The Role of Motor System in Mental Rotation: New Insights from Myotonic Dystrophy Type 1.

OBJECTIVE: This study explored mental rotation (MR) performance in patients with myotonic dystrophy 1 (DM1), an inherited neuromuscular disorder dominated by muscular symptoms, including muscle weakness and myotonia. The aim of the study was twofold: to gain new insights into the neurocognitive mechanisms of MR and to better clarify the cognitive profile of DM1 patients. To address these aims, we used MR tasks involving kinds of stimuli that varied for the extent to which they emphasized motor simulation and activation of body representations (body parts) versus visuospatial imagery (abstract objects). We hypothesized that, if peripheral sensorimotor feedback system plays a pivotal role in modulating MR performance, then DM1 patients would exhibit more difficulties in mentally rotating hand stimuli than abstract objects. METHOD: Twenty-four DM1 patients and twenty-four age- and education-matched control subjects were enrolled in the study and were required to perform two computerized MR tasks involving pictures of hands and abstract objects. RESULTS: The analysis of accuracy showed that patients had impaired MR performance when the angular disparities between the stimuli were higher. Notably, as compared to controls, patients showed slower responses when the stimuli were hands, whereas no significant differences when stimuli were objects. CONCLUSION: The findings are coherent with the embodied cognition view, indicating a tight relation between body- and motor-related processes and MR. They suggest that peripheral, muscular, abnormalities in DM1 lead to alterations in manipulation of motor representations, which in turn affect MR, especially when body parts are to mentally rotate.

Teaching an Old Molecule New Tricks: Drug Repositioning for Duchenne Muscular Dystrophy.

: Duchenne muscular dystrophy (DMD) is one of the most severe forms of inherited muscular dystrophies. The disease is caused by the lack of dystrophin, a structurally essential protein; hence, a definitive cure would necessarily have to pass through some form of gene and/or cell therapy. Cell- and genetic-based therapeutics for DMD have been explored since the 1990s and recently, two of the latter have been approved for clinical use, but their efficacy is still very low. In parallel, there have been great ongoing efforts aimed at targeting the downstream pathogenic effects of dystrophin deficiency using classical pharmacological approaches, with synthetic or biological molecules. However, as it is always the case with rare diseases, R&D costs for new drugs can represent a major hurdle for researchers and patients alike. This problem can be greatly alleviated by experimenting the use of molecules that had originally been developed for different conditions, a process known as drug repurposing or drug repositioning. In this review, we will describe the state of the art of such an approach for DMD, both in the context of clinical trials and pre-clinical studies.

Abnormal Cochlear Potentials in Friedreich's Ataxia Point to Disordered Synchrony of Auditory Nerve Fiber Activity.

BACKGROUND: Friedreich's ataxia (FRDA) is a degenerative disorder caused by mutations of the FXN gene. Sensorineural hearing loss is one of the clinical features of FRDA, and the majority of hearing-impaired patients have shown evidence of auditory neuropathy. OBJECTIVE: This study characterizes the cochlear receptor and auditory nerve potentials in a patient with FRDA who had the clinical profile of auditory neuropathy. The aim was to investigate the site of the lesion and the pathophysiological mechanisms behind the hearing dysfunction. METHODS: Using transtympanic electrocochleography, both receptor (cochlear microphonic, CM, and summating potential, SP) and auditory nerve potentials were recorded in response to trains of clicks with stimulation intensities from 60 to 120 dB SPL. The results were compared with recordings obtained from two groups of subjects, i.e. 20 normally hearing controls and 19 subjects with cochlear hearing loss. RESULTS: The results showed that the synchronized neural response seen in both normally hearing and hearing-impaired subjects was lacking in our patient, replaced by a prolonged, low-amplitude negative potential that decreased in both amplitude and duration for rapid stimulation rates, consistent with adaptation of neural sources. CMs were recorded with a normal amplitude, consistent with preserved outer hair cell function. SP peak latency was within normal limits, whereas SP amplitude was comparable with that of subjects with cochlear hearing loss, consistent with inner hair cell loss. CONCLUSION: These findings suggest that underlying auditory neuropathy in FRDA is a disordered synchrony in auditory nerve fiber discharge, possibly resulting from auditory nerve fiber degeneration and inner hair cell loss.

Coordinated and reversible reduction of enzymes involved in terminal oxidative metabolism in skeletal muscle mitochondria from a riboflavin-responsive, multiple acyl-CoA dehydrogenase deficiency patient.

In this case report we studied alterations in mitochondrial proteins in a patient suffering from recurrent profound muscle weakness, associated with ethylmalonic-adipic aciduria, who had benefited from high dose of riboflavin treatment. Morphological and biochemical alterations included muscle lipid accumulation, low muscle carnitine content, reduction in fatty acid beta-oxidation and reduced activity of complexes I and II of the respiratory chain. Riboflavin therapy partially or totally reversed these symptoms and increased the level of muscle flavin adenine dinucleotide, suggesting that aberrant flavin cofactor metabolism accounted for the disease. Proteomic investigation of muscle mitochondria revealed decrease or absence of several flavoenzymes, enzymes related to flavin cofactor-dependent mitochondrial pathways and mitochondrial or mitochondria-associated calcium-binding proteins. All these deficiencies were completely rescued after riboflavin treatment. This study indicates for the first time a profound involvement of riboflavin/flavin cofactors in modulating the level of a number of functionally coordinated polypeptides involved in fatty acyl-CoA and amino acid metabolism, extending the number of enzymatic pathways altered in riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.