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White matter abnormalities in 15 subjects with SPG76

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Abstract

Background and objectives

Hereditary spastic paraplegias (HSPs) are heterogenous genetic disorders characterized by progressive pyramidal tract involvement. SPG76 is a recently identified form of HSP, caused by biallelic calpain-1 (CAPN1) variants. The most frequently described MRI abnormality in SPG76 is mild cerebellar atrophy and non-specific white matter abnormalities were reported in only one case. Following the identification of prominent white matter abnormalities in a subject with CAPN1 variants, which delayed the diagnosis, we aimed to verify the presence of MRI patterns of white matter involvement specific to this HSP.

Methods

We performed a retrospective radiological qualitative analysis of 15 subjects with SPG76 (4 previously unreported) initially screened for white matter involvement. Moreover, we performed quantitative analyses in our proband with available longitudinal studies.

Results

We observed bilateral, periventricular white matter involvement in 12 subjects (80%), associated with multifocal subcortical abnormalities in 5 of them (33.3%). Three subjects (20%) presented only multifocal subcortical involvement. Longitudinal quantitative analyses of our proband revealed increase in multifocal white matter lesion count and increased area of periventricular white matter involvement over time.

Discussion

SPG76 should be added to the list of HSPs with associated white matter abnormalities. We identified periventricular white matter involvement in subjects with SPG76, variably associated with multifocal subcortical white matter abnormalities. These findings, in the presence of progressive spastic paraparesis, can mislead the diagnostic process towards an acquired white matter disorder.

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Data availability

Anonymized data will be shared upon reasonable request from the corresponding author.

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Funding

R. La Piana has received a Research Scholar Junior 1 award from the Fonds de Recherche du Québec en Santé (FRQS), research funds from the Canadian Radiological Foundation and from the Spastic Paraplegia Foundation.

Author information

Authors and Affiliations

  1. Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 rue University, Montreal, QC, H3A 2B4, Canada

    Abdulrahman Alkhalifa, Shihan Chen, Zehra Isik Hasiloglu, Bernard Brais, Guy Rouleau & Roberta La Piana

  2. Bahrain Defence Force Royal Medical Services, Military Hospital, Riffa, Bahrain

    Abdulrahman Alkhalifa

  3. Department of Clinical and Experimental Sciences, University of Brescia, NeMO-Brescia Clinical Center for Neuromuscular Diseases, Brescia, Italy

    Massimiliano Filosto

  4. Department of Neuromuscular Disease, University College London; The National Hospital for Neurology and Neurosurgery, London, UK

    Elisa Cali & Henry Houlden

  5. Department of Neurology and Neurosurgery, Division of Neuromuscular Diseases, Universidade Federal de São Paulo, Sao Paulo, Brazil

    Paulo Sgobbi de Souza

  6. University of Social Welfare and Rehabilitation Sciences, Genetics Research Center, Tehran, Iran

    Afagh Alavi

  7. NRGEN Team, Univ. Bordeaux, CNRS, INCIA, UMR 5287, EPHE, 33000, Bordeaux, France

    Cyril Goizet

  8. Centre de Référence Maladies Rares Neurogénétique, Service de Génétique Médicale, Bordeaux University Hospital (CHU Bordeaux), Bordeaux, France

    Cyril Goizet & Giovanni Stevanin

  9. Service de Neurologie, Hôpital Gabriel Montpied, CHU de Clermont-Ferrand, Clermont-Ferrand, France

    Frederic Taithe

  10. Genetics and Rare Diseases Research Division, Unit of Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Hospital, IRCCS, Rome, Italy

    Francesco Nicita

  11. Department of Neurosciences, Unit of Neurorehabilitation, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy

    Gessica Vasco

  12. Department of Neuroscience and Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy

    Stefano Tozza

  13. Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy

    Sirio Cocozza

  14. Department of Neurology, San Francesco Hospital, Nuoro, Italy

    Nicola Carboni

  15. Department of Radiology, San Francesco Hospital, Nuoro, Italy

    Andrea Figus

  16. National Center for Neurological Disorders and National Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China

    Jianjun Wu

  17. Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China

    Jianjun Wu

  18. Translational Medicine Research Center-NDAL, School of Medicine, Koc University, Istanbul, Turkey

    A. Nazli Basak

  19. The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Canada

    Bernard Brais, Guy Rouleau & Roberta La Piana

  20. Department of Diagnostic Radiology, McGill University, Montreal, QC, Canada

    Roberta La Piana

Authors
  1. Abdulrahman Alkhalifa
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  2. Shihan Chen
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  3. Zehra Isik Hasiloglu
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  5. Elisa Cali
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  6. Henry Houlden
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  7. Paulo Sgobbi de Souza
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  8. Afagh Alavi
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  9. Cyril Goizet
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  10. Giovanni Stevanin
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  11. Frederic Taithe
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  13. Gessica Vasco
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  14. Stefano Tozza
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  15. Sirio Cocozza
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  16. Nicola Carboni
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  17. Andrea Figus
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  18. Jianjun Wu
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  19. A. Nazli Basak
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  20. Bernard Brais
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  21. Guy Rouleau
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  22. Roberta La Piana
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Corresponding author

Correspondence to Roberta La Piana.

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Conflicts of interest

A. Alkhalifa reports no disclosures relevant to the manuscript. S. Chen reports no disclosures relevant to the manuscript. Z. I. Hasiloglu reports no disclosures relevant to the manuscript. M. Filosto reports no disclosures relevant to the manuscript. E. Cali reports no disclosures relevant to the manuscript. H. Houlden reports no disclosures relevant to the manuscript. P.V.S. de Souza reports no disclosures relevant to the manuscript. A. Alavi reports no disclosures relevant to the manuscript. C. Goizet reports no disclosures relevant to the manuscript. G. Stevanin reports a Biogen-Paris-Sciences Lettres contract unrelated to this work, and a grant support from the ASL-HSP-France Association (to GS) related to genetic studies in HSP patients. F. Taithe reports no disclosures relevant to the manuscript. F. Nicita is a member of the European Reference Network for Rare Neurological Diseases (ERN-RND). G. Vasco reports no disclosures relevant to the manuscript. S. Tozza has received personal fees for scientific events from Alnylam Pharmaceuticals and Amicus Therapeutics, travel grants to attend scientific meetings from Akcea Therapeutics. S. Cocozza has received research grants from Telethon and FISM, and fees for speaking from Amicus Therapeutics. N. Carboni reports no disclosures relevant to the manuscript. A. Figus reports no disclosures relevant to the manuscript. J. Wu reports no disclosures relevant to the manuscript. A. N. Basak reports no disclosures relevant to the manuscript. B. Brais reports no disclosures relevant to the manuscript. G. Rouleau reports no disclosures relevant to the manuscript.

Ethical standard

The Institutional Review Boards of the participating institutions have approved the use of data for this retrospective study.

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Alkhalifa, A., Chen, S., Hasiloglu, Z.I. et al. White matter abnormalities in 15 subjects with SPG76. J Neurol 270, 5784–5792 (2023). https://doi.org/10.1007/s00415-023-11918-5

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