title: Recessive ITPA mutations cause an early infantile encephalopathy.
abstract: OBJECTIVE
  To identify the etiology of a novel, heritable encephalopathy in a small group of patients.
  
  
  METHODS
  Magnetic resonance imaging (MRI) pattern analysis was used to select patients with the same pattern. Homozygosity mapping and whole exome sequencing (WES) were performed to find the causal gene mutations.
  
  
  RESULTS
  Seven patients from 4 families (2 consanguineous) were identified with a similar MRI pattern characterized by T2 signal abnormalities and diffusion restriction in the posterior limb of the internal capsule, often also optic radiation, brainstem tracts, and cerebellar white matter, in combination with delayed myelination and progressive brain atrophy. Patients presented with early infantile onset encephalopathy characterized by progressive microcephaly, seizures, variable cardiac defects, and early death. Metabolic testing was unrevealing. Single nucleotide polymorphism array revealed 1 overlapping homozygous region on chromosome 20 in the consanguineous families. In all patients, WES subsequently revealed recessive predicted loss of function mutations in ITPA, encoding inosine triphosphate pyrophosphatase (ITPase). ITPase activity in patients' erythrocytes and fibroblasts was severely reduced.
  
  
  CONCLUSIONS
  Until now ITPA variants have only been associated with adverse reactions to specific drugs. This is the first report associating ITPA mutations with a human disorder. ITPase is important in purine metabolism because it removes noncanonical nucleotides from the cellular nucleotide pool. Toxicity of accumulated noncanonical nucleotides, leading to neuronal apoptosis and interference with proteins normally using adenosine triphosphate/guanosine triphosphate, probably explains the disease. This study confirms that combining MRI pattern recognition to define small, homogeneous patient groups with WES is a powerful approach for providing a fast diagnosis in patients with an unclassified genetic encephalopathy.
authors.affiliation: Department of Child Neurology, VU University Medical Center, Amsterdam, the Netherlands.|Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands.
authors.forename: Sietske H
authors.initials: SH
authors.lastname: Kevelam
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Jörgen
authors.initials: J
authors.lastname: Bierau
authors.affiliation: Division of Biochemical Diseases, Department of Pediatrics, University of British Columbia, British Columbia Children's Hospital, Vancouver, British Columbia, Canada.
authors.forename: Ramona
authors.initials: R
authors.lastname: Salvarinova
authors.affiliation: Department of Pediatric Neurology, Birmingham Children's Hospital, Birmingham, United Kingdom.
authors.forename: Shakti
authors.initials: S
authors.lastname: Agrawal
authors.affiliation: Department of Pediatrics, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Tomas
authors.initials: T
authors.lastname: Honzik
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Dennis
authors.initials: D
authors.lastname: Visser
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Weiss
authors.affiliation: Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands.|Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Gajja S
authors.initials: GS
authors.lastname: Salomons
authors.affiliation: Department of Child Neurology, VU University Medical Center, Amsterdam, the Netherlands.|Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands.
authors.forename: Truus E M
authors.initials: TE
authors.lastname: Abbink
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Quinten
authors.initials: Q
authors.lastname: Waisfisz
authors.affiliation: Department of Child Neurology, VU University Medical Center, Amsterdam, the Netherlands.|Neuroscience Campus Amsterdam, VU University, Amsterdam, the Netherlands.|Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, VU University, Amsterdam, the Netherlands.
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
mesh_terms: D001927:Brain Diseases / Q000175:diagnosis* / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D017433:Protein Structure, Secondary; D011755:Pyrophosphatases / Q000737:chemistry / Q000235:genetics*; D000097630:Inosine Triphosphatase
chemical_list: D011755:Pyrophosphatases; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase