White matter abnormalities in 15 subjects with SPG76

Abdulrahman Alkhalifa^{1

2}, Shihan Chen¹, Zehra Isik Hasiloglu¹, Massimiliano Filosto³, Elisa Cali⁴, Henry Houlden⁴, Paulo Sgobbi de Souza⁵, Afagh Alavi⁶, Cyril Goizet^{7

8}, Giovanni Stevanin⁸, Frederic Taithe⁹, Francesco Nicita¹⁰, Gessica Vasco¹¹, Stefano Tozza¹², Sirio Cocozza¹³, Nicola Carboni¹⁴, Andrea Figus¹⁵, Jianjun Wu^{16

17}, A Nazli Basak¹⁸, Bernard Brais^{1

19}, Guy Rouleau^{1

19}, Roberta La Piana^{20

21

22}

Affiliations

¹ Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 rue University, Montreal, QC, H3A 2B4, Canada.
² Bahrain Defence Force Royal Medical Services, Military Hospital, Riffa, Bahrain.
³ Department of Clinical and Experimental Sciences, University of Brescia, NeMO-Brescia Clinical Center for Neuromuscular Diseases, Brescia, Italy.
⁴ Department of Neuromuscular Disease, University College London; The National Hospital for Neurology and Neurosurgery, London, UK.
⁵ Department of Neurology and Neurosurgery, Division of Neuromuscular Diseases, Universidade Federal de São Paulo, Sao Paulo, Brazil.
⁶ University of Social Welfare and Rehabilitation Sciences, Genetics Research Center, Tehran, Iran.
⁷ NRGEN Team, Univ. Bordeaux, CNRS, INCIA, UMR 5287, EPHE, 33000, Bordeaux, France.
⁸ Centre de Référence Maladies Rares Neurogénétique, Service de Génétique Médicale, Bordeaux University Hospital (CHU Bordeaux), Bordeaux, France.
⁹ Service de Neurologie, Hôpital Gabriel Montpied, CHU de Clermont-Ferrand, Clermont-Ferrand, France.
¹⁰ Genetics and Rare Diseases Research Division, Unit of Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Hospital, IRCCS, Rome, Italy.
¹¹ Department of Neurosciences, Unit of Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹² Department of Neuroscience and Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy.
¹³ Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.
¹⁴ Department of Neurology, San Francesco Hospital, Nuoro, Italy.
¹⁵ Department of Radiology, San Francesco Hospital, Nuoro, Italy.
¹⁶ National Center for Neurological Disorders and National Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
¹⁷ Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
¹⁸ Translational Medicine Research Center-NDAL, School of Medicine, Koc University, Istanbul, Turkey.
¹⁹ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Canada.
²⁰ Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 rue University, Montreal, QC, H3A 2B4, Canada. roberta.lapiana@mcgill.ca.
²¹ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Canada. roberta.lapiana@mcgill.ca.
²² Department of Diagnostic Radiology, McGill University, Montreal, QC, Canada. roberta.lapiana@mcgill.ca.

PMID: 37578488
DOI: 10.1007/s00415-023-11918-5

White matter abnormalities in 15 subjects with SPG76

Abdulrahman Alkhalifa et al. J Neurol. 2023 Dec.

. 2023 Dec;270(12):5784-5792.

doi: 10.1007/s00415-023-11918-5. Epub 2023 Aug 14.

Authors

Affiliations

¹ Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 rue University, Montreal, QC, H3A 2B4, Canada.
² Bahrain Defence Force Royal Medical Services, Military Hospital, Riffa, Bahrain.
³ Department of Clinical and Experimental Sciences, University of Brescia, NeMO-Brescia Clinical Center for Neuromuscular Diseases, Brescia, Italy.
⁴ Department of Neuromuscular Disease, University College London; The National Hospital for Neurology and Neurosurgery, London, UK.
⁵ Department of Neurology and Neurosurgery, Division of Neuromuscular Diseases, Universidade Federal de São Paulo, Sao Paulo, Brazil.
⁶ University of Social Welfare and Rehabilitation Sciences, Genetics Research Center, Tehran, Iran.
⁷ NRGEN Team, Univ. Bordeaux, CNRS, INCIA, UMR 5287, EPHE, 33000, Bordeaux, France.
⁸ Centre de Référence Maladies Rares Neurogénétique, Service de Génétique Médicale, Bordeaux University Hospital (CHU Bordeaux), Bordeaux, France.
⁹ Service de Neurologie, Hôpital Gabriel Montpied, CHU de Clermont-Ferrand, Clermont-Ferrand, France.
¹⁰ Genetics and Rare Diseases Research Division, Unit of Neuromuscular and Neurodegenerative Diseases, Bambino Gesù Hospital, IRCCS, Rome, Italy.
¹¹ Department of Neurosciences, Unit of Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
¹² Department of Neuroscience and Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy.
¹³ Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.
¹⁴ Department of Neurology, San Francesco Hospital, Nuoro, Italy.
¹⁵ Department of Radiology, San Francesco Hospital, Nuoro, Italy.
¹⁶ National Center for Neurological Disorders and National Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
¹⁷ Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.
¹⁸ Translational Medicine Research Center-NDAL, School of Medicine, Koc University, Istanbul, Turkey.
¹⁹ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Canada.
²⁰ Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 rue University, Montreal, QC, H3A 2B4, Canada. roberta.lapiana@mcgill.ca.
²¹ The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, Canada. roberta.lapiana@mcgill.ca.
²² Department of Diagnostic Radiology, McGill University, Montreal, QC, Canada. roberta.lapiana@mcgill.ca.

PMID: 37578488
DOI: 10.1007/s00415-023-11918-5

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.

Keywords: CAPN1; Hereditary spastic paraplegia; SPG76; White matter abnormalities.

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Cited by

Biomarkers in Hereditary Spastic Paraplegias.
Panza E, Orlacchio A. Panza E, et al. Int J Mol Sci. 2025 Feb 24;26(5):1950. doi: 10.3390/ijms26051950. Int J Mol Sci. 2025. PMID: 40076577 Free PMC article. Review.

References

1. Mackay-Sim A (2021) Hereditary spastic paraplegia: from genes, cells and networks to novel pathways for drug discovery. Brain Sci 11:403 - DOI - PubMed - PMC
1. Hirst J, Madeo M, Smets K, Edgar JR, Schols L, Li J, Yarrow A, Deconinck T, Baets J, Van Aken E, De Bleecker J, Datiles MB 3rd, Roda RH, Liepert J, Zuchner S, Mariotti C, De Jonghe P, Blackstone C, Kruer MC (2016) Complicated spastic paraplegia in patients with AP5Z1 mutations (SPG48). Neurol Genet 2:e98 - DOI - PubMed - PMC
1. Martin E, Schüle R, Smets K, Rastetter A, Boukhris A, Loureiro JL, Gonzalez MA, Mundwiller E, Deconinck T, Wessner M (2013) Loss of function of glucocerebrosidase GBA2 is responsible for motor neuron defects in hereditary spastic paraplegia. Am J Hum Genet 92:238–244 - DOI - PubMed - PMC
1. Hammer MB, Eleuch-Fayache G, Schottlaender LV, Nehdi H, Gibbs JR, Arepalli SK, Chong SB, Hernandez DG, Sailer A, Liu G, Mistry PK, Cai H, Shrader G, Sassi C, Bouhlal Y, Houlden H, Hentati F, Amouri R, Singleton AB (2013) Mutations in GBA2 cause autosomal-recessive cerebellar ataxia with spasticity. Am J Hum Genet 92:245–251 - DOI - PubMed - PMC
1. Shribman S, Reid E, Crosby AH, Houlden H, Warner TT (2019) Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches. Lancet Neurol 18:1136–1146 - DOI - PubMed

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White matter abnormalities in 15 subjects with SPG76

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White matter abnormalities in 15 subjects with SPG76

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