Hypermanganesemia due to mutations in SLC39A14: further insights into Mn deposition in the central nervous system.

BACKGROUND: The SLC39A14, SLC30A10 and SLC39A8 are considered to be key genes involved in manganese (Mn) homeostasis in humans. Mn levels in plasma and urine are useful tools for early recognition of these disorders. We aimed to explore further biomarkers of Mn deposition in the central nervous system in two siblings presenting with acute dystonia and hypermanganesemia due to mutations in SLC39A14. These biomarkers may help clinicians to establish faster and accurate diagnosis and to monitor disease progression after chelation therapy is administered. RESULTS: A customized gene panel for movement disorders revealed a novel missense variant (c.311G > T; p.Ser104Ile) in SLC39A14 gene in two siblings presenting at the age of 10 months with acute dystonia and motor regression. Mn concentrations were analyzed using inductively coupled mass spectrometry in plasma and cerebrospinal fluid, disclosing elevated Mn levels in the index case compared to control patients. Surprisingly, Mn values were 3-fold higher in CSF than in plasma. We quantified the pallidal index, defined as the ratio between the signal intensity in the globus pallidus and the subcortical frontal white matter in axial T1-weighted MRI, and found significantly higher values in the SLC39A14 patient than in controls. These values increased over a period of 10 years, suggesting the relentless pallidal accumulation of Mn. Following genetic confirmation, a trial with the Mn chelator Na2CaEDTA led to a reduction in plasma Mn, zinc and selenium levels. However, parents reported worsening of cervical dystonia, irritability and sleep difficulties and chelation therapy was discontinued. CONCLUSIONS: Our study expands the very few descriptions of patients with SLC39A14 mutations. We report for the first time the elevation of Mn in CSF of SLC39A14 mutated patients, supporting the hypothesis that brain is an important organ of Mn deposition in SLC39A14-related disease. The pallidal index is an indirect and non-invasive method that can be used to rate disease progression on follow-up MRIs. Finally, we propose that patients with inherited defects of manganese transport should be initially treated with low doses of Na2CaEDTA followed by gradual dose escalation, together with a close monitoring of blood trace elements in order to avoid side effects.

Evaluation of the bedside Quikread go® CRP test in the management of febrile infants at the emergency department.

Recently C-reactive protein (CRP) point-of-care tests have been developed. We aimed to validate a bedside CRP test (QuikRead go® CRP), to compare it with the laboratory CRP (ARCHITECT c8000 Abbott, Germany) test in children with fever without source (FWS), and to evaluate the optimal CRP cut-off value to identify those patients at a high risk for serious bacterial infection (SBI). The CRP bedside test was prospectively performed in capillary blood samples concurrently with the laboratory CRP testing for 283 well-appearing infants aged 1 to 24 months with FWS attending the emergency department (ED) between May 2013 and August 2015. The mean difference between the laboratory CRP and the QuikRead go CRP values was 0.71 mg/L (p = 0.444). Pearson's correlation coefficient between the CRPs was r = 0.929 (p < 0.001). SBI was diagnosed in 34 patients (12.0%). The area under the receiver operating characteristics (ROC) curve obtained was 0.87 (95%CI: 0.82-0.90) for an optimal CRP cut-off value of > 10 mg/L (sensitivity: 94.1%, specificity: 49.0%, positive predictive value: 20.1%, negative predictive value: 98.4%), as a predictor of SBI. Nearly 45% of the patients were at a low risk for SBI according to CRP value; thus, additional laboratory tests would have been hypothetically avoided. There was a very strong, positive correlation between the QuikRead go CRP test and laboratory CRP determination. The QuikRead go CRP test provides reliable results to rule out SBI. Its implementation at the ED would improve the management of infants with FWS.