Search

ObjectiveTo test the hypothesis that monogenic neuropathies such as Charcot-Marie-Tooth disease (CMT) contribute to frequent but often unexplained neuropathies in the elderly, we performed genetic analysis of 230 patients with unexplained axonal neuropathies and disease onset ≥35 years.MethodsWe recruited patients, collected clinical data, and conducted whole-exome sequencing (WES; n = 126) and MME single-gene sequencing (n = 104). We further queried WES repositories for MME variants and measured blood levels of the MME-encoded protein neprilysin.ResultsIn the WES cohort, the overall detection rate for assumed disease-causing variants in genes for CMT or other conditions associated with neuropathies was 18.3% (familial cases 26.4%, apparently sporadic cases 12.3%). MME was most frequently involved and accounted for 34.8% of genetically solved cases. The relevance of MME for late-onset neuropathies was further supported by detection of a comparable proportion of cases in an independent patient sample, preponderance of MME variants among patients compared to population frequencies, retrieval of additional late-onset neuropathy patients with MME variants from WES repositories, and low neprilysin levels in patients' blood samples. Transmission of MME variants was often consistent with an incompletely penetrant autosomal-dominant trait and less frequently with autosomal-recessive inheritance.ConclusionsA detectable fraction of unexplained late-onset axonal neuropathies is genetically determined, by variants in either CMT genes or genes involved in other conditions that affect the peripheral nerves and can mimic a CMT phenotype. MME variants can act as completely penetrant recessive alleles but also confer dominantly inherited susceptibility to axonal neuropathies in an aging population.

ObjectiveResistance to extended-spectrum cephalosporins (ESC) among Enterobacteriaceae (EB) is increasingly prevalent. We sought to determine the clinical outcomes associated with community-onset ESC-resistant (ESC-R) EB urinary tract infections (UTIs) in a US health system.DesignRetrospective cohort study.PatientsAll patients presenting to the emergency departments (EDs) or outpatient practices with EB UTIs between 2010 and 2013 were included. Exposed patients had ESC-R EB UTIs. Unexposed patients had ESC-susceptible EB UTIs and were matched to exposed subjects 1:1 on study year. Multivariable logistic regression analyses were performed to evaluate the association between ESC-R EB UTI and the outcomes of clinical failure and inappropriate initial antibiotic therapy (IIAT).ResultsA total of 302 patients with community-onset EB UTI were included, with 151 exposed and unexposed. On multivariable analyses, UTI due to an ESC-R EB was significantly associated with clinical failure (odds ratio [OR], 7.07; 95% confidence interval [CI], 3.16–15.82; PCitrobacter spp and need for hemodialysis. UTI due to an ESC-R EB was also significantly associated with IIAT (OR, 4.40; 95% CI, 2.64–7.33; PConclusionsCommunity-onset UTI due to an ESC-R EB organism is significantly associated with clinical failure, which may be due in part to IIAT. Further studies are needed to determine which patients in the community are at high risk for drug-resistant infection to help inform prompt diagnosis and appropriate antibiotic prescribing for ESC-R EB.

Dominant mutations in MFN2 cause a range of phenotypes, including severe, early-onset axonal neuropathy, "classical CMT2," and late-onset axonal neuropathies. We report a large family with an axonal polyneuropathy, with clinical onset in the 20s, followed by slow progression.

The use and utility of targeted gene panels for diagnosing the type of Charcot-Marie-Tooth have grown rapidly because commercial gene panels that contain most of the relevant genes are available and affordable for many patients. We used a targeted gene panel to analyze 175 patients who had an unexplained axonal polyneuropathy affecting large myelinated axons, 86 of whom reported a family history of neuropathy, and 89 of whom did not. In patients reporting a family history, the panel identified a pathogenic variant causing the neuropathy in six cases (7%); in patients not reporting a family history, the gene panel identified pathogenic variants causing neuropathy in two patients (2%). Interpretation in a tertiary referral setting, current gene panels identify the genetic cause of neuropathy in a small minority of patients who have an unexplained axonal neuropathy, even in those reporting a family history.

Background Bacterial resistance to first line antibiotics used to treat community-onset urinary tract infections (UTIs) continues to increase. We sought to create a clinical prediction tool for community-onset UTIs due to extended-spectrum cephalosporin-resistant (ESC-R) Enterobacterales (formerly Enterobacteriaceae, EB). Methods A case-control study was performed. The source population included patients presenting to an emergency department (ED) or outpatient practice with an EB UTI between 2010 and 2013. Case patients had ESC-R EB UTIs. Control patients had ESC-susceptible EB UTIs and were matched to cases 1:1 on study year. Multivariable conditional logistic regression was performed to develop the predictive model by maximizing the area under the receiver-operating curve (AUC). Internal validation was performed via bootstrapping. Results A total of 302 patients with a community-onset EB UTI were included, with 151 cases and 151 controls. After multivariable analysis, we found that presentation with an ESC-R EB community-onset UTI could be predicted by the following: (1) a history of malignancy; (2) a history of diabetes; (3) recent skilled nursing facility or hospital stay; (4) recent trimethoprim-sulfamethoxazole exposure; and (5) pyelonephritis at the time of presentation (AUC 0.73, Hosmer-Lemeshow goodness-of-fit P value 0.23). With this model, each covariate confers a single point, and a patient with ≥ 2 points is considered high risk for ESC-R EB (sensitivity 80%, specificity 54%). The adjusted AUC after bootstrapping was 0.71. Conclusions Community-onset ESC-R EB UTI can be predicted using the proposed scoring system, which can help guide diagnostic and therapeutic interventions., Bacterial resistance continues to increase in the community. We found that community-onset urinary tract infections due to extended-spectrum cephalosporin-resistant Enterobacterales (formerly Enterobacteriaceae) could be predicted with knowledge of 5 clinical factors.

International audience; Objective Charcot-Marie-Tooth (CMT) disease 4B1 and 4B2 (CMT4B1/B2) are characterized by recessive inheritance, early onset, severe course, slowed nerve conduction, and myelin outfoldings. CMT4B3 shows a more heterogeneous phenotype. All are associated with myotubularin-related protein (MTMR) mutations. We conducted a multicenter, retrospective study to better characterize CMT4B. Methods We collected clinical and genetic data from CMT4B subjects in 18 centers using a predefined minimal data set including Medical Research Council (MRC) scores of nine muscle pairs and CMT Neuropathy Score. Results There were 50 patients, 21 of whom never reported before, carrying 44 mutations, of which 21 were novel and six representing novel disease associations of known rare variants. CMT4B1 patients had significantly more-severe disease than CMT4B2, with earlier onset, more-frequent motor milestones delay, wheelchair use, and respiratory involvement as well as worse MRC scores and motor CMT Examination Score components despite younger age at examination. Vocal cord involvement was common in both subtypes, whereas glaucoma occurred in CMT4B2 only. Nerve conduction velocities were similarly slowed in both subtypes. Regression analyses showed that disease severity is significantly associated with age in CMT4B1. Slopes are steeper for CMT4B1, indicating faster disease progression. Almost none of the mutations in the MTMR2 and MTMR13 genes, responsible for CMT4B1 and B2, respectively, influence the correlation between disease severity and age, in agreement with the hypothesis of a complete loss of function of MTMR2/13 proteins for such mutations. Interpretation This is the largest CMT4B series ever reported, demonstrating that CMT4B1 is significantly more severe than CMT4B2, and allowing an estimate of prognosis. ANN NEUROL 2019

Dominant mutations in MFN2 cause a range of phenotypes, including severe, early-onset axonal neuropathy, “classical CMT2”, and late-onset axonal neuropathy. We found a novel MFN2 mutation - c.283A>G (p.Arg95Gly) - that results in an axonal neuropathy with variable clinical severity in a multigenerational family. In affected family members, electromyography showed moderate to severe, chronic denervation in distal muscles. Such variable clinical severity highlights the need to do careful assessments of at risk individuals when assessing MFN2 variants.

Objective To characterize the phenotype in individuals with OPA3-related autosomal dominant optic atrophy and cataract (ADOAC) and peripheral neuropathy (PN). Methods Two probands with multiple affected relatives and one sporadic case were referred for evaluation of a PN. Their phenotype was determined by clinical ± neurophysiological assessment. Neuropathologic examination of sural nerve and skeletal muscle, and ultrastructural analysis of mitochondria in fibroblasts were performed in one case. Exome sequencing was performed in the probands. Results The main clinical features in one family (n = 7 affected individuals) and one sporadic case were early-onset cataracts (n = 7), symptoms of gastrointestinal dysmotility (n = 8), and possible/confirmed PN (n = 7). Impaired vision was an early-onset feature in another family (n = 4 affected individuals), in which 3 members had symptoms of gastrointestinal dysmotility and 2 developed PN and cataracts. The less common features among all individuals included symptoms/signs of autonomic dysfunction (n = 3), hearing loss (n = 3), and recurrent pancreatitis (n = 1). In 5 individuals, the neuropathy was axonal and clinically asymptomatic (n = 1), sensory-predominant (n = 2), or motor and sensory (n = 2). In one patient, nerve biopsy revealed a loss of large and small myelinated fibers. In fibroblasts, mitochondria were frequently enlarged with slightly fragmented cristae. The exome sequencing identified OPA3 variants in all probands: a novel variant (c.23T>C) and the known mutation (c.313C>G) in OPA3. Conclusions A syndromic form of ADOAC (ADOAC+), in which axonal neuropathy may be a major feature, is described. OPA3 mutations should be included in the differential diagnosis of complex inherited PN, even in the absence of clinically apparent optic atrophy.

Dominant mutations in MFN2 cause a range of phenotypes, including severe, early-onset axonal neuropathy, “classical CMT2”, and late-onset axonal neuropathies. We report a large family with an axonal polyneuropathy, with clinical onset in the 20s, followed by slow progression.

Background Recent data have shown an increase in bacterial resistance to first-line antibiotics used to treat community-onset urinary tract infections (UTIs). A better understanding of the clinical outcomes associated with drug-resistant UTIs in the community is needed. We sought to determine the association between community-onset extended-spectrum cephalosporin-resistant (ESC-R) Enterobacteriaceae (EB) UTI and the risk for recurrent UTI. Methods A retrospective cohort study was performed. All patients presenting to the Emergency Departments (EDs) or outpatient practices with EB UTIs between 2010 and 2013 were included. Exposed patients had ESC-R EB UTIs. Unexposed patients had ESC-susceptible EB UTIs and were matched to exposed subjects 1:1 on study year. Multivariable Cox proportional hazard regression analyses were performed to evaluate the association between ESC-R EB UTI and time to recurrent UTI within 12 months. Patients were censored at the time of first recurrent UTI or at the end of follow-up. Results A total of 302 patients with an index community-onset EB UTI were included, with 151 exposed and unexposed. Within 12 months of the index UTI, 163 (54%) patients experienced a recurrent UTI. The median time to recurrence was 69 days (interquartile range 25–183 days). On multivariable analyses, a UTI due to an ESC-R EB was associated with an increased hazard of recurrent UTI (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.01–1.91, P = 0.04). Other variables that were independently associated with an increased hazard of recurrent UTI included a history of UTI in the 6 months prior to the index UTI (HR 1.59, 95% CI 1.17–2.15, P < 0.01) and presence of a urinary catheter at the time of the index UTI diagnosis (HR 1.59, 95% CI 1.06–2.38, P = 0.03). Conclusion Community-onset UTI due to an ESC-R EB organism is associated with a significantly increased hazard of recurrent UTI within 12 months even after adjusting for baseline factors that predispose patients to UTI recurrence. This study raises the question of whether patients with an ESC-R EB organism may require modified treatment regimens. Further study is needed to better elucidate the cause of recurrence among these patients. Disclosures All authors: No reported disclosures.

Background Urinary tract infections (UTIs) are the most common bacterial infection among adults in the community. Recent data suggest an increase in bacterial resistance to first line antibiotics used for UTI, though the impact on clinical outcomes is unclear. The objective of our study was to determine clinical outcomes associated with community-onset extended-spectrum cephalosporin-resistant (ESC-R) Enterobacteriaceae (EB) UTI. Methods A retrospective cohort study was conducted in a large health system from 2010 to 2013. All patients presenting to an emergency department or outpatient clinic with UTI due to EB were included. Exposed subjects were those with an EB demonstrating resistance to an ESC (ceftriaxone or ceftazidime). Unexposed subjects were those with ESC-susceptible EB UTIs and were matched to cases 1:1 based on study year. Multivariable logistic regression analyses were performed to evaluate the association between ESC-R EB UTI and 1) clinical failure (defined as ongoing symptoms, repeat positive culture, or need for additional antibiotics within 7 days); 2) inappropriate initial antibiotic therapy (IIAT) (defined as failure to receive an antibiotic to which the organism was susceptible within 48 hours of presentation). Results A total of 302 patients with community-onset EB UTI were included. On multivariable analyses, a UTI with an ESC-R EB was significantly associated with clinical failure (odds ratio [OR] 5.12, 95% confidence interval [CI] 2.79–9.39, P < 0.01). Other variables independently associated with clinical failure included presence of pyelonephritis at the time of UTI diagnosis (OR 2.15, 95% CI 1.14–4.03, p 0.02) and infection with Citrobacter species (OR 29.56, 95% CI 4.46–195.91, P < 0.01). ESC-R EB UTI was also associated with IIAT on multivariable analysis (OR 3.73, 95% CI 2.25–6.21, P Conclusion Community-onset UTI due to an ESC-R EB organism is associated with a significantly increased risk of clinical failure, which may be due in part to the use of inappropriate initial antibiotic therapy. Further studies are needed to determine which patients in the community are at high risk for drug-resistant infection to help inform prompt urine culture ordering and appropriate antibiotic prescribing for ESC-R EB. Disclosures All authors: No reported disclosures.