Mutations in SLC30A10 cause parkinsonism and dystonia with hypermanganesemia, polycythemia, and chronic liver disease.

Manganese is essential for several metabolic pathways but becomes toxic in excessive amounts. Manganese levels in the body are therefore tightly regulated, but the responsible protein(s) remain incompletely known. We studied two consanguineous families with neurologic disorders including juvenile-onset dystonia, adult-onset parkinsonism, severe hypermanganesemia, polycythemia, and chronic hepatic disease, including steatosis and cirrhosis. We localized the genetic defect by homozygosity mapping and then identified two different homozygous frameshift SLC30A10 mutations, segregating with disease. SLC30A10 is highly expressed in the liver and brain, including in the basal ganglia. Its encoded protein belongs to a large family of membrane transporters, mediating the efflux of divalent cations from the cytosol. We show the localization of SLC30A10 in normal human liver and nervous system, and its depletion in liver from one affected individual. Our in silico analyses suggest that SLC30A10 possesses substrate specificity different from its closest (zinc-transporting) homologs. We also show that the expression of SLC30A10 and the levels of the encoded protein are markedly induced by manganese in vitro. The phenotype associated with SLC30A10 mutations is broad, including neurologic, hepatic, and hematologic disturbances. Intrafamilial phenotypic variability is also present. Chelation therapy can normalize the manganesemia, leading to marked clinical improvements. In conclusion, we show that SLC30A10 mutations cause a treatable recessive disease with pleomorphic phenotype, and provide compelling evidence that SLC30A10 plays a pivotal role in manganese transport. This work has broad implications for understanding of the manganese biology and pathophysiology in multiple human organs.

Visual search improvement in hemianopic patients after audio-visual stimulation.

One of the most effective techniques in the rehabilitation of visual field defects is based on implementation of oculomotor strategies to compensate for visual field loss. In the present study we develop a new rehabilitation approach based on the audio-visual stimulation of the visual field. Since it has been demonstrated that audio-visual interaction in multisensory neurons can improve temporally visual perception in patients with hemianopia, the aim of the present study was to verify whether a systematic audio-visual stimulation might induce a long-lasting amelioration of visual field disorders. Eight patients with chronic visual field defects were trained to detect the presence of visual targets. During the training, the visual stimulus could be presented alone, i.e. unimodal condition, or together with an acoustic stimulus, i.e. crossmodal conditions. In the crossmodal conditions, the spatial disparity between the visual and the acoustic stimuli were systematically varied (0, 16 and 32 degrees of disparity). Furthermore, the temporal interval between the acoustic stimulus and the visual target in the crossmodal conditions was gradually reduced from 500 to 0 ms. Patients underwent the treatment for 4 h daily, over a period of nearly 2 weeks. The results showed a progressive improvement of visual detections during the training and an improvement of visual oculomotor exploration that allowed patients to efficiently compensate for the loss of vision. More interesting, there was a transfer of treatment gains to functional measures assessing visual field exploration and to daily-life activities, which was found stable at the 1 month follow-up control session. These findings are very promising with respect to the possibility of taking advantage of human multisensory capabilities to recover from unimodal sensory impairments.

Visual localization of sounds.

Circumscribed hemispheric lesions in the right hemisphere have been shown to impair auditory spatial functions. Due to a strong crossmodal links that exist between vision and audition, in the present study, we have hypothesized that multisensory integration can play a specific role in recovery from spatial representational deficits. To this aim, a patient with severe auditory localization defect was asked to indicate verbally the spatial position where the sound was presented. The auditory targets were presented at different spatial locations, at 8 degrees, 24 degrees, 40 degrees, 56 degrees to either sides of the central fixation point. The task was performed either in a unimodal condition (i.e., only sounds were presented) or in crossmodal conditions (i.e., a visual stimulus was presented simultaneously to the auditory target). In the crossmodal conditions, the visual cue was presented either at the same spatial position as the sound or at 16 degrees or 32 degrees, nasal or temporal, of spatial disparity from the auditory target. The results showed that a visual stimulus strongly improves the patient's ability to localize the sounds, but only when it was presented in the same spatial position of the auditory target.

Analysis of the anti-Parkinson drug pramipexole in human urine by capillary electrophoresis with laser-induced fluorescence detection.

A sensitive method based on capillary electrophoresis with laser-induced fluorescence detection has been developed for the analysis of the non-ergoline dopamine agonist pramipexole in human urine. Separation was carried out in uncoated fused silica capillaries (75microm internal diameter, 75.0 and 60.0cm total and effective length, respectively), with a background electrolyte composed of borate buffer (50mM, pH 10.3), tetrabutylammonium bromide (30mM), and acetone (15%, v/v). Applying a 20kV voltage, the electrophoretic run is completed within 12min. A sample pre-treatment procedure based on liquid/liquid extraction with ethyl acetate, followed by derivatisation of pramipexole with fluorescein isothiocyanate at pH 9, allows the complete removal of biological interferences, with extraction yields always higher than 94.5%. Method validation gave good linearity (r(2)=0.9992) in the 25.0-1000ngmL(-1) range; limit of detection and limit of quantitation were 10.0 and 25.0ngmL(-1), respectively; precision was 90.0. The method was applied to the analysis of urine samples from patients undergoing therapy with pramipexole.