Summary Purpose:  Pyridoxine‐dependent seizure (PDS) is a rare disorder characterized by seizures that are resistant to common anticonvulsants, and that are ultimately controlled by daily pharmacologic doses of pyridoxine (vitamin B6). Mutations of the antiquitin gene (ALDH7A1) are now recognized as the molecular basis of cases of neonatal‐onset PDS. Methods:  Bidirectional DNA sequence analysis of ALDH7A1 was undertaken along with plasma pipecolic acid (PA) measurements to determine the prevalence of ALDH7A1 mutations in a cohort of 18 North American patients with PDS. Results:  In patients with neonatal‐onset PDS, compound heterozygous or homozygous ALDH7A1 mutations were detected in 10 of 12 cases, and a single mutation was found in the remaining 2. In later‐onset cases, mutations in ALDH7A1 were detected in three of six cases. In two patients with infantile spasms responsive to pyridoxine treatment and with good clinical outcomes, no mutations were found and PA levels were normal. In total, 13 novel mutations were identified. Discussion:  Our study advances previous findings that defects of ALDH7A1 are almost always the cause of neonatal‐onset PDS and that defects in this gene are also responsible for some but not all later‐onset cases. Later‐onset cases of infantile spasms with good outcomes lacked evidence for antiquitin dysfunction, suggesting that this phenotype is less compelling for PDS.

Amyotrophic lateral sclerosis type 4 (ALS4) is a rare, early-onset, autosomal dominant form of ALS, characterized by slow disease progression and sparing of respiratory musculature. Dominant, gain-of-function mutations in the senataxin gene (SETX) cause ALS4, but the mechanistic basis for motor neuron toxicity is unknown. SETX is a RNA-binding protein with a highly conserved helicase domain, but does not possess a low-complexity domain, making it unique among ALS-linked disease proteins. We derived ALS4 mouse models by expressing two different senataxin gene mutations (R2136H and L389S) via transgenesis and knock-in gene targeting. Both approaches yielded SETX mutant mice that develop neuromuscular phenotypes and motor neuron degeneration. Neuropathological characterization of SETX mice revealed nuclear clearing of TDP-43, accompanied by TDP-43 cytosolic mislocalization, consistent with the hallmark pathology observed in human ALS patients. Postmortem material from ALS4 patients exhibited TDP-43 mislocalization in spinal cord motor neurons, and motor neurons from SETX ALS4 mice displayed enhanced stress granule formation. Immunostaining analysis for nucleocytoplasmic transport proteins Ran and RanGAP1 uncovered nuclear membrane abnormalities in the motor neurons of SETX ALS4 mice, and nuclear import was delayed in SETX ALS4 cortical neurons, indicative of impaired nucleocytoplasmic trafficking. SETX ALS4 mice thus recapitulated ALS disease phenotypes in association with TDP-43 mislocalization and provided insight into the basis for TDP-43 histopathology, linking SETX dysfunction to common pathways of ALS motor neuron degeneration.

We investigate the redshift evolution of the intrinsic alignments (IA) of galaxies in the MassiveBlackII (MBII) simulation. We select galaxy samples above fixed subhalo mass cuts (M h > 10 11,12,13 M /h) at z = 0.6 and trace their progenitors to z = 3 along their merger trees. Dark matter components of z = 0.6 galaxies are more spherical than their progenitors while stellar matter components tend to be less spherical than their progenitors. The distribution of the galaxy-subhalo misalignment angle peaks at ∼ 10 deg with a mild increase with time. The evolution of the ellipticity-direction (ED) correlation amplitude ω(r) of galaxies (which quantifies the tendency of galaxies to preferentially point towards surrounding matter overdensities) is governed by the evolution in the alignment of underlying dark matter (DM) subhaloes to the matter density of field, as well as the alignment between galaxies and their DM subhaloes. At scales ∼ 1 cMpc/h, the alignment between DM subhaloes and matter overdensity gets suppressed with time, whereas the alignment between galaxies and DM subhaloes is enhanced. These competing tendencies lead to a complex redshift evolution of ω(r) for galaxies at ∼ 1 cMpc/h. At scales > 1 cMpc/h, alignment between DM subhaloes and matter overdensity does not evolve significantly; the evolution of the galaxy-subhalo misalignment therefore leads to an increase in ω(r) for galaxies by a factor of ∼ 4 from z = 3 to 0.6 at scales > 1 cMpc/h. The balance between competing physical effects is scale dependant, leading to different conclusions at much smaller scales (∼ 0.1 Mpc/h).