Recessive XXXX mutations cause an early infantile @entity75 .

@entity1 @entity3007 @entity17 @entity410 @entity10761 @entity17262 @entity137 @entity2036 @entity75 @entity299 @entity71443 @entity1010 @entity4242 @entity204 @entity855
OBJECTIVE: To identify the etiology of a novel, heritable @entity75 in a small group of @entity1 . METHODS: Magnetic resonance imaging (MRI) pattern analysis was used to select @entity1 with the same pattern. Homozygosity mapping and whole exome sequencing (WES) were performed to find the causal gene mutations. RESULTS: Seven @entity1 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 @entity17 and progressive @entity1010 . @entity1 presented with early infantile onset @entity75 characterized by progressive @entity4242 , @entity410 , variable @entity299 , and @entity204 . Metabolic testing was unrevealing. Single nucleotide polymorphism array revealed 1 overlapping homozygous region on chromosome 20 in the consanguineous families. In all @entity1 , WES subsequently revealed recessive predicted loss of function mutations in @entity71443 , encoding @entity10761 pyrophosphatase (ITPase). ITPase activity in @entity1 ' erythrocytes and fibroblasts was severely reduced. INTERPRETATION: Until now @entity71443 variants have only been associated with adverse reactions to specific drugs. This is the first report associating @entity71443 mutations with a @entity1 disorder. ITPase is important in @entity17262 metabolism because it removes noncanonical nucleotides from the cellular nucleotide pool. @entity137 of accumulated noncanonical @entity2036 , leading to neuronal apoptosis and interference with proteins normally using @entity855 / @entity3007 , probably explains the disease. This study confirms that combining MRI pattern recognition to define small, homogeneous @entity1 groups with WES is a powerful approach for providing a fast diagnosis in @entity1 with an unclassified genetic @entity75 . Ann Neurol 2015.
