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Background: Parenting interventions during the first years of life on what and/or how to feed infants during complementary feeding can promote healthy eating habits. Objectives: An intervention promoting repeated exposure to a variety of vegetables [repeated vegetable exposure (RVE); what] and an intervention promoting responding sensitively to child signals during mealtime [video-feedback intervention to promote positive parenting-feeding infants (VIPP-FI); how] were compared, separately and combined (COMBI), with an attention control condition (AC). Primary outcomes were vegetable consumption and self-regulation of energy intake; secondary outcomes were child anthropometrics and maternal feeding practices (sensitive feeding, pressure to eat). Methods: Our 4-arm randomized controlled trial included 246 first-time Dutch mothers and their infants. Interventions started when infants were 4-6 mo old and ended at age 16 mo. The present study evaluated effects at 18 (t18) and 24 (t24) mo of age. Vegetable acceptance was assessed using three 24-h dietary recalls, self-regulation of energy intake by an eating-in-the-absence-of-hunger experiment and mother-report, and maternal feeding behavior by observation and mother-report. Results: Linear mixed model and ANOVA analyses revealed no follow-up group differences regarding child vegetable intake or self-regulatory behavior. The proportion of children with overweight was significantly lower in the COMBI group, compared with the VIPP-FI group at t18 (2% compared with 16%), and with the AC group at t24 (7% compared with 20%), although this finding needs to be interpreted cautiously due to the small number of infants with overweight and nonsignificant effects on the continuous BMI z-score measure (P values: 0.29-0.82). Finally, more sensitive feeding behavior and less pressure to eat was found in the VIPP-FI and COMBI groups, compared with the RVE and AC groups, mostly at t18 (significant effect sizes: D = 0.23-0.64). Conclusions: Interventions were not effective in increasing vegetable intake or self-regulation of energy intake. Future research might usefully focus on risk groups such as families who already experience problems around feeding. This trial is registered at clinicaltrials.gov as NCT03348176.

Background and ObjectivesCauses of stroke in young adults differ from those in the elderly individuals, and in a larger percentage, no cause can be determined. To gain more insight into the etiology of (cryptogenic) stroke in the young population, we investigated whether trigger factors, such as short-lasting exposure to toxins or infection, may play a role.MethodsPatients aged 18–49 years with a first-ever ischemic stroke or intracerebral hemorrhage (ICH) in 17 participating centers in the Netherlands completed a questionnaire about exposure to 9 potential trigger factors in hazard periods and on a regular yearly basis. A case-crossover design was used to assess relative risks (RRs) with 95% confidence intervals (95% CIs) by the Mantel-Haenszel case-crossover method, for any stroke (ischemic stroke and ICH combined) and for different etiologic subgroups of ischemic stroke.ResultsOne thousand one hundred forty-six patients completed the questionnaire (1,043 patients with an ischemic stroke and 103 with an ICH, median age 44.0 years, 52.6% men). For any stroke, an increased risk emerged within 1 hour of cola consumption (RR 2.0, 95% CI 1.5–2.8) and vigorous physical exercise (RR 2.6, 95% CI 2.2–3.0), within 2 hours after sexual activity (RR 2.4, 95% CI 1.6–3.5), within 4 hours after illicit drug use (RR 2.8, 95% CI 1.7–4.9), and within 24 hours after fever or flu-like disease (RR 14.1, 95% CI 10.5–31.2; RR 13.9, 95% CI 8.9–21.9). Four trigger factors increased the risk of other determined and cryptogenic ischemic stroke, 3 that of cardioembolic stroke, 2 that of large vessel atherosclerosis and likely atherothrombotic stroke combined and stroke with multiple causes, and none that of stroke due to small vessel disease.DiscussionWe identified cola consumption, vigorous physical exercise, sexual activity, illicit drug use, fever, and flu-like disease as potential trigger factors for stroke in the young population and found differences in the type and number of trigger factors associated with different etiologic subgroups of ischemic stroke. These findings might help in better understanding the pathophysiologic mechanisms of (cryptogenic) stroke in the young population.

Mitochondrial trifunctional protein (MTP) is involved in long-chain fatty acid β-oxidation (lcFAO). Deficiency of one or more of the enzyme activities as catalyzed by MTP causes generalized MTP deficiency (MTPD), long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHADD), or long-chain ketoacyl-CoA thiolase deficiency (LCKATD). When genetic variants result in thermo-sensitive enzymes, increased body temperature (e.g. fever) can reduce enzyme activity and be a risk factor for clinical decompensation. This is the first description of five patients with a thermo-sensitive MTP deficiency. Clinical and genetic information was obtained from clinical files. Measurement of LCHAD and LCKAT activities, lcFAO-flux studies and palmitate loading tests were performed in skin fibroblasts cultured at 37°C and 40°C. In all patients (four MTPD, one LCKATD), disease manifested during childhood (manifestation age: 2–10 years) with myopathic symptoms triggered by fever or exercise. In four patients, signs of retinopathy or neuropathy were present. Plasma long-chain acylcarnitines were normal or slightly increased. HADHB variants were identified (at age: 6–18 years) by whole exome sequencing or gene panel analyses. At 37°C, LCHAD and LCKAT activities were mildly impaired and lcFAO-fluxes were normal. Remarkably, enzyme activities and lcFAO-fluxes were markedly diminished at 40°C. Preventive (dietary) measures improved symptoms for most. In conclusion, all patients with thermo-sensitive MTP deficiency had a long diagnostic trajectory and both genetic and enzymatic testing were required for diagnosis. The frequent absence of characteristic acylcarnitine abnormalities poses a risk for a diagnostic delay. Given the positive treatment effects, upfront genetic screening may be beneficial to enhance early recognition.

Background and ObjectivesGuidelines recommend antithrombotic medication as secondary prevention for patients with ischemic stroke or transient ischemic attack (TIA) at young age based on results from trials in older patients. We investigated the long-term risk of bleeding and ischemic events in young patients after ischemic stroke or TIA.MethodsWe included 30-day survivors of first-ever ischemic stroke or TIA aged 18–50 years from the Follow-Up of TIA and Stroke Patients and Unelucidated Risk Factor Evaluation (FUTURE) study, a prospective cohort study of stroke at young age. We obtained information on recurrent ischemia based on structured data collection from 1995 until 2014 as part of the FUTURE study follow-up, complemented with information on any bleeding and ischemic events by retrospective chart review from baseline until last medical consultation or June 2020. Primary outcome was any bleeding; secondary outcome any ischemic event during follow-up. Both were stratified for sex, age, etiology, and use of antithrombotic medication at discharge. Bleeding and ischemic events were classified according to location and bleeding events also by severity.ResultsWe included 544 patients (56.1% women, median age of 42.2; interquartile range [IQR] 36.5–46.7 years) with a median follow-up of 9.6 (IQR 2.5–14.3) years. Ten-year cumulative risk of any bleeding event was 21.8% (95% CI 17.4–26.0) and 33.9% (95% CI 28.3–37.5) of any ischemic event. Risk of bleeding was higher in women with a cumulative risk of 28.2% (95% CI 21.6–34.3) vs 13.7% (95% CI 8.2–18.9) in men (p< 0.01), mainly because of gynecologic bleeds. Female sex (p< 0.001) and age between 40 and 49 years (p= 0.04) were independent predictors of bleeding.DiscussionYoung patients after ischemic stroke or TIA have a substantial long-term risk of both bleeding (especially women) and ischemic events. Future studies should investigate the effects of long-term antithrombotics in young patients, taking into account the risk of bleeding complications.

Supplemental material, sj-docx-1-eso-10.1177_23969873221132032 for Subacute cognitive impairment after first-ever transient ischemic attack or ischemic stroke in young adults: The ODYSSEY study by Mijntje MI Schellekens, Esther M Boot, Jamie I Verhoeven, Merel S Ekker, Mayte E van Alebeek, Paul JAM Brouwers, Renate M Arntz, Gert W van Dijk, Rob AR Gons, Inge WM van Uden, Tom den Heijer, Paul LM de Kort, Karlijn F de Laat, Anouk van Norden, Sarah E Vermeer, Marian SG van Zagten, Robert J van Oostenbrugge, Marieke JH Wermer, Paul J Nederkoorn, Frank G van Rooij, Ido R van den Wijngaard, Frank-Erik de Leeuw, Roy PC Kessels and Anil M Tuladhar in European Stroke Journal

Due to newborn screening for X-linked adrenoleukodystrophy (ALD), and the use of exome sequencing in clinical practice, the detection of variants of unknown significance (VUS) in the ABCD1 gene is increasing. In these cases, functional tests in fibroblasts may help to classify a variant as (likely) benign or pathogenic. We sought to establish reference ranges for these tests in ALD patients and control subjects with the aim of helping to determine the pathogenicity of VUS in ABCD1. Fibroblasts from 36 male patients with confirmed ALD, 26 healthy control subjects and 17 individuals without a family history of ALD, all with an uncertain clinical diagnosis and a VUS identified in ABCD1, were included. We performed a combination of tests: (i) a test for very-long-chain fatty acids (VLCFA) levels, (ii) a D3-C22:0 loading test to study the VLCFA metabolism and (iii) immunoblotting for ALD protein. All ALD patient fibroblasts had elevated VLCFA levels and a reduced peroxisomal ß-oxidation capacity (as measured by the D3-C16:0/D3-C22:0 ratio in the D3-C22:0 loading test) compared to the control subjects. Of the VUS cases, the VLCFA metabolism was not significantly impaired (most test results were within the reference range) in 6/17, the VLCFA metabolism was significantly impaired (most test results were within/near the ALD range) in 9/17 and a definite conclusion could not be drawn in 2/17 of the cases. Biochemical studies in fibroblasts provided clearly defined reference and disease ranges for the VLCFA metabolism. In 15/17 (88%) VUS we were able to classify the variant as being likely benign or pathogenic. This is of great clinical importance as new variants will be detected.

Importance Stroke remains the second leading cause of death worldwide. Approximately 10% to 15% of all strokes occur in young adults. Information on prognosis and mortality specifically in young adults is limited. Objective To determine short- and long-term mortality risk after stroke in young adults, according to age, sex, and stroke subtype; time trends in mortality; and causes of death. Design, Setting, and Participants Registry- and population-based study in the Netherlands of 15 527 patients aged 18 to 49 years with first stroke between 1998 and 2010, and follow-up until January 1, 2017. Patients and outcomes were identified through linkage of the national Hospital Discharge Registry, national Cause of Death Registry, and the Dutch Population Register. Exposures First stroke occurring at age 18 to 49 years, documented using International Classification of Diseases, Ninth Revision , and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision , codes for ischemic stroke, intracerebral hemorrhage, and stroke not otherwise specified. Main Outcomes and Measures Primary outcome was all-cause cumulative mortality in 30-day survivors at end of follow-up, stratified by age, sex, and stroke subtype, and compared with all-cause cumulative mortality in the general population. Results The study population included 15 527 patients with stroke (median age, 44 years [interquartile range, 38-47 years]; 53.3% women). At end of follow-up, a total of 3540 cumulative deaths had occurred, including 1776 deaths within 30 days after stroke and 1764 deaths (23.2%) during a median duration of follow-up of 9.3 years (interquartile range, 5.9-13.1 years). The 15-year mortality in 30-day survivors was 17.0% (95% CI, 16.2%-17.9%). The standardized mortality rate compared with the general population was 5.1 (95% CI, 4.7-5.4) for ischemic stroke (observed mortality rate 12.0/1000 person-years [95% CI, 11.2-12.9/1000 person-years]; expected rate, 2.4/1000 person-years; excess rate, 9.6/1000 person-years) and the standardized mortality rate for intracerebral hemorrhage was 8.4 (95% CI, 7.4-9.3; observed rate, 18.7/1000 person-years [95% CI, 16.7-21.0/1000 person-years]; expected rate, 2.2/1000 person-years; excess rate, 16.4/1000 person-years). Conclusions and Relevance Among young adults aged 18 to 49 years in the Netherlands who were 30-day survivors of first stroke, mortality risk compared with the general population remained elevated up to 15 years later.

Background and ObjectivesThere is a worldwide increase in the incidence of stroke in young adults, with major regional and ethnic differences. Advancing knowledge of ethnic and regional variation in causes and outcomes will be beneficial in implementation of regional health care services. We studied the global distribution of risk factors, causes, and 3-month mortality of young patients with ischemic stroke, by performing a patient data meta-analysis from different cohorts worldwide.MethodsWe performed a pooled analysis of individual patient data from cohort studies that included consecutive patients with ischemic stroke aged 18–50 years. We studied differences in prevalence of risk factors and causes of ischemic stroke between different ethnic and racial groups, geographic regions, and countries with different income levels. We investigated differences in 3-month mortality by mixed-effects multivariable logistic regression.ResultsWe included 17,663 patients from 32 cohorts in 29 countries. Hypertension and diabetes were most prevalent in Black (hypertension, 52.1%; diabetes, 20.7%) and Asian patients (hypertension 46.1%, diabetes, 20.9%). Large vessel atherosclerosis and small vessel disease were more often the cause of stroke in high-income countries (HICs; both p < 0.001), whereas “other determined stroke” and “undetermined stroke” were higher in low and middle-income countries (LMICs; both p < 0.001). Patients in LMICs were younger, had less vascular risk factors, and despite this, more often died within 3 months than those from HICs (odds ratio 2.49; 95% confidence interval 1.42–4.36).DiscussionEthnoracial and regional differences in risk factors and causes of stroke at young age provide an understanding of ethnic and racial and regional differences in incidence of ischemic stroke. Our results also highlight the dissimilarities in outcome after stroke in young adults that exist between LMICs and HICs, which should serve as call to action to improve health care facilities in LMICs.

Contains fulltext : 232797.pdf (Publisher’s version ) (Open Access) PURPOSE: Although various studies have reported that stereotactic body radiation therapy (SBRT) for liver metastases has high local control rates and relatively low toxicity, most series included a small number of patients. We aimed to validate these outcomes in a large multi-institution patient cohort treated in accordance with a common protocol. METHODS AND MATERIALS: A shared web-based registry of patients with liver metastases treated with SBRT was developed by 13 centers (12 in the Netherlands and 1 in Belgium). All the centers had previously agreed on the items to be collected, the fractionation schemes, and the organs-at-risk constraints to be applied. Follow-up was performed at the discretion of the centers. Patient, tumor, and treatment characteristics were entered in the registry. Only liver metastases treated individually as independent targets and with at least 1 radiologic follow-up examination were considered for local control analysis. Toxicity of grade 3 or greater was scored according to the Common Terminology Criteria of Adverse Events (v4.03). RESULTS: Between January 1, 2013, and July 31, 2019, a total of 515 patients were entered in the web-based registry. The median age was 71 years. In total, 668 liver metastases were registered, and 447 were included for local control analysis. The most common primary tumor origin was colorectal cancer (80.3%), followed by lung cancer (8.9%) and breast cancer (4%). The most-used fractionation scheme was 3x18-20 Gy (36.0%), followed by 8x7.5 Gy (31.8%), 5x11-12 Gy (25.5%), and 12x5 Gy (6.7%). The median follow-up time was 1.1 years for local control and 2.3 years for survival. Actuarial 1-year local control was 87%; 1-year overall survival was 84%. Toxicity of grade 3 or greater was found in 3.9% of the patients. CONCLUSIONS: This multi-institutional study confirms the high rates of local control and limited toxicity in a large patient cohort. Stereotactic body radiation therapy should be considered a valuable part of the multidisciplinary approach to treating liver metastases.

Contains fulltext : 237460.pdf (Publisher’s version ) (Open Access) Early detection of congenital disorders by newborn screening (NBS) programs is essential to prevent or limit disease manifestation in affected neonates. These programs balance between the detection of the highest number of true cases and the lowest number of false-positives. In this case report, we describe four unrelated cases with a false-positive NBS result for very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD). Three neonates presented with decreased but not deficient VLCAD enzyme activity and two of them carried a single heterozygous ACADVL c.1844G>A mutation. Initial biochemical investigations after positive NBS referral in these infants revealed acylcarnitine and organic acid profiles resembling those seen in multiple acyl-CoA dehydrogenase deficiency (MADD). Genetic analysis did not reveal any pathogenic mutations in the genes encoding the electron transfer flavoprotein (ETF alpha and beta subunits) nor in ETF dehydrogenase. Subsequent further diagnostics revealed decreased levels of riboflavin in the newborns and oral riboflavin administration normalized the MADD-like biochemical profiles. During pregnancy, the mothers followed a vegan, vegetarian or lactose-free diet which probably caused alimentary riboflavin deficiency in the neonates. This report demonstrates that a secondary (alimentary) maternal riboflavin deficiency in combination with reduced VLCAD activity in the newborns can result in an abnormal VLCADD/MADD acylcarnitine profile and can cause false-positive NBS. We hypothesize that maternal riboflavin deficiency contributed to the false-positive VLCADD neonatal screening results.

BACKGROUND AND PURPOSE: Cardiovascular risk factors, which are overall more prevalent in men, are considered the major risk factors for strokes amongst young adults. However, recent European data found the incidence of strokes to be higher in young women. Using a large U.S. claims sample, we examined sex differences in the index stroke rate of young adults. METHODS: We performed a retrospective cohort study of enrollees in a 10% random sample of PharMetrics, a nationally representative claims database of insured Americans from 2001 to 2014. Outcomes were index ischemic stroke events, based on inpatient admissions using ICD-9 codes. The index stroke rate was estimated from Poisson rate models with time varying covariates for two-year periods, stratified by sex and age groups. RESULTS: We identified 20,554 index strokes(50.4% women; mean age 63) including 5,198 in young adults ages 15-54. There was no difference by sex in the index stroke rate in the extremes of age groups 15-24 and ≥75 years old. However, in the 25-34 and 35-44 year age groups, more women had strokes than men (Incidence Rate Ratio(IRR) men:women 0.70, 95%CI:0.57-0.86; 0.87, 95%CI:0.78-0.98, respectively). In contrast, in the 45-54, 55-64 ,and 65-74 year age groups, more men had strokes(IRR 1.25 95%CI:1.16-1.33; 1.41 95%CI:1.18-1.34; 1.18 95%CI:1.12-125, respectively). CONCLUSIONS: More young women than men have strokes, suggesting possible importance of sex-mediated etiologies of stroke. Understanding these drivers is critical to stroke treatment and prevention efforts in young adults.

Item does not contain fulltext Patients with Parkinson's disease (PD) often compensate for their motor deficits by guiding their movements visually. A wide range of ocular and visual disorders threatens the patients' ability to benefit optimally from visual feedback. These disorders are common in patients with PD, yet they have received little attention in both research and clinical practice, leading to unnecessary - but possibly treatable - disability. Based on a literature search covering 50 years, we review the range of ocular and visual disorders in patients with PD, and classify these according to anatomical structures of the visual pathway. We discuss six common disorders in more detail: dry eyes; diplopia; glaucoma and glaucoma-like visual problems; impaired contrast and colour vision; visuospatial and visuoperceptual impairments; and visual hallucinations. In addition, we review the effects of PD-related pharmacological and surgical treatments on visual function, and we offer practical recommendations for clinical management. Greater awareness and early recognition of ocular and visual problems in PD might enable timely instalment of tailored treatments, leading to improved patient safety, greater independence, and better quality of life.

Contains fulltext : 220673.pdf (Publisher’s version ) (Closed access) Ischaemic stroke at young age is an increasing problem in both developing and developed countries due to rising incidence, high morbidity and mortality and long-term psychological, physical and social consequences. Compared with stroke in older adults, stroke in young adults is more heterogeneous due to the wide variety of possible underlying risk factors and aetiologies. In this review, we will provide an overview of the global variation in the epidemiology of stroke in young adults, with special attention to differences in geography, ethnicity/race and sex, as well as traditional and novel risk factors for early-onset ischaemic stroke, such as air pollution. Understanding global differences is an important prerequisite for better region-specific prevention and treatment of this devastating condition.

IntroductionWorldwide, 2 million patients aged 18–50 years suffer a stroke each year, and this number is increasing. Knowledge about global distribution of risk factors and aetiologies, and information about prognosis and optimal secondary prevention in young stroke patients are limited. This limits evidence-based treatment and hampers the provision of appropriate information regarding the causes of stroke, risk factors and prognosis of young stroke patients.Methods and analysisThe Global Outcome Assessment Life-long after stroke in young adults (GOAL) initiative aims to perform a global individual patient data meta-analysis with existing data from young stroke cohorts worldwide. All patients aged 18–50 years with ischaemic stroke or intracerebral haemorrhage will be included. Outcomes will be the distribution of stroke aetiology and (vascular) risk factors, functional outcome after stroke, risk of recurrent vascular events and death and finally the use of secondary prevention. Subgroup analyses will be made based on age, gender, aetiology, ethnicity and climate of residence.Ethics and disseminationEthical approval for the GOAL study has already been obtained from the Medical Review Ethics Committee region Arnhem-Nijmegen. Additionally and when necessary, approval will also be obtained from national or local institutional review boards in the participating centres. When needed, a standardised data transfer agreement will be provided for participating centres. We plan dissemination of our results in peer-reviewed international scientific journals and through conference presentations. We expect that the results of this unique study will lead to better understanding of worldwide differences in risk factors, causes and outcome of young stroke patients.

ObjectiveTo investigate incidence of stroke and its subtypes in young adults, according to sex and age, and to study trends over time.MethodsWe established a nationwide cohort through linkage of national registries (hospital discharge, cause of death, and population register) with patients aged 18–50 years and those ≥50 years with first-ever ischemic stroke, intracerebral hemorrhage, or unspecified stroke, using ICD-9/ICD-10 codes between 1998 and 2010 in the Netherlands. Outcomes were yearly incidence of stroke stratified by age, sex, and stroke subtype, its changes over time, and comparison of incidence in patients 18–50 years to patients ≥50 years.ResultsWe identified 15,257 patients (53% women; mean age 41.8 years). Incidence increased exponentially with age (R2 = 0.99) and was higher for women than men, most prominently in the youngest patients (18–44 years). The relative proportion of ischemic stroke increased with age (18–24 years: 38.3%; 44–49 years: 56.5%), whereas the relative proportion of intracerebral hemorrhage decreased (18–24 years: 34.0%; 44–49 years: 18.3%). Incidence of any stroke in young adults increased (1998: 14.0/100,000 person-years: 2010: 17.2; +23%; p < 0.001), driven by an increase in those aged over 35 years and ischemic stroke incidence (46%), whereas incidence decreased in those ≥50 years (329.1%–292.2%; −11%; p = 0.009).ConclusionsIncidence of any stroke in the young increases with age in patients over 35, is higher in women than men aged 18–44 years, and has increased by 23% in one decade, through an increase in ischemic stroke. Incidence of intracerebral hemorrhage is comparable for women and men and remained stable over time.

IntroductionFor patients with perihilar cholangiocarcinoma (CCA), surgery is the only treatment modality that can result in cure. Unfortunately, in the majority of these patients, the tumours are found to be unresectable at presentation due to either local invasive tumour growth or the presence of distant metastases. For patients with unresectable CCA, palliative chemotherapy is the standard treatment yielding an estimated median overall survival (OS) of 12–15.2 months. There is no evidence from randomised trials to support the use of stereotactic body radiation therapy (SBRT) for CCA. However, small and most often retrospective studies combining chemotherapy with SBRT have shown promising results with OS reaching up to 33–35 months.Methods and analysisThis study has been designed as a single-centre phase I feasibility trial and will investigate the addition of SBRT after standard chemotherapy in patients with unresectable perihilar CCA (T1-4 N0-1 M0). A total of six patients will be included. SBRT will be delivered in 15 fractions of 3–4.5 Gy (risk adapted). The primary objective of this study is to determine feasibility and toxicity. Secondary outcomes include local tumour control, progression-free survival (PFS), OS and quality of life. Length of follow-up will be 2 years. As an ancillary study, the personalised effects of radiotherapy will be measured in vitro, in patient-derived tumour and bile duct organoid cultures.Ethics and disseminationEthics approval for the STRONG trial has been granted by the Medical Ethics Committee of Erasmus MC Rotterdam, the Netherlands. It is estimated that all patients will be included between October 2017 and October 2018. The results of this study will be published in a peer-reviewed journal, and presented at national and international conferences.Trial registration numberNCT03307538; Pre-results.

Contains fulltext : 196605.pdf (Publisher’s version ) (Closed access) Epidemiological evidence suggests that the incidence of ischaemic stroke in young adults (18-50 years) has increased substantially. These patients have a long life expectancy after stroke, and the costs of long-term care pose huge challenges to health-care systems. Although the current recommendations for treatment of young and old (>50 years) patients with stroke are similar, the optimal management of young adult patients with stroke is unknown. They are usually not included in trials, and specific subanalyses limited to young adult patients with stroke are usually not done, owing to lower incidence of stroke and lower prevalence of vascular risk factors in young adults. Progress has been made in identifying patients with a considerable risk of stroke occurrence, such as those with patent foramen ovale. Future prevention studies might result in a decrease in the incidence of stroke and its sequelae in young adults. The development of guidelines specifically devoted to the management of stroke in young adults will be an important step in achieving this aim.

Contains fulltext : 181335.pdf (Publisher’s version ) (Open Access) 1 p.

Phytanoyl-CoA hydroxylase belongs to the family of 2-oxoglutarate-dependent dioxygenases and plays a crucial role in the α-oxidation of fatty acids. The complete α-oxidation pathway involves five different enzymes localized in peroxisomes. Thus far, phytanoyl-CoA hydroxylase deficiency has remained the only genetically determined inborn error of metabolism affecting the α-oxidation pathway. In this chapter we describe the current state of knowledge on fatty acid α-oxidation with special emphasis on phytanoyl-CoA hydroxylase and its deficiency in Refsum disease.

Objective: Mutations in the transient receptor potential vanilloid 4 gene ( TRPV4) can induce a great diversity of neuropathies. Together with these neuropathies, hearing loss can occur. This study is focused on providing an audiometric phenotype description of a Dutch family with spinal muscular atrophy caused by a mutation in TRPV4. Methods: A neurological examination was repeated and pure tone and speech audiometry were performed. Results: A large variety in neurological symptoms as well as variation in audiometric characteristics was observed. The severity of hearing loss is mild to moderate and the audiogram configuration is highly variable. The hearing loss of these patients has a progressive nature in general. The frequencies that deteriorate significantly differ between family members. When compared to presbyacusis patients, speech recognition scores of patients with a TRPV4 mutation are not clearly different. Conclusion: The function of TRPV4 in the inner ear is still elusive but it is suggested that TRPV4 is required for maintenance of cochlear function in stress conditions, like acoustic injury. We can neither confirm nor reject this based on the results obtained in this family. Therefore, one might consider advising patients with a TRPV4 mutation to avoid exposure to environmental influences such as noise exposure.

Background Peroxisomes are organelles that proliferate continuously and play an indispensable role in human metabolism. Consequently, peroxisomal gene defects can cause multiple, often severe disorders, including the peroxisome biogenesis disorders. Currently, 13 different PEX proteins have been implicated in various stages of peroxisome assembly and protein import. Defects in any of these proteins result in a peroxisome biogenesis disorder. The authors present here a novel genetic defect specifically affecting the division of peroxisomes.Methods The authors have studied biochemical and microscopical peroxisomal parameters in cultured patient fibroblasts, sequenced candidate PEX genes and determined the consequence of the identified PEX11 beta gene defect on peroxisome biogenesis in patient fibroblasts at different temperatures.Results The patient presented with congenital cataracts, mild intellectual disability, progressive hearing loss, sensory nerve involvement, gastrointestinal problems and recurrent migraine-like episodes. Although microscopical investigations of patient fibroblasts indicated a clear defect in peroxisome division, all biochemical parameters commonly used for diagnosing peroxisomal disorders were normal. After excluding mutations in all PEX genes previously implicated in peroxisome biogenesis disorders, it was found that the defect was caused by a homozygous non-sense mutation in the PEX11 beta gene. The peroxisome division defect was exacerbated when the patient's fibroblasts were cultured at 40 degrees C, which correlated with a marked decrease in the expression of PEX11 gamma.Conclusions This novel isolated defect in peroxisome division expands the clinical and genetic spectrum of peroxisomal disorders and indicates that peroxisomal defects exist, which cannot be diagnosed by standard laboratory investigations.

Peroxisomal biogenesis disorders typically cause severe multisystem disease and early death. We describe a child and an adult of normal intelligence with progressive ataxia, axonal motor neuropathy, and decreased vibration sense. Both patients had marked cerebellar atrophy. Peroxisomal studies revealed a peroxisomal biogenesis disorder. Two mutations in PEX10 were found in the child, c.992G>A (novel) and c.764_765insA, and in the adult, c.2T>C (novel) and c.790C>T. Transfection with wild-type PEX10 corrected the fibroblast phenotype. Bile acid supplements and dietary restriction of phytanic acid were started. Peroxisomal biogenesis disorders should be considered in the differential diagnosis of autosomal recessive ataxia. ANN NEUROL 2010;68:259-263

Mutations in 12 different PEX genes can cause a generalized peroxisomal biogenesis disorder with clinical phenotypes ranging from Zellweger syndrome to infantile Refsum disease. To identify the specific PEX gene to be sequenced, complementation analysis is first performed in fibroblasts using catalase immunofluorescence. A patient with a relatively mild phenotype of infantile cholestasis, hypotonia and motor delay had elevated plasma very long-chain fatty acids and bile acid precursors, but fibroblast studies revealed normal or only mildly abnormal peroxisomal parameters and mosaic catalase immunofluorescence. This mosaicism persisted even when the incubation temperature was increased from 37 degrees C to 40 degrees C, a maneuver previously shown to abolish mosaicism by exacerbating peroxisomal dysfunction. As mosaicism precludes complementation analysis, a candidate gene approach was employed. After PEX1 sequencing was unrewarding, PEX12 sequencing revealed homozygosity for a novel c.102A>T (p.R34S) missense mutation affecting a partially conserved residue in the N-terminal region important for localization to peroxisomes. Transfection of patient fibroblasts with wild-type PEX12 cDNA confirmed that a PEX12 defect was the basis for the PBD. Homozygosity for c.102A>T was identified in a second patient of similar ethnic origin also presenting with a mild phenotype. PEX12 is a highly probable candidate gene for direct sequencing in the context of a mild clinical phenotype with mosaicism and minimally abnormal peroxisomal parameters in fibroblasts

s ingediend voor het Amsterdam Kindersymposium 2013 21 Chemical chaperones improve peroxisomal biogenesis in fibroblasts of mild Zellweger syndrome spectrum patients Kevin Bere ndse (1,2), Merel S. Ebberink (1), Lodewijk IJlst (1), Bwee Tien Poll-The (2), Ronald J.A. Wanders(1), Hans R. Waterham (1) (1) Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, the Netherlands (2) Department of Paediatric Neurology, Emma Children’s Hospital, Academic Medical Center, Amsterdam, the Netherlands INTRODUCTION Zellweger syndrome spectrum (ZSS) disorders are multisystem genetic disorders which lack functional peroxisomes due to a defect in one of the PEX genes. The ZSS include three phenotypes, which represent a spectrum of disease severity with Zellweger syndrome (ZS) being the most severe. In contrast to patients with the ZS phenotype, mild patients can be characterized by very mildly abnormal peroxisomal parameters in cultured skin fi broblasts, including a mosaic catalase immunofl uorescence pattern. Such a mosaic pattern is described for specifi c missense mutations in various PEX genes. Possibly, these missense mutations cause an unstable and/or incorrect folded native state of the protein. We hypothesize that the functional activity of the mutant PEX1 can be enhanced by promoting protein folding with chemical chaperones (e.g. glycerol or arginine) and thereby stimulating peroxisome biogenesis. METHODS Fibroblasts from four patients with a defect in PEX1 and two controls were cultured for up to three weeks in DMEM medium with diff erent concentrations of arginine or glycerol. To determine the eff ect of diff erent chemicals on peroxisome biogenesis we studied the following parameters: (1) the levels of PEX1 protein, (2) the peroxisomal protein import capacity, (3) the levels of intra peroxisomal processed protein, and (4) the capacity to β-oxidize very long chain fatty acids. CONCLUSION The addition of arginine or glycerol to the medium improved both the peroxisomal biogenesis and the peroxisomal metabolic state of fi broblasts with a missense mutation in PEX1. We hypothesize that a signifi cant number of ZSS patients may benefi t from arginine treatment.

Purpose/objective(s) Patients with perihilar cholangiocarcinoma (pCCA) can only be cured by surgery. The standard of care for those with inoperable tumors is palliative chemotherapy. In an attempt to control the disease locally without adding severe toxicity in patients with unresectable pCCA, we investigated the safety and feasibility of adding stereotactic body radiation therapy (SBRT) after chemotherapy. Materials/methods Patients were eligible with a diagnosis of unresectable pCCA, stage T1-T4N0-N1M0 (AJCC staging 7th edition), ECOG performance status of 0-1, and having finished 6-8 cycles chemotherapy treatment (cisplatin and gemcitabine). SBRT was planned in 15 fractions of 3.0-4.5Gy, aiming for a biologically effective dose > 80.5Gy, while not exceeding organs at risk (OAR) constraints. The primary endpoints were feasibility, defined as completing SBRT as planned, and toxicity evaluated within 3 months of treatment. A conventional '3+3'-design was used, corresponding to a sample size of 6 patients. Toxicity was scored with the CTCAE v4.03 grading system. Dose-limiting toxicity (DLT) was defined as grade ≥4 hepatobiliary or grade ≥3 gastrointestinal toxicity. Secondary endpoints, measured from start of radiotherapy, were local control, progression-free survival (RECIST 1.1), overall survival, and quality of life (QoL). QoL was measured using the QLQ-C30, EQ-5D-5L, and QLQ-BIL21 questionnaires. Results Six patients were enrolled between 1 November 2017 and 30 March 2020. All patients completed 6-8 cycles of chemotherapy. They were staged T4N0-1M0, each with unresectable disease due to vascular involvement. SBRT was completed as planned. A dose of 60Gy (15×4.0Gy) was prescribed at the 80% isodose. Due to OAR constraints, especially duodenum, the median PTV coverage was limited to 82.4% (75.7%-89.6%). No SBRT related DLT was observed. The most common grade ≥3 toxicity was cholangitis (n = 5), which could be resolved by improving biliary drainage. The 12-month local control rate was 80%. Metastases emerged in the form of peritoneal metastases/ascites (n = 3) and/or liver metastases (n = 1). Three of the 4 patients who developed distant metastases had lymph-node-positive disease at baseline. After a median follow up of 14 months, 4 of 6 patients were still alive. We observed no substantial changes in QoL. Median QLQ-C30 'global health status' scores were 75.0 at baseline, 3 months and 12 months. Conclusion Fractionated SBRT following standard chemotherapy was a feasible and safe local therapy option for unresectable pCCA, albeit with the use of hard constraints for OAR. Cholangitis was often observed, but was reversible and QoL was maintained. Based upon the observed safety and the promising local control, additional evaluation of effectiveness in larger studies is warranted.