title: Mutation in GM2A Leads to a Progressive Chorea-dementia Syndrome.
abstract: BACKGROUND
  The etiology of many cases of childhood-onset chorea remains undetermined, although advances in genomics are revealing both new disease-associated genes and variant phenotypes associated with known genes.
  
  
  METHODS
  We report a Saudi family with a neurodegenerative course dominated by progressive chorea and dementia in whom we performed homozygosity mapping and whole exome sequencing.
  
  
  RESULTS
  We identified a homozygous missense mutation in GM2A within a prominent block of homozygosity. This mutation is predicted to impair protein function.
  
  
  CONCLUSIONS
  Although discovered more than two decades ago, to date, only five patients with this rare form of GM2 gangliosidosis have been reported. The phenotype of previously described GM2A patients has been typified by onset in infancy, profound hypotonia and impaired volitional movement, intractable seizures, hyperacusis, and a macular cherry red spot. Our findings expand the phenotypic spectrum of GM2A mutation-positive gangliosidosis to include generalized chorea without macular findings or hyperacusis and highlight how mutations in neurodegenerative disease genes may present in unexpected ways.
authors.affiliation: Division of Pediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Salih
authors.affiliation: Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.
authors.forename: Mohammed Z
authors.initials: MZ
authors.lastname: Seidahmed
authors.affiliation: Division of Pediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Heba Y
authors.initials: HY
authors.lastname: El Khashab
authors.affiliation: Division of Pediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Muddathir H A
authors.initials: MH
authors.lastname: Hamad
authors.affiliation: Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bosley
authors.affiliation: Division of Medical Genetics, Sanford Children's Hospital, Sioux Falls, SD, USA.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Burn
authors.affiliation: Division of Medical Genetics, Sanford Children's Hospital, Sioux Falls, SD, USA ; Sanford Children's Health Research Center, Sanford Research Sioux Falls, SD, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Myers
authors.affiliation: Division of Medical Genetics, Sanford Children's Hospital, Sioux Falls, SD, USA ; Sanford Children's Health Research Center, Sanford Research Sioux Falls, SD, USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Landsverk
authors.affiliation: Division of Medical Genetics, Sanford Children's Hospital, Sioux Falls, SD, USA ; Sanford Children's Health Research Center, Sanford Research Sioux Falls, SD, USA.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Crotwell
authors.affiliation: Department of Genetics, Yale School of Medicine, Yale Center for Genome Analysis, West Haven, CT, USA.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilguvar
authors.affiliation: Department of Genetics, Yale School of Medicine, Yale Center for Genome Analysis, West Haven, CT, USA.
authors.forename: Shrikant
authors.initials: S
authors.lastname: Mane
authors.affiliation: Division of Medical Genetics, Sanford Children's Hospital, Sioux Falls, SD, USA ; Sanford Children's Health Research Center, Sanford Research Sioux Falls, SD, USA ; Sanford Neurogenetics & Neurometabolic Disorders Clinic and Pediatric Movement Disorders Clinic, Division of Pediatric Neurology, Sanford Children's Specialty Clinic Sioux Falls, SD, USA ; Departments of Pediatrics & Neurosciences, Sanford College of Medicine, University of South Dakota, Vermillion, SD, USA ; Department of Chemistry & Biochemistry, South Dakota State University, Brookings, SD, USA ; University of Arizona College of Medicine, Department of Child Health, Phoenix, AZ ; Barrow Neurological Institute and Ronald A. Matricaria Institute for Molecular Medicine, Phoenix Children's Hospital, Phoenix, AZ.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Kruer
keywords: Chorea; GM2 gangliosidosis; dementia; neurodegeneration