Long-term neurologic and cardiac correction by intrathecal gene therapy in Pompe disease.

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.

Clinical and histopathologic characterization of a central and peripheral axonopathy in Rouge-des-prés (Maine Anjou) calves.

BACKGROUND: Recently, a progressive pelvic limb ataxia and paraparesis leading invariably to recumbency has been reported in Rouge-des-prés 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 Rouge-des-prés calves. An inherited defect is highly suspected.

[Microscopic vascular study of the colon with the corrosion casting technique]. / Etude vasculaire microscopique du colon par la technique d'injection-corrosion.

The aim of this study is, firstly, to assess the accuracy of vascular casts obtained at various times after death and secondly to describe the mucosal microvascular architecture of the cat colon. Two injections were realized, the first one on a non-embalmed human corpse, 12 days after the death, and the other one on a cat, immediately following euthanasia. Results show that this second cast seems finer and more detailed than the cast stemming from the human corpse; indeed, the finest vessels obtained are about 6 microns while they are about 15 microns on the human corpse. This could be explained by a post-mortem obstruction of microvessels, that prevented the passage of the injected product or by an insufficient amount of product injected. Finally, the vascular cast of the cat colic mucosa presents a regular honeycomb-like network that bounds the colonic mucosal glands, a finding consistent with the results reported previously.

[A study of the early stages of biliary extrahepatic ducts organogenesis in the rat (Rattus norvegicus albinos) (author's transl)]. / De l'organogenèse des voies biliaires extrahépatiques chez le rat (Rattus norvegicus albinos). Contribution à l'étude des premiers stades.

In the early stages of morphogenesis, the hepatic diverticulum of the rat develops as in other mammals. Its anterior part gives rise to epithelial cell-cords bound by an epithelial primary plate to a single hepatic duct which joins the liver to the midgut. The interlobular bile-ducts develop from secondary epithelial plates which derivate from the primary one. The posterior part of diverticulum gives rise to a duct which may be assimilated by its position, structure and evolution, to the initial cystic duct of other mammals. This duct never participates to the formation of biliary extrahepatic ducts, but builds the ventral pancreas. Cellular necrosis is observed in relation with the development of the anterior part of diverticulum during the three first days of the hepatic morphogenesis.