Recessive ITPA mutations cause an early infantile encephalopathy. Issue 4 (21st August 2015)

• Record Type: Journal Article
• Authors: Kevelam, Sietske H.; Bierau, Jörgen; Salvarinova, Ramona; Agrawal, Shakti; Honzik, Tomas; Visser, Dennis; Weiss, Marjan M.; Salomons, Gajja S.; Abbink, Truus E. M.; Waisfisz, Quinten; van der Knaap, Marjo S.
• Is Part Of: Annals of neurology. Volume 78:Issue 4(2015:Oct.)
• Page Start: 649
• Page End: 658
• Publication Date: 2015-08-21
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.24496
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ana24496-sec-0001" sec-type="section"> <title>Objective</title> <p>To identify the etiology of a novel, heritable encephalopathy in a small group of patients.</p> </sec> <sec id="ana24496-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="ana24496-sec-0003" sec-type="section"> <title>Results</title> <p>Seven patients from 4 families (2 consanguineous) were identified with a similar MRI pattern characterized by T<sub>2</sub> 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 <italic>ITPA</italic>, encoding inosine triphosphate pyrophosphatase (ITPase). ITPase activity in patients' erythrocytes and fibroblasts was severely reduced.</p> </sec> <sec id="ana24496-sec-0004" sec-type="section"> <title>Interpretation</title> <p>Until now <italic>ITPA</italic> variants have only been associated with adverse reactions to specific drugs. This is the first report associating <italic>ITPA</italic> 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. Ann Neurol 2015;78:649–658</p> </sec> </abstract>