Mucopolysaccharidosis (MPS) type IIIB is a genetic deficiency of α-N-acetylglucosaminidase, inducing accumulation of partially degraded heparan sulfate (HS) oligosaccharides in tissues. In the central nervous system, this accumulation is associated with microglial activation, neurodegeneration, and oxidative stress. We have already shown that HS activates microglial cells through toll-like receptor 4 (TLR4) and triggers neuroinflammation. The present study investigates whether oxidative stress is a direct consequence of inflammation or is an independent event directly caused by HS accumulation. The present study addresses causative links between oxidative stress and inflammation by analyzing the corresponding markers in the cortex of control mice, MPSIIIB mice (with neuroinflammation), and double mutant TLR4 knockout MPSIIIB mice (without neuroinflammation at early stages). Results showed that, although inflammation was not present in the cortex of 10-day-old double mutant MPSIIIB/TLR4(-/-) mice, the enzymatic activity of total superoxide dismutase (SOD) was already greater than in control animals. Moreover, at 3 and 8 months of age, the total enzymatic activities of glutathione peroxidase, SOD, and carbonyl protein levels in the cortex of MPSIIIB/TLR4(-/-) mice were similar to those measured in MPSIIIB mice and were higher than those in controls. The results indicate that the oxidative stress present at a very early stage in the brain of MPSIIIB mice is not the consequence of neuroinflammation. Insofar as it has an impact on the development of neurological disease, reducing oxidative stress might prevent or slow the progression of MPSIIIB.
Ictal and interictal ocular motor abnormalities in EAs, including DBN, have been mostly described in EA2/PxMD-CACNA1A and are believed to be rare or absent in EA1/PxMD-KCNA1. 1 Previously, only interictal gaze-evoked nystagmus has been described in a single EA1/PxMD-KCNA1 patient. 2 Here, we expand interictal ocular motor impairment in EA1/PxMD-KCNA1 by showing the presence of central positional DBN, suggesting involvement of cerebellar nodulus, uvula, and/or tonsil. 3 The midline cerebellar atrophy found in our patients is consistent with this finding. 1,3 Ictally, there was spontaneous DBN in two of our patients, further suggesting transient floccular/parafloccular dysfunction. 3 Genetic assessment showed a novel disease-causing KCNA1 variant. Most pathogenic variants in EA1/PxMD-KCNA1 are missense changes, which ultimately disturb Kv1.1 channel opening, leading to excessive GABA release into Purkinje cells and reduced cerebellar inhibitory output. 4 In sum, interictal positional DBN, ictal spontaneous DBN, and cerebellar atrophy can be present in EA1/PxMD-KCNA1. The use of self-recording of eye movements, occlusive ophthalmoscopy, and positional testing with the help of video-oculography in the dark might further increase the detection of interictal and ictal forms of nystagmus in EAs.
Informed Consent and Ethics Committee ApprovalWritten informed consent was obtained from the patients for the anonymized information to be published in this article. Ethics committee approval was also obtained.
We report the case of an 80-year-old woman who presented one episode of cardiopulmonary arrest and two episodes of acute airway obstruction. We found in this patient the presence of tracheomalacia caused by megaesophagus compression secondary to achalasia probably responsible for episodes of acute airway obstruction and cardiopulmonary arrest.
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