Categories: Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 123811 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2008

Cross-species summary: Renaemd from 'Neonatal encephalopathy with seizures' to 'Neonatal encephalopathy with seizures, ATF2-related' [11/06/2024]

Species-specific symbol: NEWS

Species-specific description: The disorder is characterized by pups that are small at birth, fail to nurse or thrive, then develop neurological signs and usually die by 7 weeks of age. A genetic test is available.

Mapping: The locus for NEWS was mapped by linkage analysis with microsatellites in a large family with 20 affected dogs. Maximum LOD scores exceeding 7 were obtained on CFA36 between markers UMC0297 and REN252E18 (Chen et al., 2008). The ATF2 gene was identified as a positional and functional candidate gene within the 2.87 Mb critical interval.

Molecular basis: The causative variant is a missense c.152T>G transversion causing a p.M51R methionine to arginine substitution in ATF2 (Chen et al., 2008). The mutation lies in a hydrophobic docking site for protein kinases that activate ATF2. Mutant ATF2 retains partial activity (Chen et al., 2008).

Clinical features: Affected puppies are small at birth and do not develop normally. They initially nurse poorly, but begin nursing sufficiently after several days (Chen et al., 2008). At approximately 3 weeks of age, weakness, ataxia, whole-body tremors, wide-based stance with increased extensor tone, and axial muscle weakness with neck ventroflexion is observed. Affected pups do not interact with the dam or littermates and have slow responses to external stimuli (Chen et al., 2008). At approximately 3 to 6 weeks of age, affected puppies develop generalized clonic-tonic seizures that quickly become refractory to treatment. They become laterally recumbent with extensor rigidity and opisthotonus, and usually die or are euthanized before 7 weeks of age (Chen et al., 2008; Yu et al. 2020).

Pathology: The cerebellum is smaller than normal and contains dysplastic foci of cells from the granular layer intermixed with those from the Purkinje layer (Chen et al., 2008). Yu et al. (2020): "Magnetic resonance imaging showed reduced whole-brain size, dilated ventricles, developmental abnormalities of the white matter of the cerebrum, white matter signal abnormalities in the occipital lobe, and abnormal morphology of the cerebellum. Histopathology included previously unrecognized irregular neuronal migration in the subventricular zone around the lateral ventricles in the frontal lobe and white matter rarefaction especially at the level of the occipital lobe in the cerebrum ..,."

Prevalence: Of 1038 standard poodles genotyped, 36% were carriers and 2.7% were affected (Chen et al., 2008).

Control: Relatives of affected pups should be tested to identify carriers. Matings of carriers is discouraged, although breeding them to noncarriers will avoid production of affected pups.

Genetic testing: A test is available.

Breed: Poodle, Standard (Dog) (VBO_0201056).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: