Neonatal encephalopathy

(NEWS - neonatal encephalopathy with seizures)

Neonatal encephalopathy (NEWS - neonatal encephalopathy with seizures) is an inherited fatal brain disease of the standard puddle puppies. Affected puppies are smaller and weaker at birth than the sound puppies and many die in their first week of life. Those surviving past 1 week develop ataxia, tremor and severe generalized clonic-tonic seizures by 4 to 6 weeks of age. None survives to 7 weeks of age.  The cerebella from the affected puppies are reduced in size and often contain dysplastic foci consisting of clusters of intermixed granule and Purkinje neurons.

Samples of 78-member family of standard poodles, which included 20 puppies with NEWS, were used for mapping the locus responsible for the NEWS disease in standard poodles (Chen et al. 2007).  In all puppies affected with NEWS was identified a T>G transversion  in exon 3 (c.152T>G) of ATF2 gene, which predicts a methionine-to-arginine substitution in amino acid position 51 (Chen et al. 2007). The ATF2-gene (activation transcription factor 2) encodes transcription factor ATF-2, which participates in the cellular response to a wide variety of stimuli. Methionine in position 51 lies within a hydrophobic docking site for mitogen-activated protein kinases (MAP-kinases) that activate ATF-2 so the arginine substitution is likely to interfere with ATF-2-activation.

The casual mutation disease NEWS was examined on a population of American standard puddles and results of 1,035 standard poodles were published:

• 638 family members (61.46%) were homozygous for the allele without mutation,  this genotype corresponded to a clinically normal family member
• 371 family members (35.74 %) were heterozygous  for casual mutation; they were carriers of the disease
• 29 family members (2.79 %) were homozygous for casual mutation causing the NEWS disease and did not survive 7 weeks of their lives.

NEWS in standard poodles is an autosomal recessively inherited disease and it means that the disease develops only in individuals, which inherited from their parents both mutant alleles (P/P - positive/positive - m mutant homozygote). An individual, which inherits the mutant allele from one parent (result N/P - negative/positive) is heterozygous and a carrier of the disease; this individual transfers this mutant allele to its offsprings. If both parents are heterozygous (carriers of NEWS), then theoretically, 25 % of the puppies born will be affected.

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References:

Chen, X., Johnson, GS., Schnabel, RD., Taylor, JF., Johnson, GC., Parker, HG., Patterson, EE., Katz, ML., Awano, T., Khan, S., O'Brien, DP.:A neonatal encephalopathy with seizures in standard poodle dogs with a missense mutation in the canine ortholog of ATF2., Neurogenetics 9:41-9, 2008.