BackgroundA significant component of the variation in cognitive disability that is observed in Duchenne muscular dystrophy (DMD) is known to be under genetic regulation. In this study we report correlations between standardised measures of intelligence and mutational class, mutation size, mutation location and the involvement of dystrophin isoforms.Methods and ResultsSixty two male subjects were recruited as part of a study of the cognitive spectrum in boys with DMD conducted at the Sydney Children's Hospital (SCH). All 62 children received neuropsychological testing from a single clinical psychologist and had a defined dystrophin gene (DMD) mutation; including DMD gene deletions, duplications and DNA point mutations. Full Scale Intelligence Quotients (FSIQ) in unrelated subjects with the same mutation were found to be highly correlated (r = 0.83, p = 0.0008), in contrast to results in previous publications. In 58 cases (94%) it was possible to definitively assign a mutation as affecting one or more dystrophin isoforms. A strong association between the risk of cognitive disability and the involvement of groups of DMD isoforms was found. In particular, improvements in the correlation of FSIQ with mutation location were identified when a new classification system for mutations affecting the Dp140 isoform was implemented.SignificanceThese data represent one of the largest studies of FSIQ and mutational data in DMD patients and is among the first to report on a DMD cohort which has had both comprehensive mutational analysis and FSIQ testing through a single referral centre. The correlation between FSIQ results with the location of the dystrophin gene mutation suggests that the risk of cognitive deficit is a result of the cumulative loss of central nervous system (CNS) expressed dystrophin isoforms, and that correct classification of isoform involvement results in improved estimates of risk.

The authors examined the difference in errors made by eight subjects in setting a bar of light in an otherwise darkened room to either visually perceived vertical (VPV) or visually perceived horizontal (VPH) during maintained roll-tilted positions around the naso-occipital axis. Two viewing distances were examined, 25 and 60 cm. Subjects were tested at roll-tilt angles of 10 degrees intervals from upright to body horizontal (both left ear down (LED) and right ear down (RED)) in a randomized fashion. Settings were made only after a 1 min delay at each tilt angle to allow for decay of the semicircular canal signal. Chair rotation speed was 2 degrees/s with subjects being re-tested using 1/2 degree/s (at 25 cm) to determine the effect of rotation speed. Average errors for vertical versus horizontal were significantly different from each other (P < 0.01) at both the 25 and 60 cm viewing distances. The errors follow a complex function, with VPH showing smaller errors than VPV for large roll-tilts, while the opposite was true for medium-sized roll-tilts. This was true at both chair velocities. That is, VPV and VPH are not orthogonal to one another under the conditions examined. There are large differences between individuals but each individual showed a repeatable pattern. The average extent of non-orthogonality was found to be as high as 7 degrees at some large roll-tilt angles. These findings raise questions about the appropriateness of comparing the results of studies using the different tasks VPV and VPH. Factors that might contribute to this effect are discussed, including somatosensory input and ocular counterrolling (OCR).

To establish a link between otolith anatomy and function it is necessary to know the regions of the utricular and saccular maculae, which are stimulated by any arbitrary linear acceleration stimulus. That requires accurate information about the location and orientation of the spatially extended maculae in head-fixed coordinates and referred to head-fixed landmarks (such as Reid's line). New data showing the location of the otolithic maculae in the guinea pig with respect to head-fixed stereotaxic coordinates are presented. Guinea pigs were perfused with Karnovsky's fixative and the maculae were exposed while the head was held in a guinea pig stereotaxic device. An electrolytically sharpened fine wire held in a calibrated micromanipulator was touched to points all over the surface of each macula under visual observation with the aid of a high-power operating microscope. The x, y, z coordinates of these points were plotted using a three-dimensional plotting program. Both maculae have pronounced curvature so that dorsoventral shear forces will stimulate regions of both the utricular and saccular maculae.

To test a hypothesis about how otoliths resolve roll-tilts from translations, we measured human ocular torsion position [ocular counterrolling (OCR)] to maintained linear acceleration stimuli. All subjects (n = 8) were tested in two conditions where the same magnitude of shear along an interaural axis was generated in one of two ways: either by roll-tilt on a tilt-chair in a 1-g environment, or by centripetal linear acceleration during constant velocity rotation 1 m from the axis of rotation on a fixed-chair human centrifuge. The interaural shear to the otoliths was the same for these two conditions, but the dorsoventral shear was different and for all eight subjects the OCR on the centrifuge was significantly greater than the torsion on the tilt-chair, although the resultant angle was in fact smaller on the centrifuge than on the tilt-chair. The results confirm that dorsoventral shear is important for determining OCR. The otoliths may resolve potential stimulus ambiguities between tilts and translations by virtue of the different patterns of interaural and dorsoventral shear that these stimuli generate.

Unilateral sternocleidomastoid muscle vibration was applied to 21 normal and six unilateral vestibular deafferented (uVD) human subjects at head erect and during 30 degrees left and right whole body roll-tilt. In normal subjects, neck vibration had no effect upon the settings of a visual bar to subjective visual horizontal (SVH) in any roll-tilt condition. In uVD subjects settings to SVH were significantly altered by neck vibration, with ipsilesional neck vibration increasing the SVH bias at head erect. Further, during contralesional roll-tilt, ipsilesional neck vibration in uVD subjects significantly increased the E-effect. These results suggest that compensation after vestibular loss allows cervical signals to influence visual perception of roll-tilt.