2. Academic Validation
  3. New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49)

New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49)

  • Brain Commun. 2022 Feb 10;4(2):fcac030. doi: 10.1093/braincomms/fcac030.
Marc Corral-Juan 1,  Pilar Casquero 2,  Natalia Giraldo-Restrepo 2,  Steve Laurie 3,  Alicia Martinez-Piñeiro 4,  Raidili Cristina Mateo-Montero 2,  Lourdes Ispierto 5,  Dolores Vilas 5 6,  Eduardo Tolosa 6,  Victor Volpini 7,  Ramiro Alvarez-Ramo 5,  Ivelisse Sánchez 1,  Antoni Matilla-Dueñas 1
Affiliations

Affiliations

  • 1 Functional and Translational Neurogenetics Unit, Department of Neuroscience, Research Institute Germans Trias i Pujol (IGTP), Universitat Autònoma de Barcelona-Can Ruti Campus, Badalona, Barcelona, Spain.
  • 2 Neurology and Neurophysiology Section, Hospital Mateu Orfila, Mahón, Menorca, Spain.
  • 3 Centro Nacional de Análisis Genómico (CNAG-CRG), Center for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
  • 4 Neuromuscular and Functional Studies Unit, Neurology Service, University Hospital Germans Trias i Pujol (HUGTiP), Universitat Autònoma de Barcelona-Can Ruti Campus, Badalona, Barcelona, Spain.
  • 5 Neurodegenerative Diseases Unit, Neurology Service, Department of Neuroscience, University Hospital Germans Trias i Pujol (HUGTiP), Universitat Autònoma de Barcelona-Can Ruti Campus, Badalona, Barcelona, Spain.
  • 6 Parkinson Disease and Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED: CB06/05/0018-ISCIII), Barcelona, Spain.
  • 7 IDIBELL, L'Hospitalet, Barcelona, Spain.
PMID: 35310830 DOI: 10.1093/braincomms/fcac030
Abstract

Spinocerebellar ataxias consist of a highly heterogeneous group of inherited movement disorders clinically characterized by progressive cerebellar ataxia variably associated with additional distinctive clinical signs. The genetic heterogeneity is evidenced by the myriad of associated genes and underlying genetic defects identified. In this study, we describe a new spinocerebellar ataxia subtype in nine members of a Spanish five-generation family from Menorca with affected individuals variably presenting with ataxia, nystagmus, dysarthria, polyneuropathy, pyramidal signs, cerebellar atrophy and distinctive cerebral demyelination. Affected individuals presented with horizontal and vertical gaze-evoked nystagmus and hyperreflexia as initial clinical signs, and a variable age of onset ranging from 12 to 60 years. Neurophysiological studies showed moderate axonal sensory polyneuropathy with altered sympathetic skin response predominantly in the lower limbs. We identified the c.1877C > T (p.Ser626Leu) pathogenic variant within the SAMD9L gene as the disease causative genetic defect with a significant log-odds score (Z max = 3.43; θ = 0.00; P < 3.53 × 10-5). We demonstrate the mitochondrial location of human SAMD9L protein, and its decreased levels in patients' fibroblasts in addition to mitochondrial perturbations. Furthermore, mutant SAMD9L in zebrafish impaired mobility and vestibular/sensory functions. This study describes a novel spinocerebellar ataxia subtype caused by SAMD9L mutation, SCA49, which triggers mitochondrial alterations pointing to a role of SAMD9L in neurological motor and sensory functions.

Keywords

SAMD9L; SCA49; mitochondria; spinocerebellar ataxia; zebrafish.

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