Phenotype and molecular characterization of Wilson's disease in Morocco.

BACKGROUND AND STUDY AIMS: In Morocco the prevalence of Wilson disease (WD) and the spectrum of mutations are not known. The aim of the present study was to estimate the prevalence of WD in Morocco, to evaluate the phenotype among a large cohort of WD patients, and to characterize ATP7B variants in a subgroup of WD patients. PATIENTS AND METHODS: We collected data from 226 patients admitted to five university hospital centers in Morocco between 2008 and 2020. The diagnosis was based on clinical manifestations, function tests and biochemical parameters. The genotype was characterized in 18 families diagnosed at the University Hospital Center of Marrakesh, by next generation sequencing. RESULTS: The mean annual prevalence in Morocco was 3.88 per 100,000 and the allele frequency was 0.15 %. Among the 226 patients included (121 males and 105 females), 196 were referred for a hepatic or neurological involvement and 30 were asymptomatic. The mean age at diagnosis was 13 ± 5.1 years (range: 5 - 42 years). Consanguinity was found in 63.3 % of patients. The mean duration of illness was 2.8 ± 1.9 years. Kayser-Fleischer rings were found in 131 (67.9 %) of 193 patients. Among the 196 symptomatic patients, 141/159 (88.7 %) had low serum ceruloplasmin (<0.2 g/L) and a high 24-hours urinary copper (>100 µg/day) was found in 173/182 (95.1 %) patients. The initial treatment was D-penicillamine in 207 patients, zinc acetate in five, zinc sulfate in five, and nine patients were not treated; 60/207 (29 %) patients have stopped treatment. A total of 72 patients died; the mortality rate was 31.9 %. Eight different ATP7B variants were identified among the 18 patients studied, of which two were novel (p.Cys1104Arg and p.Gln1277Hisfs*52), and six previously published (p.Gln289Ter, p.Cys305Ter, p.Thr1232Pro, p.Lys1020Arg, p.Glu583ArgfsTer25 and c.51+4A>T). All informative patients were homozygous for the disease-causing mutation. CONCLUSION: In Morocco, a high prevalence due to consanguinity and a high mortality rate due to the difficulty of diagnosis and lack of treatment were observed in WD patients. NGS sequencing identified new ATP7B variants in WD patients from Morocco.

Histological features of liver disease development in the Atp7b-/- mouse: a model of Wilson's disease.

AIMS: Wilson's disease (WD) is caused by mutations in the ATP7B gene, resulting in copper accumulation and toxicity in liver and brain tissues. Due to the initial asymptomatic liver involvement, the progression of liver injuries in WD stays primarily unknown. Atp7b-/- knockout mice have been shown to be an appropriate model of WD for liver involvement. METHODS: A total of 138 Atp7b-/- mice were included and separated into five groups according to age as follows: 6, 20, 39 and 50 weeks without treatment, and 50 weeks with copper chelator treatment from 39 to 50 weeks of age and compared with 101 wild-type (WT) mice at the same stages. The evolution of histological liver lesions was analysed and compared between groups. RESULTS: Significant changes were observed in Atp7b-/- mice compared with WT. Copper deposits in hepatocytes appeared as early as 6 weeks but no significant increase over time was observed. Inflammation appeared as early as 6 weeks and progressed henceforth. Lobular and periportal acidophilic bodies appeared after 20 weeks. Significant atypia was also observed at 20 weeks and increased over time to reach a severe stage at 39 weeks. Fibrosis also became apparent at 20 weeks, progressing subsequently to precirrhotic stages at 50 weeks. Copper content, inflammation and fibrosis scores were significantly reduced in the treated group. No bile duct lesions or dysplastic changes were noted. CONCLUSIONS: Copper accumulation leads to progressive changes in Atp7b-/- mice regarding inflammation, fibrosis and atypia. The severity of liver damage is lessened by chelation therapy.

Minerals and Antioxidant Micronutrients Levels and Clinical Outcome in Older Patients Hospitalized for COVID-19 during the First Wave of the Pandemic.

Excessive inflammatory response has been implicated in severe respiratory forms of coronavirus disease 2019 (COVID-19). Trace elements such as zinc, selenium, and copper are known to modulate inflammation and immunity. This study aimed to assess the relationships between antioxidant vitamins and mineral trace elements levels as well as COVID-19 severity in older adults hospitalized. In this observational retrospective cohort study, the levels of zinc, selenium, copper, vitamin A, ß-carotene, and vitamin E were measured in 94 patients within the first 15 days of hospitalization. The outcomes were in-hospital mortality secondary to COVID-19 or severe COVID-19. A logistic regression analysis was conducted to test whether the levels of vitamins and minerals were independently associated with severity. In this cohort (average age of 78 years), severe forms (46%) were associated with lower zinc (p = 0.012) and ß-carotene (p < 0.001) concentrations, and in-hospital mortality (15%) was associated with lower zinc (p = 0.009), selenium (p = 0.014), vitamin A (p = 0.001), and ß-carotene (p = 0.002) concentrations. In regression analysis, severe forms remained independently associated with lower zinc (aOR 2.13, p = 0.018) concentrations, and death was associated with lower vitamin A (aOR = 0.165, p = 0.021) concentrations. Low plasma concentrations of zinc and vitamin A were associated with poor prognosis in older people hospitalized with COVID-19.

Review of nutritional components in Covid-19: what about micronutrients? / Revue des facteurs nutritionnels dans la Covid-19 : qu'en est-il des micronutriments ?

Nutritional status is an important protection factor against viral infections. Both undernutrition and malnutrition cause deficits in micronutrients, trace elements and vitamins necessary for various physiological functions and the appropriate functioning of the immune system. These deficiencies and infectious diseases often coexist, with complex interactions. An assessment of the micro-nutrient nutritional status of Covid-19 patients has not been at the center of priorities and recommendations, due to both the medical emergency and the absence of direct evidence and rapid effects of supplementation. Few recommendations have come from learned societies due to the lack of significant evidence of the effects of supplementation in positive patients and a need for robust studies. Essential trace elements and vitamins are necessary for the differentiation, activation and execution of many functions of immune cells, but their specific role has yet to be defined. This review article discusses in the context of Covid-19 the importance of micronutrients (selenium, copper, zinc, vitamins C, D, A and those of group B) in the host to tend towards an optimization of the immune response to infections. A nutritional balance remains the key word for achieving micronutrient homeostasis. Attention had to be paid to micronutrients in primary prevention, in the general population, in order to reduce the risk of impaired nutritional status in case of major health situations.

Le statut nutritionnel est important pour protéger des infections virales. La dénutrition comme la malnutrition induisent des déficits en micronutriments, éléments-trace et vitamines nécessaires aux fonctions physiologiques et au fonctionnement du système immunitaire. Ces carences et les maladies infectieuses coexistent souvent en complexes interactions. Une évaluation de l'état nutritionnel en micronutriments des patients Covid-19 n'a pas été au centre des priorités face à l'urgence médicale et à l'absence de preuves directes et rapides des effets de supplémentation. Peu de recommandations ont émané des sociétés savantes par manque de preuves significatives des effets de supplémentations, avec une nécessité d'études robustes. S'il est reconnu que les oligo-éléments essentiels et les vitamines sont nécessaires à la différenciation, l'activation et l'exécution de fonctions des cellules immunitaires, leur rôle spécifique reste encore à définir. Cette synthèse aborde dans la Covid-19 l'importance des micronutriments (sélénium, cuivre, zinc, vitamines C, D, A et groupe B) chez l'hôte pour tendre vers une optimisation de la réponse immunitaire aux infections. En prévention primaire, en population générale, un équilibre nutritionnel reste central pour atteindre l'homéostasie des micronutriments, pour diminuer le risque des situations de déséquilibre et de fragilisation face à des situations sanitaires d'ampleur.

Long-Term Urinary Copper Excretion and Exchangeable Copper in Children With Wilson Disease Under Chelation Therapy.

OBJECTIVES: Determining 24-hour urinary copper excretion (UCE) levels is useful for diagnosing Wilson's disease (WD) and for treatment monitoring. Exchangeable copper (ExC) is a novel potential marker, but its long-term changes have never been described in patients under chelation therapy. Our aim was to describe the long-term changes in ExC levels compared to UCE levels in symptomatic WD pediatric patients under chelation therapy. METHODS: A retrospective, descriptive, and analytical study including all patients under 18 years of age, diagnosed between 2006 and 2020, and treated with chelation therapy was conducted at the National Reference Center for WD in Lyon. Ceruloplasmin levels, serum copper, 24 h-UCE, ExC, and liver enzymes at diagnosis and during follow-up were analyzed. RESULTS: Our study included 36 patients, predominantly with hepatic form of WD (n = 31). The median [interquartile range (IQR)] age at diagnosis was 10.5 (8.4-13.1) years, and the median (IQR) follow-up duration was 6.3 (3.3-8.8) years. At diagnosis, the median (IQR) ExC value was 1.01 (0.60-1.52) µmol/L. There was a significant decrease during the first year of chelation treatment ( P = 0.0008), then a stabilization. The median (IQR) ExC values was 0.38 (0.22-0.63) µmol/L at 12-18 months and 0.43 (0.31-0.54) µmol/L at 5 years of chelation treatment ( P = 0.4057). Similarly, there was a significant decrease in 24-hour UCE ( P < 0.001) during the first year of chelation treatment, then a stabilization. CONCLUSIONS: Our study showed a significant decrease in ExC and 24-hour UCE levels during the first year of follow-up; The dynamics of both biomarkers were similar along the follow-up, demonstrating their usefulness in clinical practice for monitoring WD.

Maintenance therapy simplification using a single daily dose: A preliminary real-life feasibility study in patients with Wilson disease.

BACKGROUND: Single daily dose (SDD) is a good way to improve adherence by simplifying treatment. Efficacy data concerning patients with Wilson disease (WD) taking an SDD are lacking. AIM: To report the effectiveness of the use of SDD for the treatment of WD. METHODS: This retrospective study included WD patients followed in the French National Network who received an SDD in maintenance phase. The treatment failure was defined as a composite criterion with the occurrence of at least one of the following criterion: death, transplantation, increase of transaminases >2xULN, hepatic decompensation, neurological aggravation, severe side effects related to treatment, and/or discontinuation of treatment. RESULTS: A total of 26 patients received an SDD (D-penicillamine=13, trientine=8, zinc=5) after a median interval of 152 months after diagnosis. After one year, two patients had treatment failure: transaminitis in one, continuation of neurological deterioration in the other related to a poor compliance. After a median duration of 41 months on SDD, 3 other patients had treatment failure (transaminitis=2, treatment discontinuation=1). There was no death, no liver transplantation, no hepatic decompensation, and no severe side effects related to treatment during the follow-up. Moreover, transaminases and serum exchangeable copper were not significantly different 1 year post-switch and at last follow-up compared to baseline. CONCLUSIONS: Maintenance therapy simplification through the use of an SDD could be considered in some WD patients. In this pilot study, SDD was effective in 21/26 patients (81%) without any concern regarding safety.

Release of metal elements from the Essure implant: A prospective cohort study.

OBJECTIVE(S): The causal mechanistic relationships between Essure® and adverse effects are unclear, but corrosion in the in-vivo environment with release of metal ions may be suspected. Here we evaluated the concentrations of nickel (Ni), chromium (Cr) and tin (Sn) in the peritoneal fluid (PF) and in the fallopian tube (FT) during laparoscopic Essure® removal compared to a control group. STUDY DESIGN: Ni, Cr and Sn concentrations were determined in the PF and FT from two groups(group A: symptomatic patients with Essure®) vs group B (control group without Essure®) by Inductively Coupled Plasma Mass Spectrometry analysis. Correlation between metal elements concentrations and reported pre-operative symptoms was also investigated. RESULTS: There were 131 patients in group A vs 92 control patients in group B. The concentrations of Cr and Ni in PF between both groups were significantly different (p < 0.0001) while there was no statistical difference for Sn (p = 0.58). There was also a significantly higher concentration in the FT for the 3 metal elements in group A than in group B (p < 0.0001). There were differential dynamics of the levels of metal elements based on the length of time between the placement and removal of Essure®. CONCLUSIONS: There was a chronic exposure to metal elements in symptomatic patients with Essure® raising the question of the relationship between adverse effects and these potential toxic metals.

Vitamin D and COVID-19 Severity in Hospitalized Older Patients: Potential Benefit of Prehospital Vitamin D Supplementation.

Studies involving the associations between vitamin D supplementation taken before the onset of COVID-19 infection and the clinical outcomes are still scarce and this issue remains controversial. This study aimed to assess the relationships between vitamin D (VitD) status and supplementation and coronavirus disease 2019 (COVID-19) severity in older adults (average age of 78 years) hospitalized for COVID-19. We conducted an observational retrospective cohort study with 228 older hospitalized patients during the first wave of the COVID-19 pandemic. The outcomes were in-hospital mortality secondary to COVID-19 or critically severe COVID-19. A logistic regression analysis was conducted to test whether pre-hospital VitD supplementation was independently associated with severity. In this study, 46% of patients developed a severe form and the overall in-hospital mortality was 15%. Sixty-six (29%) patients received a VitD supplement during the 3 months preceding the infection onset. Additionally, a VitD supplement was associated with fewer severe COVID-19 forms (OR = 0.426, p = 0.0135) and intensive care unit (ICU) admissions (OR = 0.341, p = 0.0076). As expected, age > 70 years, male gender and BMI ≥ 35 kg/m2 were independent risk factors for severe forms of COVID-19. No relationship between serum 25(OH)D levels and the severity of the COVID-19 was identified. VitD supplementation taken during the 3 months preceding the infection onset may have a protective effect on the development of severe COVID-19 forms in older adults. Randomized controlled trials and large-scale cohort studies are necessary to strengthen this observation.

Comparative diagnosis interest of NfL and pNfH in CSF and plasma in a context of FTD-ALS spectrum.

OBJECTIVE: The 'Frontotemporal dementia-Amyotrophic lateral sclerosis Spectrum' (FAS) encompasses different phenotypes, including cognitive disorders (frontotemporal dementia, FTD) and/or motor impairments (amyotrophic lateral sclerosis, ALS). The aim of this study was to apprehend the specific uses of neurofilaments light chain (NfL) and phosphorylated neurofilaments heavy chain (pNfH) in a context of FAS. METHODS: First, NfL and pNfH were measured in 39 paired cerebrospinal fluid (CSF) and plasma samples of FAS and primary psychiatric disorders (PPD) patients, considered as controls. Secondly, additional plasma samples were included to examine a larger cohort of 81 samples composed of symptomatic FAS and PPD patients, presymptomatic and non-carrier relatives individuals. The measures were performed using Simoa technology. RESULTS: There was a positive correlation between CSF and plasma values for NfL (p < 0.0001) and for pNfH (p = 0.0036). NfL values were higher for all phenotypes of symptomatic FAS patients compared to PPD patients (p = 0.0016 in CSF; p = 0.0003 in plasma). On the contrary, pNfH values were solely increased in FAS patients exhibiting motor impairment. Unlike symptomatic FAS patients, presymptomatic cases had comparable concentrations with non-carrier individuals. CONCLUSION: NfL, but not pNfH, appeared to be useful in a context of differential diagnosis between FTD and psychiatric patients. Nevertheless, pNfH seem more specific for the diagnosis and follow-up of motor impairments. In each specific indication, measures in CSF and plasma will provide identical interpretations.

ATP7B variant spectrum in a French pediatric Wilson disease cohort.

BACKGROUND/AIM: The spectrum of ATP7B variants varies significantly according to geographic distribution, and there is insufficient data on the variants observed in the French population. METHODS: Clinical data of 113 children included in the French WD national registry were gathered from March 01, 1995 to July 01, 2020. Data included epidemiological, clinical, laboratory, genetics. RESULTS: Diagnosis was made at a mean age of 11.0 ± 4.1 years (range 1-18 years). At diagnosis, 91 patients (79.8 %) had hepatic manifestations, 18 (15.8 %) presented neurological manifestations, and 4 patients (3.5 %) were asymptomatic. Only 29 patients (25 %) were homozygous for a variant. We have found a total of 102 different variants including 14 novel variants. Recurrent variant p.His1069Gln was the most prevalent, n = 31 alleles (14,2%), with only seven homozygous; in contrast 55% of variants are identified in only one family. 45% were truncating variants. In respect of mutated exon, the three most prevalent were exon 14 (16.5%), exon 8 (13.8%), and exon 3 (11.5%). When considering patients with two Nonsense / Frameshift variants as a group and those with two Missense variants, we found significantly lower ceruloplasmin for the former: 2.8 ± 0.7 mg/dl vs 8.4 ± 5mg/dl (p<0.05). CONCLUSION: p.His1069Gln is the most frequent variant (14,2%) and exons 14, 8, and 2 of the ATP7B gene account for 41.7% of total variants. However, there is significant heterogeneity in the French population concerning the other ATP7B variants. Nonsense / Frameshift variants were associated with lower ceruloplasmin levels.

Pediatric Wilson's Disease: Phenotypic, Genetic Characterization and Outcome of 182 Children in France.

OBJECTIVES: To describe a cohort of Wilson disease (WD) pediatric cases, and to point out the diagnostic particularities of this age group and the long-term outcome. METHODS: Clinical data of 182 pediatric patients included in the French WD national registry from 01/03/1995 to 01/06/2019 were gathered. RESULTS: Diagnosis of WD was made at a mean age of 10.7 ±â€Š4.2 years (range 1-18 years). At diagnosis, 154 patients (84.6%) had hepatic manifestations, 19 (10.4%) had neurological manifestations, and 9 patients (4.9%) were asymptomatic. The p.His1069Gln mutation was the most frequently encountered (14% of patients).Neurological patients were diagnosed at least 1 year after they presented their first symptoms. At diagnosis, the median urinary copper excretion (UCE) was 4.2 µmol/24 hours (0.2-253). The first-line treatment was d-penicillamine (DP) for 131 (72%) patients, zinc salts for 24 (13%) patients, and Trientine for 17 (9%) patients. Liver transplantation was performed in 39 (21.4%) patients, for hepatic indications in 33 of 39 patients or for neurological deterioration in 6 of 39 patients, mean Unified Wilson's Disease Rating Scale of the latter went from 90 ±â€Š23.1 before liver transplantation (LT) to 26.8 ±â€Š14.1 (P < 0.01) after a mean follow-up of 4.3 ±â€Š2.5 years. Overall survival rate at 20 years of follow-up was 98%, patient and transplant-free combined survival was 84% at 20 years. CONCLUSION: Diagnosis of WD can be challenging in children, particularly at the early stages of liver disease and in case of neurological presentation; hence the support of clinical scores and genetic testing is essential. Diagnosis at early stages and proper treatment ensure excellent outcomes, subject to good long-term treatment compliance. LT is a valid option for end-stage liver disease not responding to treatment and can be discussed for selected cases of neurological deterioration.

The blood copper isotopic composition is a prognostic indicator of the hepatic injury in Wilson disease.

Wilson disease (WD) is an autosomal recessive disorder of copper (Cu) metabolism. The gene responsible for WD, ATP7B, is involved in the cellular transport of Cu, and mutations in the ATP7B gene induce accumulation of Cu in the liver and ultimately in the brain. In a pilot study, the natural variations of copper stable isotope ratios (65Cu/63Cu) in the serum of WD patients have been shown to differ from that of healthy controls. In the present study, we challenged these first results by measuring the 65Cu/63Cu ratios in the blood of treated (n = 25), naïve patients (n = 11) and age matched healthy controls (n = 75). The results show that naïve patients and healthy controls exhibit undistinguishable 65Cu/63Cu ratios, implying that the Cu isotopic ratio cannot serve as a reliable diagnostic biomarker. The type of treatment (d-penicillamine vs. triethylenetetramine) does not affect the 65Cu/63Cu ratios in WD patients, which remain constant regardless of the type and duration of the treatment. In addition, the 65Cu/63Cu ratios do not vary in naïve patients after the onset of the treatment. However, the 65Cu/63Cu ratios decrease with the degree of liver fibrosis and the gradient of the phenotypic presentation, i.e. presymptomatic, hepatic and neurologic. To get insights into the mechanisms at work, we study the effects of the progress of the WD on the organism by measuring the Cu concentrations and the 65Cu/63Cu ratios in the liver, feces and plasma of 12 and 45 week old Atp7b-/- mice. The evolution of the 65Cu/63Cu ratios is marked by a decrease in all tissues. The results show that 63Cu accumulates in the liver preferentially to 65Cu due to the preferential cellular entry of 63Cu and the impairment of the 63Cu exit by ceruloplasmin. The hepatic accumulation of monovalent 63Cu+ is likely to fuel the production of free radicals, which is potentially an explanation of the pathogenicity of WD. Altogether, the results suggest that the blood 65Cu/63Cu ratio recapitulates WD progression and is a potential prognostic biomarker of WD.

Potential release of toxic metal elements from Essure® device in symptomatic patients: First results of the French Ablimco cohort.

OBJECTIVE: Many patients with Essure® devices request the removal of these implants due to persistent adverse effects. The pathophysiology remains unknown, but a corrosion of the implants in the in-vivo environment leading to metal ion release may be suspected. The implants consist of polyester fibers, nickel-titanium alloy and other metals including chromium. The purpose of this study is to deliver the first results on the concentrations of nickel and chromium (two potential toxic metal elements) in peritoneal fluid and in the fallopian tube tissue during laparoscopic removal of Essure®. STUDY DESIGN: In this prospective observational study conducted in a French academic research hospital (University hospital of Lyon), nickel and chromium concentrations were determined in the fallopian tube tissue and peritoneal liquid from symptomatic patients with Essure® by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) analysis in a PerkinElmer NexION 350. RESULTS: Significant metal element concentrations were showed in the peritoneal fluid. There was also a differential concentration in the fallopian tube tissue with higher concentration close to the implant then lower at a distance from this implant. There was a correlation between the concentrations of the two metals. CONCLUSION: The presence of nickel and chromium in the fallopian tube tissue and the peritoneal fluid raises the question of a possible relationship between the symptoms attributed to Essure® implants and the dissemination of potential toxic metals due to galvanic corrosion of the devices.

PIPAC versus HIPEC: cisplatin spatial distribution and diffusion in a swine model.

Purpose: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel approach for delivering intraperitoneal chemotherapy and offers perspective in the treatment of peritoneal carcinomatosis. Concept is based on a 12 mmHg capnoperitoneum loaded with drug changed in microdoplets. It was postulated to guarantee a more homogeneous drug distribution and tissular uptake than hyperthermic intraperitoneal chemotherapy (HIPEC). The aim of this study was to compare cisplatin peritoneal distribution and pharmacokinetic between HIPEC and PIPAC procedures in a healthy swine model.Methods: Two groups of eight pigs underwent either HIPEC with cisplatin (70 mg/m2) at 43 °C for 60 min, or PIPAC with cisplatin (7.5 mg/m2) for 30 min. Postoperatively, peritoneal areas were biopsied allowing peritoneal cavity cartography. Tissular and plasmatic cisplatin concentrations were analyzed.Results: Cisplatin distribution was heterogeneous in both the groups with higher concentrations obtained closed to the delivery sites. Median total platinum peritoneal concentration by pig was higher in the HIPEC group than in the PIPAC group (18.0 µg/g versus 4.3 µg/g, p < .001) but the yield was 2.2 times better with PIPAC. Platinum concentrations were higher in the HIPEC group in all stations. At each time-point, cisplatin plasmatic concentrations were higher in the HIPEC group (p < .001) but beneath the toxicity threshold.Conclusions: With doses used in clinical practice, HIPEC guaranteed a higher cisplatin peritoneal uptake than PIPAC in this swine model. Spatial drug distribution was heterogeneous with both technics, with hotspots closed to the drug delivery sites. Nevertheless, considering the dose ratio, IP drug uptake yield was better with PIPAC.

Predictive testing for Huntington disease over 24 years: Evolution of the profile of the participants and analysis of symptoms.

BACKGROUND: Huntington disease (HD) is a devastating neurodegenerative autosomal dominant genetic condition. Predictive testing (PT) is available through a defined protocol for at-risk individuals. We analyzed the over-24-years evolution of practices regarding PT for HD in a single center. METHODS: We gathered data from the files of all individuals seeking PT for HD in Lyon, France, from 1994 to 2017. RESULTS: 448 out of 567 participants had exploitable data. Age at consultation dichotomized over 24 years toward an eightfold increase in individuals aged >55 (2/94 vs. 30/183; 2% to 16%; p < .0001) and twice as many individuals aged 18-20 (3/94 vs. 12/183; 3%-7%; p < .05). Motives for testing remained stable. The rate of withdrawal doubled over 24 years (9/94 vs. 38/183; 9%-21%; p < .02). Independently of the time period, less withdrawal was observed for married, accompanied, at 50% risk, and symptomatic individuals, and in those able to explicit the motives for testing or taking the test to inform their children. We also assessed the consistency between the presence of subtle symptoms compatible with HD found before the test by the team's neurologist, and the positivity of the molecular test. The concordance was 100% (17/17) for associated motor and cognitive signs, 87% (27/31) for isolated motor signs, and 70% (7/10) for isolated cognitive signs. Furthermore, 91% (20/22) of individuals who requested testing because they thought they had symptoms, were indeed found carriers. CONCLUSION: This over-24 years study underlines an increasing withdrawal from protocol and a dichotomization of participants' age. We also show a strong concordance between symptoms perceived by the neurologist or by the patient, and the subsequent positivity of the predictive molecular test.

Evaluation of the accuracy of exchangeable copper and relative exchangeable copper (REC) in a mouse model of Wilson's disease.

Wilson's disease (WD) is caused by mutations in the ATP7B gene responsible for a toxic copper overload mainly in the liver and the central nervous system. Phenotypic heterogeneity may challenge the diagnostic confirmation. Exchangeable copper (CuEXC) has recently been proposed as a new marker of WD, and its ratio to the total serum copper (Cus), Relative Exchangeable Copper (REC = CuEXC/Cus), as a diagnostic marker. This study aimed to investigate whether this could be confirmed in Atp7b-/- mice, an engineered WD animal model. Atp7b-/- (n = 137) and wild type (WT; n = 101) mice were investigated under the same conditions at 6-8, 20, 39, or 50 weeks of age. Twenty-four Atp7b-/- mice received D-penicillamine treatment from 39 to 50 weeks of age. Serum and liver [histology and intrahepatic copper (IHCu)] data were evaluated. In the WT group, all serum and liver data were normal. Atp7b-/- livers developed a chronic injury from isolated moderate inflammation (6-8 weeks: 16/33 = 48%) to inflammatory fibrosis with cirrhosis (50 weeks: 25/25 = 100% and 16/25 = 64% respectively). Cus and CuEXC increased until week 39, whereas IHCu and REC were stable with increasing age and much higher than in WT mice (mean ±â€¯SD: 669 ±â€¯269 vs. 13 ±â€¯3 µg/g dry liver and 39 ±â€¯12 vs. 11 ±â€¯3%, respectively). A threshold value of 20% for REC provided a diagnostic sensitivity and specificity of 100%, regardless of sex, age, or the use of D-penicillamine. Eleven weeks of 100 mg/kg D-penicillamine reduced liver fibrosis (p = 0.001), IHCu (p = 0.026) and CuEXC (p = 0.175). In conclusion, this study confirms REC as a WD diagnostic marker in a mouse model of chronic liver disease caused by copper overload. Further studies are needed to assess the usefulness of CuEXC to monitor the evolution of WD, particularly during treatment.

C9orf72 Protein Plasmatic Concentrations Are Similar between C9ORF72 Expansion Carriers and Noncarriers in Frontotemporal Dementia.

BACKGROUND/AIMS: The aim of the study was to assess the theory of haploinsufficiency in C9ORF72 expansion carriers, the most frequent causative gene of frontotemporal dementia. METHODS: Plasmatic concentrations of C9orf72 protein were measured in 33 patients suspected of familial frontotemporal dementia using an enzyme-linked immunosorbent assay. RESULTS: No difference was observed between C9ORF72 expansion carriers (21.2% of patients) and noncarriers (78.8% of patients). C9orf72 protein determination is not a suitable biomarker for screening C9ORF72 expansion carriers. CONCLUSION: Our results provide new evidence against the hypothesis of haploinsufficiency leading to frontotemporal dementia in C9ORF72 expansion carriers.