Primary familial brain calcification (PFBC) is a neurological disease characterized by calcium phosphate deposits in the basal ganglia and other brain regions, thus far associated with SLC20A2, PDGFB, or PDGFRB mutations. We identified in multiple PFBC families mutations in XPR1, a gene encoding a retroviral receptor with phosphate export function. These mutations alter phosphate export, providing a direct evidence of an impact of XPR1 and phosphate homeostasis in PFBC.

Familial idiopathic basal ganglia calcification (IBGC) or Fahr’s disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient’s disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41 % of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.

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Purpose The incidence of carbapenem-resistant Enterobacteriaceae (CRE) has been increasing worldwide. Ertapenem resistance is mediated by non-carbapenemase mechanisms, and has less of an effect on susceptibility to imipenem and meropenem. This study aimed to study the epidemiology of CRE, and to compare risk factors and related mortality between non-susceptibility to ertapenem alone Enterobacteriaceae (NSEE), with non-susceptibility to other carbapenems (imipenem, meropenem, or doripenem) Enterobacteriaceae (NSOCE) at a tertiary care hospital in Thailand. Methods All CRE isolated were identified between December 2011 and December 2016. Quarterly incidence rate was estimated. Hospital-wide carbapenem consumption was calculated as defined daily doses (DDD). Relationships between hospital-wide carbapenem consumption and incidence of CRE were tested. Factors associated with NSEE and NSOCE, and risk factors associated with 14- and 30-day mortality in patients with CRE infection were determined. Results The quarterly CRE incidence increased significantly from 3.37 per 100,000 patient-days in the last quarter of 2011 to 32.49 per 100,000 patient-days in the last quarter of 2016. ( P for trend <0.001). Quarterly hospital-wide carbapenem consumption increased 1.58 DDD per 1,000 patient-days ( P for trend=0.004). The Poisson regression showed the expected increase of CRE incidence was 1.02 per 100,000 patient-days for a 1 DDD per 1,000 patient-days increase in carbapenem consumption ( P <0.001). There were 40 patients with NSEE and 134 patients with NSOCE in the 5-year study period. The NSEE group had significantly lower carbapenem exposure compared with the NSOCE group (adjusted odds ratio: 0.25; P =0.001). No difference in 14-day and 30-day all-cause mortality between the two groups was observed. Conclusion The incidence of CRE has risen significantly at our institution. Previous carbapenem use was associated with NSOCE. This hospital-wide carbapenem use was significantly associated with the increasing incidence of CRE.