Abnormalities in eye movement measures are a sensitive biomarker in the prediagnostic and early stages of Huntington disease (HD). These measures may be more sensitive to prediagnostic changes in HD than the currently employed neurologic motor assessment.

Background: Despite the need for significant clinical intervention owing to the psychiatric manifestations of Huntington disease (HD), there has been a paucity of studies specifically designed to evaluate these symptoms prior to disease diagnosis.Objectives: To investigate whether the Symptom Checklist 90-Revised (SCL-90-R) and the Center for Epidemiological Studies Depression Scale can be used to detect psychiatric manifestations among preclinical mutation carriers with absent or minimal motor signs of HD.

Disturbances of visual perception frequently accompany neurodegenerative disorders but have been little studied in Huntington's disease (HD) gene carriers. We used psychophysical tests to assess visual perception among individuals in the prediagnostic and early stages of HD. The sample comprised four groups, which included 201 nongene carriers (NG), 32 prediagnostic gene carriers with minimal neurological abnormalities (PD1); 20 prediagnostic gene carriers with moderate neurological abnormalities (PD2), and 36 gene carriers with diagnosed HD. Contrast sensitivity for stationary and moving sinusoidal gratings, and tests of form and motion discrimination, were used to probe different visual pathways. Patients with HD showed impaired contrast sensitivity for moving gratings. For one of the three contrast sensitivity tests, the prediagnostic gene carriers with greater neurological abnormality (PD2) also had impaired performance as compared with NG. These findings suggest that early stage HD disrupts visual functions associated with the magnocellular pathway. However, these changes are only observed in individuals diagnosed with HD or who are in the more symptomatic stages of prediagnostic HD. (JINS, 2008, 14, 446-453.)

DDX39B is a member of the DEAD-box family of ATP-dependent RNA helicases. DEAD-box proteins are ubiquitously expressed from yeast to humans and perform essential functions associated with mRNA metabolism. DDX39B is also a crucial component of the TRanscription-EXport (TREX) super protein complex, which recent studies have highlighted the important role of its subunits in neurodevelopmental disorders. Here, we describe six individuals from five families, four with novel de novo missense variants in DDX39B, and one carrying an inherited splicing variant, all presenting with mild to severe global developmental delay, congenital hypotonia, epilepsy, short stature, skeletal abnormalities and variable dysmorphic features. 3D molecular modeling predicts these variants would alter protein structure. DDX39B is a conserved gene and Drosophila melanogaster (fruit flies) studies were conducted. We generated a new Hel25E Kozak-GAL4 allele which disrupts the fly gene and allows expression of transgenes. We also generated transgenic DDX39B-reference and variant flies. However, human reference DDX39B when overexpressed ubiquitously leads to lethality but the variants found in the patients do not recapitulate the lethality suggesting that the mutants are loss of function alleles. Blood transcriptomics revealed a significant excess of aberrant splicing events, indicating a disrupted mRNA processing as anticipated from the role of DDX39B in mRNA metabolism. Our human genetic data, coupled with in silico and in vivo data supports that DDX39B is a novel candidate gene in a potential group of disorders named TREX-complex-related neurodevelopmental syndrome.

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