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Context - Dopamine β-hydroxylase (DBH) deficiency is a rare genetic disorder characterized by failure to convert dopamine to norepinephrine. DBH-deficient patients lack sympathetic adrenergic function and are therefore predisposed to orthostatic hypotension. DBH-deficient mice exhibit hyperinsulinemia, lower plasma glucose levels, and insulin resistance due to loss of tonic sympathetic inhibition of insulin secretion. The impact of DBH deficiency on glucose homeostasis in humans is unknown.
Case Description - We describe the metabolic profile of an adolescent female DBH-deficient patient. The patient underwent genetic testing, cardiovascular autonomic function testing, and evaluation of insulin secretion and sensitivity with hyperglycemic clamp under treatment-naive conditions. All procedures were repeated after 1 year of treatment with the norepinephrine prodrug droxidopa (300 mg, 3 times a day). Genetic testing showed a homozygous mutation in the DBH gene (rs74853476). Under treatment-naive conditions, she had undetectable plasma epinephrine and norepinephrine levels, resulting in sympathetic noradrenergic failure and orthostatic hypotension (-32 mm Hg supine to seated). She had high adiposity (41%) and fasting plasma insulin levels (25 μU/mL), with normal glucose (91 mg/dL). Hyperglycemic clamp revealed increased glucose-stimulated insulin secretion and insulin resistance. Droxidopa restored plasma norepinephrine and improved orthostatic tolerance, with modest effects on glucose homeostasis.
Conclusions - We provide evidence for impairment in cardiovascular autonomic regulation, hyperinsulinemia, enhanced glucose-stimulated insulin secretion, and insulin resistance in a DBH-deficient patient. These metabolic derangements were not corrected by chronic droxidopa treatment. These findings provide insight into the pathophysiology and treatment of DBH deficiency and into the importance of catecholaminergic mechanisms to resting metabolism.
Copyright © 2017 by the Endocrine Society

Using exome sequencing, we identified a de novo mutation (c.2971A>G; T991A) in SLC12A6, the gene encoding the K(+)-Cl(-) cotransporter KCC3, in a patient with an early-onset, progressive, and severe peripheral neuropathy primarily affecting motor neurons. Normally, the WNK kinase-dependent phosphorylation of T(991) tonically inhibits KCC3; however, cell swelling triggers Thr(991) dephosphorylation to activate the transporter and restore cell volume. KCC3 T991A mutation in patient cells abolished Thr(991) phosphorylation, resulted in constitutive KCC3 activity, and compromised cell volume homeostasis. KCC3(T991A/T991A) mutant mice exhibited constitutive KCC3 activity and recapitulated aspects of the clinical, electrophysiological, and histopathological findings of the patient. These results suggest that the function of the peripheral nervous system depends on finely tuned, kinase-regulated KCC3 activity and implicate abnormal cell volume homeostasis as a previously unreported mechanism of axonal degeneration.
Copyright © 2016, American Association for the Advancement of Science.

IMPORTANCE - To our knowledge, no evidence-based guidelines are available for the best medical management of blood pressure, blood glucose levels, and temperature in pediatric patients after arterial ischemic stroke.
OBJECTIVE - To determine the prevalence of abnormal blood pressure, blood glucose levels, and temperature in pediatric patients with acute arterial ischemic stroke and to explore any association between these measures and neurological outcome.
DESIGN, SETTING, AND PARTICIPANTS - We performed a retrospective review of children aged 29 days to 18 years with their first arterial ischemic stroke between January 2009 and December 2013 at a tertiary academic children's hospital. Ninety-eight children with stroke were identified by an International Classification of Diseases, Ninth Revision, code search and medical record review. Blood pressure, blood glucose, and temperature data were collected for 5 days after the stroke. Hypertension was defined as systolic blood pressure at or above the 95th percentile for age, sex, and height for 2 consecutive recordings and 2 consecutive days. Hypotension was defined as systolic and/or diastolic blood pressure below the fifth percentile for age, sex, and height for 2 consecutive recordings. Hyperglycemia was defined as a blood glucose level of 200 mg/dL or greater. Morbidity and mortality at 3 months were documented. Data analyses were performed from July 1, 2014, to December 31, 2015.
INTERVENTIONS OR EXPOSURES - Abnormal blood pressure, blood glucose levels, and fever in the setting of arterial ischemic stroke.
MAIN OUTCOMES AND MEASURES - The a priori outcome measure was poor clinical outcome, defined as a Pediatric Stroke Outcome Measure score of 1 or greater, which represents a moderate neurological deficit.
RESULTS - The median (interquartile range) age of the 98 children was 6.0 (0.6-14.3) years, and 58 (59.2%) were male. Hypertension was present in 64 (65.3%), hypotension in 67 (68.4%), hyperglycemia in 17 (18.1%), and fever in 37 (37.8%). The strongest association with poor neurological outcome was an infarct size of 4% or greater of brain volume (odds ratio, 5.6; 95% CI, 2.0-15.4; P = .001). Hyperglycemia was also independently associated with poor neurological outcome (odds ratio, 3.9; 95% CI, 1.2-12.4; P = .02). Hypertension and fever were not significantly associated with infarct size, poor outcome, or death. Hypertension was not documented in 24 of 87 surviving children (27.6%) at 3-month follow-up and was not associated with poor neurological outcome.
CONCLUSIONS AND RELEVANCE - Abnormalities of blood pressure, blood glucose levels, and temperature are prevalent in children with arterial ischemic stroke. Infarct volume and hyperglycemia were associated with poor neurological outcome but hypertension and fever were not. Prospective studies that systematically record blood pressure, blood glucose, and temperature data are required to further assess the associations between these potentially modifiable physiological parameters and pediatric stroke outcome.

BACKGROUND - Sarcoidosis is a presumptive autoimmune disorder characterized by the presence of noncaseating granulomas and is usually treated successfully with immunosuppression.
METHODS AND RESULTS - Here, we describe the case of a 63-year-old male renal transplant recipient with a remote history of pulmonary sarcoidosis on chronic immunosuppression who developed recurrent aseptic meningitis and underwent brain biopsy revealing a diagnosis of neurosarcoidosis.
CONCLUSIONS - This case highlights the possibility of recurrence of sarcoidosis in the setting of maintenance immunosuppression, the need for heightened awareness of alternative sites of recurrence of autoimmune disease, and future studies to determine the underlying mechanism of recurrence in organ transplant recipients.

BACKGROUND - Patients with pulmonary arterial hypertension (PAH) are routinely instructed to avoid performing the Valsalva maneuver for fear of syncope or sudden cardiac death. The mechanism of this action has not been elucidated. We conducted a case-control trial of nine patients with PAH and 15 healthy control subjects to determine if systemic hemodynamic changes during the Valsalva maneuver in these patients invoke greater susceptibility to syncope than healthy control subjects. Metrics commonly employed in autonomic testing were used to assess the degree of autonomic failure.
METHODS - Common Valsalva parameters, including adrenergic baroreflex sensitivity, pressure recovery time, systolic BP (SBP) recovery, diastolic BP (DBP) recovery, mean arterial pressure recovery, and the Valsalva ratio, were calculated. Mann-Whitney U tests were used to compare continuous variables. The primary end point was adrenergic baroreflex sensitivity.
RESULTS - Patients with PAH had lower adrenergic baroreflex sensitivity (9.7 ± 4.6 mm Hg/s vs 18.8 ± 9.2 mm Hg/s; P = .005), longer pressure recovery time (3.6 ± 2.5 s vs 1.7 ± 0.8 s; P = .008), similar SBP recovery (-13 ± 11 mm Hg vs -12 ± 23 mm Hg; P = .640), less DBP recovery (-1 ± 12 mm Hg vs 13 ± 14 mmHg; P = .025), less mean arterial pressure recovery (-5 ± 11 mm Hg vs 5 ± 17 mm Hg; P = .048), and a decreased Valsalva ratio (1.25 ± 0.11 vs 1.60 ± 0.22; P < .001) compared with healthy control subjects.
CONCLUSIONS - Compared with healthy control subjects, patients with PAH are more susceptible to syncope during the Valsalva maneuver because of autonomic dysfunction causing cerebral hypoperfusion. These study patients with PAH exhibited a degree of susceptibility to syncope similar to a spectrum of patients with intermediate autonomic failure who typically experience a SBP drop of 10 to 30 mm Hg with standing.
Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

BACKGROUND - This study examines whether different sources of cognitive complaint (i.e., self and informant) predict Alzheimer's disease (AD) neuropathology in elders with mild cognitive impairment (MCI).
METHODS - Data were drawn from the National Alzheimer's Coordinating Center Uniform and Neuropathology Datasets (observational studies) for participants with a clinical diagnosis of MCI and postmortem examination (n = 1843, 74±8 years, 52% female). Cognitive complaint (0.9±0.5 years prior to autopsy) was classified into four mutually exclusive groups: no complaint, self-only, informant-only, or mutual (both self and informant) complaint. Postmortem neuropathological outcomes included amyloid plaques and neurofibrillary tangles. Proportional odds regression related complaint to neuropathology, adjusting for age, sex, race, education, depressed mood, cognition, APOE4 status, and last clinical visit to death interval.
RESULTS - Mutual complaint related to increased likelihood of meeting NIA/Reagan Institute (OR = 6.58, p = 0.004) and Consortium to Establish a Registry for Alzheimer's Disease criteria (OR = 5.82, p = 0.03), and increased neurofibrillary tangles (OR = 3.70, p = 0.03), neuritic plaques (OR = 3.52, p = 0.03), and diffuse plaques (OR = 4.35, p = 0.02). Informant-only and self-only complaint was not associated with any neuropathological outcome (all p-values>0.12).
CONCLUSIONS - In MCI, mutual cognitive complaint relates to AD pathology whereas self-only or informant-only complaint shows no relation to pathology. Findings support cognitive complaint as a marker of unhealthy brain aging and highlight the importance of obtaining informant corroboration to increase confidence of underlying pathological processes.

K(+)-Cl(-) cotransporters (KCCs) were originally characterized as regulators of red blood cell (RBC) volume. Since then, four distinct KCCs have been cloned, and their importance for volume regulation has been demonstrated in other cell types. Genetic models of certain KCCs, such as KCC3, and their inhibitory WNK-STE20/SPS1-related proline/alanine-rich kinase (SPAK) serine-threonine kinases, have demonstrated the evolutionary necessity of these molecules for nervous system cell volume regulation, structure, and function, and their involvement in neurological disease. The recent characterization of a swelling-activated dephosphorylation mechanism that potently stimulates the KCCs has pinpointed a potentially druggable switch of KCC activity. An improved understanding of WNK/SPAK-mediated KCC cell volume regulation in the nervous system might reveal novel avenues for the treatment of multiple neurological diseases.
Copyright © 2015 Elsevier Ltd. All rights reserved.

Despite broad biochemical relevance, our understanding of the physiochemical reactions that limit the assembly and cellular trafficking of integral membrane proteins remains superficial. In this work, we report the first experimental assessment of the relationship between the conformational stability of a eukaryotic membrane protein and the degree to which it is retained by cellular quality control in the secretory pathway. We quantitatively assessed both the conformational equilibrium and cellular trafficking of 12 variants of the α-helical membrane protein peripheral myelin protein 22 (PMP22), the intracellular misfolding of which is known to cause peripheral neuropathies associated with Charcot-Marie-Tooth disease (CMT). We show that the extent to which these mutations influence the energetics of Zn(II)-mediated PMP22 folding is proportional to the observed reduction in cellular trafficking efficiency. Strikingly, quantitative analyses also reveal that the reduction of motor nerve conduction velocities in affected patients is proportional to the extent of the mutagenic destabilization. This finding provides compelling evidence that the effects of these mutations on the energetics of PMP22 folding lie at the heart of the molecular basis of CMT. These findings highlight conformational stability as a key factor governing membrane protein biogenesis and suggest novel therapeutic strategies for CMT.

Vincristine, a critical component of combination chemotherapy treatment for pediatric acute lymphoblastic leukemia (ALL), can lead to vincristine-induced peripheral neuropathy (VIPN). Longitudinal VIPN assessments were obtained over 12 months from newly diagnosed children with ALL (N = 128) aged 1-18 years who received vincristine at one of four academic children's hospitals. VIPN assessments were obtained using the Total Neuropathy Score-Pediatric Vincristine (TNS©-PV), National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE©), Balis© grading scale, and Pediatric Neuropathic Pain Scale©-Five (PNPS©-5). Of children who provided a full TNS©-PV score, 85/109 (78%) developed VIPN (TNS©-PV ≥4). Mean TNS©-PV, grading scale, and pain scores were low. CTCAE©-derived grades 3 and 4 sensory and motor VIPN occurred in 1.6%/0%, and 1.9%/0% of subjects, respectively. VIPN did not resolve in months 8-12 despite decreasing dose density. VIPN was worse in older children. Partition cluster analysis revealed 2-3 patient clusters; one cluster (n = 14) experienced severe VIPN. In this population, VIPN occurs more commonly than previous research suggests, persists throughout the first year of treatment, and can be severe.
© 2015 Peripheral Nerve Society.