Case Report

Acta Neuropathologica

, Volume 125, Issue 5, pp 753-769

Open Access This content is freely available online to anyone, anywhere at any time.

α-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson’s disease and multiple system atrophy?

  • Aoife P. KielyAffiliated withQueen Square Brain Bank, UCL Institute of NeurologyDepartment of Molecular Neuroscience, UCL Institute of Neurology Email author 
  • , Yasmine T. AsiAffiliated withQueen Square Brain Bank, UCL Institute of NeurologyDepartment of Molecular Neuroscience, UCL Institute of Neurology
  • , Eleanna KaraAffiliated withDepartment of Molecular Neuroscience, UCL Institute of NeurologyReta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology
  • , Patricia LimousinAffiliated withUnit of Functional Neurosurgery, UCL Institute of NeurologySobell Department of Motor Neuroscience and Movement Disorders, University College London
  • , Helen LingAffiliated withQueen Square Brain Bank, UCL Institute of NeurologyDepartment of Molecular Neuroscience, UCL Institute of NeurologyDepartment of Molecular Neuroscience, UCL Institute of NeurologyReta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology
  • , Patrick LewisAffiliated withDepartment of Molecular Neuroscience, UCL Institute of NeurologyReta Lila Weston Institute of Neurological Studies, UCL Institute of NeurologySchool of Pharmacy, University of Reading
  • , Christos ProukakisAffiliated withDepartment of Clinical Neuroscience, UCL Institute of Neurology
  • , Niall QuinnAffiliated withNational Hospital for Neurology and Neurosurgery
  • , Andrew J. LeesAffiliated withQueen Square Brain Bank, UCL Institute of NeurologyDepartment of Molecular Neuroscience, UCL Institute of NeurologyDepartment of Molecular Neuroscience, UCL Institute of NeurologyReta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology
    • , John HardyAffiliated withQueen Square Brain Bank, UCL Institute of NeurologyDepartment of Molecular Neuroscience, UCL Institute of NeurologyDepartment of Molecular Neuroscience, UCL Institute of NeurologyReta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology
    • , Tamas ReveszAffiliated withQueen Square Brain Bank, UCL Institute of NeurologyDepartment of Molecular Neuroscience, UCL Institute of Neurology
    • , Henry HouldenAffiliated withDepartment of Molecular Neuroscience, UCL Institute of NeurologyReta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology
    • , Janice L. HoltonAffiliated withQueen Square Brain Bank, UCL Institute of NeurologyDepartment of Molecular Neuroscience, UCL Institute of Neurology

Abstract

We report a British family with young-onset Parkinson’s disease (PD) and a G51D SNCA mutation that segregates with the disease. Family history was consistent with autosomal dominant inheritance as both the father and sister of the proband developed levodopa-responsive parkinsonism with onset in their late thirties. Clinical features show similarity to those seen in families with SNCA triplication and to cases of A53T SNCA mutation. Post-mortem brain examination of the proband revealed atrophy affecting frontal and temporal lobes in addition to the caudate, putamen, globus pallidus and amygdala. There was severe loss of pigmentation in the substantia nigra and pallor of the locus coeruleus. Neuronal loss was most marked in frontal and temporal cortices, hippocampal CA2/3 subregions, substantia nigra, locus coeruleus and dorsal motor nucleus of the vagus. The cellular pathology included widespread and frequent neuronal α-synuclein immunoreactive inclusions of variable morphology and oligodendroglial inclusions similar to the glial cytoplasmic inclusions of multiple system atrophy (MSA). Both inclusion types were ubiquitin and p62 positive and were labelled with phosphorylation-dependent anti-α-synuclein antibodies In addition, TDP-43 immunoreactive inclusions were observed in limbic regions and in the striatum. Together the data show clinical and neuropathological similarities to both the A53T SNCA mutation and multiplication cases. The cellular neuropathological features of this case share some characteristics of both PD and MSA with additional unique striatal and neocortical pathology. Greater understanding of the disease mechanism underlying the G51D mutation could aid in understanding of α-synuclein biology and its impact on disease phenotype.

Keywords

Parkinson’s disease Multiple system atrophy α-Synuclein SNCA