Human Genetics

, Volume 131, Issue 3, pp 435–442

Exome sequencing identifies GCDH (glutaryl-CoA dehydrogenase) mutations as a cause of a progressive form of early-onset generalized dystonia

  • Jose Felix Marti-Masso
  • Javier Ruiz-Martínez
  • Vladimir Makarov
  • Adolfo López de Munain
  • Ana Gorostidi
  • Alberto Bergareche
  • Seungtai Yoon
  • Joseph D. Buxbaum
  • Coro Paisán-Ruiz
Original Investigation

DOI: 10.1007/s00439-011-1086-6

Cite this article as:
Marti-Masso, J.F., Ruiz-Martínez, J., Makarov, V. et al. Hum Genet (2012) 131: 435. doi:10.1007/s00439-011-1086-6

Abstract

Dystonias are a clinically and genetically heterogeneous group of movement disorders characterized by involuntary, sustained muscular contractions affecting one or more sites of the body, and abnormal postures. In this study, we describe an autosomal recessive family that presents with a progressive and early-onset form of generalized dystonia. The nuclear family consists of two healthy parents and two affected daughters. To elucidate the genetic causes underlying disease, whole-exome sequencing analysis was performed in one affected sibling, followed by validation, biochemical analyses and MRI brain imaging. A homozygous, disease-segregating mutation (p.Val400Met) was identified in the glutaryl-CoA dehydrogenase (GCDH) gene at chromosome 19p13. The mutation, in an amino acid that is highly conserved among species, was absent in large number of neurologically normal individuals. Biochemical analyses demonstrated increased 3-hydroxy glutaric acid present in urine samples from both patients. MRI imaging revealed a T2 and flair hyperintense signal in lenticular nuclei with bilateral and symmetrical distribution. We conclude that both GCDH activity and GCDH mutation analysis should be considered in the differential diagnosis of progressive forms of early-onset generalized dystonia and that mitochondrial fatty acid metabolism is one important pathway in the development of dystonia. As lysine restriction and l-carnitine supplementation are important treatments for GCDH deficiency, identification of this deficiency in patients with progressive forms of early-onset generalized dystonia has potential treatment implications.

Supplementary material

439_2011_1086_MOESM1_ESM.tif (1.5 mb)
Supplemental Figure 1: IGV plots for the p.V400M mutation (TIFF 1520 kb)

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Jose Felix Marti-Masso
    • 1
  • Javier Ruiz-Martínez
    • 1
    • 2
  • Vladimir Makarov
    • 3
  • Adolfo López de Munain
    • 1
  • Ana Gorostidi
    • 4
  • Alberto Bergareche
    • 1
  • Seungtai Yoon
    • 3
    • 5
  • Joseph D. Buxbaum
    • 3
    • 5
    • 6
    • 7
    • 9
  • Coro Paisán-Ruiz
    • 3
    • 7
    • 8
    • 9
  1. 1.Neurology DepartmentDonostia HospitalSan SebastiánSpain
  2. 2.Centro de investigación biomédica en Red para enfermedades Neurodegenerativas (CIBERNED), Carlos III Health InstituteMadridSpain
  3. 3.Department of PsychiatryMount Sinai School of MedicineNew YorkUSA
  4. 4.Neuroscience DepartmentBiodonostiaSan SebastiánSpain
  5. 5.The Seaver Autism Center for Research and TreatmentMount Sinai School of MedicineNew YorkUSA
  6. 6.Department of NeuroscienceMount Sinai School of MedicineNew YorkUSA
  7. 7.Department of Genetics and Genomic SciencesMount Sinai School of MedicineNew YorkUSA
  8. 8.Department of NeurologyMount Sinai School of MedicineNew YorkUSA
  9. 9.Friedman Brain InstituteMount Sinai School of MedicineNew YorkUSA