Diagnosis of CoPAN by whole exome sequencing: Waking up a sleeping tiger's eye

Christina Evers; Angelika Seitz; Birgit Assmann; Thomas Opladen; Stephanie Karch; Katrin Hinderhofer; Martin Granzow; Nagarajan Paramasivam; Roland Eils; Nicolle Diessl; Claus R Bartram; Ute Moog

doi:10.1002/ajmg.a.38252

Diagnosis of CoPAN by whole exome sequencing: Waking up a sleeping tiger's eye

Am J Med Genet A. 2017 Jul;173(7):1878-1886. doi: 10.1002/ajmg.a.38252. Epub 2017 May 10.

Authors

Affiliations

¹ Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
² Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany.
³ Center for Child and Adolescent Medicine, Pediatric Neurology, Heidelberg University Hospital, Heidelberg, Germany.
⁴ Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵ Medical Faculty Heidelberg, Heidelberg University, Germany.
⁶ Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany.
⁷ Genomics and Proteomics Core Facility (GPCF), High Throughput Sequencing, German Cancer Research Center (DKFZ), Heidelberg, Germany.

PMID: 28489334
DOI: 10.1002/ajmg.a.38252

Abstract

Neurodegeneration with brain iron accumulation (NBIA) is a group of neurodegenerative disorders characterized by iron accumulation in the basal ganglia. Recently, mutations in CoA synthase (COASY) have been identified as a cause of a novel NBIA subtype (COASY Protein-Associated Neurodegeneration, CoPAN) in two patients with dystonic paraparesis, parkinsonian features, cognitive impairment, behavior abnormalities, and axonal neuropathy. COASY encodes an enzyme required for Coenzyme A (CoA) biosynthesis. Using whole exome sequencing (WES) we identified compound heterozygous COASY mutations in two siblings with intellectual disability, ataxic gait, progressive spasticity, and obsessive-compulsive behavior. The "eye-of-the tiger-sign," a characteristic hypointense spot within the hyperintense globi pallidi on MRI found in the most common subtype of NBIA (Pantothenate Kinase-Associated Neurodegeneration, PKAN), was not present. Instead, bilateral hyperintensity and swelling of caudate nucleus, putamen, and thalamus were found. In addition, our patients showed a small corpus callosum and frontotemporal and parietal white matter changes, expanding the brain phenotype of patients with CoPAN. Metabolic investigations showed increased free carnitine and decreased acylcarnitines in the patientś dried blood samples. Carnitine palmitoyl transferase 1 (CPT1) deficiency was excluded by further enzymatic and metabolic investigations. As CoA and its derivate Acetyl-CoA play an essential role in fatty acid metabolism, we assume that abnormal acylcarnitine profiles are a result of the COASY mutations. This report not only illustrates that WES is a powerful tool to elucidate the etiology of rare genetic diseases, but also identifies unique neuroimaging and metabolic findings that may be key features for an early diagnosis of CoPAN.

Keywords: CoPAN; Coenzyme A synthase; COASY; COASY Protein-Associated Neurodegeneration; CoA synthase; NBIA; Neurodegeneration with Brain Iron Accumulation; eye of the tiger sign; neurodegeneration.