Andrea Ciammola1, Paola Carrera2, Alessio Di Fonzo3, Jenny Sassone4, Roberta Villa5, Barbara Poletti1, Maurizio Ferrari6, Floriano Girotti1, Edoardo Monfrini3, Gabriele Buongarzone3, Vincenzo Silani7, Claudia Maria Cinnante8, Maria Lidia Mignogna9, Patrizia D'Adamo9, Maria Teresa Bonati10. 1. IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, Milan, Italy. 2. IRCCS San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Unit of Genomics for Human Disease Diagnosis, Milan, Italy; IRCCS San Raffaele Scientific Institute Laboratory of Clinical Molecular Biology, Milan, Italy. 3. IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy. 4. San Raffaele Scientific Institute and Vita-Salute University, Milan, Italy. 5. Clinic of Medical Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy. 6. IRCCS San Raffaele Scientific Institute Laboratory of Clinical Molecular Biology, Milan, Italy; Vita-Salute San Raffaele University, Chair of Clinical Pathology, Milan, Italy. 7. IRCCS Istituto Auxologico Italiano, Department of Neurology and Laboratory of Neuroscience, Milan, Italy; Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy. 8. Neuroradiology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. 9. Molecular Genetics of Intellectual Disabilities Unit, Division of Neuroscience at IRCCS San Raffaele Scientific Institute, Milan, Italy. 10. Clinic of Medical Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy. Electronic address: mt.bonati@auxologico.it.
Abstract
BACKGROUND: RAB39B pathogenic variants cause X-linked Parkinsonism associated with Intellectual Disability, known as Waisman syndrome, a very rare disorder that has been mainly identified through exome sequencing in large Parkinson's disease cohorts. In this study we searched for pathogenic variants in RAB39B in two Italian families affected by X-linked early-onset Parkinsonism and Intellectual Disability. METHODS: Three patients received neurological evaluation and underwent RAB39B sequencing. RESULTS: Two novel RAB39B frameshift variants were found to result in the absence of RAB39B protein (family 1: c.137dupT; family 2: c.371delA). Patients showed unilateral rest tremor and bradykinesia; one of them also displayed an early-onset postural tremor. Paramagnetic substance deposition in the substantia nigra, globus pallidi, red nucleus, putamen and pulvinar was assessed by brain imaging. Two patients also showed moderate calcification of globus pallidi. CONCLUSION: In this study we highlight the evidence that X-linked early-onset Parkinsonism associated with Intellectual Disability occurs as a pattern of clinical and neuroimaging features attributable to RAB39B pathogenic variants.
BACKGROUND:RAB39B pathogenic variants cause X-linked Parkinsonism associated with Intellectual Disability, known as Waisman syndrome, a very rare disorder that has been mainly identified through exome sequencing in large Parkinson's disease cohorts. In this study we searched for pathogenic variants in RAB39B in two Italian families affected by X-linked early-onset Parkinsonism and Intellectual Disability. METHODS: Three patients received neurological evaluation and underwent RAB39B sequencing. RESULTS: Two novel RAB39B frameshift variants were found to result in the absence of RAB39B protein (family 1: c.137dupT; family 2: c.371delA). Patients showed unilateral rest tremor and bradykinesia; one of them also displayed an early-onset postural tremor. Paramagnetic substance deposition in the substantia nigra, globus pallidi, red nucleus, putamen and pulvinar was assessed by brain imaging. Two patients also showed moderate calcification of globus pallidi. CONCLUSION: In this study we highlight the evidence that X-linked early-onset Parkinsonism associated with Intellectual Disability occurs as a pattern of clinical and neuroimaging features attributable to RAB39B pathogenic variants.
Authors: Yann Le Guen; Valerio Napolioni; Michael E Belloy; Eric Yu; Lynne Krohn; Jennifer A Ruskey; Ziv Gan-Or; Gabriel Kennedy; Sarah J Eger; Michael D Greicius Journal: Ann Neurol Date: 2021-03-06 Impact factor: 11.274
Authors: David J Koss; Odeta Bondarevaite; Sara Adams; Marta Leite; Flaviano Giorgini; Johannes Attems; Tiago F Outeiro Journal: Brain Pathol Date: 2020-08-25 Impact factor: 7.611