Hereditary spastic paraparesis type 46 (SPG46): new GBA2 variants in a large Italian case series and review of the literature

• Published in: Neurogenetics 2024-04, Vol.25 (2), p.51-67
• Main Authors: Cioffi, Ettore, Coppola, Gianluca, Musumeci, Olimpia, Gallone, Salvatore, Silvestri, Gabriella, Rossi, Salvatore, Piemonte, Fiorella, D’Amico, Jessica, Tessa, Alessandra, Santorelli, Filippo Maria, Casali, Carlo
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Age; Blood cells; Central nervous system; Central nervous system diseases; Cerebellar ataxia; Cerebellum; Child; Cognitive ability; Enzymatic activity; Female; Genetic screening; Glucosylceramidase - genetics; Hereditary spastic paraplegia; Human Genetics; Humans; Italy; Literature reviews; Male; Medicine; Medicine & Public Health; Middle Aged; Molecular Medicine; Motor neurons; Movement disorders; Mutation; Mutation - genetics; Neuroimaging; Neurology; Neurosciences; Pedigree; Peripheral blood; Phenotype; Phenotypes; Review; Scoliosis; Sjogren's syndrome; Spastic Paraplegia, Hereditary - diagnosis; Spastic Paraplegia, Hereditary - genetics; Young Adult
• ISSN: 1364-6753; 1364-6745; 1364-6753
• DOI: 10.1007/s10048-024-00749-9

Hereditary spastic paraparesis (HSP) is a group of central nervous system diseases primarily affecting the spinal upper motor neurons, with different inheritance patterns and phenotypes. SPG46 is a rare, early-onset and autosomal recessive HSP, linked to biallelic GBA2 mutations. About thirty families have been described worldwide, with different phenotypes like complicated HSP, recessive cerebellar ataxia or Marinesco-Sjögren Syndrome. Herein, we report five SPG46 patients harbouring five novel GBA2 mutations, the largest series described in Italy so far. Probands were enrolled in five different centres and underwent neurological examination, clinical cognitive assessment, column imaging for scoliosis assessment, ophthalmologic examination, brain imaging, GBA2 activity in peripheral blood cells and genetic testing. Their phenotype was consistent with HSP, with notable features like upper gaze palsy and movement disorders. We review demographic, genetic, biochemical and clinical information from all documented cases in the existing literature, focusing on the global distribution of cases, the features of the syndrome, its variable presentation, new potential identifying features and the significance of measuring GBA2 enzyme activity.