Diego Lopergolo1,2, Gianna Berti1,2, Francesca Mari3,4, Enrico Bertini5, Alessandra Rufa1,2, Carla Battisti1,2, Francesco Sicurelli1,2, Alessandra Renieri3,4, Antonio Federico1,2, Konrad Sandhoff6, Alessandro Malandrini7,8. 1. Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy. 2. UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero Universitaria Senese, Policlinico Le Scotte, Viale Bracci, 2, 53100, Siena, Italy. 3. Medical Genetics, University of Siena, Siena, Italy. 4. Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy. 5. Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 6. Membrane Biology and Lipid Biochemistry Unit, LIMES Institute, University of Bonn, Bonn, Germany. 7. Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy. alessandro.malandrini@unisi.it. 8. UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero Universitaria Senese, Policlinico Le Scotte, Viale Bracci, 2, 53100, Siena, Italy. alessandro.malandrini@unisi.it.
Abstract
INTRODUCTION: Spastic paraplegia type 11 (SPG11) is the most frequent autosomal recessive HSP. Studies on SPG11 patients' fibroblasts, post-mortem brains, and mouse models revealed endolysosomal system dysfunction and lipid accumulation, especially gangliosides. We report a patient with early clinical findings mimicking a GM2-gangliosidosis. METHODS: A clinical, biochemical, and metabolic characterization was performed. Electron microscopy analysis was completed on rectal mucosa and skin biopsy specimens. A NGS panel of genes associated to neuronal ceroid lipofuscinosis and HSP was analyzed. RESULTS: The patient presented with worsening walking difficulty and psychomotor slowdown since childhood; to exclude a neurometabolic storage disease, skin and rectal biopsies were performed: enteric neurons showed lipofuscin-like intracellular inclusions, thus suggesting a possible GM2-gangliosidosis. However, further analysis did not allow to confirm such hypothesis. In adulthood we detected flaccid paraplegia, nystagmus, axonal motor neuropathy, carpus callosum atrophy, and colon atony. Surprisingly, the NGS panel detected two already reported SPG11 mutations in compound heterozygosity. CONCLUSIONS: We describe for the first time pathological hallmarks of SPG11 in enteric neuron from a rectal mucosa biopsy. The report illustrates the possible overlap between SPG11 and GM2-gangliosidosis, especially in the first disease phases and helps to improve our knowledge about SPG11 physiopathology.
INTRODUCTION: Spastic paraplegia type 11 (SPG11) is the most frequent autosomal recessive HSP. Studies on SPG11 patients' fibroblasts, post-mortem brains, and mouse models revealed endolysosomal system dysfunction and lipid accumulation, especially gangliosides. We report a patient with early clinical findings mimicking a GM2-gangliosidosis. METHODS: A clinical, biochemical, and metabolic characterization was performed. Electron microscopy analysis was completed on rectal mucosa and skin biopsy specimens. A NGS panel of genes associated to neuronal ceroid lipofuscinosis and HSP was analyzed. RESULTS: The patient presented with worsening walking difficulty and psychomotor slowdown since childhood; to exclude a neurometabolic storage disease, skin and rectal biopsies were performed: enteric neurons showed lipofuscin-like intracellular inclusions, thus suggesting a possible GM2-gangliosidosis. However, further analysis did not allow to confirm such hypothesis. In adulthood we detected flaccid paraplegia, nystagmus, axonal motor neuropathy, carpus callosum atrophy, and colon atony. Surprisingly, the NGS panel detected two already reported SPG11 mutations in compound heterozygosity. CONCLUSIONS: We describe for the first time pathological hallmarks of SPG11 in enteric neuron from a rectal mucosa biopsy. The report illustrates the possible overlap between SPG11 and GM2-gangliosidosis, especially in the first disease phases and helps to improve our knowledge about SPG11 physiopathology.
Authors: Paola S Denora; Katrien Smets; Federica Zolfanelli; Chantal Ceuterick-de Groote; Carlo Casali; Tine Deconinck; Anne Sieben; Michael Gonzales; Stephan Zuchner; Frédéric Darios; Dirk Peeters; Alexis Brice; Alessandro Malandrini; Peter De Jonghe; Filippo M Santorelli; Giovanni Stevanin; Jean-Jacques Martin; Khalid H El Hachimi Journal: Brain Date: 2016-03-25 Impact factor: 13.501