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Abstract: Aicardi–Goutières syndrome is an autosomal recessive encephalopathy characterised by acquired microcephaly, basal ganglia calcifications, leukodystrophy, cerebral atrophy, chronic cerebrospinal lymphocytosis, and raised titres of interferon alpha in the cerebrospinal fluid. The disease onset is generally within the first months of life. We here report a case of Aicardi–Goutières syndrome presenting atypically as a sub-acute leukoencephalopathy following satisfactory psychomotor development up to the age of 16 months. This case highlights the importance of considering Aicardi–Goutières syndrome in the differential diagnosis of an unexplained leukoencephalopathy and the possibility of later onset of the disease. [Copyright &y& Elsevier]

Background: The findings of variants of uncertain significance (VUS) on a clinical genetic testing report pose a challenge for attending healthcare professionals (HCPs) in patient care. Here, we describe the outcomes of multidisciplinary VUS Rounds, implemented at a neurological disease tertiary care centre, which aid in interpreting and communicating VUS identified in our neurogenetics patient population., Methods: VUS Rounds brought together genetic counsellors, molecular geneticists and scientists to evaluate VUS against genomic and phenotypic evidence and assign an internal temperature classification of 'VUS Hot', 'True VUS' or 'VUS Cold', corresponding to potential pathogenicity. Biweekly meetings were held among the committee to deliberate variant classifications, determine additional clinical management actions and discuss nuances of VUS result communication., Results: In total, 143 VUS identified in 72 individuals with neurological disease were curated between October 2022 and December 2023. Of these, 12.6% were classified as VUS Hot, carried by 22.2% of the individuals, allowing for prioritisation of additional evaluation to determine potential pathogenicity of the variants, such as clinical follow-up or segregation analysis. In contrast, 45.4% of VUS were Cold and could be eliminated from further consideration in the carrier's care. We thoroughly evaluated the various evidence that contributed to our VUS classifications and resulting clinical actions., Conclusions: The assessment of VUS leveraging multidisciplinary collaboration allowed us to delineate required follow-up analyses for our neurology patient population. Integration of VUS Rounds into healthcare practices ensures equitable knowledge dissemination among HCPs and effective incorporation of uncertain genetic results into patient care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The complexity in diagnosing hereditary degenerative ataxias lies not only in their rarity, but also in the variety of different genetic conditions that can determine sometimes similar and overlapping clinical findings. In this light, Magnetic Resonance Imaging (MRI) plays a key role in the evaluation of these conditions, being a fundamental diagnostic tool needed not only to exclude other causes determining the observed clinical phenotype, but also to proper guide to an adequate genetic testing. Here, we propose an MRI-based diagnostic algorithm named CHARON (Characterization of Hereditary Ataxias Relying On Neuroimaging), to help in disentangling among the numerous, and apparently very similar, hereditary degenerative ataxias. Being conceived from a neuroradiological standpoint, it is based primarily on an accurate evaluation of the observed MRI findings, with the first and most important being the pattern of cerebellar atrophy. Along with the evaluation of the presence, or absence, of additional signal changes and/or supratentorial involvement, CHARON allows for the identification of a small groups of ataxias sharing similar imaging features. The integration of additional MRI findings, demographic, clinical and laboratory data allow then for the identification of typical, and in some cases pathognomonic, phenotypes of hereditary ataxias., (© 2024. The Author(s).)

Background and Objectives: Most individuals with spinal muscular atrophy (SMA) on disease-modifying therapies continue to have chronic motor impairment. Insights into brain involvement in SMA may open new pathways for adjunctive therapies to optimize outcomes. We aimed to characterize macrostructural brain abnormalities detected by MRI in individuals with SMA compared with peer controls., Methods: We conducted a cross-sectional case-control study of children and adults with a confirmed genetic diagnosis of 5q SMA, and peer controls matched by age and sex. Brain MRIs acquired on a 3T MRI scanner through a standardized research protocol were reviewed to qualitatively assess the presence of macrostructural changes. The primary outcome was the presence of any structural brain anomaly on MRI. In addition, the total volume of each participant's lateral ventricles was quantified by volumetry using MRIcron. Genetic and clinical variables, including SMN2 copy number and motor function (Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module scores), were then correlated with neuroimaging findings., Results: A total of 42 participants completed the study (mean age 17.4, range 7-40; 67% male). Of the 21 individuals with 5q SMA, 9 (43%) had macrostructural brain abnormalities identified on MRI compared with 2 of 21 (10%) peer controls (odds ratio 7.1, 95% confidence interval 1.4-34.0). In patients with SMA, the most common structural changes were widening of the arachnoid spaces (n = 4) and ventriculomegaly (n = 4). Individuals with SMA had larger median lateral ventricular volume than their normally developing peers (9.3 mL, interquartile range [IQR] 5.5-13.1 vs 5.3 mL, IQR 3.8-9.8; p = 0.034). Structural brain abnormalities were more frequent in those with 2 SMN2 copies (3/5, 60%) compared with 3 or 4 SMN2 copies (4/10, 40% and 2/6, 33% respectively), not reaching significance. We found no association between structural changes and motor function scores., Discussion: Individuals with SMA have higher rates of macrostructural brain abnormalities than their neurotypical peers, suggesting CNS involvement in SMA. Understanding changes in the brain architecture of the SMA population can inform the development of adjunct therapies targeting the CNS and potentially guide rehabilitation strategies., Competing Interests: E. Groulx-Boivin, A. Oliveira-Carneiro, H. Carlson, A. Floer, and A. Kirton report no disclosures relevant to the manuscript; J.K. Mah. received research grants from Biogen, Italfarmaco SpA, Novartis, NS Pharma, Pfizer, PTC Therapeutics, ReveraGen Biopharma, Roche, Sarepta Therapeutics, and the Alberta Children's Hospital Foundation; C. Saint-Martin reports no disclosures relevant to the manuscript; R. La Piana is a junior 1 research scholar of the Fonds de Recherche du Quebec - Santé, she received research funds from Roche Canada, consulting honoraria from Novoglia, and speaking honoraria from Novartis; M. Oskoui is a senior clinical research scholar of the Fonds de Recherche du Québec—Santé. Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and hereditary spastic paraplegia type 7 (SPG7) represent the most common genotypes of spastic ataxia (SPAX). To date, their magnetic resonance imaging (MRI) features have only been described qualitatively, and a pure neuroradiological differential diagnosis between these two conditions is difficult to achieve., Objectives: To test the performance of MRI measures to discriminate between ARSACS and SPG7 (as an index of common SPAX disease)., Methods: In this prospective multicenter study, 3D-T1-weighted images of 59 ARSACS (35.4 ± 10.3 years, M/F = 33/26) and 78 SPG7 (54.8 ± 10.3 years, M/F = 51/27) patients of the PROSPAX Consortium were analyzed, together with 30 controls (45.9 ± 16.9 years, M/F = 15/15). Different linear and surface measures were evaluated. A receiver operating characteristic analysis was performed, calculating area under the curve (AUC) and corresponding diagnostic accuracy parameters., Results: The pons area proved to be the only metric increased exclusively in ARSACS patients (P = 0.02). Other different measures were reduced in ARSACS and SPG7 compared with controls (all with P ≤ 0.005). A cut-off value equal to 1.67 of the pons-to-superior vermis area ratio proved to have the highest AUC (0.98, diagnostic accuracy 93%, sensitivity 97%) in discriminating between ARSACS and SPG7., Conclusions: Evaluation of the pons-to-superior vermis area ratio can discriminate ARSACS from other SPAX patients, as exemplified here by SPG7. Hence, we hereby propose this ratio as the Magnetic Resonance Index for the Assessment and Recognition of patients harboring SACS mutations (MRI-ARSACS), a novel diagnostic tool able to identify ARSACS patients and useful for discriminating ARSACS from other SPAX patients undergoing MRI. © 2024 International Parkinson and Movement Disorder Society., (© 2024 International Parkinson and Movement Disorder Society.)

Background: Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Spastic Paraplegia Type 7 (SPG7) are paradigmatic spastic ataxias (SPAX) with suggested white matter (WM) involvement. Aim of this work was to thoroughly disentangle the degree of WM involvement in these conditions, evaluating both macrostructure and microstructure via the analysis of diffusion MRI (dMRI) data., Material and Methods: In this multi-center prospective study, ARSACS and SPG7 patients and Healthy Controls (HC) were enrolled, all undergoing a standardized dMRI protocol and a clinimetrics evaluation including the Scale for the Assessment and Rating of Ataxia (SARA). Differences in terms of WM volume or global microstructural WM metrics were probed, as well as the possible occurrence of a spatially defined microstructural WM involvement via voxel-wise analyses, and its correlation with patients' clinical status., Results: Data of 37 ARSACS (M/F = 21/16; 33.4 ± 12.4 years), 37 SPG7 (M/F = 24/13; 55.7 ± 10.7 years), and 29 HC (M/F = 13/16; 42.1 ± 17.2 years) were analyzed. While in SPG7, only a mild mean microstructural damage was found compared to HC, ARSACS patients present a severe WM involvement, with a reduced global volume (p < 0.001), an alteration of all microstructural metrics (all with p < 0.001), without a spatially defined pattern of damage but with a prominent involvement of commissural fibers. Finally, in ARSACS, a correlation between microstructural damage and SARA scores was found (p = 0.004)., Conclusion: In ARSACS, but not SPG7 patients, we observed a complex and multi-faced involvement of brain WM, with a clinically meaningful widespread loss of axonal and dendritic integrity, secondary demyelination and, overall, a reduction in cellularity and volume., (© 2024. The Author(s).)

Background: GAA- FGF14 ataxia (SCA27B) is a recently reported late-onset ataxia caused by a GAA repeat expansion in intron 1 of the FGF14 gene. Initial studies revealed cerebellar atrophy in 74-97% of patients. A more detailed brain imaging characterization of GAA- FGF14 ataxia is now needed to provide supportive diagnostic features and earlier disease recognition., Methods: We performed a retrospective review of the brain MRIs of 35 patients (median age at MRI 63 years; range 28-88 years) from Quebec (n=27), Nancy (n=3), Perth (n=3) and Bengaluru (n=2) to assess the presence of atrophy in vermis, cerebellar hemispheres, brainstem, cerebral hemispheres, and corpus callosum, as well as white matter involvement. Following the identification of the superior cerebellar peduncles (SCPs) involvement, we verified its presence in 54 GAA- FGF14 ataxia patients from four independent cohorts (Tübingen n=29; Donostia n=12; Innsbruck n=7; Cantabria n=6). To assess lobular atrophy, we performed quantitative cerebellar segmentation in 5 affected subjects with available 3D T1-weighted images and matched controls., Results: Cerebellar atrophy was documented in 33 subjects (94.3%). We observed SCP involvement in 22 subjects (62.8%) and confirmed this finding in 30/54 (55.6%) subjects from the validation cohorts. Cerebellar segmentation showed reduced mean volumes of lobules X and IV in the 5 affected individuals., Conclusions: Cerebellar atrophy is a key feature of GAA- FGF14 ataxia. The frequent SCP involvement observed in different cohorts may facilitate the diagnosis. The predominant involvement of lobule X correlates with the frequently observed downbeat nystagmus., Competing Interests: Conflicts of Interests A. Duquette has received consultancy honoraria from AavantiBio, Novartis, Pfizer Canada, PTC Therapeutics, and Reata Pharmaceuticals, all unrelated to the present manuscript. M. Synofzik has received consultancy honoraria from Ionis, UCB, Prevail, Orphazyme, Servier, Reata, GenOrph, AviadoBio, Biohaven, Zevra, Lilly, and Solaxa, all unrelated to the present manuscript. B. Bender is Co-Founder, shareholder and CTO of AIRAmed GmbH. R. La Piana has received speaking honoraria from Novartis unrelated to the present manuscript.

Background: Induced pluripotent stem cell-derived microglia (iMGL) represent an excellent tool in studying microglial function in health and disease. Yet, since differentiation and survival of iMGL are highly reliant on colony-stimulating factor 1 receptor (CSF1R) signaling, it is difficult to use iMGL to study microglial dysfunction associated with pathogenic defects in CSF1R., Methods: Serial modifications to an existing iMGL protocol were made, including but not limited to changes in growth factor combination to drive microglial differentiation, until successful derivation of microglia-like cells from an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) patient carrying a c.2350G > A (p.V784M) CSF1R variant. Using healthy control lines, the quality of the new iMGL protocol was validated through cell yield assessment, measurement of microglia marker expression, transcriptomic comparison to primary microglia, and evaluation of inflammatory and phagocytic activities. Similarly, molecular and functional characterization of the ALSP patient-derived iMGL was carried out in comparison to healthy control iMGL., Results: The newly devised protocol allowed the generation of iMGL with enhanced transcriptomic similarity to cultured primary human microglia and with higher scavenging and inflammatory competence at ~ threefold greater yield compared to the original protocol. Using this protocol, decreased CSF1R autophosphorylation and cell surface expression was observed in iMGL derived from the ALSP patient compared to those derived from healthy controls. Additionally, ALSP patient-derived iMGL presented a migratory defect accompanying a temporal reduction in purinergic receptor P2Y12 (P2RY12) expression, a heightened capacity to internalize myelin, as well as heightened inflammatory response to Pam 3 CSK 4 . Poor P2RY12 expression was confirmed to be a consequence of CSF1R haploinsufficiency, as this feature was also observed following CSF1R knockdown or inhibition in mature control iMGL, and in CSF1R WT/KO and CSF1R WT/E633K iMGL compared to their respective isogenic controls., Conclusions: We optimized a pre-existing iMGL protocol, generating a powerful tool to study microglial involvement in human neurological diseases. Using the optimized protocol, we have generated for the first time iMGL from an ALSP patient carrying a pathogenic CSF1R variant, with preliminary characterization pointing toward functional alterations in migratory, phagocytic and inflammatory activities., (© 2024. The Author(s).)

The association of cerebellar ataxia and hypogonadism occurs in a heterogeneous group of disorders, caused by different genetic mutations often associated with a recessive inheritance. In these patients, magnetic resonance imaging (MRI) plays a pivotal role in the diagnostic workflow, with a variable involvement of the cerebellar cortex, alone or in combination with other brain structures. Neuroimaging involvement of the pituitary gland is also variable. Here, we provide an overview of the main clinical and conventional brain and pituitary gland MRI imaging findings of the most common genetic mutations associated with the clinical phenotype of ataxia and hypogonadism, with the aim of helping neuroradiologists in the identification of these disorders., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Despite the enormous advancements seen in recent years, curative therapies for patients with genetic leukoencephalopathies are available for only a relatively small number of disorders. Therefore, symptomatic treatment and preventive management of the multiple clinical manifestations of patients with genetic leukoencephalopathies are critical in their care. The goals of the symptomatic treatment are to improve patients' quality of life, increase their survival, and reduce the impact on medical resources and related expenses. The coordinated work of a multidisciplinary team, including all specialists involved in the care of these patients, is the gold standard approach to manage and treat their complex and evolving clinical picture. Along with a multidisciplinary team, the relationship and close collaboration with the patient and their caregivers are essential. Their insight into the disease manifestations and management of the different issues should be integrated with the assessments of the multidisciplinary team to prevent clinical complications and preserve the quality of life of patients and their caregivers. Genetic leukoencephalopathies are very heterogeneous in terms of age of onset, clinical features, and disease course. However, many clinical features and problems are shared by most forms. Consequently, common therapeutic strategies apply to the majority of these diseases. This chapter presents the symptomatic approach for shared core clinical features presented by patients with genetic leukoencephalopathies divided by systems and, for each system, the specificities of some genetic leukoencephalopathies., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background and Objectives: Hereditary spastic paraplegias (HSPs) are heterogenous genetic disorders characterized by progressive pyramidal tract involvement. SPG76 is a recently identified form of HSP, caused by biallelic calpain-1 (CAPN1) variants. The most frequently described MRI abnormality in SPG76 is mild cerebellar atrophy and non-specific white matter abnormalities were reported in only one case. Following the identification of prominent white matter abnormalities in a subject with CAPN1 variants, which delayed the diagnosis, we aimed to verify the presence of MRI patterns of white matter involvement specific to this HSP., Methods: We performed a retrospective radiological qualitative analysis of 15 subjects with SPG76 (4 previously unreported) initially screened for white matter involvement. Moreover, we performed quantitative analyses in our proband with available longitudinal studies., Results: We observed bilateral, periventricular white matter involvement in 12 subjects (80%), associated with multifocal subcortical abnormalities in 5 of them (33.3%). Three subjects (20%) presented only multifocal subcortical involvement. Longitudinal quantitative analyses of our proband revealed increase in multifocal white matter lesion count and increased area of periventricular white matter involvement over time., Discussion: SPG76 should be added to the list of HSPs with associated white matter abnormalities. We identified periventricular white matter involvement in subjects with SPG76, variably associated with multifocal subcortical white matter abnormalities. These findings, in the presence of progressive spastic paraparesis, can mislead the diagnostic process towards an acquired white matter disorder., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Dominantly inherited GAA repeat expansions in FGF14 are a common cause of spinocerebellar ataxia (GAA-FGF14 ataxia; spinocerebellar ataxia 27B). Molecular confirmation of FGF14 GAA repeat expansions has thus far mostly relied on long-read sequencing, a technology that is not yet widely available in clinical laboratories. We developed and validated a strategy to detect FGF14 GAA repeat expansions using long-range PCR, bidirectional repeat-primed PCRs, and Sanger sequencing. We compared this strategy to targeted nanopore sequencing in a cohort of 22 French Canadian patients and next validated it in a cohort of 53 French index patients with unsolved ataxia. Method comparison showed that capillary electrophoresis of long-range PCR amplification products significantly underestimated expansion sizes compared to nanopore sequencing (slope, 0.87 [95% CI, 0.81 to 0.93]; intercept, 14.58 [95% CI, - 2.48 to 31.12]) and gel electrophoresis (slope, 0.84 [95% CI, 0.78 to 0.97]; intercept, 21.34 [95% CI, - 27.66 to 40.22]). The latter techniques yielded similar size estimates. Following calibration with internal controls, expansion size estimates were similar between capillary electrophoresis and nanopore sequencing (slope: 0.98 [95% CI, 0.92 to 1.04]; intercept: 10.62 [95% CI, - 7.49 to 27.71]), and gel electrophoresis (slope: 0.94 [95% CI, 0.88 to 1.09]; intercept: 18.81 [95% CI, - 41.93 to 39.15]). Diagnosis was accurately confirmed for all 22 French Canadian patients using this strategy. We also identified 9 French patients (9/53; 17%) and 2 of their relatives who carried an FGF14 (GAA) ≥250 expansion. This novel strategy reliably detected and sized FGF14 GAA expansions, and compared favorably to long-read sequencing., (© 2023. The Author(s).)

The purpose of this study is to document the wide spectrum of white matter abnormalities associated with FOXC1 pathogenic variants. We report two adult individuals-a 60-year-old individual and a 24-year-old one, presenting with hearing loss, anterior eye segment dysgenesis, and very different severity of cerebral small vessel disease. Molecular testing documented the presence of FOXC1 pathogenic variants in both individuals. Our paper documents the broad spectrum of radiological white matter involvement in adult individuals with FOXC1-related disorders. Mild forms of FOXC1-related small vessel disease, as we observed in individual 2, should be included in the list of genetic mimickers of MS., (© 2023 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)

Background: The late-onset cerebellar ataxias (LOCAs) have largely resisted molecular diagnosis., Methods: We sequenced the genomes of six persons with autosomal dominant LOCA who were members of three French Canadian families and identified a candidate pathogenic repeat expansion. We then tested for association between the repeat expansion and disease in two independent case-control series - one French Canadian (66 patients and 209 controls) and the other German (228 patients and 199 controls). We also genotyped the repeat in 20 Australian and 31 Indian index patients. We assayed gene and protein expression in two postmortem cerebellum specimens and two induced pluripotent stem-cell (iPSC)-derived motor-neuron cell lines., Results: In the six French Canadian patients, we identified a GAA repeat expansion deep in the first intron of FGF14 , which encodes fibroblast growth factor 14. Cosegregation of the repeat expansion with disease in the families supported a pathogenic threshold of at least 250 GAA repeats ([GAA] ≥250 ). There was significant association between FGF14 (GAA) ≥250 expansions and LOCA in the French Canadian series (odds ratio, 105.60; 95% confidence interval [CI], 31.09 to 334.20; P<0.001) and in the German series (odds ratio, 8.76; 95% CI, 3.45 to 20.84; P<0.001). The repeat expansion was present in 61%, 18%, 15%, and 10% of French Canadian, German, Australian, and Indian index patients, respectively. In total, we identified 128 patients with LOCA who carried an FGF14 (GAA) ≥250 expansion. Postmortem cerebellum specimens and iPSC-derived motor neurons from patients showed reduced expression of FGF14 RNA and protein., Conclusions: A dominantly inherited deep intronic GAA repeat expansion in FGF14 was found to be associated with LOCA. (Funded by Fondation Groupe Monaco and others.)., (Copyright © 2022 Massachusetts Medical Society.)

Parkinson's disease (PD) can be classified into an akinetic-rigid (AR) and a tremor-dominant (TD) subtype based on predominant motor symptoms. Patients with different motor subtypes often show divergent clinical manifestations; however, the underlying neural mechanisms remain unclear. This study aimed to characterize the cortical and subcortical morphological alterations in motor subtypes of PD. T1-weighted MRI images were obtained for 90 patients with PD (64 with the AR subtype and 26 with the TD subtype) and 56 healthy controls (HCs). Cortical surface area, sulcal depth (measured by Freesurfer's Sulc index), and subcortical volume were computed to identify the cortical and subcortical morphological alterations in the two motor subtypes. Compared with HCs, we found widespread surface area reductions in the AR subtype yet sparse surface area reductions in the TD subtype. We found no significant Sulc change in the AR subtype yet increased Sulc in the right supramarginal gyrus in the TD subtype. The hippocampal volumes in both subtypes were lower than those of HCs. In PD patients, the surface area of left posterior cingulate cortex was positively correlated with Mini-Mental State Examination (MMSE) score, while the Sulc value of right middle frontal gyrus was positively correlated with severity of motor impairments. Additionally, the hippocampal volumes were positively correlated with MMSE and Montreal Cognitive Assessment scores and negatively correlated with severity of motor impairments and Hoehn & Yahr scores. Taken together, these findings may contribute to a better understanding of the neural substrates underlying the distinct symptom profiles in the two PD subtypes., (© 2022. The Author(s).)

Introduction: Adult genetic leukoencephalopathies are rare neurological disorders that present unique diagnostic challenges due to their clinical and radiological overlap with more common white matter diseases, notably multiple sclerosis (MS). In this context, a strong collaborative multidisciplinary network is beneficial for shortening the diagnostic odyssey of these patients and preventing misdiagnosis. The White Matter Rounds (WM Rounds) are multidisciplinary international online meetings attended by more than 30 physicians and scientists from 15 participating sites that gather every month to discuss patients with atypical white matter disorders. We aim to present the experience of the WM Rounds Network and demonstrate the value of collaborative multidisciplinary international case discussion meetings in differentiating and preventing misdiagnoses between genetic white matter diseases and atypical MS., Methods: We retrospectively reviewed the demographic, clinical and radiological data of all the subjects presented at the WM Rounds since their creation in 2013., Results: Seventy-four patients (mean age 44.3) have been referred and discussed at the WM Rounds since 2013. Twenty-five (33.8%) of these patients were referred by an MS specialist for having an atypical presentation of MS, while in most of the remaining cases, the referring physician was a geneticist (23; 31.1%). Based on the WM Rounds recommendations, a definite diagnosis was made in 36/69 (52.2%) patients for which information was available for retrospective review. Of these diagnosed patients, 20 (55.6%) had a genetic disease, 8 (22.2%) had MS, 3 (8.3%) had both MS and a genetic disorder and 5 (13.9%) had other non-genetic conditions. Interestingly, among the patients initially referred by an MS specialist, 7/25 were definitively diagnosed with MS, 5/25 had a genetic condition (e.g., X-linked adrenoleukodystrophy and hereditary small vessel diseases like Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) and COL4A1 -related disorder), and one had both MS and a genetic demyelinating neuropathy. Thanks to the WM Rounds collaborative efforts, the subjects who currently remain without a definite diagnosis, despite extensive investigations performed in the clinical setting, have been recruited in research studies aimed at identifying novel forms of genetic MS mimickers., Conclusions: The experience of the WM Rounds Network demonstrates the benefit of collective discussions on complex cases to increase the diagnostic rate and decrease misdiagnosis in patients with rare or atypical white matter diseases. Networks of this nature allow physicians and scientists to compare and share information on challenging cases from across the world, provide a basis for future multicenter research studies, and serve as model for other rare diseases., (Copyright © 2022 Huang, Giacomini, Massie, Venkateswaran, Trudelle, Fadda, Sharifian-Dorche, Boudjani, Poliquin-Lasnier, Airas, Saveriano, Ziller, Miller, Martinez-Rios, Wilson, Davila, Rush, Longbrake, Longoni, Macaron, Bernard, Tampieri, Antel, Brais and La Piana.)

Peroxisome biogenesis disorders-Zellweger spectrum disorders (PBD-ZSD)-are primarily autosomal recessive disorders caused by mutations in any of 13 PEX genes involved in peroxisome assembly. Compared to other PEX-related disorders, some PEX16 defects are associated with an atypical phenotype consisting of spasticity, cerebellar dysfunction, preserved cognition, and prolonged survival. In this case series, medical records and brain MRIs from 7 patients with this PEX16 presentation were reviewed to further characterize this phenotype. Classic PBD features such as sensory deficits and amelogenesis imperfecta were absent in all 7 patients, while all patients had hypertonia. Five patients were noted to have dystonia and received a treatment trial of levodopa/carbidopa. Four treated patients had partial but significant improvements in their dystonia and tremors, and 1 patient had only minimal response. Brain MRI studies commonly showed T2/FLAIR hyperintensities in the brainstem, superior and middle cerebellar peduncles, corticospinal tracts, and splenium of the corpus callosum. Genetic analysis revealed novel biallelic variants in 3 probands (c.683C > T/372delG; c.692A > G homozygous; c.865C > G/451C > T) and 1 novel variant (c.956&#95;958delCGC) in another proband. We demonstrated residual PEX16 protein amounts by immunoblotting in fibroblasts available from 5 patients with this atypical PEX16 disease (3 from this series, 2 previously reported), in contrast to the absence of PEX16 protein in fibroblasts from a patient with the severe ZSD presentation. This study further characterizes the phenotype of PEX16 defects by highlighting novel and distinctive clinical, neuroradiological, and molecular features of the disease and proposes a potential treatment for the dystonia. ClinicalTrials.gov Identifier: NCT01668186. Date of registration: January 2012., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Preterm very low birth weight infants (VLBWi) are known to be at greater risk of adverse neurodevelopmental outcome. Identifying early factors associated with outcome is essential in order to refer patients for early intervention. Few studies have investigated neurodevelopmental outcome in Italian VLBWi. The aim of our longitudinal study is to describe neurodevelopmental outcome at 24 months of corrected age in an eleven-year cohort of 502 Italian preterm VLBWi and to identify associations with outcome. At 24 months, Griffiths' Mental Developmental Scales were administered. Neurodevelopmental outcome was classified as: normal, minor sequelae (minor neurological signs, General Quotient between 76 and 87), major sequelae (cerebral palsy; General Quotient ≤ 75; severe sensory impairment). 75.3% showed a normal outcome, 13.9% minor sequelae and 10.8% major sequelae (3.8% cerebral palsy). Male gender, bronchopulmonary dysplasia, abnormal neonatal neurological assessment and severe brain ultrasound abnormalities were independently associated with poor outcome on multivariate ordered logistic regression. Rates of major sequelae are in line with international studies, as is the prevalence of developmental delay over cerebral palsy. Analysis of perinatal complications and the combination of close cUS monitoring and neurological assessment are still essential for early identification of infants with adverse outcome., (© 2021. The Author(s).)

Background: We evaluated the rates of placental pathologic lesions and their relationship with two-year neurodevelopmental outcomes in very-low-birth-weight (VLBW) infants., Methods: This is a cohort observational study comprising 595 VLBW infants during 2007 to 2015. Neurodevelopmental assessment was carried out at 24 months corrected age., Results: In univariate analysis the rates of survival with normal neurodevelopmental outcomes were lower in pregnancies with severe histologic chorioamnionitis (38 of 43, 88.4% when compared with 305 of 450, 67.8%), severe maternal vascular malperfusion (MVM) (17 of 37, 45.9% when compared with 326/492, 66.3%), and intravillous hemorrhage (37 of 82, 45.1% when compared with 306 of 449, 68.1%). In logistic models, severe MVM (adjusted odds ratio [adj. OR] = 0.45, 95% confidence interval [CI] = 0.22 to 0.92), severe fetal vascular malperfusion (FVM) (adj. OR = 0.46, 95% CI = 0.22 to 0.45), and intravillous hemorrhage (adj. OR = 0.38, 95% CI = 0.22 to 0.62) were associated with lower rates of infant survival with normal neurodevelopmental outcome. FVM (adj. OR = 0.46, 95% CI = 0.21 to 0.97) and intravillous hemorrhage (adj. OR = 0.37, 95% CI = 0.22 to 0.62) were also the only placental lesions that were independent predictors of a lower rate of intact survival in stepwise analysis for prognostic factors of the entire cohort., Conclusions: Placental pathologic findings such as severe MVM, FVM, and intravillous hemorrhage are significant predictors of neonatal survival and subsequent adverse neurodevelopmental outcomes. Data on the placental pathology could be useful in the neurodevelopmental follow-up of VLBW infants., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The investigators aimed to provide clinical and MRI guidelines for determining when genetic workup should be considered in order to exclude hereditary leukoencephalopathies in affected patients with a psychiatric presentation., Methods: A systematic literature review was conducted, and clinical cases are provided. Given the central role of MRI pattern recognition in the diagnosis of white matter disorders, the investigators adapted an MRI algorithm that guides the interpretation of MRI findings and thus directs further investigations, such as genetic testing., Results: Twelve genetic leukoencephalopathies that can present with psychiatric symptoms were identified. As examples of presentations that can occur in clinical practice, five clinical vignettes from patients assessed at a referral center for adult genetic leukoencephalopathies are provided., Conclusions: Features such as drug-resistant symptoms, presence of long-standing somatic features, trigger events, consanguinity, and positive family history should orient the clinician toward diagnostic workup to exclude the presence of a genetic white matter disorder. The identification of MRI white matter abnormalities, especially when presenting a specific pattern of involvement, should prompt genetic testing for known forms of genetic leukoencephalopathies.

Introduction: The Coronavirus disease-19 (COVID-19) pandemic continues to expand across the world. This pandemic has had a significant impact on patients with chronic diseases. Among patients with demyelinating diseases of the central nervous system (CNS), such as Multiple Sclerosis (MS) or Neuromyelitis Optica Spectrum Disorder (NMOSD), concerns remain about the potential impact of COVID-19 on these patients given their treatment with immunosuppressive or immunomodulatory therapies. In this study, we review the existing literature investigating the impact of disease-modifying therapies(DMT) on COVID-19 risks in this group of patients., Method: For this systematic review, we searched PubMed from January 1, 2020, to December 3, 2020. The following keywords were used: "COVID-19" AND "Multiple Sclerosis" OR "Neuromyelitis Optica." Articles evaluating COVID-19 in patients with demyelinating diseases of CNS were included. This study evaluates the different aspects of the DMTs in these patients during the COVID-19 era., Results and Conclusion: A total of 262 articles were found. After eliminating duplicates and unrelated research papers, a total of 84 articles met the final inclusion criteria in our study. Overall, the experiences of 2493 MS patients and 37 NMOSD patients with COVID-19 were included in this review. Among them, 46(1.8%) MS patients died(the global death-to-case ratio of Covid-19 was reported about 2.1%). Among DMTs, Rituximab had the highest mortality rate (4%). Despite controversies, especially concerning anti-CD20 monoclonal antibody therapies, a relation between DMT-use and COVID-19 disease- course was not found in many studies. This observation reinforces the recommendation of not stopping current DMTs. Other variables such as age, higher expanded disability status scale (EDSS) scores, cardiac comorbidities, and obesity were independent risk factors for severe COVID-19. Despite the risks of infection, most patients were willing to continue their DMT during the pandemic because of more significant concern about the risk of relapse or worsening MS symptoms. After the infection, an immune response's attenuation was seen in the patients on Fingolimod and anti-CD20 monoclonal antibodies. This may be a critical finding in future vaccinations., (Copyright © 2021. Published by Elsevier B.V.)

Objective: Although epileptic seizures occur in approximately a quarter of patients with Aicardi-Goutières syndrome (AGS), their phenotypic and electrophysiological characterization remains elusive. The aim of our study was to characterize epilepsy phenotypes and electroencephalographic (EEG) patterns in AGS and look for possible correlations with clinical, genetic and neuroradiological features., Methods: We selected patients with an established AGS diagnosis followed at three Italian reference centers. Medical records, EEGs and MRI/CT findings were reviewed. EEGs were independently and blindly reviewed by three board-certified pediatric epileptologists. Chi square and Fisher's exact tests were used to test associations between epilepsy and EEG feature categories and clinical, radiological and genetic variables., Results: Twenty-seven patients were enrolled. We reviewed 63 EEGs and at least one brain MRI scan per patient. Epilepsy, mainly in the form of epileptic spasms and focal seizures, was present in 37 % of the cohort; mean age at epilepsy onset was 9.5 months (range 1-36). The presence of epilepsy was associated with calcification severity (p = 0.016) and startle reactions (p = 0.05). Organization of EEG electrical activity appeared to be disrupted or markedly disrupted in 73 % of cases. Severe EEG disorganization correlated with microcephaly (p < 0.001) and highly abnormal MRI T2-weighted signal intensity in white matter (p = 0.022). Physiological organization of the EEG was found to be better preserved during sleep (87 %) than wakefulness (38 %). Focal slow activity was recorded in more than one third of cases. Fast activity, either diffuse or with frontal location, was more frequent in the awake state (78 %) than in sleep (50 %). Interictal epileptiform discharges (IEDs) were present in 33 % of awake and 45 % of sleep recordings. IEDs during sleep were associated with a higher risk of a epileptic seizures (p = 0.008)., Significance: The hallmarks of EEG recordings in AGS were found to be: disruption of electrical organization, the presence of focal slow and fast activity, and the presence of IEDs, both in patients with and in those without epilepsy. The associations between epilepsy and calcification and between EEG pattern and the finding of a highly abnormal white matter T2 signal intensity suggest a common anatomical correlate. However, the complex anatomical-electroclinical basis of AGS-related epilepsy still requires further elucidation., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Hypomyelinating leukodystrophies are a group of genetic disorders characterized by insufficient myelin deposition during development. A subset of hypomyelinating leukodystrophies, named RNA polymerase III (Pol III or POLR3)-related leukodystrophy or 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) leukodystrophy, was found to be caused by biallelic variants in genes encoding subunits of the enzyme Pol III, including POLR3A, POLR3B, POLR3K, and POLR1C. Pol III is one of the three nuclear RNA polymerases that synthesizes small non-coding RNAs, such as tRNAs, 5S RNA, and others, that are involved in the regulation of essential cellular processes, including transcription, translation and RNA maturation. Affinity purification coupled with mass spectrometry (AP-MS) revealed that a number of mutations causing POLR3-related leukodystrophy impair normal assembly or biogenesis of Pol III, often causing a retention of the unassembled subunits in the cytoplasm. Even though these proteomic studies have helped to understand the molecular defects associated with leukodystrophy, how these mutations cause hypomyelination has yet to be defined. In this review we propose two main hypotheses to explain how mutations affecting Pol III subunits can cause hypomyelination., Competing Interests: The authors declare that they have no competing interests.No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed., (Copyright: © 2021 Coulombe B et al.)

Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date., Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy., Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated., Setting: This was a multicenter retrospective study using information collected from 3 predominant centers., Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included., Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts., Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients., Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.)

Glycogen storage diseases (GSDs) result from the deficiency of enzymes involved in glycogen synthesis and breakdown into glucose. Mutations in the gene PHKA2 encoding phosphorylase kinase regulatory subunit alpha 2 have been linked to GSD type IXa. We describe a family with two adult brothers with neonatal hepatosplenomegaly and later onset of hearing loss, cognitive impairment, and cerebellar involvement. Whole-exome sequencing was performed on both subjects and revealed a shared hemizygous missense variant (c.A1561G; p.T521A) in exon 15 of PHKA2. The phenotype broadens the clinical and magnetic resonance imaging spectrum of GSD type IXa to include later onset neurological manifestations.

Purpose: Developmental in nature, brain arteriovenous malformations (AVM) have the potential to affect whole brain organization. Here we investigated the impact of AVM on functional and structural brain organization using resting-state functional MRI (rsfMRI) and cortical thickness measures., Methods: We investigated brain functional organization and structure using rsfMRI in conjunction with cortical thickness analyses in 23 patients with cerebral arteriovenous malformations (AVMs) and 20 healthy control subjects., Results: Healthy controls showed the expected anti-correlation between activity in the default mode network (DMN) and frontal areas that are part of the attentional control network. By contrast, patients demonstrated a disruption of this anti-correlation. Disruptions to this anti-correlation were even observed in a subgroup of patients with lesions remote from the main nodes of the DMN and were unrelated to differences in perfusion. Functional connectivity differences were accompanied by reduced cortical thickness in frontal attentional areas in patients compared to the controls., Conclusions: These results contribute to the discussion that AVMs affect whole brain networks and not simply the area surrounding the lesion.