Novel WWOX deleterious variants cause early infantile epileptic encephalopathy, severe developmental delay and dysmorphism among Yemenite Jews.

The human WW Domain Containing Oxidoreductase (WWOX) gene was originally described as a tumor suppressor gene. However, recent reports have demonstrated its cardinal role in the pathogenesis of central nervous systems disorders such as epileptic encephalopathy, intellectual disability, and spinocerebellar ataxia. We report on six patients from three unrelated families of full or partial Yemenite Jewish ancestry exhibiting early infantile epileptic encephalopathy and profound developmental delay. Importantly, four patients demonstrated facial dysmorphism. Exome sequencing revealed that four of the patients were homozygous for a novel WWOX c.517-2A > G splice-site variant and two were compound heterozygous for this variant and a novel c.689A > C, p.Gln230Pro missense variant. Complementary DNA sequencing demonstrated that the WWOX c.517-2A > G splice-site variant causes skipping of exon six. A carrier rate of 1:177 was found among Yemenite Jews. We provide the first detailed description of patients harboring a splice-site variant in the WWOX gene and propose that the clinical synopsis of WWOX related epileptic encephalopathy should be broadened to include facial dysmorphism. The increased frequency of the c.517-2A > G splice-site variant among Yemenite Jews coupled with the severity of the phenotype makes it a candidate for inclusion in expanded preconception screening programs.

An initial evaluation of work fatigue and circadian changes as assessed by multiplate posturography.

The sensitivity of postural responses to the effects of work fatigue and circadian changes was explored in a pilot study using a specific method of multiplate posturography based on the differential assessment of vertical pressure on four separate platforms for each heel and set of toes of each foot, respectively 8 normal subjects, M.D.s, were given six posturographic examinations immediately before and after three 8-hr. work shifts in the emergency room of a major hospital in Tel-Aviv. 3 posturographic measures (stability, spectral power of postural sway at low frequency of 0.1-0.25 Hz, and unilateral weakening of heel-toe synchronisation) were significantly affected by work fatigue whilst also showing interaction with circadian rhythm. 2 additional measures (power of sway at high frequency of 1.00-3.00 Hz and dysharmonic distribution of weight over the four platforms) were not related to workload but showed significant circadian changes. These effects appeared only on positions involving restricted visual and somatosensory feedback causing vestibular stress. Results justify the application of multiplate posturography as an ancillary tool in measuring objectively the effects of fatigue and circadian changes as well as the interaction between endogenous chronobiological processes and their external conditioning factors (Zeitgebers). Pragmatic implications of the findings in the context of industrial medicine and interdisciplinary efforts to prevent road and air accidents are discussed.