Off-resonance saturation as an MRI method to quantify mineral- iron in the post-mortem brain

PURPOSE: To employ an off‐resonance saturation method to measure the mineral‐iron pool in the postmortem brain, which is an endogenous contrast agent that can give information on cellular iron status. METHODS: An off‐resonance saturation acquisition protocol was implemented on a 7 Tesla preclinical scanner, and the contrast maps were fitted to an established analytical model. The method was validated by correlation and Bland‐Altman analysis on a ferritin‐containing phantom. Mineral‐iron maps were obtained from postmortem tissue of patients with neurological diseases characterized by brain iron accumulation, that is, Alzheimer disease, Huntington disease, and aceruloplasminemia, and validated with histology. Transverse relaxation rate and magnetic susceptibility values were used for comparison. RESULTS: In postmortem tissue, the mineral‐iron contrast colocalizes with histological iron staining in all the cases. Iron concentrations obtained via the off‐resonance saturation method are in agreement with literature. CONCLUSIONS: Off‐resonance saturation is an effective way to detect iron in gray matter structures and partially mitigate for the presence of myelin. If a reference region with little iron is available in the tissue, the method can produce quantitative iron maps. This method is applicable in the study of diseases characterized by brain iron accumulation and can complement existing iron‐sensitive parametric methods

Social-cognitive functioning and social skills in patients with early treated phenylketonuria:a PKU-COBESO study

OBJECTIVE: Early treatment of phenylketonuria (ET-PKU) prevents mental retardation, but many patients still show cognitive and mood problems. In this study, it was investigated whether ET-PKU-patients have specific phenylalanine (Phe-)related problems with respect to social-cognitive functioning and social skills. METHODS: Ninety five PKU-patients (mean age 21.6 ± 10.2 years) and 95 healthy controls (mean age 19.6 ± 8.7 years) were compared on performance of computerized and paper-and-pencil tasks measuring social-cognitive abilities and on parent- and self-reported social skills, using multivariate analyses of variance, and controlling for general cognitive ability (IQ-estimate). Further comparisons were made between patients using tetrahydrobiopterin (BH4, N = 30) and patients not using BH4. Associations with Phe-levels on the day of testing, during childhood, during adolescence and throughout life were examined. RESULTS: PKU-patients showed poorer social-cognitive functioning and reportedly had poorer social skills than controls (regardless of general cognitive abilities). Quality of social-cognitive functioning was negatively related to recent Phe-levels and Phe-levels between 8 and 12 years for adolescents with PKU. Quality of social skills was negatively related to lifetime phenylalanine levels in adult patients, and specifically to Phe-levels between 0 and 7, and between 8 and 12 years. There were no differences with respect to social outcome measures between the BH4 and non-BH4 groups. CONCLUSION: PKU-patients have Phe-related difficulties with social-cognitive functioning and social skills. Problems seem to be more evident among adolescents and adults with PKU. High Phe-levels during childhood and early adolescence seem to be of greater influence than current and recent Phe-levels for these patients

Medical and financial burden of acute intermittent porphyria

Introduction: A small proportion of patients with acute intermittent porphyria (AIP) suffer from recurrent porphyric attacks, with a severely diminished quality of life. In this retrospective case-control study, the burden of disease is quantified and compared among three AIP patient subgroups: cases with recurrent attacks, cases with one or occasional attacks and asymptomatic carriers. Methods: Data from patient records and questionnaires were collected in patients between 1960 and 2016 at the Erasmus Medical Center, Rotterdam, the Netherlands. We collected symptoms related to porphyria, porphyria related complications, attack frequency, hospitalisation frequency, hospitalisation days related to acute porphyric attacks, frequency of heme infusions and medical healthcare costs based on hospitalisations and heme therapy. Results: In total 11 recurrent AIP cases, 24 symptomatic AIP cases and 53 AIP carriers as controls were included. All recurrent patients reported porphyria related symptoms, such as pain, neurological and/or psychiatric disorders, and nearly all developed complications, such as hypertension and chronic kidney disease. In the recurrent cases group, the median lifelong number of hospitalisation days related to porphyric attacks was 82 days per patient (range 10–374), and they spent a median of 346 days (range 34–945) at a day-care facility for prophylactic heme therapy; total follow-up time was 243 person-years (PYRS). In the symptomatic non-recurrent group the median lifelong number of hospitalisation days related to porphyric attacks was 7 days per patient (range 1–78), total follow-up time was 528 PYRS. The calculated total medical healthcare cost for recurrent cases group was €5.8 million versus €0.3 million for the symptomatic cases group

Retrospective evaluation of the Dutch pre-newborn screening cohort for propionic acidemia and isolated methylmalonic acidemia:What to aim, expect, and evaluate from newborn screening?

Evidence for effectiveness of newborn screening (NBS) for propionic acidemia (PA) and isolated methylmalonic acidemia (MMA) is scarce. Prior to implementation in the Netherlands, we aim to estimate the expected health gain of NBS for PA and MMA. In this national retrospective cohort study, the clinical course of 76/83 Dutch PA and MMA patients, diagnosed between January 1979 and July 2019, was evaluated. Five clinical outcome parameters were defined: adverse outcome of the first symptomatic phase, frequency of acute metabolic decompensations (AMD), cognitive function, mitochondrial complications, and treatment-related complications. Outcomes of patients identified by family testing were compared with the outcomes of their index siblings. An adverse outcome due to the first symptomatic phase was recorded in 46% of the clinically diagnosed patients. Outcome of the first symptomatic phase was similar in 5/9 sibling pairs and better in 4/9 pairs. Based on the day of diagnosis of the clinically diagnosed patients and sibling pair analysis, a preliminary estimated reduction of adverse outcome due to the first symptomatic phase from 46% to 36%-38% was calculated. Among the sibling pairs, AMD frequency, cognitive function, mitochondrial, and treatment-related complications were comparable. These results suggest that the health gain of NBS for PA and MMA in overall outcome may be limited, as only a modest decrease of adverse outcomes due to the first symptomatic phase is expected. With current clinical practice, no reduced AMD frequency, improved cognitive function, or reduced frequency of mitochondrial or treatment-related complications can be expected

Social-cognitive functioning and social skills in patients with early treated phenylketonuria: a PKU-COBESO study

Objective: Early treatment of phenylketonuria (ET-PKU) prevents mental retardation, but many patients still show cognitive and mood problems. In this study, it was investigated whether ET-PKU-patients have specific phenylalanine (Phe-)related problems with respect to social-cognitive functioning and social skills. Methods: Ninety five PKU-patients (mean age 21.6 ± 10.2 years) and 95 healthy controls (mean age 19.6 ± 8.7 years) were compared on performance of computerized and paper-and-pencil tasks measuring social-cognitive abilities and on parent- and self-reported social skills, using multivariate analyses of variance, and controlling for general cognitive ability (IQ-estimate). Further comparisons were made between patients using tetrahydrobiopterin (BH4, N = 30) and patients not using BH4. Associations with Phe-levels on the day of testing, during childhood, during adolescence and throughout life were examined. Results: PKU-patients showed poorer social-cognitive functioning and reportedly had poorer social skills than controls (regardless of general cognitive abilities). Quality of social-cognitive functioning was negatively related to recent Phe-levels and Phe-levels between 8 and 12 years for adolescents with PKU. Qu

Retrospective evaluation of the Dutch pre-newborn screening cohort for propionic acidemia and isolated methylmalonic acidemia: What to aim, expect, and evaluate from newborn screening?

Evidence for effectiveness of newborn screening (NBS) for propionic acidemia (PA) and isolated methylmalonic acidemia (MMA) is scarce. Prior to implementation in the Netherlands, we aim to estimate the expected health gain of NBS for PA and MMA. In this national retrospective cohort study, the clinical course of 76/83 Dutch PA and MMA patients, diagnosed between January 1979 and July 2019, was evaluated. Five clinical outcome parameters were defined: adverse outcome of the first symptomatic phase, frequency of acute metabolic decompensations (AMD), cognitive function, mitochondrial complications, and treatment-related complications. Outcomes of patients identified by family testing were compared with the outcomes of their index siblings. An adverse outcome due to the first symptomatic phase was recorded in 46% of the clinically diagnosed patients. Outcome of the first symptomatic phase was similar in 5/9 sibling pairs and better in 4/9 pairs. Based on the day of diagnosis of the clinically diagnosed patients and sibling pair analysis, a preliminary estimated reduction of adverse outcome due to the first symptomatic phase from 46% to 36%-38% was calculated. Among the sibling pairs, AMD frequency, cognitive function, mitochondrial, and treatment-related complications were comparable. These results suggest that the health gain of NBS for PA and MMA in overall outcome may be limited, as only a modest decrease of adverse outcomes due to the first symptomatic phase is expected. With current clinical practice, no reduced AMD frequency, improved cognitive function, or reduced frequency of mitochondrial or treatment-related complications can be expected

Position statement on the role of healthcare professionals, patient organizations and industry in European Reference Networks

A call from the EU for the set-up of European Reference Networks (ERNs) is expected to be launched in the first quarter of 2016. ERNs are intended to improve the care for patients with low prevalent or rare diseases throughout the EU by, among other things, facilitating the pooling and exchange of experience and knowledge and the development of protocols and guidelines. In the past, for example where costly orphan drugs have been concerned, industry has played an important role in facilitating consensus meetings and publication of guidelines. The ERNs should provide a unique opportunity for healthcare professionals and patients to lead these activities in an independent way. However, currently costs for networking activities are not to be covered by EU funds and alternative sources of funding are being explored. There is growing concern that any involvement of the industry in the funding of ERNs and their core activities may create a risk of undue influence. To date, the European Commission has not been explicit in how industry will be engaged in ERNs. We believe that public funding and a conflict of interest policy are needed at the level of the ERNs, Centers of Expertise (CEs), healthcare professionals and patient organizations with the aim of maintaining scientific integrity and independence. Specific attention is needed where it concerns the development of clinical practice guidelines. A proposal for a conflict of interest policy is presented, which may support the development of a framework to facilitate collaboration, safeguard professional integrity and to establish and maintain public acceptability and trust among patients, their organizations and the general public

EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks

Abstract Acute hepatic porphyria comprises a group of rare, genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months prior to the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a healthcare facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased healthcare utilization. Conclusions: Patients experienced attacks often requiring treatment in a healthcare facility and/or with hemin, as well as chronic symptoms that adversely influence day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. This article is protected by copyright. All rights reserved.Peer reviewe

Neurocognitive outcome and mental health in children with tyrosinemia type 1 and phenylketonuria:A comparison between two genetic disorders affecting the same metabolic pathway

Tyrosinemia type 1 (TT1) and phenylketonuria (PKU) are both inborn errors of phenylalanine-tyrosine metabolism. Neurocognitive and behavioral outcomes have always featured in PKU research but received less attention in TT1 research. This study aimed to investigate and compare neurocognitive, behavioral, and social outcomes of treated TT1 and PKU patients. We included 33 TT1 patients (mean age 11.24 years; 16 male), 31 PKU patients (mean age 10.84; 14 male), and 58 age- and gender-matched healthy controls (mean age 10.82 years; 29 male). IQ (Wechsler-subtests), executive functioning (the Behavioral Rating Inventory of Executive Functioning), mental health (the Achenbach-scales), and social functioning (the Social Skills Rating System) were assessed. Results of TT1 patients, PKU patients, and healthy controls were compared using Kruskal-Wallis tests with post-hoc Mann-Whitney U tests. TT1 patients showed a lower IQ and poorer executive functioning, mental health, and social functioning compared to healthy controls and PKU patients. PKU patients did not differ from healthy controls regarding these outcome measures. Relatively poor outcomes for TT1 patients were particularly evident for verbal IQ, BRIEF dimensions "working memory", "plan and organize" and "monitor", ASEBA dimensions "social problems" and "attention problems", and for the SSRS "assertiveness" scale (all p value

EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks

BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. (Hepatology 2020;71:1546-1558)