Treatment of Lesch-Nyhan disease with S-adenosylmethionine: experience with five young Malaysians, including a girl.

BACKGROUND: Lesch-Nyhan disease (LND) is a rare X-linked recessive neurogenetic disorder caused by deficiency of the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT, EC 2.4.2.8) which is responsible for recycling purine bases into purine nucleotides. Affected individuals have hyperuricemia leading to gout and urolithiasis, accompanied by a characteristic severe neurobehavioural phenotype with compulsive self-mutilation, extrapyramidal motor disturbances and cognitive impairment. AIM: For its theoretical therapeutic potential to replenish the brain purine nucleotide pool, oral supplementation with S-adenosylmethionine (SAMe) was trialed in 5 Malaysian children with LND, comprising 4 related Malay children from 2 families, including an LND girl, and a Chinese Malaysian boy. RESULTS: Dramatic reductions of self-injury and aggressive behaviour, as well as a milder reduction of dystonia, were observed in all 5 patients. Other LND neurological symptoms did not improve during SAMe therapy. DISCUSSION: Molecular mechanisms proposed for LND neuropathology include GTP depletion in the brain leading to impaired dopamine synthesis, dysfunction of G-protein-mediated signal transduction, and defective developmental programming of dopamine neurons. The improvement of our LND patients on SAMe, particularly the hallmark self-injurious behaviour, echoed clinical progress reported with another purine nucleotide depletion disorder, Arts Syndrome, but contrasted lack of benefit with the purine disorder adenylosuccinate lyase deficiency. This first report of a trial of SAMe therapy in LND children showed remarkably encouraging results that warrant larger studies.

Comparing the functional representations of central and border whiskers in rat primary somatosensory cortex.

The anatomical representations of the large facial whiskers, termed barrels, are topographically organized and highly segregated in the posteromedial barrel subfield (PMBSF) of rat layer IV primary somatosensory cortex. Although the functional representations of single whiskers are aligned with their appropriate barrels, their areal extents are rather large, spreading outward from the appropriate barrel along the tangential plane and thereby spanning multiple neighboring and non-neighboring barrels and septal regions. To date, single-whisker functional representations have been characterized primarily for whiskers whose corresponding barrels are located centrally within the PMBSF (central whiskers). Using intrinsic signal imaging verified with post-imaging single-unit recording, we demonstrate that border whiskers, whose barrels are located at the borders of the PMBSF, also evoke large activity areas that are similar in size to those of central whiskers but spread beyond the PMBSF and sometimes beyond primary somatosensory cortex into the neighboring dysgranular zones. This study indicates that the large functional representation of a single whisker is a basic functional feature of the rat whisker-to-barrel system and, combined with results from other studies, suggest that a large functional representation of a small, point-like area on the sensory epithelium may be a functional feature of primary sensory cortex in general.

Visualizing and quantifying evoked cortical activity assessed with intrinsic signal imaging.

Intrinsic signal imaging (ISI) measures changes in light reflectance from the illuminated cortex (intrinsic signals or IS) attributed to various vascular and metabolic sources that, when using illumination in the 600 nm range, appear to co-localize with neuronal activity. Given the multiple sources contributing to the collected IS, the common practice of averaging across an extended post-stimulus time epoch before dividing by baseline data typically visualizes evoked IS overlying both the cortical tissue and the large surface blood vessels. In rat PMBSF, the contribution from these vessels are problematic as they do not co-localize with known PMBSF function. Determining a means for quantifying the evoked IS area poses an additional challenge. Here, we describe how exploiting IS collected shortly after stimulus onset (within 1.5 s), which coincides with fast oxygen consumption of active neurons, visualizes evoked IS overlying the cortical tissue without the large surface vessels. We also describe how the use of absolute thresholds combined with a baseline determined from data collected immediately prior to stimulus onset (within 1 s) targets most precisely a specific evoked IS amplitude, a method that should be especially useful when evoked areas are expected to occupy a substantial portion of the total imaged area and/or when peak activity is expected to differ between subjects.

Two directions of plasticity in the sensory-deprived adult cortex.

Damage or deprivation of a localized region of the skin surface has been shown to induce a selective expansion of adjacent skin surface representations in the adult somatosensory cortex. Here, we use repeated optical imaging in conjunction with single unit recordings to assess the plasticity of a single whisker's functional representation in the adult rat. We observed a large-scale expansion of a single whisker's functional representation following innocuous removal of all neighboring whiskers. Surprisingly, the same manipulation can also induce a large-scale contraction of the representation if the animal is removed from its home cage and given a brief opportunity to use its whiskers for active exploration of a different environment. Both the expansion and contraction reverse upon regrowth of the deprived whiskers. Thus, allowing the animal to use its deprived receptor organ in active exploration can determine the direction of plasticity in the adult cortex.

Varying the degree of single-whisker stimulation differentially affects phases of intrinsic signals in rat barrel cortex.

Using intrinsic signal optical imaging (ISI), we have shown previously that the point spread of evoked activity in the rat barrel cortex in response to single-whisker stimulation encompasses a surprisingly large area. Given that our typical stimulation consists of five deflections at 5 Hz, the large area of evoked activity might have resulted from repetitive stimulation. Thus in the present study, we use ISI through the thinned skull to determine whether decreasing the degree of single-whisker stimulation decreases the area of the cortical point spread. We additionally outline a protocol to quantify stimulus-related differences in the temporal characteristics of intrinsic signals at a fine spatial scale. In 10 adult rats, whisker C2 was stimulated randomly with either one or five deflections delivered in a rostral-to-caudal fashion. Each deflection consisted of a 0.5-mm displacement of the whisker as measured at the point of contact, 15 mm from the snout. The number of whisker deflections did not affect the area or peak magnitude of the cortical point spread based on the intrinsic signal activity occurring from 0.5 up to 1.5 s poststimulus onset. In contrast, the magnitude and time course of intrinsic signal activity collected after 1.5-s poststimulus onset did reflect the difference in the degree of stimulation. Thus decreasing the degree of stimulation differentially affected the early and late phases of the evoked intrinsic signal response. The implications of the present results are discussed in respect to probable differences in the signal source underlying the early versus later phases of evoked intrinsic signals.

Areal extent quantification of functional representations using intrinsic signal optical imaging.

An important parameter often investigated in the characterization of cortical functional organization is the areal extent of functional modules. Because it allows the visualization of functional modules with high spatial resolution in a noninvasive way to the cortex, intrinsic signal optical imaging (ISI) can be employed for the quantification of these areal extents. The present paper describes the use of the normalized threshold analysis of areal extent quantification for the objective assessment of single-whisker functional representations in the primary somatosensory cortex of adult rats. As the success of areal extent quantification depends on the ability of ISI to allow visualization of cortical representations with minimal stimulus-dependent blood vessel representations, which are commonly encountered by ISI, the present paper also describes the further development of the intratrial analysis of visualization for minimizing these vessel representations. Both analyses are discussed with respect to their advantages as well as their inherent limitations.

Variability and interhemispheric asymmetry of single-whisker functional representations in rat barrel cortex.

1. The rat whisker-to-barrel system was used to investigate the variability and interhemispheric asymmetry in the functional organization of primary somatosensory cortex as assessed with intrinsic signal optical imaging. The areal extent of whisker D1 functional representation was determined for both the left and right barrel cortex of each of 10 adult male rats. The average size of whisker D1 functional representation and the amount of variability away from this average across animals were determined. In addition, interhemispheric asymmetry was addressed at both the population level and the individual level. The degree of side preference for thigmotactic scanning (typical whisker-related rodent behavior) was determined for each rat in an attempt to find a behavioral correlate for the degree of interhemispheric asymmetry in the size of whisker D1 functional representation. 2. The average areal extent of whisker D1 functional representation (defined as area at half-height) was large (1.95 +/- 0.14 mm2, mean +/- SE, N = 10 rats), suggesting that stimulation of a single whisker evokes activity over a large cortical area that includes other whisker representations. 3. The average size of whisker D1 functional representation was not significantly different between the left (1.86 +/- 0.21 mm2) and right (2.04 +/- 0.15 mm2) hemispheric side, suggesting that interhemispheric functional asymmetry of barrel cortex is not systematic toward a specific hemispheric side at the population level. 4. The degree of variability in the size of whisker D1 functional representation from the left hemisphere ranged between 54.6% smaller than to 50.6% larger than the left average areal extent. A large degree of variability was also observed for the right D1 representation, 37.6% smaller than to 34.9% larger than the right average areal extent. Thus it appears that a large variability in the size of unmanipulated single-whisker functional representations exists across animals from the same species and is not exclusive to a particular hemispheric side. 5. In 5 of 10 rats, the size of whisker D1 functional representation between the two hemispheres differed by > or = 25% within an individual animal. Of these five rats, four had a larger representation in their right hemisphere. The degree and direction of behavioral asymmetry was not linearly correlated with the interhemispheric asymmetry in the size of D1 functional representation (r = 0.494). 6. The large size of a single-whisker functional representation as defined with intrinsic signal optical imaging is discussed with respect to previous anatomic and 2-deoxyglucose autoradiography studies, whereas the large variability in this size across animals is discussed with respect to the individuality of each animal. In addition, the results of the present study have implications for projects that plan to investigate relative changes in the size of single-whisker functional representations.