Pompe disease is a lysosomal storage disorder caused by acid-α-glucosidase (GAA) deficiency, leading to glycogen storage. The disease manifests as a fatal cardiomyopathy in infantile form. Enzyme replacement therapy (ERT) has recently prolonged the lifespan of these patients, revealing a new natural history. The neurologic phenotype and the persistence of selective muscular weakness in some patients could be attributed to the central nervous system (CNS) storage uncorrected by ERT. GAA-KO 6neo/6neo mice were treated with a single intrathecal administration of adeno-associated recombinant vector (AAV) mediated gene transfer of human GAA at 1 month and their neurologic, neuromuscular, and cardiac function was assessed for 1 year. We demonstrate a significant functional neurologic correction in treated animals from 4 months onward, a neuromuscular improvement from 9 months onward, and a correction of the hypertrophic cardiomyopathy at 12 months. The regions most affected by the disease i.e. the brainstem, spinal cord, and the left cardiac ventricular wall all show enzymatic, biochemical and histological correction. Muscle glycogen storage is not affected by the treatment, thus suggesting that the restoration of muscle functionality is directly related to the CNS correction. This unprecedented global and long-term CNS and cardiac cure offer new perspectives for the management of patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-017-0464-2) contains supplementary material, which is available to authorized users.

ackground: Recently, a progressive pelvic limb ataxia and paraparesis leading invariably to recumbency has been reported in Rouge-des-pre´s calves.Objectives: To characterize the clinical and pathological findings of this newly reported disease and to investigate its potential causes.Animals: Nine calves from 7 different farms were prospectively studied from initial diagnosis through postmortem examination.Methods: Physical and neurological examinations, blood tests, cerebrospinal fluid (CSF) analysis, and myelographic examinations were performed. Neuropathology was carried out on both central and peripheral nervous systems. Copper deficiency and organophosphate intoxication also were investigated. Pedigrees were analyzed.Results: Age of onset varied from 2 to 6 weeks. Initial signs included pelvic limb ataxia and paraparesis. The neurological signs systematically progressed, over a 1-3-month period, to severe pelvic limb and truncal ataxia along with moderate paraparesis, leading to permanent recumbency. Animals remained alert. Cranial nerve function was normal. Muscle atrophy was not observed and spinal reflexes were normal. Blood tests, CSF analysis, and myelographic examination did not identify any abnormality. Neuropathology indicated neuronal fiber degeneration particularly in the dorsolateral and ventromedial funiculi of the spinal cord and in the peripheral nerves. Degenerative lesions also were observed in lateral vestibular and thoracic nuclei.No environmental factors such as copper deficiency or organophosphate intoxication could be incriminated as the cause of this axonopathy. Pedigree analysis suggested an inherited defect.Conclusions and Clinical Importance: The first description of a central and peripheral axonopathy is reported in Rougedes-pre´s calves. An inherited defect is highly suspected.

Feline SMA is a fully penetrant, autosomal recessive lower motor neuron disease in domestic cats that clinically resembles human SMA Type III. A whole genome linkage scan identified a ~140 kilobase deletion that abrogates expression of LIX1, a novel SMA candidate gene of unknown function. To characterize the progression of feline SMA, we assessed pathological changes in muscle and spinal cord from 3 days of age to beyond onset of clinical signs. EMG analysis indicating denervation occurred between 10 and 12 weeks, with the first neurological signs occurring at the same time. CMAP amplitudes were significantly reduced in the soleus and extensor carpi radialis muscles at 8 to 11 weeks. Quadriceps femoris muscle fibers from affected cats appeared smaller at 10 weeks; by 12 weeks atrophic fibers were more prevalent than in age-matched controls. In affected cats, significant loss of L5 ventral root axons was observed at 12 weeks. By 21 weeks of age, affected cats had 40% fewer L5 motor axons than normal. There was no significant difference in total L5 soma number, even at 21 weeks; thus degeneration begins distal to the cell body and proceeds retrogradely. Morphometric analysis of L5 ventral roots and horns revealed that 4 weeks prior to axon loss, motor axons in affected cats failed to undergo radial enlargement, suggesting a role for the putative disease gene, LIX1, in radial growth of axons.