Familial autoimmune myastenia gravis: four patients involving three generations.

BACKGROUND: Familial autoimmune myasthenia gravis (MG) is rare, although a genetic role for the development of autoimmune MG is suggested by concordance in monozygotic twins and the increased frequency of other autoimmune diseases in family members of myasthenics. METHODS: A patient with a family history of MG was evaluated in hospital. Relatives were interviewed and medical records examined for details regarding the diagnosis of MG in three other family members. RESULTS: The index case first experienced symptoms of MG at age 75 years. She developed generalized MG and required corticosteroids and immunosuppressive therapy to control her disease. Her father developed predominantly bulbar symptoms of MG at age 75 years. He died of complications experienced following a gastrostomy placed for continued difficulty swallowing. His brother developed similar symptoms of MG in his early 60s and died shortly after thymectomy. A 46-year-old nephew of the index case is also beginning to exhibit signs of generalized MG. Acetylcholine receptor antibodies were strongly positive in the index case and her nephew. (The assay was not available for her father and uncle). CONCLUSIONS: Four individuals in three successive generations had diagnoses of autoimmune MG. Study of familial cases such as these may clarify the contribution of genetic factors to the development of this disease.

Prolonged delivery of brain-derived neurotrophic factor by adenovirus-infected Müller cells temporarily rescues injured retinal ganglion cells.

In this study, we demonstrate that: (i) injection of an adenovirus (Ad) vector containing the brain-derived neurotrophic factor (BDNF) gene (Ad.BDNF) into the vitreous chamber of adult rats results in selective transgene expression by Müller cells; (ii) in vitro, Müller cells infected with Ad.BDNF secrete BDNF that enhances neuronal survival; (iii) in vivo, Ad-mediated expression of functional BDNF by Müller cells, temporarily extends the survival of axotomized retinal ganglion cells (RGCs); 16 days after axotomy, injured retinas treated with Ad.BDNF showed a 4.5-fold increase in surviving RGCs compared with control retinas; (iv) the transient expression of the BDNF transgene, which lasted approximately 10 days, can be prolonged with immunosuppression for at least 30 days, and such Ad-mediated BDNF remains biologically active, (v) persistent expression of BDNF by infected Müller cells does not further enhance the survival of injured RGCs, indicating that the effect of this neurotrophin on RGC survival is limited by changes induced by the lesion within 10-16 days after optic nerve transection rather than the availability of BDNF. Thus, Ad-transduced Müller cells are a novel pathway for sustained delivery of BDNF to acutely-injured RGCs. Because these cells span the entire thickness of the retina, Ad-mediated gene delivery to Müller cells may also be useful to influence photoreceptors and other retinal neurons.

Different forms of the neurotrophin receptor trkB mRNA predominate in rat retina and optic nerve.

The expression of TrkB mRNAs was investigated in rat retina and optic nerve. A 11.5 kb transcript that encodes full-length TRKB was found to predominate in Northern blots of retinal RNA. By in situ hybridization, this trkB expression was concentrated in the ganglion cell and inner nuclear layers. Furthermore, an antibody to the full-length TRKB immunostained retinal ganglion cells and their axons. In contrast, Northern blots of optic nerve RNA showed a prominent 9.5 kb band that encoded a form of the TRKB receptor lacking the tyrosine kinase domain. This species was also detected in both the sciatic nerve and cultured astrocytes and C6 glioma cells. These results suggest that neurons express the full-length TRKB containing the tyrosine kinase domain, while non-neuronal cells express the truncated form of the receptor. These two classes of TRKB may mediate different neurotrophic actions in the retina and optic nerve.

Calcium binding protein (calbindin D28k) immunoreactivity in the hamster superior colliculus: ultrastructure and lack of co-localization with GABA.

The expression of specific calcium binding proteins is being used increasingly as a potential neuroanatomical marker for neurons with similar functions. In this study, the distribution of calbindin D28k in the superior colliculus (SC) of adult hamsters was examined by light and electron microscopy. Calbindin immunoreactivity was prominent in specific regions and laminae of the SC throughout its rostrocaudal extent, and was found to label horizontal, vertical and stellate cell types. In addition, calbindin label highlighted "bridges" of neuronal processes in the intermediate layers. The most frequent calbindin-immunoreactive profiles seen in the electron microscope were dendrites, some of which were post-synaptic to apparent retinal ganglion cell axon terminals. Labelled axons and axon terminals were less frequently encountered. There was considerable overlap between the size distribution of calbindin D28k-immunoreactive neurons and that of GABA-immunoreactive or Nissl stained neurons in the SC. However, using a double fluorescent labelling technique, and examination of the tissue with confocal laser microscopy, no neurons were observed in the hamster SC that showed immunoreactivity for both calbindin and GABA. In this regard, the SC is similar to the mammalian lateral geniculate nucleus and the pretectum, but differs from the neocortex, where calbindin and GABA are colocalized. The demonstration in the SC, as well as other parts of the nervous system, of sub-populations of neurons that contain distinct calcium-binding proteins suggests that these neurons have different functional properties. Correlative studies may clarify the relevance of these cytoplasmic components as cell markers, as well as their different patterns of association with neurotransmitters and peptides.

Influences of the glial environment on the elongation of axons after injury: transplantation studies in adult rodents.

Tissue transplantation methods, previously used to study neural development, myelination and inherited disorders of myelin can be applied also to the investigation of repair and regeneration in the mammalian CNS. The elongation of axons from injured peripheral nerve of CNS has been studied in adult mice and rats by observing the growth of axons into PNS or CNS tissue grafts. Following spinal cord injury and also after transplantation of optic nerves into the PNS there is axonal sprouting but these neuronal processes fail to elongate more than a few mm into the surrounding glia. On the other hand if segments of a peripheral nerve are grafted into the transected spinal cord, axons arising from spinal neurons and dorsal root ganglia become associated with the transplanted Schwann cells and elongate along the graft, approximately 1 cm. Recently the elongation of axons from spinal and medullary neurones was studied using a new experimental model which employed PNS grafts as 'bridges' to connect the spinal cord and the brain stem. In a series of adult C57BL/6J mice and Sprague Dawley rats, autologous segments of sciatic nerve were used to create 'bridges' between the lower cervical or upper thoracic spinal cord and the medulla oblongata. The spinal cord between these two levels was left intact. Grafted segments examined by light and electron microscope 1-7 months after surgery were well innervated by Schwann cell ensheathed axons that had grown the entire length of the graft (2 cm in mice and 3.5 cm in rats). The origin and termination of these axons were determined by transecting the regenerated grafts and applying horseradish peroxidase to the cut ends. Retrogradely labelled neurones were found to be distributed widely in the gray matter of the spinal cord and medulla near the sites of insertion of the graft. Anterogradely labelled fibres coursing within the graft penetrated the CNS for short distances, approximately 2 mm. These new results indicate that following CNS injury a conducive glial environment does allow spinal and brain stem neurones to elongate axons for distances that can be greater than those they usually extend for in the intact animal. This evidence that the regenerative response of similar axons differs in CNS and PNS neuroglia supports the hypothesis that influences arising from the environment play an important role in the success or failure of regeneration. The regenerative potentiality of central neurones may be expressed only when the CNS neuroglial environment is changed to resemble that in the PNS.

Ouabain binding sites in skeletal muscle from normal and dystrophic mice.

The specific binding of tritiated ouabain was used to estimate the density of Na+-K+-ATPase sites ("Na+-pump" sites) in segments of skeletal muscle from normal and dystrophic mice. Ouabain binding was approximately 4 times greater in red (soleus) muscle than in white (superficial gastrocnemius) muscle from normal animals. In dystrophic soleus muscles, ouabain binding was decreased by nearly one-half. Because Na+-K+-ATPase activity is associated with plasma membranes, these observations constitute further evidence for a sarcolemmal abnormality in dystrophic mice.