The aim of the study was to enhance our understanding of the pathogenesis of the ataxia of Charlevoix-Saguenay, based on the findings presented herein. Five patients with a molecular diagnosis of this disease underwent clinical, radiological, ophthalmologic and electrophysiological examinations. Five novel mutations, which included nonsense and missense variants, were identified, with these resulting in milder phenotypes. In addition to the usual manifestations, a straight dorsal spine was found in every case, and imaging techniques showed loss of the dorsal kyphosis. Cranial MRI demonstrated hypointense linear striations at the pons. Tensor diffusion MRI sequences revealed that these striations corresponded with hyperplastic pontocerebellar fibres, and tractographic sequences showed interrupted pyramidal tracts at the pons. Ocular coherence tomography demonstrated abnormal thickness of the nerve fibre layer. Electrophysiological studies showed nerve conduction abnormalities compatible with a dysmyelinating neuropathy, with signs of chronic denervation in distal muscles. The authors suggest that the hyperplastic pontocerebellar fibres compress the pyramidal tracts at the pons, and that the amount of retinal fibres traversing the optic discs is enlarged. These facts point to the contribution of an abnormal developmental mechanism in the ataxia of Charlevoix-Saguenay. Accordingly, spasticity would be mediated by compression of the pyramidal tracts, neuromuscular symptoms by secondary axonal degeneration superimposed on the peripheral myelinopathy, while the cause of the progressive ataxia remains speculative. The distinctive aspect of the dorsal spine could be of help in the clinical diagnosis.
The aim of this paper has been to obtain normative data for the major components of the visually evoked potentials obtained by flash stimulus (F-PEV) in the newborn, and to analyse the evolution of these responses during the first 24 weeks of life. In order to do so, F-VEP were recorded in 109 normal full-term newborn infants. Fifty-five of these infants were also studied longitudinally at 4, 8, 12 and 24 weeks. We recorded responses in all newborns. A great morphological variability was observed. P2 was the only component present in all of these infants. Early components, which were always present from the fourth week of life on, were recorded in 34% of the newborns. There were significant differences according to waking/sleep state. At 24 weeks the most characteristic response was a triphasic waveform with clear negative-positive-negative components at 67.9, 110 and 158.3 ms. The morphological variability observed in the F-PEV of the newborn and the presence of early components in some cases, suggest differences in the maturation of the specific and unspecific visual system at birth. The study of these responses provides us with information about certain aspects of visual maturation. The relative stability of P2 response of the newborn and of the early negative components later on, made them the most useful components to be used in paediatric clinical work . The latency of P2 in the newborn is the parameter that showed lower variability, and therefore the most suitable one to establish normative data.
The aim of this work was to investigate the efficacy of the GABAergic drug gabapentin in the treatment of the cerebellar signs caused by cortical cerebellar atrophy (CCA). Ten patients with CCA received gabapentin in single doses of 400 mg in an open-label study; thereafter, daily administration of 900–1,600 mg of gabapentin was continued during at least 4 weeks. An ataxia scale based on clinical findings was used to evaluate the cerebellar signs at baseline and after administration of the drug. A statistically significant improvement of the ataxia scores was found after single doses of 400 mg of gabapentin and after the administration of 900–1,600 mg of this drug during 4 weeks, as compared to the results obtained at baseline. An important clinical amelioration was also evident. Gabapentin has been demonstrated to be capable of improving the cerebellar signs in cases of CCA, after single doses and after continued administration of the drug during 4 weeks. GABAergic enhancement or supplementation could play an important role in the treatment of diseases of the cerebellar cortex associated with a deficit of GABA.
Objective To report a kindred with an association between hereditary primary lateral sclerosis (PLS) and progressive nonfluent aphasia. Patients and methods Six members from a kindred with 15 affected individuals spanning three generations, suffered from spasticity without muscle atrophy or fasciculation, starting in the lower limbs and spreading to the upper limbs and bulbar musculature, followed by effortful speech, nonfluent language and dementia, in 5 deceased members. Disease onset was during the sixth decade of life, or later. Cerebellar ataxia was the inaugural manifestation in two patients, and parkinsonism, in another. Results Neuropathological examination in two patients demonstrated degeneration of lateral corticospinal tracts in the spinal cord, without loss of spinal, brainstem, or cerebral motor neurons. Greater loss of corticospinal fibers at sacral and lumbar, rather than at cervical or medullary levels was demonstrated, supporting a central axonal dying-back pathogenic mechanism. Marked reduction of myelin and nerve fibers in the frontal lobes was also present. Argyrophilic grain disease and primary age-related tauopathy were found in one case each, and considered incidental findings. Genetic testing, including exome sequencing aimed at PLS, ataxia, hereditary spastic paraplegia, and frontotemporal lobe dementia, triplet-repeated primed polymerase chain reaction aimed at dominant spinocerebellar ataxias, and massive sequencing of the human genome, yielded negative results. Conclusion A central distal axonopathy affecting the corticospinal tract, exerted a pathogenic role in the dominantly inherited PLS-progressive nonfluent aphasia association, described herein. Further molecular studies are needed to identify the causative mutation in this disease.
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