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New neuropathological findings in Unverricht–Lundborg disease: neuronal intranuclear and cytoplasmic inclusions

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Abstract

Unverricht–Lundborg disease (EPM1A), also known as Baltic myoclonus, is the most common form of progressive myoclonic epilepsy. It is inherited as an autosomal recessive trait, due to mutations in the Cystatin-B gene promoter region. Although there is much work on rodent models of this disease, there is very little published neuropathology in patients with EPM1A. Here, we present the neuropathology of a patient with genetically confirmed EPM1A, who died at the age of 76. There was atrophy and gliosis affecting predominantly the cerebellum, frontotemporal cortex, hippocampus and thalamus. We have identified neuronal cytoplasmic inclusions containing the lysosomal proteins, Cathepsin-B and CD68. These inclusions also showed immunopositivity to both TDP-43 and FUS, in some cases associated with an absence of normal neuronal nuclear TDP-43 staining. There were also occasional ubiquitinylated neuronal intranuclear inclusions, some of which were FUS immunopositive. This finding is consistent with neurodegeneration in EPM1A as at least a partial consequence of lysosomal damage to neurons, which have reduced Cystatin-B-related neuroprotection. It also reveals a genetically defined neurodegenerative disease with both FUS and TDP-43 related pathology.

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Abbreviations

CSTB:

Cystatin B

EPM1A:

Epilepsy, progressive, myoclonic, type 1A

FTLD:

Frontotemporal lobar degeneration

FTLD-U:

Frontotemporal lobar degeneration with ubiquitinylated inclusions

mRNA:

Messenger ribonucleic acid

NCI:

Neuronal cytoplasmic inclusion

NII:

Neuronal intranuclear inclusion

NIFID:

Neuronal intermediate filament inclusion disease

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Acknowledgments

The authors would like to acknowledge the contribution of Dr Greg Monteith, Associate Specialist in Histopathology, St Richard’s Hospital, Chichester, to this work. Mrs Jean Buontempo, senior biomedical scientist and Mrs Sammy Reynolds, specialist biomedical scientist, Southampton General Hospital, were responsible for processing the tissue and developing the immunohistochemistry protocols. This work was, in part, funded by a Jean Shanks Foundation award from the Royal College of Pathologists to the first author.

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Authors and Affiliations

  1. Cellular Pathology, Southampton General Hospital, Southampton, SO16 6YD, UK

    Nicola R. Cohen & James A. R. Nicoll

  2. Wessex Neurological Centre, Southampton General Hospital, Southampton, SO16 6YD, UK

    Simon R. Hammans

  3. Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, SP2 8BJ, UK

    James Macpherson

  4. Clinical Neurosciences, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD, UK

    James A. R. Nicoll

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  1. Nicola R. Cohen
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  2. Simon R. Hammans
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  4. James A. R. Nicoll
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Correspondence to Nicola R. Cohen.

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Cohen, N.R., Hammans, S.R., Macpherson, J. et al. New neuropathological findings in Unverricht–Lundborg disease: neuronal intranuclear and cytoplasmic inclusions. Acta Neuropathol 121, 421–427 (2011). https://doi.org/10.1007/s00401-010-0738-2

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  • DOI: https://doi.org/10.1007/s00401-010-0738-2

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