Expanding the Clinical Spectrum of DRP2-Associated Charcot-Marie-Tooth Disease.

BACKGROUND AND OBJECTIVES: Germline truncating variants in the DRP2 gene (encoding dystrophin-related protein 2) cause the disruption of the periaxin-DRP2-dystroglycan complex and have been linked to Charcot-Marie-Tooth disease. However, the causality and the underlying phenotype of the genetic alterations are not clearly defined. METHODS: This cross-sectional retrospective observational study includes 9 patients with Charcot-Marie-Tooth disease (CMT) with DRP2 germline variants evaluated at 6 centers throughout Spain. RESULTS: We identified 7 Spanish families with 4 different DRP2 likely pathogenic germline variants. In agreement with an X-linked inheritance, men harboring hemizygous DRP2 variants presented with an intermediate form of CMT, whereas heterozygous women were asymptomatic. Symptom onset was variable (36.6 ± 16 years), with lower limb weakness and multimodal sensory loss producing a mild-to-moderate functional impairment. Nerve echography revealed an increase in the cross-sectional area of nerve roots and proximal nerves. Lower limb muscle magnetic resonance imaging confirmed the presence of a length-dependent fatty infiltration. Immunostaining in intradermal nerve fibers demonstrated the absence of DRP2 and electron microscopy revealed abnormal myelin thickness that was also detectable in the sural nerve sections. DISCUSSION: Our findings support the causality of DRP2 pathogenic germline variants in CMT and further define the phenotype as a late-onset sensory and motor length-dependent neuropathy, with intermediate velocities and thickening of proximal nerve segments.

Antioxidant Effect of Hydroxytyrosol, Hydroxytyrosol Acetate and Nitrohydroxytyrosol in a Rat MPP+ Model of Parkinson's Disease.

3,4-Dihydroxyphenyl ethanol, known as hydroxytyrosol (HTy), is a phenylpropanoid found in diverse vegetable species. Several studies have demonstrated that HTy is a potent antioxidant. Thus, our study is aimed to evaluate the antioxidant effect of HTy and its derivatives, hydroxytyrosol acetate (HTyA) and nitrohydroxytyrosol (HTyN), in a model of oxidative stress induced by 1-methyl-4-phenylpyridinium (MPP+) in rats. Rats were administered intravenously (i.v.) in the tail with 1 mL saline solution or polyphenol compound (1.5 mg/kg) 5 min before intrastriatal infusion of 10 µg MPP+/8 µL. We found that rats injured with MPP+, pretreatment with HTy, HTyA or HTyN significantly decreased ipsilateral turns. This result was consistent with a significant preservation of striatal dopamine levels and decreased lipid fluorescence products (LFP), a marker of oxidative stress. Brain GSH/GSSG ratio, from rats pretreated with HTy or HTyN showed a significant preservation of that marker, decreased as a consequence of MPP+-induced oxidative damage. These results show an antioxidant effect of HTy, HTyA and HTyN in the MPP+ model of Parkinson's disease in the rat.

Ultrasonography of cervical nerve roots: cross-sectional reference values according to age.

INTRODUCTION: The aim of this study is to describe the normal cross-sectional area (CSA) and appearance of cervical nerve roots in ultrasound, correlating it to age and other patient somatic parameters. METHODS: One hundred healthy volunteers were included. We aimed to achieve uniform representation throughout all age groups. Ultrasound of the cervical nerve roots was performed bilaterally. CSA and margins description were obtained. RESULTS: C5 nerve, 8.32 ± 2.30; C6 nerve, 11.88 ± 3.36; C7 nerve, 12.79 ± 3.85; C8 nerve, 11.20 ± 3.45. Significant correlation between CSA and age was demonstrated, but not for body mass index. Blurred margins were present in up to 23.71% cervical nerves, more frequently in older individuals and in C7 nerve. DISCUSSION: If ultrasound morphology of cervical nerve roots is used as a diagnostic parameter, the normal range of CSA values and percentage of blurred margins according to age should be considered.

Very early Guillain-Barré syndrome: A clinical-electrophysiological and ultrasonographic study.

Objectives: Using recent optimized electrodiagnostic criteria sets, we primarily aimed at verifying the accuracy of the initial electrophysiological test in very early Guillain-Barré syndrome (VEGBS), ≤4 days of onset, compared with the results of serial electrophysiology. Our secondary objective was to correlate early electrophysiological results with sonographic nerve changes. Methods: This is a retrospective study based on consecutive VEGBS patients admitted to the hospital. Each patient had serial nerve conduction studies (NCS) in at least 4 nerves. Initial NCS were done within 4 days after onset, and serial ones from the second week onwards. Electrophysiological recordings of each case were re-evaluated, GBS subtype being established accordingly. Nerve ultrasonography was almost always performed within 2 weeks after onset. Results: Fifteen adult VEGBS patients were identified with a mean age of 57.8 years. At first NCS, VEGBS sub-typing was only possible in 3 (20%) cases that showed an axonal pattern, the remaining patterns being mixed (combining axonal and demyelinating features) in 6 (40%), equivocal in 5 (33.3%), and normal in 1 (6.7%). Upon serial NCS, 7 (46.7%) cases were categorized as acute demyelinating polyneuropathy, 7 (46.7%) as axonal GBS, and 1 (6.6%) as unclassified syndrome. Antiganglioside reactivity was detected in 5 out of the 7 axonal cases. Nerve US showed that lesions mainly involved the ventral rami of scanned cervical nerves. Conclusions: Serial electrophysiological evaluation is necessary for accurate VEGBS subtype classification. Ultrasonography helps delineate the topography of nerve changes. Significance: We provide new VEGBS pathophysiological insights into nerve conduction alterations within the first 4 days of the clinical course.

A unicenter, prospective study of Guillain-Barré syndrome in Spain.

OBJECTIVE: We report a prospective study analysing clinical characteristics, subtyping and prognosis in Guillain-Barré syndrome (GBS). METHOD: The study was based on consecutive GBS patients admitted between 2009 and 2017. Disability was serially assessed using the GBS disability scale. RESULTS: Fifty-six GBS patients were identified with an average age of 55 years (range, 5-86 years) and a male/female ratio of 2.1. The interval to nadir was <7 days in 59% of cases, and 7 to 28 days in the remainder; at nadir, 35.5% of patients were able to walk unaided, and 64.5% did not. Mechanical ventilation was needed in 20% of cases. There were two fatal cases. Clinical variants included paraparetic GBS seven cases, Miller Fisher syndrome one case, and acute sensory ataxic neuropathy (ASAN) one case. Serial electrophysiology showed a demyelinating pattern in 62.5% of cases, axonal in 28.5%, inexcitable in 1.8%, equivocal in 1.8%, and normal in 5.4%. Very early (1 to 4 days after onset) electrophysiology was done in 18 patients; equivocal or normal features in six of them evolved into an axonal pattern in four. Reversible conduction failure of sensitive nerves occurred in ASAN. Antiganglioside antibodies were only detected in axonal GBS. At 24-month follow-up, functional outcome did not differ between demyelinating and axonal GBS. Clinico-pathological correlation in an early fatal case is reported. CONCLUSIONS: This GBS study demonstrates comparable clinical features to previous investigations from well-defined populations. There was a relatively high prevalence of axonal GBS. We provide new pathophysiological insights on nerve conduction alterations.

Prognostic factors for survival with nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer in real-life practice: the ANICE-PaC study.

BACKGROUND: Treatment with nab-paclitaxel plus gemcitabine increases survival in patients with metastatic pancreatic cancer. However, the assessment of treatment efficacy and safety in non-selected patients in a real-life setting may provide useful information to support decision-making processes in routine practice. METHODS: Retrospective, multicenter study including patients with metastatic pancreatic cancer, who started first-line treatment with nab-paclitaxel plus gemcitabine between December 2013 and June 2015 according to routine clinical practice. In addition to describing the treatment pattern, overall survival (OS) and progression-free survival (PFS) were assessed for the total sample and the exploratory subgroups based on the treatment and patients' clinical characteristics. RESULTS: All 210 eligible patients had a median age of 65.0 years (range 37-81). Metastatic pancreatic adenocarcinoma was recurrent in 46 (21.9%) patients and de novo in 164 (78.1%); 38 (18%) patients had a biliary stent. At baseline, 33 (18.1%) patients had an ECOG performance status ≥2. Patients received a median of four cycles of treatment (range 1-21), with a median duration of 3.5 months; 137 (65.2%) patients had a dose reduction of nab-paclitaxel and/or gemcitabine during treatment, and 33 (17.2%) discontinued treatment due to toxicity. Relative dose intensity (RDI) for nab-paclitaxel, gemcitabine, and the combined treatment was 66.7%. Median OS was 7.2 months (95% CI 6.0-8.5), and median PFS was 5.0 months (95% CI 4.3-5.9); 50 patients achieved either a partial or complete response (ORR 24.6%). OS was influenced by baseline ECOG PS, NLR and CA 19.9, but not by age ≥ 70 years and/or the presence of hepatobiliary stent or RDI < 85%. All included variables, computed as dichotomous, showed a significant contribution to the Cox regression model to build a nomogram for predicting survival in these patients: baseline ECOG 0-1 vs. 2-3 (p = 0.030), baseline NLR > 3 vs. ≤ 3 (p = 0.043), and baseline CA 19.9 > 37 U/mL vs. ≤37 U/mL (p = 0.004). CONCLUSIONS: Nab-Paclitaxel plus gemcitabine remain effective in a real-life setting, despite the high burden of dose reductions and poorer performance of these patients. A nomogram to predict survival using baseline ECOG performance status, NLR and CA 19.9 is proposed.

Comparison of the anti-angiogenic potential of hydroxytyrosol and five derivatives.

Hydroxytyrosol is a phenolic compound present in extra virgin olive oil, either in free form or as derivatives, and related to some of the health benefits described for olive oil intake. We have demonstrated previously that hydroxytyrosol inhibits angiogenesis both in vitro and in vivo. In the present study, we evaluate the anti-angiogenic potential of five hydroxytyrosol derivatives. Three of these derivatives contain a nitro group and they exhibit a much weaker effect than hydroxytyrosol in the tubule formation assay on Matrigel and therefore were not studied further. In contrast, both hydroxytyrosyl acetate and ethyl hydroxytyrosyl ether show more potent inhibitory effects than hydroxytyrosol in both the in vitro tubule formation assay on Matrigel and the in vivo chorioallantoic membrane assay. Additionally, these three compounds had slight pro-apoptotic effects and decreased matrix metalloproteinase-2 levels in cell extracts.

Clinical indications for musculoskeletal ultrasound updated in 2017 by European Society of Musculoskeletal Radiology (ESSR) consensus.

OBJECTIVES: To update the 2012 European Society of Musculoskeletal Radiology (ESSR) clinical consensus guidelines for musculoskeletal ultrasound referral in Europe. METHODS: Twenty-one musculoskeletal imaging experts from the ESSR participated in a consensus study based on a Delphic process. Two independent (non-voting) authors facilitated the procedure and resolved doubtful issues. Updated musculoskeletal ultrasound literature up to July 2017 was scored for shoulder, elbow, wrist/hand, hip, knee, and ankle/foot. Scoring of ultrasound elastography was included. The strength of the recommendation and level of evidence was scored by consensus greater than 67% or considered uncertain when the consensus was consensus less than 67%. RESULTS: A total of 123 new papers were reviewed. No evidence change was found regarding the shoulder. There were no new relevant articles for the shoulder, 10 new articles for the elbow, 28 for the hand/wrist, 3 for the hip, 7 for the knee, and 4 for the ankle/foot. Four new evidence levels of A were determined, one for the hip (gluteal tendons tears), one for the knee (meniscal cysts), one for the ankle (ankle joint instability), and one for the foot (plantar plate tear). There was no level A evidence for elastography, although for Achilles tendinopathy and lateral epicondylitis evidence level was B with grade 3 indication. CONCLUSIONS: Four new areas of level A evidence were included in the guidelines. Elastography did not reach level A evidence. Whilst ultrasound is of increasing importance in musculoskeletal medical practice, the evidence for elastography remains moderate. KEY POINTS: • Evidence and expert consensus shows an increase of musculoskeletal ultrasound indications. • Four new A evidence levels were found for the hip, knee, ankle, and foot. • There was no level A evidence for elastography.

Intermediate Charcot-Marie-Tooth disease: an electrophysiological reappraisal and systematic review.

Charcot-Marie-Tooth disease (CMT) is the most frequent form of inherited neuropathy with great variety of phenotypes, inheritance patterns, and causative genes. According to median motor nerve conduction velocity (MNCV), CMT is divided into demyelinating (CMT1) with MNCV below 38 m/s, axonal (CMT2) with MNCV above 38 m/s, and intermediate CMT with MNCV between 25 and 45 m/s. In each category, transmission may be autosomal dominant, autosomal recessive, or X-linked. The nosology of intermediate CMT is controversial because of concerns about electrophysiological delimitation. A systematic computer-based literature search was conducted on PubMed, using the following MeSH: (1) intermediate Charcot-Marie-Tooth; (2) X-linked intermediate Charcot-Marie-Tooth; and (3) X-linked Charcot-Marie-Tooth and electrophysiology. We retrieved 225 articles reporting X-linked CMT or intermediate CMT with electrophysiological information. After eligibility, 156 papers were used for this review. In assessing median MNCV, compound muscle action potential (CMAP) amplitudes were taken into account. In cases with attenuated CMAP and wherever possible, proximal median MNCV was used for accurate definition of conduction slowing in the intermediate range. In the vast majority of males with X-linked CMT associated with GJB1 mutation (CMTX1), median MNCV was intermediate. CMT associated with DRP2 mutation is another well-documented X-linked intermediate disorder. Autosomal dominant intermediate CMT (DI-CMT) encompasses 11 different types; six of them with assigned phenotype MIM number and the remaining five being unnumbered. Based on available electrophysiological information, we wonder if DI-CMTA should be reclassified within CMT2. Autosomal recessive intermediate CMT (RI-CMT) covers four numbered MIM phenotypes though, in accordance with reported electrophysiology, two of them (RI-CMTB and RI-CMTD) should probably be reclassified within AR-CMT2. We conclude that intermediate CMT is a complex inherited syndrome, whose characterization requires a specific electrophysiological protocol comprising evaluation of upper limb proximal nerve trunks when distal CMAP amplitudes are reduced, and that an updated version of MIM phenotype numbering is needed.

Proximal nerve lesions in early Guillain-Barré syndrome: implications for pathogenesis and disease classification.

Guillain-Barré syndrome (GBS) is an acute-onset, immune-mediated disorder of the peripheral nervous system. In early GBS, arbitrarily established up to 10 days of disease onset, patients could exhibit selective manifestations due to involvement of the proximal nerves, including nerve roots, spinal nerves and plexuses. Such manifestations are proximal weakness, inaugural nerve trunk pain, and atypical electrophysiological patterns, which may lead to delayed diagnosis. The aim of this paper was to analyze the nosology of early GBS reviewing electrophysiological, autopsy and imaging studies, both in acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor/motor-sensory axonal neuropathy (AMAN/AMSAN). Early electrophysiology showed either well-defined demyelinating or axonal patterns, or a non-diagnostic pattern with abnormal late responses; there may be attenuated M responses upon lumbar root stimulation as the only finding. Pathological changes predominated in proximal nerves, in some studies, most prominent at the sides where the spinal roots unite to form the spinal nerves; on very early GBS endoneurial inflammatory edema was the outstanding feature. In the far majority of cases, spinal magnetic resonance imaging showed contrast enhancement of cauda equina, selectively involving anterior roots in AMAN. Both in AIDP and AMAN/AMSAN, ultrasonography has demonstrated frequent enlargement of ventral rami of C5-C7 nerves with blurred boundaries, whereas sonograms of upper and lower extremity peripheral nerves exhibited variable and less frequent abnormalities. We provide new insights into the pathogenesis and classification of early GBS.

Neuroendocrine Gastroenteropancreatic Tumors: Where Are We?

AIMS: Neuroendocrine gastroenteropancreatic tumors are infrequently found neoplasms. Our objective was to analyze the survival rates for all sites that they occur in by studying different variables. MATERIALS AND METHODS: A retrospective study was carried out using records for a 7-year period from January 1, 2008 to December 31, 2014 on neuroendocrine gastroenteropancreatic tumors patients diagnosed at the Pontevedra-Salnés Hospital Complex. The variables used were as follows: age at diagnosis, tumor size, presence or absence of metastases at diagnosis, cell proliferation index, Ki-67 of each tumor, treatments received, postdiagnosis survival time, existence or not of tumor progression, and time from diagnosis to progression and from diagnosis to mortality. In relation to treatments, the information recorded was whether the treatment was endoscopic, surgical, or pharmacological. RESULTS: Ninety-three neuroendocrine tumors made up a ratio of 4.42 cases per 100,000 inhabitants per annum. The median patient follow-up time was 44 months. The overall 5-year survival rate for patients who were followed up for a minimum of 60 months (49 patients) was 65.3%. The progression-free survival was 75.6% for 41 patients who were followed up for a minimum of 60 months. The survival rate for patients receiving endoscopic treatment was 100%, as there was no patient mortality recorded for those treated by endoscopic resection during the follow-up period. CONCLUSION: Pancreatic neuroendocrine tumors may be managed conservatively in elderly patients by either monitoring them with imaging studies or treating them with somatostatin analogs. In the case of digestive tract tumors (stomach, duodenum, and rectum) that meet the criteria for endoscopic resection, this is a reliable and safe technique in the long term.

Charcot-Marie-Tooth disease type 2G redefined by a novel mutation in LRSAM1.

OBJECTIVE: To identify the unknown genetic cause in a large pedigree previously classified with a distinct form of axonal Charcot-Marie-Tooth disease type 2G (CMT2G) and to explore its transcriptional consequences. METHODS: Clinical reevaluation of the pedigree was performed, followed by linkage analysis with the redefined disease statuses, and whole genome and exome sequencing. The impact of the mutation was investigated by immunoblotting and transcriptome sequencing. RESULTS: Thirteen affected individuals over 3 generations displayed mild and quiescent lower-limb axonal sensorimotor neuropathy. Magnetic resonance imaging (MRI) of lower-limb musculature systematically showed fatty atrophy in clinical and subclinical mutation carriers. We redefined the disease-linked region to chr9q31.3-q34.2 and subsequently identified a novel missense variant in the E3 ubiquitin-protein ligase LRSAM1 (p.Cys694Tyr). Unlike previous reports, we demonstrated in patients' lymphoblasts that the mutation does not influence overall protein levels of LRSAM1, nor of its ubiquitylation target TSG101. The mutation is associated with several transcriptional changes, including a significant upregulation of another E3 ubiquitin-protein ligase, NEDD4L, and of TNFRSF21, a key regulator of axonal degeneration. INTERPRETATION: Our findings demonstrate that the isolated genetic entity CMT2G is caused by a missense mutation in LRSAM1 and should be reclassified as CMT2P. MRI of lower-limb musculature can be used to detect minimal signs of the disease. Transcriptome analysis of patients' cells highlights novel molecular players associated with LRSAM1 dysfunction, and reveals pathways and therapeutic targets shared with amyotrophic lateral sclerosis and Alzheimer disease. Ann Neurol 2016;80:823-833.

A nomogram for predicting complications in patients with solid tumours and seemingly stable febrile neutropenia.

BACKGROUND: We sought to develop and externally validate a nomogram and web-based calculator to individually predict the development of serious complications in seemingly stable adult patients with solid tumours and episodes of febrile neutropenia (FN). PATIENTS AND METHODS: The data from the FINITE study (n=1133) and University of Salamanca Hospital (USH) FN registry (n=296) were used to develop and validate this tool. The main eligibility criterion was the presence of apparent clinical stability, defined as events without acute organ dysfunction, abnormal vital signs, or major infections. Discriminatory ability was measured as the concordance index and stratification into risk groups. RESULTS: The rate of infection-related complications in the FINITE and USH series was 13.4% and 18.6%, respectively. The nomogram used the following covariates: Eastern Cooperative Group (ECOG) Performance Status ⩾2, chronic obstructive pulmonary disease, chronic cardiovascular disease, mucositis of grade ⩾2 (National Cancer Institute Common Toxicity Criteria), monocytes <200/mm(3), and stress-induced hyperglycaemia. The nomogram predictions appeared to be well calibrated in both data sets (Hosmer-Lemeshow test, P>0.1). The concordance index was 0.855 and 0.831 in each series. Risk group stratification revealed a significant distinction in the proportion of complications. With a ⩾116-point cutoff, the nomogram yielded the following prognostic indices in the USH registry validation series: 66% sensitivity, 83% specificity, 3.88 positive likelihood ratio, 48% positive predictive value, and 91% negative predictive value. CONCLUSIONS: We have developed and externally validated a nomogram and web calculator to predict serious complications that can potentially impact decision-making in patients with seemingly stable FN.

Synthesis and Antioxidant Activity of Alkyl Nitroderivatives of Hydroxytyrosol.

A series of alkyl nitrohydroxytyrosyl ether derivatives has been synthesized from free hydroxytyrosol (HT), the natural olive oil phenol, in order to increase the assortment of compounds with potential neuroprotective activity in Parkinson's disease. In this work, the antioxidant activity of these novel compounds has been evaluated using Ferric Reducing Antioxidant Power (FRAP), 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), and Oxygen Radical Scavenging Capacity (ORAC) assays compared to that of nitrohydroxytyrosol (NO2HT) and free HT. New compounds showed variable antioxidant activity depending on the alkyl side chain length; compounds with short chains (2-4 carbon atoms) maintained or even improved the antioxidant activity compared to NO2HT and/or HT, whereas those with longer side chains (6-8 carbon atoms) showed lower activity than NO2HT but higher than HT.

Evaluation of the Bioavailability and Metabolism of Nitroderivatives of Hydroxytyrosol Using Caco-2 and HepG2 Human Cell Models.

Considering that nitrocatechols present putative effects against Parkinson's disease, the absorption and metabolism of nitroderivatives of hydroxytyrosol (HT) were assessed using human cell model systems. The test compounds nitrohydroxytyrosol (NO2HT), nitrohydroxytyrosyl acetate (NO2HT-A), and ethyl nitrohydroxytyrosyl ether (NO2HT-E) were efficiently transferred across human Caco-2 cell monolayers as an intestinal barrier model, NO2HT-A and NO2HT-E being better (p < 0.05) absorbed (absorption rate (AR) = 1.4 ± 0.1 and 1.5 ± 0.2, respectively) than their precursor, NO2HT (AR = 1.1 ± 0.1). A significant amount of the absorbed compounds remained unconjugated (81, 70, and 33% for NO2HT, NO2HT-A, and NO2HT-E, respectively) after incubation in Caco-2 cells, being available for hepatic metabolism. Nitrocatechols were extensively taken up and metabolized by human hepatoma HepG2 cells as a model of the human liver. Both studies revealed extensive hydrolysis of NO2HT-A into NO2HT, whereas NO2HT-E was not hydrolyzed. Glucuronide (75-55%), methylglucuronide (25-33%), and methyl derivatives (0-12%) were the main nitrocatechol metabolites detected after metabolism in Caco-2 and HepG2 cells. In conclusion, NO2HT, NO2HT-A, and NO2HT-E show high in vitro bioavailability and are extensively metabolized by hepatic cells.

NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype.

The purpose of this study was to describe a pedigree with NEFL N98S mutation associated with a dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) and heterogeneous early-onset phenotype. The pedigree comprised two patients, the proband and her son, aged 38 and 5 years. The proband, evaluated at age 31, showed delayed motor milestones that, as of the second decade, evolved into severe phenotype consisting of sensorimotor neuropathy, pes cavus, clawing hands, gait and kinetic cerebellar ataxia, nystagmus and dysarthria, she being wheelchair bound. By then, a working diagnosis of sporadic early onset cerebellar ataxia with peripheral neuropathy was established. Screening of mutations associated with SCA and autosomal recessive cerebellar ataxias was negative. Her son showed a mild phenotype characterized by delayed motor milestones, and lower-limb hypotonia and areflexia. Electrophysiology in both patients showed nerve conduction slowing in the intermediate range, both in proximal and distal nerve segments, but where compound muscle action potentials exhibited severe attenuation there was conduction slowing down to the demyelinating range. In the proband, cranial magnetic resonance imaging (MRI) showed cerebellar atrophy, electromyography disclosed active denervation in tibialis anterior, and MRI of lower-limb musculature demonstrated widespread and distally accentuated muscle fatty atrophy; furthermore, on water sensitive MRI sequences there was edema of calf muscles. We conclude that the NEFL N98S mutation is associated with a DI-CMT phenotype characterized by early-onset sensorimotor neuropathy delaying motor milestones, which may evolve into a severe and complex clinical picture including cerebellar ataxia.

Effect of intracerebral hydroxytyrosol and its nitroderivatives on striatal dopamine metabolism: A study by in vivo microdialysis.

AIMS: The natural phenolic oil compound hydroxytyrosol (HTy) is widely studied because of its antioxidant and neuroprotective properties. Nitroderivatives of HTy have been studied in order to evaluate their putative effects on catechol-O-methyltransferase (COMT) activity. MAIN METHODS: To study its effect on dopamine metabolism, nitrohydroxytyrosol and its lipophilic derivatives (nitrohydroxytyrosyl acetate and ethyl nitrohydroxytyrosyl ether), were administered into the rat corpus striatum through a microdialysis probe. Other catechols (HTy and the known COMT inhibitor Ro 41-0960) were also studied for comparison. KEY FINDINGS: The olive oil phenolic compounds (nitroderivatives and HTy) increased extracellular levels of 3,4-dihydroxyphenylacetic acid during the perfusion with similar maximum values to that of Ro 41-0960 when comparing to basal dialysate levels (approximately 140%). None of the compound series produced a decrease in the homovanillic acid extracellular levels below 75%. Among all novel compounds studied, both lipophilic nitrocatechols (nitrohydroxytyrosyl acetate and ethyl nitrohydroxytyrosyl ether) showed a long-acting effect over time once the perfusion through the microdialysis probe ended. SIGNIFICANCE: In accordance with the actual design of novel COMT inhibitors with a long profile, our results suggest a certain influence of the side chain substituent on the COMT activity that could provide new lipophilic COMT inhibitors.