Background and purpose
Little is known about hypomyelinating leukodystrophies (HLDs) in adults. The aim of this study was to investigate HLD occurrence, clinical features, and etiology among ...undefined leukoencephalopathies in adulthood.
Methods
We recruited the patients with cerebral hypomyelinating magnetic resonance imaging pattern (mild T2 hyperintensity with normal or near‐normal T1 signal) from our cohort of 62 adult index cases with undefined leukoencephalopathies, reviewed their clinical features, and used a leukoencephalopathy‐targeted next generation sequencing panel.
Results
We identified 25/62 patients (~40%) with hypomyelination. Cardinal manifestations were spastic gait and varying degree of cognitive impairment. Etiology was determined in 44% (definite, 10/25; likely, 1/25). Specifically, we found pathogenic variants in the POLR3A (n = 2), POLR1C (n = 1), RARS1 (n = 1), and TUBB4A (n = 1) genes, which are typically associated with severe early‐onset HLDs, and in the GJA1 gene (n = 1), which is associated with oculodentodigital dysplasia. Duplication of a large chromosome X region encompassing PLP1 and a pathogenic GJC2 variant were found in two patients, both females, with early‐onset HLDs persisting into adulthood. Finally, we found likely pathogenic variants in PEX3 (n = 1) and PEX13 (n = 1) and potentially relevant variants of unknown significance in TBCD (n = 1), which are genes associated with severe, early‐onset diseases with central hypomyelination/dysmyelination.
Conclusions
A hypomyelinating pattern characterizes a relevant number of undefined leukoencephalopathies in adulthood. A comprehensive genetic screening allows definite diagnosis in about half of patients, and demonstrates the involvement of many disease‐causing genes, including genes associated with severe early‐onset HLDs, and genes causing peroxisome biogenesis disorders.
A brain MRI pattern suggestive of hypomyelination can be the prominent feature of adult‐onset genetic conditions. Adult neurologists should be trained in recognizing this pattern, as its presence implies different diagnostic work‐up and prognosis. An inclusive genetic screening can allow diagnosis in almost half of cases.
Results of an extended survey on the production and quality of sewage sludge produced in Italy are herewith reported and discussed. Data are relevant to 2015. They were provided by 84 Italian water ...utilities responsible for municipal wastewater treatment serving approximately 35 million persons. Total production was estimated at about 395,000 t dry solids/year, of which 9.9% is used in agriculture without further treatments, 26.4% is sent to external plants for compost production, 5.6% is sent to external plant for production of a soil conditioner called 'chalk of defecation', 17.2% is disposed to landfill, and 5.9% is sent to incineration or co-incineration plants. The rest (35%) is sent to external sludge centres for further treatments (manly chemical and physical processes) before recovery/disposal. Regarding chemical characterization the following parameters were investigated: TOC, total nitrogen, total phosphorus, potassium, arsenic, cadmium, copper, nickel, lead, zinc, mercury, total chromium, chromium VI, selenium, hydrocarbons C10-C40, sum of polycyclic aromatic hydrocarbons, sum of polychlorinated biphenyls, sum of polychlorinated dibenzo-p-dioxins/dibenzo-p-furanes (toxic equivalent) salmonella, faecal coliforms, sulphur, sum of absorbable halogenated organic compounds, nonylphenol and nonylphenolethoxylates with one or two ethoxy groups, and di(2-ethylhexyl)phthalate. All the parameters showed that the quality of Italian sewage sludge is consistent with a typical sludge in Europe, Asia and America and the maximum concentrations of pollutants are well below the fixed standards of the European Directive 86/278 and the third draft of the European Commission's Working Document on Sludge.
A cooperative NHC/nickel catalytic methodology has been developed for the synthesis of ketones employing aromatic aldehydes and tertiary alkyl iodides. All key steps of the postulated catalytic cycle ...were validated with comprehensive stoichiometric and electrochemical studies, including reduction of NiII by the deprotonated Breslow intermediate, Ni0 promoted halogen-atom abstraction to generate transient tertiary alkyl radicals, and coupling between the latter with the persistent acyl thiazolium radical intermediate. Such a broadly proposed and accepted, yet elusive, acyl thiazolium radical intermediate has been isolated and studied by a single-crystal X-ray diffraction study.
Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop ...life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy.
ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2–3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18–65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL SD 20%) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing.
Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 81% of 77 patients receiving leriglitazone and 34 87% of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean SD change from baseline leriglitazone: –27·7 41·4 m; placebo: –30·3 60·5 m; least-squares mean difference –1·2 m; 95% CI –22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 70% of 77 vs nine 23% of 39 patients, respectively) and peripheral oedema (49 64% of 77 vs seven 18% of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six 5% of 116 patients, all of whom were in the placebo group.
The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy.
Minoryx Therapeutics.
INTRODUCTION:X-linked adrenoleukodystrophy (X-ALD) encompasses several clinical and neuroimaging phenotypes, including cerebral X-ALD, the most common phenotype in children, and ...adrenomyeloneuropathy, the most common phenotype in adults. A spinocerebellar variant of X-ALD has been described in individuals from the Far East, but the criteria for its diagnosis are unclear.
CASE REPORT:A 35-year-old man from Albania was assessed because of a familial, slowly progressive spastic-ataxic gait associated with neurogenic bladder, sexual dysfunctions, and manic-like behavior. There was no definite clinical feature that suggested cerebellar involvement (eg, cerebellar limb ataxia, nystagmus, and dysarthria). A few months earlier, he had received a diagnosis of Addison disease. Brain magnetic resonance imaging showed a leukoencephalopathy with predominant cerebellum and brainstem involvement, and FDG-PET revealed marked cerebellar hypometabolism. The diagnosis of X-ALD was made because we found an increase of very long chain fatty acids, and a new ABCD1 mutation (c.1627C>T, p.Pro543Ser).
CONCLUSIONS:X-ALD should be included in the differential diagnosis of adult leukoencephalopathies with predominant involvement of infratentorial structures, that is, the cerebellum and brainstem. From a classification perspective, our patient (of white origin), like others (all of Asian origin), should be considered as suffering from a variant of adrenomyeloneuropathy rather than from spinocerebellar X-ALD. Actually, the term “spinocerebellar” or similar ones, such as “cerebello-brainstem dominant form,” should be limited to those exceptional cases, in which both the clinical and neuroimaging findings point exclusively (or at least predominantly) to the involvement of infratentorial structures.
Background
Adrenoleukodystrophy (ALD) encompasses different neurological phenotypes, ranging from the most severe cerebral forms (C-ALD) to the less severe adrenomyeloneuropathy (AMN). As visual ...system can be varyingly involved, we aimed at exploring whether optical coherence tomography (OCT) may detect retinal abnormalities and their longitudinal changes in adult ALD patients.
Methods
In this cross-sectional and longitudinal study, we measured the thicknesses of peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell complex (mGCC), and segmented inner and outer macula at baseline and their changes over time in 11 symptomatic adult ALD males and 10 age- and sex-matched healthy controls. Statistical analyses were performed for the patients as complete group, and splitting them into two subgroups, one (C-ALD) with and the other (AMN) without cerebral parieto-occipital white matter (WM) lesions.
Results
In the complete ALD group and in the C-ALD subgroup, the average pRNFL, mGCC, and inner macula were significantly thinner than in controls (
p
≤ 0.01), whereas in the AMN subgroup, they were constantly, though non-significantly, thinner. Significant outer macula thinning was also observed (
p
< 0.01). In the complete ALD group, follow-up assessment (mean 26.8 months, range 8–48) showed mildly progressive thinning of inferior pRNFL, average mGCC, and inner macula.
Conclusions
In adult ALD patients, OCT can reveal retinal abnormalities which are prominent in the more compromised patients, namely those with parieto-occipital WM lesions. The inferior pRNFL, average mGCC and inner macula thicknesses might be sensitive-to-change OCT parameters, but their utility and consistency for short-term longitudinal studies deserve further investigations.
When dealing with risk reduction, a number of risk assessment methods are currently used to design and implement appropriate safeguarding. At present time, it is crucial for the industry to operate ...plants at minimum risk levels and optimum capacity. Determining generally accepted risk tolerability criteria is paramount in order to avoid both over- and under-engineering.This study has been conducted in order to investigate thresholds of tolerability that have been applied in real LOPA (Layer of Protection Analysis) studies. Risk matrix studies have also been analyzed for comparison. The differences and commonalities in the projects have been studied and average results have been consolidated into a reference Risk Matrix. The general Risk Matrix thus obtained represents current industry common practice with respect to guaranteeing personal safety. This tool can be used as a practical reference in risk assessment. For small and middle end-users and for independent consultants, the tool can provide a valid starting point for risk reduction considerations in new projects.Since the whole Functional Safety framework in a plant rests on the applied risk tolerability criteria, the author considers this study relevant, and would like to use this opportunity to share our findings beyond the national borders.This paper is developed with written permission from the original authors, based on the paper of the SIL Platform
An anaplerotic diet with the odd-chain triglyceride (triheptanoin-C7TG) supplementation was tested as a therapy for Adult Polyglucosan Body Disease (APBD) and is currently being assessed for various ...metabolic disorders. The aim of this study was to determine any unknown long-term effect of C7TG supplementation on the nutritional status, body composition, resting energy expenditure and biochemical parameters of two siblings with APBD.
Two adult siblings with APBD were treated over a 2-year period with a high fat, low carbohydrate diet, with C7TG oil representing about 30% of the daily caloric intake. We carried out a long-term longitudinal study to determine weight, height, waist circumference; total, intra and extra cellular water by bioimpedance; body fat, lean mass, and bone mineral density by DEXA; resting energy expenditure by indirect calorimeter; glucose and lipid profiles.
C7TG supplementation failed to prevent APBD progression, corroborating recent literature. However, long-term C7TG supplementation did not produce any appreciable changes in nutritional status, body composition, resting energy expenditure or biochemical parameters, and no evidence was found of potential adverse effects.
Our data suggest that maintenance of C7TG over a 2-year period still leaves a good safety profile in terms of nutritional status, body composition, resting energy expenditure, and biochemical parameters. However further studies involving larger sample sizes, also other diseases, are needed for a deeper understanding of its long-term effects.
