Batten disease and perioperative complications: a retrospective descriptive study.

PURPOSE: Batten disease or neuronal ceroid lipofuscinosis is the most prevalent neurodegenerative disorder of childhood. Previously reported perioperative complications in children with Batten disease have come mainly from single case reports. The primary aim of the current study was to investigate perioperative complications of patients with Batten disease in the largest cohort known to date. The secondary objective was to characterize the anesthetic management including the use of propofol and to assess its association with adverse events. METHOD: We conducted a single center, retrospective descriptive study by querying the hospital's electronic medical record to identify patients with a diagnosis of Batten disease or ICD10 E75.4 who received anesthetic care from December 2014 to May 2019. RESULTS: Thirty-five patients who underwent a total of 93 anesthetic encounters (range 1-11) were included in the analysis. A total of 29 adverse events were identified. Hypotension (N = 6, 6.5%) and bradycardia (N = 7, 7.5%) requiring treatment with medications were the most common adverse events. Other adverse events include oxygen desaturation (N = 4, 4.3%), seizures (N = 4, 4.3%), unanticipated hospital or ICU admission (N = 1, 1.1%), PACU phase 1 stay > 120 min (N = 2, 2.2%), hypothermia (N = 4, 4.3%), agitation (N = 1, 1.1%), and laryngospasm requiring treatment (N = 1, 1.1%). The number of preoperative anti-epileptic drugs (AEDs) had a positive correlation with the rate of perioperative adverse events. There was no statistical relationship of adverse events with intraoperative use of propofol (odds ratio 1.03, 95% CI 0.42-2.51). CONCLUSIONS: The majority of these patients were managed without clinically significant perioperative complications. As previously reported, bradycardia, hypotension, and hypothermia were the most common adverse events. Routine avoidance of propofol in patients with Batten disease does not appear warranted.

Allostery between two binding sites in the ion channel subunit TRIP8b confers binding specificity to HCN channels.

Tetratricopeptide repeat (TPR) domains are ubiquitous structural motifs that mediate protein-protein interactions. For example, the TPR domains in the peroxisomal import receptor PEX5 enable binding to a range of type 1 peroxisomal targeting signal motifs. A homolog of PEX5, tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), binds to and functions as an auxiliary subunit of hyperpolarization-activated cyclic nucleotide (HCN)-gated channels. Given the similarity between TRIP8b and PEX5, this difference in function raises the question of what mechanism accounts for their binding specificity. In this report, we found that the cyclic nucleotide-binding domain and the C terminus of the HCN channel are critical for conferring specificity to TRIP8b binding. We show that TRIP8b binds the HCN cyclic nucleotide-binding domain through a 37-residue domain and the HCN C terminus through the TPR domains. Using a combination of fluorescence polarization- and co-immunoprecipitation-based assays, we establish that binding at either site increases affinity at the other. Thus, allosteric coupling of the TRIP8b TPR domains both promotes binding to HCN channels and limits binding to type 1 peroxisomal targeting signal substrates. These results raise the possibility that other TPR domains may be similarly influenced by allosteric mechanisms as a general feature of protein-protein interactions.

Characterization of hyperpolarization-activated cyclic nucleotide-gated channels in oligodendrocytes.

Mature oligodendrocytes (OLG) are the myelin-forming cells of the central nervous system. Recent work has shown a dynamic role for these cells in the plasticity of neural circuits, leading to a renewed interest in voltage-sensitive currents in OLG. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and their respective current (Ih) were recently identified in mature OLG and shown to play a role in regulating myelin length. Here we provide a biochemical and electrophysiological characterization of HCN channels in cells of the oligodendrocyte lineage. We observed that mice with a nonsense mutation in the Hcn2 gene (Hcn2ap/ap) have less white matter than their wild type counterparts with fewer OLG and fewer oligodendrocyte progenitor cells (OPCs). Hcn2ap/ap mice have severe motor impairments, although these deficits were not observed in mice with HCN2 conditionally eliminated only in oligodendrocytes (Cnpcre/+; Hcn2F/F). However, Cnpcre/+; Hcn2F/F mice develop motor impairments more rapidly in response to experimental autoimmune encephalomyelitis (EAE). We conclude that HCN2 channels in OLG may play a role in regulating metabolism.