availability

The data supporting the findings of this study are available within the article and its supplementary materials.

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Acknowledgements

The study was partially supported by a grant from the Italian Association for Ataxic Syndromes (AISA) to A.F.

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    Authors and Affiliations

    1. Department of Neurosciences and Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy

      Giovanna De Michele, Diletta Dello Iacovo, Elena Salvatore, Alessandro Filla & Giuseppe De Michele

    2. IRCCS Fondazione Stella Maris, Pisa, Italy

      Daniele Galatolo, Melissa Barghigiani, Rosanna Trovato, Alessandra Tessa & Filippo M. Santorelli

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    Giovanna De Michele and Daniele Galatolo shared the first position.

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    After submission, two articles have been published, describing three novel SCA48 families, two from the USA [58] and one from the Netherlands [59]. The papers confirm the complex phenotype of the disease and add valuable information on its neuropathology. Both studies describe marked loss of Purkinje cells (PC) with Bergmann gliosis, and both did not find TDP-43 or alpha-synuclein positive inclusions. The Dutch study also revealed severe neuronal loss in the mesencephalon and medulla oblongata. Aberrant STUB1 localization in the distal PC dendritic arbors [58] and ubiquitin/p62-positive neuronal inclusions in the cerebellum, neocortex, and brainstem [59] have been also described.

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    De Michele, G., Galatolo, D., Barghigiani, M. et al. Spinocerebellar ataxia type 48: last but not least. Neurol Sci 41, 2423–2432 (2020). https://doi.org/10.1007/s10072-020-04408-3

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