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1.
Neurobiol Dis ; 16(1): 14-20, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15207257

ABSTRACT

Hearing deficit occurs in several lysosomal storage disorders but has so far not been recognized as a symptom of Pompe's disease (glycogen storage disease type II). We discovered quite unexpectedly 30-90 dB hearing loss in four infants with Pompe's disease, who participated in a study on the safety and efficacy of enzyme replacement therapy. Three other patients with juvenile Pompe's disease did not have this symptom. The ABR (auditory brainstem response) thresholds but not the interpeak latency times were increased. This pointed to middle or inner ear pathology rather than to involvement of the central auditory nervous system. The possible occurrence of cochlear pathology was supported by the absence of oto-acoustic emissions. We investigated this hypothesis in a knockout mouse model of Pompe's disease and found glycogen storage in the inner and outer hair cells of the cochlea, the supporting cells, the stria vascularis, and the spiral ganglion cells. We conclude that cochlear pathology is the most likely cause of hearing loss in infantile Pompe's disease and possibly a characteristic feature of this clinical subtype.


Subject(s)
Cochlea/pathology , Glycogen Storage Disease Type II/pathology , Hearing Loss/pathology , Acoustic Stimulation/methods , Adolescent , Adult , Animals , Child , Child, Preschool , Disease Models, Animal , Evoked Potentials, Auditory, Brain Stem/genetics , Glycogen Storage Disease Type II/genetics , Glycogen Storage Disease Type II/physiopathology , Hearing Loss/genetics , Hearing Loss/physiopathology , Humans , Mice , Mice, Knockout
2.
Pediatr Res ; 55(1): 69-75, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14605249

ABSTRACT

Cystic fibrosis (CF) disease severity is characterized by a broad variability that has been attributed, in addition to the CF transmembrane conductance regulator (CFTR) genotype, to modulating factors such as CFTR-mediated residual chloride (Cl-) secretion. Moreover, CFTR has been suggested to function as a receptor for Pseudomonas aeruginosa (PA). In this study, we investigated whether or not the presence of residual Cl- secretion protects against early chronic PA colonization of patients' airways. Excluding influences on the phenotype caused by different CFTR mutations, we evaluated a cohort of F508del homozygous individuals with respect to the correlation between residual Cl- secretion and the age of onset of PA colonization as an important marker of clinical phenotype. A group with early chronic PA colonization before the age of 7 y (n = 14) was compared with a cohort that had no initial PA detection at least until the age of 13 y (n = 10). We determined the Cl- transport properties by using the intestinal current measurement in rectal suction biopsies. Residual Cl- secretion, most likely due to the CFTR Cl- channel, was observed in 63% of subjects, more frequently in early chronically PA colonized than among late or not colonized patients. These results demonstrate the presence of some active F508del-CFTR in the apical cell membrane and imply that factors other than the CFTR-mediated residual Cl- secretion determine the age of onset of PA colonization.


Subject(s)
Chlorides/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Cystic Fibrosis/physiopathology , Pseudomonas Infections/physiopathology , Adolescent , Adult , Age of Onset , Child , Child, Preschool , Chronic Disease , Cystic Fibrosis/complications , Cystic Fibrosis/metabolism , Electrophysiology , Epithelial Cells/physiology , Female , Homozygote , Humans , Male , Mutation , Phenotype , Pseudomonas Infections/complications , Pseudomonas Infections/metabolism , Respiratory Function Tests
3.
J Neurosci ; 23(11): 4700-11, 2003 Jun 01.
Article in English | MEDLINE | ID: mdl-12805309

ABSTRACT

Compensatory mechanisms after genetic manipulations have been documented extensively for the nervous system. In many cases, these mechanisms involve genetic regulation at the transcription or expression level of existing isoforms. We report a novel mechanism by which single neurons compensate for changes in network connectivity by retuning their intrinsic electrical properties. We demonstrate this mechanism in the inferior olive, in which widespread electrical coupling is mediated by abundant gap junctions formed by connexin 36 (Cx36). It has been shown in various mammals that this electrical coupling supports the generation of subthreshold oscillations, but recent work revealed that rhythmic activity is sustained in knock-outs of Cx36. Thus, these results raise the question of whether the olivary oscillations in Cx36 knock-outs simply reflect the status of wild-type neurons without gap junctions or the outcome of compensatory mechanisms. Here, we demonstrate that the absence of Cx36 results in thicker dendrites with gap-junction-like structures with an abnormally wide interneuronal gap that prevents electrotonic coupling. The mutant olivary neurons show unusual voltage-dependent oscillations and an increased excitability that is attributable to a combined decrease in leak conductance and an increase in voltage-dependent calcium conductance. Using dynamic-clamp techniques, we demonstrated that these changes are sufficient to transform a wild-type neuron into a knock-out-like neuron. We conclude that the absence of Cx36 in the inferior olive is not compensated by the formation of other gap-junction channels but instead by changes in the cytological and electroresponsive properties of its neurons, such that the capability to produce rhythmic activity is maintained.


Subject(s)
Connexins/deficiency , Nerve Net/physiopathology , Neurons/pathology , Neurons/physiology , Olivary Nucleus/physiopathology , Adaptation, Physiological/genetics , Adaptation, Physiological/physiology , Animals , Biological Clocks/physiology , Calcium/metabolism , Connexins/genetics , Dendrites/pathology , Dendrites/ultrastructure , Electrophysiology , Gap Junctions/genetics , Gap Junctions/pathology , Gap Junctions/ultrastructure , Immunohistochemistry , In Situ Hybridization , In Vitro Techniques , Mice , Mice, Knockout , Nervous System Diseases/genetics , Nervous System Diseases/pathology , Nervous System Diseases/physiopathology , Neuropil/pathology , Olivary Nucleus/metabolism , Olivary Nucleus/pathology , Patch-Clamp Techniques , Periodicity , RNA, Messenger/biosynthesis , Gap Junction delta-2 Protein
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