POLR3A variants with striatal involvement and extrapyramidal movement disorder

Biallelic variants in POLR3A cause 4H leukodystrophy, characterized by hypomyelination in combination with cerebellar and pyramidal signs and variable non-neurological manifestations. Basal ganglia are spared in 4H leukodystrophy, and dystonia is not prominent. Three patients with variants in POLR3A, an atypical presentation with dystonia, and MR involvement of putamen and caudate nucleus (striatum) and red nucleus have previously been reported. Genetic, clinical findings and 18 MRI scans from nine patients with homozygous or compound heterozygous POLR3A variants and predominant striatal changes were retrospectively reviewed in order to characterize the striatal variant of POLR3A-associated disease. Prominent extrapyramidal involvement was the predominant clinical sign in all patients. The three youngest children were severely affected with muscle hypotonia, impaired head control, and choreic movements. Presentation of the six older patients was milder. Two brothers diagnosed with juvenile parkinsonism were homozygous for the c.1771-6C > G variant in POLR3A; the other seven either carried c.1771-6C > G (n = 1) or c.1771-7C > G (n = 7) together with another variant (missense, synonymous, or intronic). Striatal T2-hyperintensity and atrophy together with involvement of the superior cerebellar peduncles were characteristic. Additional MRI findings were involvement of dentate nuclei, hila, or peridentate white matter (3, 6, and 4/9), inferior cerebellar peduncles (6/9), red nuclei (2/9), and abnormal myelination of pyramidal and visual tracts (6/9) but no frank hypomyelination. Clinical and MRI findings in patients with a striatal variant of POLR3A-related disease are distinct from 4H leukodystrophy and associated with one of two intronic variants, c.1771-6C > G or c.1771-7C > G, in combination with another POLR3A variant

Modified Delphi procedure-based expert consensus on endpoints for an international disease registry for Metachromatic Leukodystrophy:The European Metachromatic Leukodystrophy initiative (MLDi)

BACKGROUND: Metachromatic Leukodystrophy (MLD) is a rare lysosomal disorder. Patients suffer from relentless neurological deterioration leading to premature death. Recently, new treatment modalities, including gene therapy and enzyme replacement therapy, have been developed. Those advances increase the need for high-quality research infrastructure to adequately compare treatments, execute post-marketing surveillance, and perform health technology assessments (HTA). To facilitate this, a group of MLD experts started the MLD initiative (MLDi) and initiated an academia-led European MLD registry: the MLDi. An expert-based consensus procedure, namely a modified Delphi procedure, was used to determine the data elements required to answer academic, regulatory, and HTA research questions. RESULTS: Three distinct sets of data elements were defined by the 13-member expert panel. The minimal set (n = 13) contained demographics and basic disease characteristics. The core set (n = 55) included functional status scores in terms of motor, manual, speech and eating abilities, and causal and supportive treatment characteristics. Health-related quality of life scores were included that were also deemed necessary for HTA. The optional set (n = 31) contained additional clinical aspects, such as findings at neurological examination, detailed motor function, presence of peripheral neuropathy, gall bladder involvement and micturition. CONCLUSION: Using a modified Delphi procedure with physicians from the main expert centers, consensus was reached on a core set of data that can be collected retrospectively and prospectively. With this consensus-based approach, an important step towards harmonization was made. This unique dataset will support knowledge about the disease and facilitate regulatory requirements related to the launch of new treatments. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13023-022-02189-w

X-linked hypomyelination with spondylometaphyseal dysplasia (H-SMD) associated with mutations in AIFM1

An X-linked condition characterized by the combination of hypomyelinating leukodystrophy and spondylometaphyseal dysplasia (H-SMD) has been observed in only four families, with linkage to Xq25-27, and recent genetic characterization in two families with a common AIFM1 mutation. In our study, 12 patients (6 families) with H-SMD were identified and underwent comprehensive assessment accompanied by whole-exome sequencing (WES). Pedigree analysis in all families was consistent with X-linked recessive inheritance. Presentation typically occurred between 12 and 36 months. In addition to the two disease-defining features of spondylometaphyseal dysplasia and hypomyelination on MRI, common clinical signs and symptoms included motor deterioration, spasticity, tremor, ataxia, dysarthria, cognitive defects, pulmonary hypertension, nystagmus, and vision loss due to retinopathy. The course of the disease was slowly progressive. All patients had maternally inherited or de novo mutations in or near exon 7 of AIFM1, within a region of 70 bp, including synonymous and intronic changes. AIFM1 mutations have previously been associated with neurologic presentations as varied as intellectual disability, hearing loss, neuropathy, and striatal necrosis, while AIFM1 mutations in this small region present with a distinct phenotype implicating bone. Analysis of cell lines derived from four patients identified significant reductions in AIFM1 mRNA and protein levels in osteoblasts. We hypothesize that AIFM1 functions in bone metabolism and myelination and is responsible for the unique phenotype in this condition.</p

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate

Newborn screening in metachromatic leukodystrophy – European consensus-based recommendations on clinical management

Introduction: Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder resulting from arylsulfatase A enzyme deficiency, leading to toxic sulfatide accumulation. As a result affected individuals exhibit progressive neurodegeneration. Treatments such as hematopoietic stem cell transplantation (HSCT) and gene therapy are effective when administered pre-symptomatically. Newborn screening (NBS) for MLD has recently been shown to be technically feasible and is indicated because of available treatment options. However, there is a lack of guidance on how to monitor and manage identified cases. This study aims to establish consensus among international experts in MLD and patient advocates on clinical management for NBS-identified MLD cases. Methods: A real-time Delphi procedure using eDELPHI software with 22 experts in MLD was performed. Questions, based on a literature review and workshops, were answered during a seven-week period. Three levels of consensus were defined: A) 100%, B) 75–99%, and C) 50–74% or >75% but >25% neutral votes. Recommendations were categorized by agreement level, from strongly recommended to suggested. Patient advocates participated in discussions and were involved in the final consensus. Results: The study presents 57 statements guiding clinical management of NBS-identified MLD patients. Key recommendations include timely communication by MLD experts with identified families, treating early-onset MLD with gene therapy and late-onset MLD with HSCT, as well as pre-treatment monitoring schemes. Specific knowledge gaps were identified, urging prioritized research for future evidence-based guidelines. Discussion: Consensus-based recommendations for NBS in MLD will enhance harmonized management and facilitate integration in national screening programs. Structured data collection and monitoring of screening programs are crucial for evidence generation and future guideline development. Involving patient representatives in the development of recommendations seems essential for NBS programs

Dating low-grade metamorphism and deformation of the Espinhaço Supergroup in the Chapada Diamantina (Bahia, NE Brazil): a K/Ar fine-fraction study

This study focuses on the northernmost part of the Mesoproterozoic Espinhaço Supergroup that crops out in the Chapada Diamantina. The fine-fraction K/Ar dating obtained on slightly metamorphosed sediments of the siliciclastic Espinhaço Supergroup shows a polyphase deformation history that corresponds to the Brasiliano (Pan-African) orogenic cycle. The isotopic results are interpreted to indicate three age domains coincident with three structurally different domains. Constrained by the Kübler Index ('illite crystallinity') and illite polytypism, the thermal conditions generated during the tectonic activity show a gradual trend from the craton margins to the interior from epizonal to diagenetic. The northern Chapada Diamantina is situated in the foreland of the Riacho do Pontal belt and comprises the sediments of the Espinhaço Supergroup northeast of the Irecê basin. The K/Ar ages for < 2 µm illite fractions range between 645 and 621 Ma [mean 637±9 Ma (2s)] and for < 0.2 µm fraction range between 625 and 603 Ma [mean 614±9 Ma (2s)]. Samples from the central Chapada Diamantina east of the Irecê basin are not affected by a Brasiliano deformation event and therefore, the N-S-trending structures are assumed to be older. The deformation of the southern Chapada Diamantina was established in conjunction with the formation of the Araçuai orogenesis and the inversion and reactivation of the Paramirim impactogen. The last stage of deformation in this area is recorded by the K/Ar fine-fraction dating between 470 and 460 Ma

2D-perfusion angiography for intra-procedural endovascular treatment response assessment in chronic mesenteric ischemia: a feasibility study

Background Endovascular revascularization has become the first-line treatment of chronic mesenteric ischemia (CMI). The qualitative visual analysis of digital subtraction angiography (DSA) is dependent on observer experience and prone to interpretation errors. We evaluate the feasibility of 2D-Perfusion Angiography (2D-PA) for objective, quantitative treatment response assessment in CMI. Methods 49 revascularizations in 39 patients with imaging based evidence of mesenteric vascular occlusive disease and clinical signs of CMI were included in this retrospective study. To assess perfusion changes by 2D-PA, DSA-series were post-processed using a dedicated, commercially available software. Regions of interest (ROI) were placed in the pre- and post-stenotic artery segment. In aorto-ostial disease, the inflow ROI was positioned at the mesenteric artery orifice. The ratios outflow to inflow ROI for peak density (PD), time to peak and area-under-the-curve (AUC) were computed and compared pre- and post-interventionally. We graded motion artifacts by means of a four-point scale. Feasibility of 2D-PA and changes of flow parameters were evaluated. Results Motion artifacts due to a mobile vessel location beneath the diaphragm or within the mesenteric root, branch vessel superimposition and inadequate contrast enhancement at the inflow ROI during manually conducted DSA-series via selective catheters owing to steep vessel angulation, necessitated exclusion of 26 measurements from quantitative flow evaluation. The feasibility rate was 47%. In 23 technically feasible assessments, PD$_{outflow}$/PD$_{inflow}$ increased by 65% (p  0.05). Conclusions Compared to other vascular territories and indications, the feasibility of 2D-PA in mesenteric revascularization for CMI was limited. Unfavorable anatomic conditions contributed to a high rate of inconclusive 2D-PA results

Dating low-grade metamorphism and deformation of the Espinhaço Supergroup in the Chapada Diamantina (Bahia, NE Brazil): a K/Ar fine-fraction study

This study focuses on the northernmost part of the Mesoproterozoic Espinhaço Supergroup that crops out in the Chapada Diamantina. The fine-fraction K/Ar dating obtained on slightly metamorphosed sediments of the siliciclastic Espinhaço Supergroup shows a polyphase deformation history that corresponds to the Brasiliano (Pan-African) orogenic cycle. The isotopic results are interpreted to indicate three age domains coincident with three structurally different domains. Constrained by the Kübler Index ('illite crystallinity') and illite polytypism, the thermal conditions generated during the tectonic activity show a gradual trend from the craton margins to the interior from epizonal to diagenetic. The northern Chapada Diamantina is situated in the foreland of the Riacho do Pontal belt and comprises the sediments of the Espinhaço Supergroup northeast of the Irecê basin. The K/Ar ages for < 2 µm illite fractions range between 645 and 621 Ma [mean 637±9 Ma (2s)] and for < 0.2 µm fraction range between 625 and 603 Ma [mean 614±9 Ma (2s)]. Samples from the central Chapada Diamantina east of the Irecê basin are not affected by a Brasiliano deformation event and therefore, the N-S-trending structures are assumed to be older. The deformation of the southern Chapada Diamantina was established in conjunction with the formation of the Araçuai orogenesis and the inversion and reactivation of the Paramirim impactogen. The last stage of deformation in this area is recorded by the K/Ar fine-fraction dating between 470 and 460 Ma

Use of monoclonal antibodies to assess expression of anaphylatoxin receptors in tubular epithelial cells of human, murine and rat kidneys

To assess published evidence of anaphylatoxin receptor expression in renal tubular epithelia] cells, monoclonal antibodies (mAbs) against human, mouse and rat receptors for C5a and C3a (C5aR, C3aR) were raised using receptor-expressing transfectants as immunogens. Applying these reagents in immunohistochemistry, we observed that mAbs with reactivities against three distinct epitopes of human C5aR N-terminus recognized tissue macrophages but not at all renal tubular epithelial cells. These findings were surprising, as strong tubular staining had been previously demonstrated by mAbs raised against a synthetic N-terminal C5aR peptide. To extend our study to mammalian kidneys, renal specimens from normal rats as well as LPS-treated Balb/c and MRL/1pr mice, which suffered from lupus-type nephritis, were examined. Similar to humans, mAbs against murine or rat C5aR strongly recognized infiltrating leukocytes in situ whereas tubular epithelial cells remained negative. As a mAb has been previously used to document C3aR expression in renal tubular epithelia] cells, kidney specimens were examined using newly established mAbs against different epitopes of human, murine and rat C3aR. In contrast to published evidence, C3aR was detectable exclusively in interstitial leukocytes but not in epithelia] tubular cells of normal and diseased tissues. Taken together, our findings question a direct involvement of tubular epithelial cells in anaphylatoxin-mediated renal inflammation. Furthermore, as we demonstrate in the case of anaphylatoxin receptors, cross-reactivities of mAbs may constitute as yet underestimated pitfalls in immunohistochemical antigen detection. (c) 2006 Elsevier GmbH. All rights reserved

Metachromatic leukodystrophy: natural course of cerebral MRI changes in relation to clinical course

Objective Metachromatic Leukodystrophy (MLD) is a rare disorder leading to demyelination and neurological impairment. A natural history study within the German leukodystrophy network analyzed MRI changes with respect to the clinical course. Methods 113 MR images of 68 patients (33 late-infantile, 35 juvenile) were studied cross-sectionally and longitudinally. MRI and motor deterioration were assessed using standardized scoring systems. Results The temporal and spatial patterns of MR severity scores differed between the late-infantile and juvenile form. Although early (involving central white matter, corpus callosum) and late signs (involving pons, cerebellum, cerebral atrophy) were similar, high MRI scores (mean 18, SD 1.2, p < 0.001) were evident in the juvenile form already at the onset of first symptoms and even in presymptomatic patients. The progression rate of the MRI score was clearly higher and more uniform in the late-infantile (on average 8 per year, p < 0.0001) than in the juvenile patients (on average 0.4 per year, p < 0.08). In late-infantile patients, MRI changes correlated highly with motor deterioration (rho = 0.73, p < 0.001), this was less remarkable in the juvenile form (rho = 0.50, p < 0.01). Severe motor dysfunction was associated with U-fiber involvement and cerebellar changes (p < 0.05). Conclusions MRI showed a typical spatial pattern, which evolved gradually and uniformly during disease progression in late-infantile MLD. In juvenile MLD MRI changes were already observed at disease onset and temporal patterns were more variable. As therapeutic options for MLD are evolving, these findings are not only important for patient counseling but also for the evaluation of therapeutic interventions