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Background: Metachromatic leukodystrophy (MLD) is a rare autosomal recessive disorder that causes demyelination of both the central (CNS) and peripheral nervous systems (PNS). Objective: This study aims to report a unique MLD case presenting with cranial neuropathies and ataxia, initially without white matter changes on MRI, leading to diagnostic uncertainty. Results: A 20-month-old presented with bilateral abduction deficits, facial diplegia, and ataxia, raising the possibility of an acquired demyelinating condition. An MRI scan showed the enhancement of multiple cranial nerves, but normal white matter. A follow-up MRI showed new white matter changes that spared the U-fibers, suggesting a leukodystrophy. Biochemical assays were suggestive of metachromatic leukodystrophy, which was confirmed with genetic testing demonstrating a homozygous c.848+3A > G variant in ARSA. Conclusions: Our patient suggests that the initial presentation of MLD may mimic an acquired demyelinating condition and manifest with multiple cranial nerve palsies before more typical white matter changes evolve. [ABSTRACT FROM AUTHOR]

A couple presented to the office with an apparently healthy infant for a thorough clinical assessment, as they had previously lost two male children to a neurodegenerative disorder. They also reported the death of a male cousin abroad with a comparable condition. We aimed to evaluate a novel coding pathogenic variant c.1097T>A, PLA2G6, within the affected family, previously identified in a deceased cousin, but its clinical significance remained undetermined. A 200 bp PCR product of target genome (including codon 366 of PLA2G6) was amplified followed by enzymatic digestion (MboI) and sequencing. Structural pathogenic variant analysis was performed using PyMOL 2.5.4. In RFLP analysis, the mutant-type allele produced a single band of 200 bp, and the wild-type allele manifested as two bands of 112 bp and 88 bp. The pathogenic variant was identified in nine family members, including two heterozygous couples with consanguineous marriages resulting in affected children. It was predicted to be deleterious by multiple bioinformatic tools. The substitution of nonpolar isoleucine with polar asparagine of iPLA2 (Ile366Asn) resulted in a eense pathogenic variant (ATC>AAC). A missense variant (p. Ile366Asn) in the PLA2G6 gene is associated with clinically evident infantile neuroaxonal dystrophy, which is transmitted in an autosomal recessive pattern, and is also predicted to be dysfunctional by bioinformatic analyses. [ABSTRACT FROM AUTHOR]

Background: RNA polymerase III (POLR3)-related leukodystrophy is a rare, neurodegenerative disorder characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. Despite the challenges of caring for a child with POLR3-related leukodystrophy, few studies have examined parents' disease burden. We sought to investigate quality of life and stress levels amongst parents of children with POLR3-related leukodystrophy. Methods: 43 parents of 32 children completed questionnaires on demographics, stress, quality of life, coping mechanisms, and experience of injustice. Detailed clinical data was collected from all patients. Results: Mothers (t [27] = –8.66, P <.001) and fathers (t[16] = –4.47, P <.001) had lower quality of life scores compared to the normative population, yet 80% of parents' stress scores fell within the normal stress range. Parents' experience of injustice scores were high (>60). Correlations were found between and within parents' scores. Years since disease onset and certain life circumstances correlated to mothers' quality of life scores; however, no correlation was found between modifiable factors and fathers' quality of life scores. Helpful coping mechanisms included those that allowed parents to be involved in their child's life. Conclusions: This is the first study to assess stress and quality of life in this population. These results shed light on the importance of implementing services and social support to improve the well-being of parents. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is one of the most common and debilitating neurological diseases. Brain magnetic resonance imaging (MRI) is critical to determine the prognosis of MS. Using simple and accessible techniques is one of the researchers' concerns. So far, limited studies have been conducted on evaluating the relationship between the Bi-caudate ratio (BCR) and white matter atrophy in brain MRI of patients with MS. Therefore, in this study, we decided to evaluate this relationship. Materials and Methods: In this cross-sectional study, which was conducted to determine the relationship between BCR and white matter atrophy in brain MRI patients with MS, patients with MS who were evaluated by MRI at Imam Hossein Hospital (Tehran-Iran) in 2022 were assessed. BCR is determined by dividing the shortest distance between two caudate nuclei by the length of the brain at the imaging. The symbol digit modalities test (SDMT) was used to check the cognitive function of patients, and the relationship between BCR and MS-related parameters was evaluated. Expanded disability status score (EDSS) was also evaluated. A significance level was considered less than 0.05. Results: Eighty-five patients with a mean age of 40.73 ± 8.45 years and female gender was more prevalent (65.9%). The mean EDSS in all participants was 2.64 ± 2.49, and the mean BCR was 0.11 ± 0.03. EDSS score, age of the disease onset, SDMT score, and BCR were significantly different between different MS types (secondary progressive MS, primary progressive MS, and relapsing-remitting MS) (P-values<0.05). There was a statistically significant relationship between age, disease duration, EDSS score, onset age of the disease, and SDMT score with BCR (P<0.05). There was a statistically significant difference in the amount of BCR between sexes (P<0.045). Conclusion: BCR is a valuable method for evaluating the condition of multiple sclerosis, and it can be used as a simple and accessible technique for evaluating MS conditions. [ABSTRACT FROM AUTHOR]

Introduction: Lesion load (LL), deep gray matter (DGM) and normal-appearing white matter (NAWM) susceptibility and morphometry may help in monitoring brain changes in multiple sclerosis (MS) patients. We aimed at evaluating the feasibility of a fully automated segmentation and the potential interrelation between these biomarkers and clinical disability. Methods: Sixty-six patients with brain MRIs and clinical evaluations (Expanded Disability Status Scale [EDSS]) were retrospectively included. Automated prototypes were used for the segmentation and morphometry of brain regions (MorphoBox) and MS lesions (LeManPV). Susceptibility maps were estimated using standard post-processing (RESHARP and TVSB). Spearman's rho was computed to evaluate the interrelation between biomarkers and EDSS. Results: We found (i) anticorrelations between the LL and right thalamus susceptibility (rho = −0.46, p < 0.001) and between the LL and NAWM susceptibility (rho = [−0.68 to −0.25], p ≤ 0.05); (ii) an anticorrelation between LL and DGM (rho = [−0.71 to −0.36], p < 0.04) and WM morphometry (rho = [−0.64 to −0.28], p ≤ 0.01); and (iii) a positive correlation between EDSS and LL (rho = [0.28 to 0.5], p ≤ 0.03) and anticorrelation between EDSS and NAWM susceptibility (rho = [−0.29 to −0.38], p < 0.014). Conclusions: Fully automated brain morphometry and susceptibility monitoring is feasible in MS patients. The lesion load, thalamus and NAWM susceptibility values and trophicity are interrelated and correlate with disability. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons in the brain and spinal cord. Accumulation of misfolded proteins is central to the pathogenesis of ALS and the glymphatic system is emerging as a potential therapeutic target to reduce proteinopathy. Using diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) to assess glymphatic function, we performed a longitudinal analysis of glymphatic function in ALS and compared it to a disorder in the motor neuron disease spectrum, primary lateral sclerosis (PLS). From a cohort of 45 participants from the Calgary site in the CALSNIC study (Canadian ALS Neuroimaging Consortium), including 18 ALS, 5 PLS and 22 control participants, DTI-ALPS was analysed and correlated to clinical features (age, sex, disease presentation, disease severity and progression rate) and white matter hyperintensity burden. This included longitudinal measurements at three time points, 4 months apart. The DTI-ALPS index was reduced in ALS participants compared with PLS and control participants across all three time points. There was no association with clinical factors; however, the index tended to decline with advancing age. Our study suggests heterogeneity in glymphatic dysfunction in motor neuron diseases that may be related to the underlying pathogenesis. [ABSTRACT FROM AUTHOR]

A 12‐day‐old, male Holstein Friesian calf was presented to the hospital due to progressive ataxia and tremors since birth. A diffuse central nervous system disorder primarily affecting white matter was suspected based on clinical neurological examination. Blood tests were unremarkable, except for positive serology for Schmallenberg virus. Magnetic resonance imaging of the brain demonstrated severe, diffuse abnormalities primarily affecting the white matter regions of the encephalon and cranial cervical spinal cord, consistent with leukoencephalomyelopathy. Euthanasia was performed at 8 weeks of age after no clinical improvement. A postmortem examination was performed. Histopathological examination of the central nervous system revealed changes compatible with hypomyelinating leukodystrophy, with no signs of infectious agents observed. The disorder was considered most likely to be hereditary, as Schmallenberg virus infections during pregnancy in cattle have not been reported to result in such clinical, magnetic resonance imaging or histopathological findings, and no viral genomic material was identified with polymerase chain reaction. [ABSTRACT FROM AUTHOR]

Background: Iron–sulfur cluster assembly 2 (ISCA2) deficiency is linked to an autosomal recessive disorder known as multiple mitochondrial dysfunctions syndrome 4 (MMDS4). This disorder is characterized by leukodystrophy and neuroregression. Currently, most of the reported patients are from Saudi Arabia. All these patients carry a homozygous founder variant (NM_194279.2:c.229G>A:p.Gly77Ser) in ISCA2. Methods: We describe a patient who underwent full clinical evaluation, including metabolic, neurological, and radiological examinations. Standard genetic testing, including whole exome sequencing coupled with autozygome analysis, was undertaken, as were assessments of mitochondrial DNA (mtDNA) copy number and mtDNA sequencing on DNA extracted from blood and cultured fibroblasts. Functional workup consisted of splicing assessment of ISCA2 using RT-PCR, biochemical assessment of complex I status using dipstick assays, and mitochondrial respiration measurements using a Seahorse XFp analyzer. Results: We present the clinical and functional characterization of a novel homozygous ISCA2 missense variant (NM_194279.3:c.70A>G:p.Arg24Gly), leading to aberrant splicing in a patient presenting with neuroregression, generalized spasticity with exaggerated deep tendon reflexes and head lag, and progressive loss of acquired milestones. The novel variant was fully segregated in a wider family and was absent in a large control cohort, ethnically matching in-house exomes, local databases such as CGMdb and Saudi Human Genome Program, and ClinVar. Conclusions: Our analyses revealed that the variant is pathogenic, disrupting normal ISCA2 splicing and presumably leading to a truncated protein that disturbs metabolic pathways in patient-derived cells. [ABSTRACT FROM AUTHOR]

Perfusion changes in white matter (WM) lesions and normal‐appearing brain regions play an important pathophysiological role in multiple sclerosis (MS). However, most perfusion imaging methods require exogenous contrast agents, the repeated use of which is discouraged. Using resting‐state functional MRI (rs‐fMRI), we aimed to investigate differences in perfusion between white matter lesions and normal‐appearing brain regions in MS and healthy participants. A total of 41 MS patients and 41 age‐ and sex‐matched healthy participants received rs‐fMRI, from which measures of cerebral hemodynamics and oxygenation were extracted and compared across brain regions and study groups using within‐ and between‐group nonparametric tests, linear mixed models, and robust multiple linear regression. We found longer blood arrival times and lower blood volumes in lesions than in normal‐appearing WM. Higher blood volumes were found in MS patients' deep WM lesions compared to healthy participants, and blood arrival time was more delayed in MS patients' deep WM lesions than in healthy participants. Delayed blood arrival time in the cortical grey matter was associated with greater cognitive impairment in MS patients. Perfusion imaging using rs‐fMRI is useful for WM lesion characterization. rs‐fMRI‐based blood arrival times and volumes are associated with cognitive function. [ABSTRACT FROM AUTHOR]

Background: Tubulins are dimeric proteins expressed in all eukaryotic cells, serving as the fundamental building blocks of microtubule filaments. The TUBB4A gene encodes the protein β-tubulin. Mutations of TUBB4A have been associated with two neurodegenerative diseases with very different clinical characteristics: dystonia type 4 (DYT4) and Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum (H-ABC). Several cases of patients with H-ABC or unclassified leukoencephalopathy show spastic ataxia with or without leukodystrophy in association with mutations in exon 5 of TUBB4A gene. Case presentation: We report the case of a 65-year-old woman who has been complaining of progressive difficulty in walking since childhood. The neurological examination revealed, among all, a spastic gait, difficulties in standing on the toes and heels, brisk deep tendon reflexes at upper limbs, clonic patellar reflexes, brisk ankle reflexes, as well as bilateral Babinski and Hoffmann sign, brisk jaw jerk and severe lower limb spasticity. NGS studies for inherited cases of spastic paraplegia revealed a novel variant of unknown significance (VUS) (c.1249A > G, p.D417N), in TUBB4A. To the best of our knowledge, this variant has not been reported in the literature or any databases in association with these diseases. Conclusion: We report the case of a patient carrying a variant of uncertain significance (VUS) of the TUBB4A gene, showing a progressive, spastic paraparesis, supporting the extension of the phenotypic spectrum up to include spastic paraplegia. [ABSTRACT FROM AUTHOR]

Objective: We aimed to elucidate the pathogenic mechanisms underlying autosomal dominant adult‐onset demyelinating leukodystrophy (ADLD), and to understand the genotype/phenotype correlation of structural variants (SVs) in the LMNB1 locus. Background: Since the discovery of 3D genome architectures and topologically associating domains (TADs), new pathomechanisms have been postulated for SVs, regardless of gene dosage changes. ADLD is a rare genetic disease associated with duplications (classical ADLD) or noncoding deletions (atypical ADLD) in the LMNB1 locus. Methods: High‐throughput chromosome conformation capture, RNA sequencing, histopathological analyses of postmortem brain tissues, and clinical and neuroradiological investigations were performed. Results: We collected data from >20 families worldwide carrying SVs in the LMNB1 locus and reported strong clinical variability, even among patients carrying duplications of the entire LMNB1 gene, ranging from classical and atypical ADLD to asymptomatic carriers. We showed that patients with classic ADLD always carried intra‐TAD duplications, resulting in a simple gene dose gain. Atypical ADLD was caused by LMNB1 forebrain‐specific misexpression due to inter‐TAD deletions or duplications. The inter‐TAD duplication, which extends centromerically and crosses the 2 TAD boundaries, did not cause ADLD. Our results provide evidence that astrocytes are key players in ADLD pathology. Interpretation: Our study sheds light on the 3D genome and TAD structural changes associated with SVs in the LMNB1 locus, and shows that a duplication encompassing LMNB1 is not sufficient per se to diagnose ADLD, thereby strongly affecting genetic counseling. Our study supports breaking TADs as an emerging pathogenic mechanism that should be considered when studying brain diseases. ANN NEUROL 2024;96:855–870 [ABSTRACT FROM AUTHOR]

Background: Cerebral white matter lesion (WML) formation in people with multiple sclerosis (pwMS) is linked to the death of myelin‐producing oligodendrocytes. Current MS treatment strategies focus on limiting WML accumulation and disability. Using a pathology‐supported genetic testing (PSGT) program, we identified specific risk factors for MS, categorized as deficiencies and aggravators. We developed a novel clinical methodology to mitigate these risk factors, including personalized lifestyle interventions and optimization of cerebral nutrients to prevent oligodendrocyte demise and promote remyelination. Objective: To conduct a pilot case‐control study over a 10‐year period to ascertain whether the PSGT Program can reduce or prevent WML formation in pwMS. Methods: MRI was performed at baseline as well as after an interval period of at least 10 years or longer in 22 pwMS. WML volumes were determined using Sequence Adaptive Multimodal SEGmentation (SAMSEG) software, part of FreeSurfer 7.2. Other variables included age at MRI, disease duration, disability status, and medication. Results: PwMS (n = 13) who had followed the PSGT program for more than 10 years, had significantly smaller lesion volumes (mm3) compared to pwMS who did not adhere to the program (n = 9) (4950 ± 5303 vs. 17934 ± 11139; p = 0.002). WML volumes were significantly associated (p = 0.02) with disability (EDSS) but not with age (p = 0.350), disease duration (p = 0.709), or Interferon‐β treatment (p = 0.70). Conclusion: Dietary and lifestyle changes may lower the risk of developing cerebral WMLs in pwMS and potentially slow disease progression. Larger studies are required to confirm the effectiveness of such interventions in pwMS. [ABSTRACT FROM AUTHOR]

Deleterious variations in STXBP1 are responsible for early infantile epileptic encephalopathy type 4 (EIEE4, OMIM # 612164) because of its dysfunction in the central nervous system. The clinical spectrum of the neurodevelopmental delays associated with STXBP1 aberrations is collectively defined as STXBP1 encephalopathy (STXBP1-E), the conspicuous features of which are highlighted by early-onset epileptic seizures without structural brain anomalies. A girl was first diagnosed with unexplained disorders of movement and cognition, which later developed into STXBP1-E with unexpected leukoaraiosis and late onset of seizures. Genetic screening and molecular tests alongside neurological examinations were employed to investigate the genetic etiology and establish the diagnosis. A heterozygous mutation of c.37+2dupT at the STXBP1 splice site was identified as the pathogenic cause in the affected girl. The de novo mutation (DNM) did not result in any truncated proteins but immediately triggered mRNA degradation by nonsense-mediated mRNA decay (NMD), which led to the haploinsufficiency of STXBP1. The patient showed atypical phenotypes characterized by hypomyelinating leukodystrophy, and late onset of epileptic seizures, which had never previously been delineated in STXBP1-E. These findings strongly indicated that the haploinsufficiency of STXBP1 could also exhibit divergent clinical phenotypes because of the genetic heterogeneity in the subset of encephalopathies. [ABSTRACT FROM AUTHOR]

Background: White matter hyperintensities (WMH) observed in T2 fluidattenuated inversion recovery (FLAIR) images have emerged as potential markers of neurodegenerative diseases like Multiple Sclerosis (MS). Lacking comprehensive automated WMH classification systems in current research, there is a need to develop accurate detection and classification methods for WMH that will benefit the diagnosis and monitoring of brain diseases. Objective: Juxtacortical WMH (JCWMH) is a less explored subtype of WMH, primarily due to the hard definition of the cortex in FLAIR images, which is escalated by the presence of lesions to obtain appropriate gray matter (GM) masks. Methods: In this study, we present a method to perform a specialized GM segmentation developed for the classification of WMH, especially JCWMH. Using T1 and FLAIR images, we propose a pipeline to integrate masks of white matter, cerebrospinal fluid, ventricles, and WMH to create a unique mask to refine the primary GM map. Subsequently, we utilize this pipeline to generate paired data for training a conditional generative adversarial network (cGAN) to substitute the pipeline and reduce the inputs to only FLAIR images. The classification of WMH is then based on the distances between WMH and ventricular and GM masks. Due to the lack of multi-class labeled WMH datasets and the need for extensive data for training deep learning models, we attempted to collect a large local dataset and manually segment and label some data for WMH and ventricles. Results: In JCWMH classification, the proposed method exhibited a Dice similarity coefficient, precision, and sensitivity of 0.76, 0.69, and 0.84, respectively. With values of 0.66, 0.55, and 0.81, the proposed method clearly outperformed the approach commonly used in the literature, which uses extracted GM masks from registered T1 images on FLAIR. Conclusion: After training, the method proves its efficiency by providing results in less than one second. In contrast, the usual approach would require at least two minutes for registration and segmentation alone. The proposed method is automated and fast and requires no initialization as it works exclusively with FLAIR images. Such innovative methods will undoubtedly facilitate accurate and meaningful analysis of WMH in clinical practice by reducing complexity and increasing efficiency. [ABSTRACT FROM AUTHOR]

Purpose: Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by arylsulfatase A deficiency, which leads to progressive demyelination in both the central and peripheral nervous systems, resulting in significant gross motor deterioration. This study aimed to analyze data concerning neuroimaging and clinical phenotypes of MLD patients, categorized by disease subtype. Methods: Patients diagnosed with MLD based on arylsulfatase A enzymatic activity, demyelination observed in brain magnetic resonance images, and/or pathogenic mutations were included in this study. The medical charts of 10 patients with confirmed MLD were retrospectively reviewed. We used a simplified magnetic resonance imaging (MRI) scoring system and clinical status, including survival. We analyzed the correlations between the scores of specific neuroimaging lesions and clinical status in two groups, categorized as late-infantile and juvenile types based on the age at symptom onset. Results: We detected a positive relationship between clinical function deterioration and MRI score (rho=0.59, P=0.002) in patients with MLD. This correlation was stronger in the late-infantile type (rho=0.700, P=0.003) than in the juvenile type (rho=0.513, P=0.029). A strong relationship was also noted in patients with high signal intensities in the pons and basal ganglia, and cerebellar atrophy, but not in those with lesions in the midbrain. MLD with a high MRI score was associated with poor clinical function. Conclusion: The identified correlations between modified MRI scores and clinical function scales may help predict the prognosis of patients with MLD, thereby aiding in the identification of treatment options and enhancing the quality of life for these patients. [ABSTRACT FROM AUTHOR]

Summary: Aicardi‐Goutières syndrome (AGS) is a progressive genetic encephalopathy caused by pathogenic mutations in genes controlling cellular anti‐viral responses and nucleic acid metabolism. The mutations initiate autoinflammatory processes in the brain and systemically that are triggered by chronic overproduction of type I interferon (IFN), including IFN‐alpha. Emerging disease‐directed therapies aim to dampen autoinflammation and block cellular responses to IFN production, creating an urgent and unmet need to understand better which cells, compartments, and mechanisms underlying disease pathogenesis. In this review, we highlight existing pre‐clinical models of AGS and our current understanding of how causative genetic mutations promote disease in AGS, to promote new model development and a continued focus on improving and directing future therapies. [ABSTRACT FROM AUTHOR]

Introduction: LMNB1-related autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurodegenerative disorder caused by overexpression of LMNB1. We retrospectively reviewed charts of all ADLD patients seen at Mayo Clinic. Methods: All available data from molecularly confirmed ADLD patients was reviewed. Results: Of eight patients identified, three were male. Age at symptom onset ranged from 33 to 64 years. In males, the first symptom was erectile dysfunction (2/3) or neurogenic bladder (1/3) and, in females, weakness (3/5), bladder dysfunction (2/5), or depression (1/5). Diagnostic delay from symptom onset was a median of 6 (IQR 2.3–10) years. Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8). Family history was positive in 6. All eight patients had LMNB1 duplication. Eighteen brain MRIs were reviewed from 7 patients. All showed symmetric confluent T2W deep cerebral and periventricular white matter hyperintensities with involvement of the posterior limb of the internal capsule, corpus callosum, corticospinal tract in brain stem, and superior and middle cerebellar peduncles. Seven spine MRIs from six patients showed moderate diffuse atrophy of the spinal cord. Conclusion: Typical clinical symptoms and characteristic MRI changes should prompt genetic testing for ADLD. [ABSTRACT FROM AUTHOR]

Leukodystrophies are rare genetic white matter disorders that have been regarded as mainly occurring in childhood. This perception has been altered in recent years, as a growing number of leukodystrophies have been described as having an onset in adulthood. Still, many adult patients presenting with white matter changes remain without a specific molecular diagnosis. We describe a novel adult onset leukodystrophy in 16 patients from eight families carrying one of four different stop-gain or frameshift dominant variants in the CST3 gene. Clinical and radiological features differ markedly from the previously described Icelandic cerebral amyloid angiopathy found in patients carrying p.Leu68Asn substitution in CST3. The clinical phenotype consists of recurrent episodes of hemiplegic migraine associated with transient unilateral focal deficits and slowly progressing motor symptoms and cognitive decline in mid to older adult ages. In addition, in some cases acute onset clinical deterioration led to a prolonged episode with reduced consciousness and even early death. Radiologically, pathognomonic changes are found at typical predilection sites involving the deep cerebral white matter sparing a periventricular and directly subcortical rim, the middle blade of corpus callosum, posterior limb of the internal capsule, middle cerebellar peduncles, cerebral peduncles and specifically the globus pallidus. Histopathologic characterization in two autopsy cases did not reveal angiopathy, but instead micro- to macrocystic degeneration of the white matter. Astrocytes were activated at early stages and later displayed severe degeneration and loss. In addition, despite the loss of myelin, elevated numbers of partly apoptotic oligodendrocytes were observed. A structural comparison of the variants in CST3 suggests that specific truncations of cystatin C result in an abnormal function, possibly by rendering the protein more prone to aggregation. Future studies are required to confirm the assumed effect on the protein and to determine pathophysiologic downstream events at the cellular level. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Trichothiodystrophy (TTD) is caused by homozygous or compound heterozygous variants in genes associated with DNA repair. The ERCC2 gene encoded a protein, XPD, that is a subunit of the general transcription factor TFIIH and important in both DNA repair and transcription. Disease‐causing variants in ERCC2 can partially inactivate these activities, giving rise to symptoms seen in TTD, Cockayne syndrome (CS) and xeroderma pigmentosa (XP). Although generalized cerebral white matter abnormalities is reported in TTD, myelination disorders specifically linked to ERCC2 gene variants are exceptionally uncommon. Here, we introduce a thorough investigation of a patient exhibiting classic TTD symptoms alongside progressive cerebral hypomyelination with ERCC2 variants. Methods In a non‐consanguineous family, we conducted Autism/ID gene Panel on a 5‐year‐old affected child who presented with microcephaly, failure to thrive, developmental delay, and progressive hypomyelination on three serial brain imaging over 5‐years follow‐up. Our investigation aimed to elucidate the genetic underpinnings of the observed phenotype. We also conducted a comprehensive review of the genetic profiles of all documented ERCC2‐related patients exhibiting myelination disorders. Results Autism/ID gene Panel identified a compound heterozygous variant in ERCC2 gene causing TTD. Clinical and paraclinical findings enabled differentiation of TTD from Cockayne syndrome and XP. Segregation analysis revealed that, the variation in the paternal allele was a splice junction loss (c.2190 + 1delG), and the other alteration in the maternal allele was a pathogenic variant (c.1479 + 2dupT). It has been noted that these variants were reported in previous studies in homozygous or compound heterozygous form in patients with TTD, but none of them exhibited hypomyelinating leukodystrophy. Conclusion The identification of hypomyelination in TTD due to ERCC2 sheds a light on the molecular diagnosis and contributing to the limited literature on ERCC2 variants and associated hypomyelinating leukodystrophy in patients with TTD.

Abstract Background/Aim Leukodystrophies comprise a group of genetic white matter disorders that lead to progressive motor and cognitive impairment. Recent development of novel therapies has led to an increase in clinical trials for leukodystrophies. To enable recruitment of individuals with a leukodystrophy into clinical trials, clinical trial acceptability should be ascertained. We sought therefore, to identify the motivations for and barriers to clinical trial participation in addition to clinical trial features that may be of concern to individuals with a leukodystrophy and/or their carers. Methods Adults with a leukodystrophy and parents/carers of individuals with a leukodystrophy were recruited through the Australian Leukodystrophy Registry and through online advertisements. Qualitative semi-structured interviews were used to explore participants views on what clinical trials involve, the perceived risks and benefits of clinical trials, their desire to participate in clinical trials and their personal experience with leukodystrophy. Thematic analysis of data was performed with co-coding of interview transcripts. Results 5 interviews were held with parents of children with leukodystrophy, 4 with parents of adults with leukodystrophy and 3 with adults diagnosed with leukodystrophy. Motivations for clinical trial enrolment include access to potentially lifesaving novel treatments and improved prognostic outcomes. Participants were concerned about adverse clinical trial outcomes, including side effects and exacerbation of illness. Despite this, majority of participants were willing to try anything in clinical trials, demonstrating a high tolerance for first in human trials and trials utilising invasive treatment options. Conclusions Interviewees communicated a strong desire to participate in interventional clinical trials involving novel therapies. To support enrolment into future leukodystrophy clinical trials we suggest the provision of transparent information regarding clinical trial treatments, consideration of alternative trial control measures, and inclusion of treating clinicians in the trial recruitment process. Clinicians play an integral role in initiating transparent conversations regarding trial risks and adverse outcomes.

ABSTRACT Importance Aicardi–Goutières syndrome (AGS) is a rare genetic disorder mainly affecting the central nervous system and autoimmunity. However, research on AGS among Chinese patients is limited. Objective To summarize the neurologic phenotypes and genetic causes in pediatric AGS patients, providing insights for early recognition and diagnosis in the Chinese population. Methods Clinical features and neuroimaging results of the patients diagnosed with AGS from Beijing Children's Hospital between January 2018 and January 2022 were collected. Whole exome sequencing was used for genetic analysis. Results A total of 15 patients was included, all presenting with various neurological symptoms, including developmental delay (100%), motor skill impairment (100%), language disability (78.6%), dystonia (93.3%), microcephaly (73.3%), sleep disorders (26.7%), regression (20.0%), vessel disease (6.7%), and epilepsy (6.7%). Neuroimaging revealed intracranial calcification (86.7%), cerebral atrophy (73.3%), and leukodystrophy (73.3%). Seven genes were identified, with TREX1 being the most common (40.0%, 6/15), followed by IFIH1 (20.0%, 3/15). Variant c.294dupA (p.C99Mfs*3) was detected in four unrelated patients, accounting for 66.7% (4/6) patients with the TREX1 variant. A literature review showed that TREX1 gene mutations in 35.6% (21/59) of AGS patients among the Chinese population. Interpretation Neurological symptoms are the most prevalent and severe presentation of AGS. Diagnosis may be considered when symptoms such as developmental delay, dystonia, microcephaly, brain calcification, and leukodystrophy emerge. TREX1 mutations are predominant in the Chinese population.

Background/Aim: Leukodystrophies comprise a group of genetic white matter disorders that lead to progressive motor and cognitive impairment. Recent development of novel therapies has led to an increase in clinical trials for leukodystrophies. To enable recruitment of individuals with a leukodystrophy into clinical trials, clinical trial acceptability should be ascertained. We sought therefore, to identify the motivations for and barriers to clinical trial participation in addition to clinical trial features that may be of concern to individuals with a leukodystrophy and/or their carers. Methods: Adults with a leukodystrophy and parents/carers of individuals with a leukodystrophy were recruited through the Australian Leukodystrophy Registry and through online advertisements. Qualitative semi-structured interviews were used to explore participants views on what clinical trials involve, the perceived risks and benefits of clinical trials, their desire to participate in clinical trials and their personal experience with leukodystrophy. Thematic analysis of data was performed with co-coding of interview transcripts. Results: 5 interviews were held with parents of children with leukodystrophy, 4 with parents of adults with leukodystrophy and 3 with adults diagnosed with leukodystrophy. Motivations for clinical trial enrolment include access to potentially lifesaving novel treatments and improved prognostic outcomes. Participants were concerned about adverse clinical trial outcomes, including side effects and exacerbation of illness. Despite this, majority of participants were willing to try anything in clinical trials, demonstrating a high tolerance for first in human trials and trials utilising invasive treatment options. Conclusions: Interviewees communicated a strong desire to participate in interventional clinical trials involving novel therapies. To support enrolment into future leukodystrophy clinical trials we suggest the provision of transparent information regarding clinical trial treatments, consideration of alternative trial control measures, and inclusion of treating clinicians in the trial recruitment process. Clinicians play an integral role in initiating transparent conversations regarding trial risks and adverse outcomes. [ABSTRACT FROM AUTHOR]

CSF1R-related disorder (CSF1R-RD) is a neurodegenerative condition that predominantly affects white matter due to genetic alterations in the CSF1R gene, which is expressed by microglia. We studied an elderly man with a hereditary, progressive dementing disorder of unclear etiology. Standard genetic testing for leukodystrophy and other neurodegenerative conditions was negative. Brain autopsy revealed classic features of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), including confluent white matter degeneration with axonal spheroids and pigmented glial cells in the affected white matter, consistent with CSF1R-RD. Subsequent long-read sequencing identified a novel deletion in CSF1R that was not detectable with short-read exome sequencing. To gain insight into potential mechanisms underlying white matter degeneration in CSF1R-RD, we studied multiple brain regions exhibiting varying degrees of white matter pathology. We found decreased CSF1R transcript and protein across brain regions, including intact white matter. Single nuclear RNA sequencing (snRNAseq) identified two disease-associated microglial cell states: lipid-laden microglia (expressing GPNMB, ATG7, LGALS1, LGALS3) and inflammatory microglia (expressing IL2RA, ATP2C1, FCGBP, VSIR, SESN3), along with a small population of CD44+ peripheral monocyte-derived macrophages exhibiting migratory and phagocytic signatures. GPNMB+ lipid-laden microglia with ameboid morphology represented the end-stage disease microglia state. Disease-associated oligodendrocytes exhibited cell stress signatures and dysregulated apoptosis-related genes. Disease-associated oligodendrocyte precursor cells (OPCs) displayed a failure in their differentiation into mature myelin-forming oligodendrocytes, as evidenced by upregulated LRP1, PDGFRA, SOX5, NFIA, and downregulated NKX2-2, NKX6.2, SOX4, SOX8, TCF7L2, YY1, ZNF488. Overall, our findings highlight microglia–oligodendroglia crosstalk in demyelination, with CSF1R dysfunction promoting phagocytic and inflammatory microglia states, an arrest in OPC differentiation, and oligodendrocyte depletion. [ABSTRACT FROM AUTHOR]

Purpose: To characterize Vanishing White Matter Disease (VWM) cases from a Brazilian University Tertiary hospital, focusing on brain magnetic resonance image (MRI) aspects, clinical and molecular data. Methods: Medical records and brain MRI of 13 genetically confirmed VWM patients were reviewed. Epidemiological data such as age at symptom onset, gender and main symptoms were analyzed, along with genetic mutations and MRI characteristics, such as the distribution of white matter lesions and atrophy. Results: The majority of patients were female, with the age of symptom onset ranging from 1 year and 6 months to 40 years. All mutations were identified in the EIF2B5 gene, the most prevalent being c.338G > A (p.Arg113His), and a novel mutation related to the disease was discovered, c.1051G > A (p.Gly351Ser). Trauma or infection were significant triggers. The most frequent symptoms were ataxia and limb spasticity. All MRI scans displayed deep white matter involvement, cystic degeneration, with U-fibers relatively spared and a predilection for the frontoparietal region. Lesions in the corpus callosum and posterior fossa were present in all patients. Follow-up exams revealed the evolution of white matter lesions and cerebral atrophy, which correlated with clinical deterioration. Conclusions: VWM affects various age groups, with a significant clinical and genetic variability. A novel mutation associated with the disease is highlighted. MRI reveals a typical pattern of white matter involvement, characterized by diffuse lesions in the periventricular and deep regions, with subsequent extension to the subcortical areas, accompanied by cystic degeneration, and plays a crucial role in diagnosis and follow-up. [ABSTRACT FROM AUTHOR]

Pelizaeus‐Merzbacher disease (PMD) is a rare childhood hypomyelinating leukodystrophy. Quantification of the pronounced myelin deficit and delineation of subtle myelination processes are of high clinical interest. Quantitative magnetic resonance imaging (qMRI) techniques can provide in vivo insights into myelination status, its spatial distribution, and dynamics during brain maturation. They may serve as potential biomarkers to assess the efficacy of myelin‐modulating therapies. However, registration techniques for image quantification and statistical comparison of affected pediatric brains, especially those of low or deviant image tissue contrast, with healthy controls are not yet established. This study aimed first to develop and compare postprocessing pipelines for atlas‐based quantification of qMRI data in pediatric patients with PMD and evaluate their registration accuracy. Second, to apply an optimized pipeline to investigate spatial myelin deficiency using myelin water imaging (MWI) data from patients with PMD and healthy controls. This retrospective single‐center study included five patients with PMD (mean age, 6 years ± 3.8) who underwent conventional brain MRI and diffusion tensor imaging (DTI), with MWI data available for a subset of patients. Three methods of registering PMD images to a pediatric template were investigated. These were based on (a) T1‐weighted (T1w) images, (b) fractional anisotropy (FA) maps, and (c) a combination of T1w, T2‐weighted, and FA images in a multimodal approach. Registration accuracy was determined by visual inspection and calculated using the structural similarity index method (SSIM). SSIM values for the registration approaches were compared using a t test. Myelin water fraction (MWF) was quantified from MWI data as an assessment of relative myelination. Mean MWF was obtained from two PMDs (mean age, 3.1 years ± 0.3) within four major white matter (WM) pathways of a pediatric atlas and compared to seven healthy controls (mean age, 3 years ± 0.2) using a Mann–Whitney U test. Our results show that visual registration accuracy estimation and computed SSIM were highest for FA‐based registration, followed by multimodal, and T1w‐based registration (SSIMFA = 0.67 ± 0.04 vs. SSIMmultimodal = 0.60 ± 0.03 vs. SSIMT1 = 0.40 ± 0.14). Mean MWF of patients with PMD within the WM pathways was significantly lower than in healthy controls MWFPMD = 0.0267 ± 0.021 vs. MWFcontrols = 0.1299 ± 0.039. Specifically, MWF was measurable in brain structures known to be myelinated at birth (brainstem) or postnatally (projection fibers) but was scarcely detectable in other brain regions (commissural and association fibers). Taken together, our results indicate that registration accuracy was highest with an FA‐based registration pipeline, providing an alternative to conventional T1w‐based registration approaches in the case of hypomyelinating leukodystrophies missing normative intrinsic tissue contrasts. The applied atlas‐based analysis of MWF data revealed that the extent of spatial myelin deficiency in patients with PMD was most pronounced in commissural and association and to a lesser degree in brainstem and projection pathways. [ABSTRACT FROM AUTHOR]

Introduction: Alexander disease (AxD) is a rare leukodystrophy caused by dominant gain-of-function mutations in the gene encoding the astrocyte intermediate filament, glial fibrillary acidic protein (GFAP). However, there is an urgent need for biomarkers to assist in monitoring not only the progression of disease but also the response to treatment. GFAP is the obvious candidate for such a biomarker, as it is measurable in body fluids that are readily accessible for biopsy, namely cerebrospinal fluid and blood. However, in the case of ASOs, the treatment that is furthest in development, GFAP is the target of therapy and presumably would go down independent of disease status. Hence, there is a critical need for biomarkers that are not directly affected by the treatment strategy. Methods: We explored the potential utility of biomarkers currently being studied in other neurodegenerative diseases and injuries, specifically neurofilament light protein (NfL), phosphorylated forms of tau, and amyloid-β peptides (Aβ42/40). Results and Conclusions: Here, we report that GFAP is elevated in plasma of all age groups afflicted by AxD, including those with adult onset. NfL and p-tau are also elevated, but to a much lesser extent than GFAP. In contrast, the levels of Aß40 and Aß42 are not altered in AxD. [ABSTRACT FROM AUTHOR]

Background: Leukodystrophies are a group of rare genetic diseases that primarily affect the white matter of the central nervous system. The broad spectrum of metabolic and pathological causes leads to manifestations at any age, most often in childhood and adolescence, and a variety of symptoms. Leukodystrophies are usually progressive, resulting in severe disabilities and premature death. Progressive visual impairment is a common symptom. Currently, no overview of the manifold neuro-ophthalmologic manifestations and visual impact of leukodystrophies exists. Methods: Data from 217 patients in the Hamburg leukodystrophy cohort were analyzed retrospectively for neuro-ophthalmologic manifestations, age of disease onset, and magnetic resonance imaging, visual evoked potential, and optical coherence tomography findings and were compared with data from the literature. Results: In total, 68% of the patients suffered from neuro-ophthalmologic symptoms, such as optic atrophy, visual neglect, strabismus, and nystagmus. Depending on the type of leukodystrophy, neuro-ophthalmologic symptoms occurred early or late during the course of the disease. Magnetic resonance imaging scans revealed pathologic alterations in the visual tract that were temporally correlated with symptoms. Conclusions: The first optical coherence tomography findings in Krabbe disease and metachromatic leukodystrophy allow retinal assessments. Comprehensive literature research supports the results of this first overview of neuro-ophthalmologic findings in leukodystrophies. [ABSTRACT FROM AUTHOR]

AI-CDSS can significantly enhance the decision-making performance of physicians who are not specialists in diagnosing rare diseases. Acceptance of the AI-CDSS is crucial for its effective use. In the Leuko-Expert project, the factors influencing physician acceptance of AI-CDSS were examined. This article introduces how these influencing factors were identified through a systematic review. Subsequently, semi-structured interviews were conducted to explore additional influencing factors for the use of AI-CDSS in the context of leukodystrophy. Finally, we discuss the limitations of transferring these findings to other rare disease cases and suggest directions for future research. [ABSTRACT FROM AUTHOR]

The CSF1R gene, located on chromosome 5, encodes a 108 kDa protein and plays a critical role in regulating myeloid cell function. Mutations in CSF1R have been identified as a cause of a rare white matter disease called adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP, also known as CSF1R-related leukoencephalopathy), characterized by progressive neurological dysfunction. This study aimed to broaden the genetic basis of ALSP by identifying novel CSF1R variants in patients with characteristic clinical and imaging features of ALSP. Genetic analysis was performed through whole-exome sequencing or panel analysis for leukodystrophy genes. Variant annotation and classification were conducted using computational tools, and the identified variants were categorized following the recommendations of the American College of Medical Genetics and Genomics (ACMG). To assess the evolutionary conservation of the novel variants within the CSF1R protein, amino acid sequences were compared across different species. The study identified six previously unreported CSF1R variants (c.2384G>T, c.2133_2919del, c.1837G>A, c.2304C>A, c.2517G>T, c.2642C>T) in seven patients with ALSP, contributing to the expanding knowledge of the genetic diversity underlying this rare disease. The analysis revealed considerable genetic and clinical heterogeneity among these patients. The findings emphasize the need for a comprehensive understanding of the genetic basis of rare diseases like ALSP and underscored the importance of genetic testing, even in cases with no family history of the disease. The study's contribution to the growing spectrum of ALSP genetics and phenotypes enhances our knowledge of this condition, which can be crucial for both diagnosis and potential future treatments. [ABSTRACT FROM AUTHOR]

The balance between a protective and a destructive immune response can be precarious, as exemplified by inborn errors in nucleotide metabolism. This class of inherited disorders, which mimics infection, can result in systemic injury and severe neurologic outcomes. The most common of these disorders is Aicardi Goutières syndrome (AGS). AGS results in a phenotype similar to "TORCH" infections (Toxoplasma gondii, Other [Zika virus (ZIKV), human immunodeficiency virus (HIV)], Rubella virus, human Cytomegalovirus [HCMV], and Herpesviruses), but with sustained inflammation and ongoing potential for complications. AGS was first described in the early 1980s as familial clusters of "TORCH" infections, with severe neurology impairment, microcephaly, and basal ganglia calcifications (Aicardi & Goutières, Ann Neurol, 1984;15:49–54) and was associated with chronic cerebrospinal fluid (CSF) lymphocytosis and elevated type I interferon levels (Goutières et al., Ann Neurol, 1998;44:900–907). Since its first description, the clinical spectrum of AGS has dramatically expanded from the initial cohorts of children with severe impairment to including individuals with average intelligence and mild spastic paraparesis. This broad spectrum of potential clinical manifestations can result in a delayed diagnosis, which families cite as a major stressor. Additionally, a timely diagnosis is increasingly critical with emerging therapies targeting the interferon signaling pathway. Despite the many gains in understanding about AGS, there are still many gaps in our understanding of the cell‐type drivers of pathology and characterization of modifying variables that influence clinical outcomes and achievement of timely diagnosis. [ABSTRACT FROM AUTHOR]

Importance: Aicardi–Goutières syndrome (AGS) is a rare genetic disorder mainly affecting the central nervous system and autoimmunity. However, research on AGS among Chinese patients is limited. Objective: To summarize the neurologic phenotypes and genetic causes in pediatric AGS patients, providing insights for early recognition and diagnosis in the Chinese population. Methods: Clinical features and neuroimaging results of the patients diagnosed with AGS from Beijing Children's Hospital between January 2018 and January 2022 were collected. Whole exome sequencing was used for genetic analysis. Results: A total of 15 patients was included, all presenting with various neurological symptoms, including developmental delay (100%), motor skill impairment (100%), language disability (78.6%), dystonia (93.3%), microcephaly (73.3%), sleep disorders (26.7%), regression (20.0%), vessel disease (6.7%), and epilepsy (6.7%). Neuroimaging revealed intracranial calcification (86.7%), cerebral atrophy (73.3%), and leukodystrophy (73.3%). Seven genes were identified, with TREX1 being the most common (40.0%, 6/15), followed by IFIH1 (20.0%, 3/15). Variant c.294dupA (p.C99Mfs*3) was detected in four unrelated patients, accounting for 66.7% (4/6) patients with the TREX1 variant. A literature review showed that TREX1 gene mutations in 35.6% (21/59) of AGS patients among the Chinese population. Interpretation: Neurological symptoms are the most prevalent and severe presentation of AGS. Diagnosis may be considered when symptoms such as developmental delay, dystonia, microcephaly, brain calcification, and leukodystrophy emerge. TREX1 mutations are predominant in the Chinese population. [ABSTRACT FROM AUTHOR]

Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two neuroprotective and anti-inflammatory molecules of the central nervous system (CNS). Both bind to three G protein-coupled receptors, namely PAC1, VPAC1 and VPAC2, to elicit their beneficial effects in various CNS diseases, including multiple sclerosis (MS). In this study, we assessed the expression and distribution of PACAP/VIP receptors in the normal-appearing white matter (NAWM) of MS donors with a clinical history of either relapsing–remitting MS (RRMS), primary MS (PPMS), secondary progressive MS (SPMS) or in aged-matched non-MS controls. Gene expression studies revealed MS-subtype specific changes in PACAP and VIP and in the receptors' levels in the NAWM, which were partly corroborated by immunohistochemical analyses. Most PAC1 immunoreactivity was restricted to myelin-producing cells, whereas VPAC1 reactivity was diffused within the neuropil and in axonal bundles, and VPAC2 in small vessel walls. Within and around lesioned areas, glial cells were the predominant populations showing reactivity for the different PACAP/VIP receptors, with distinctive patterns across MS subtypes. Together, these data identify the differential expression patterns of PACAP/VIP receptors among the different MS clinical entities. These results may offer opportunities for the development of personalized therapeutic approaches to treating MS and/or other demyelinating disorders. [ABSTRACT FROM AUTHOR]

In addition to focal lesions, diffusely abnormal white matter (DAWM) is seen on brain MRI of multiple sclerosis (MS) patients and may represent early or distinct disease processes. The role of MRI-observed DAWM is understudied due to a lack of automated assessment methods. Supervised deep learning (DL) methods are highly capable in this domain, but require large sets of labeled data. To overcome this challenge, a DL-based network (DAWM-Net) was trained using semi-supervised learning on a limited set of labeled data for segmentation of DAWM, focal lesions, and normal-appearing brain tissues on multiparametric MRI. DAWM-Net segmentation performance was compared to a previous intensity thresholding-based method on an independent test set from expert consensus (N = 25). Segmentation overlap by Dice Similarity Coefficient (DSC) and Spearman correlation of DAWM volumes were assessed. DAWM-Net showed DSC > 0.93 for normal-appearing brain tissues and DSC > 0.81 for focal lesions. For DAWM-Net, the DAWM DSC was 0.49 ± 0.12 with a moderate volume correlation (ρ = 0.52, p < 0.01). The previous method showed lower DAWM DSC of 0.26 ± 0.08 and lacked a significant volume correlation (ρ = 0.23, p = 0.27). These results demonstrate the feasibility of DL-based DAWM auto-segmentation with semi-supervised learning. This tool may facilitate future investigation of the role of DAWM in MS. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy (MLD) is a fatal, progressive neurodegenerative disorder caused by biallelic pathogenic mutations in the ARSA (Arylsulfatase A) gene. With the advent of presymptomatic diagnosis and the availability of therapies with a narrow window for intervention, it is critical to define a standardized approach to diagnosis, presymptomatic monitoring, and clinical care. To meet the needs of the MLD community, a panel of MLD experts was established to develop disease-specific guidelines based on healthcare resources in the United States. This group developed a consensus opinion for best-practice recommendations, as follows: (i) Diagnosis should include both genetic and biochemical testing; (ii) Early diagnosis and treatment for MLD is associated with improved clinical outcomes; (iii) The panel supported the development of newborn screening to accelerate the time to diagnosis and treatment; (iv) Clinical management of MLD should include specialists familiar with the disease who are able to follow patients longitudinally; (v) In early onset MLD, including late infantile and early juvenile subtypes, ex vivo gene therapy should be considered for presymptomatic patients where available; (vi) In late-onset MLD, including late juvenile and adult subtypes, hematopoietic cell transplant (HCT) should be considered for patients with no or minimal disease involvement. This document summarizes current guidance on the presymptomatic monitoring of children affected by MLD as well as the clinical management of symptomatic patients. Future data-driven evidence and evolution of these recommendations will be important to stratify clinical treatment options and improve clinical care. [ABSTRACT FROM AUTHOR]

Objective: POLR3-HLD or 4H leukodystrophy is an autosomal recessive disorder characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, and caused by variants in POLR3A, POLR3B, POLR1C, or POLR3K genes. Neurological and non-neurological clinical features and disease severity vary. While previous studies reference variable cognition, this is the first report of 4H detailing a comprehensive neuropsychological assessment. Method: The current study presents a 20-year-old, English-speaking, right-handed, non-Hispanic White female with 12 years of education with genetically confirmed 4H POLR3B-related leukodystrophy without hormonal replacement treatment. Results: At age 4, developmental delays, ataxia, hearing loss, and abnormal dentition were present. Imaging, endocrinology, and neurologic examinations revealed hypomyelination, reduced cerebellar volume, delayed bone age density, osteopenia, and evidence of adrenarche without signs of true puberty. Neuropsychological assessment at age 20 revealed global cognitive impairment with intellectual, attention, verbal memory retrieval, construction, executive (e.g. processing speed, sustained attention) and math computation deficits, along with behavioral dysregulation. Conclusion: We present the first detailed neuropsychological assessment of a patient with 4H leukodystrophy. The neuropsychological assessment revealed cognitive and behavioral dysexecutive deficits aligning with hypomyelination observed on imaging. Further longitudinal studies are needed to shed light on the neurobehavioral presentation associated with this disorder to assist care providers, patients, and their families. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy (MLD) is a neuro-metabolic disorder due to arylsulfatase A deficiency, causing demyelination of the central and peripheral nervous system. Hematopoietic cell transplantation (HCT) can provide a symptomatic and survival benefit for pre-symptomatic and early symptomatic patients by stabilizing CNS disease. This case series, however, illustrates the occurrence of severely progressive polyneuropathy shortly after HCT in two patients with late-infantile, one with late-juvenile, and one with adult MLD, leading to the inability to walk or sit without support. The patients had demyelinating polyneuropathy before HCT, performed at the ages of 2 years in the first two patients and at 14 and 23 years in the other two patients. The myeloablative conditioning regimen consisted of busulfan, fludarabine and, in one case, rituximab, with anti-thymocyte globulin, cyclosporine, steroids, and/or mycophenolate mofetil for GvHD prophylaxis. Polyneuropathy after HCT progressed parallel with tapering immunosuppression and paralleled bouts of infection and graft-versus-host disease (GvHD). Differential diagnoses included MLD progression, neurological GvHD or another (auto)inflammatory cause. Laboratory, electroneurography and pathology investigations were inconclusive. In two patients, treatment with immunomodulatory drugs led to temporary improvement, but not sustained stabilization of polyneuropathy. One patient showed recovery to pre-HCT functioning, except for a Holmes-like tremor, for which a peripheral origin cannot be excluded. One patient showed marginal response to immunosuppressive treatment and died ten months after HCT due to respiratory failure. The extensive diagnostic and therapeutic attempts highlight the challenge of characterizing and treating progressive polyneuropathy in patients with MLD shortly after HCT. We advise to consider repeat electro-neurography and possibly peripheral nerve biopsy in such patients. Nerve conduction blocks, evidence of the presence of T lymphocytes and macrophages in the neuronal and surrounding nerve tissue, and beneficial effects of immunomodulatory drugs may indicate a partially (auto)immune-mediated pathology. Polyneuropathy may cause major residual disease burden after HCT. MLD patients with progressive polyneuropathy could potentially benefit from a more intensified immunomodulatory drug regime following HCT, especially at times of immune activation. [ABSTRACT FROM AUTHOR]

Cell-based interception and precision medicine is a novel approach aimed at improving healthcare through the early detection and treatment of diseased cells. Here, we describe our recent progress towards developing cell-based interception and precision medicine to detect, understand, and advance the development of novel therapeutic approaches through a single-cell omics and drug screening platform, as part of a multi-laboratory collaborative effort, for a group of neurodegenerative disorders named leukodystrophies. Our strategy aims at the identification of diseased cells as early as possible to intercept progression of the disease prior to severe clinical impairment and irreversible tissue damage. [ABSTRACT FROM AUTHOR]

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder characterized by arylsulfatase A (ASA) deficiency, leading to sulfatide accumulation and myelin degeneration in the central nervous system. While primarily considered a white matter (WM) disease, gray matter (GM) is also affected in MLD, and hematopoietic stem cell transplantation (HSCT) may have limited effect on GM atrophy. We cross‐sectionally and longitudinally studied GM volumes using volumetric MRI in a cohort of 36 (late‐infantile, juvenile and adult type) MLD patients containing untreated and HSCT treated subjects. Cerebrum, cortical GM, (total) CSF, cerebellum, deep gray matter (DGM) (excluding thalamus) and thalamus volumes were analyzed. Longitudinal correlations with measures of cognitive and motor functioning were assessed. Cross‐sectionally, juvenile and adult type patients (infantiles excluded based on limited numbers) were compared with controls at earliest scan, before possible treatment. Patients had lower cerebrum, cortical GM, DGM and thalamus volumes. Differences were most pronounced for adult type patients. Longitudinal analyses showed substantial and progressive atrophy of all regions and increase of CSF in untreated patients. Similar, albeit less pronounced, effects were seen in treated patients for cerebrum, cortical GM, CSF and thalamus volumes. Deterioration in motor performance (all patients) was related to atrophy, and increase of CSF, in all regions. Cognitive functioning (data available for treated patients) was related to cerebral, cortical GM and thalamus atrophy; and to CSF increase. Our findings illustrate the importance of recognizing GM pathology as a potentially substantial, clinically relevant part of MLD, apparently less amenable to treatment. [ABSTRACT FROM AUTHOR]

BackgroundIron–sulfur cluster assembly 2 (ISCA2) deficiency is linked to an autosomal recessive disorder known as multiple mitochondrial dysfunctions syndrome 4 (MMDS4). This disorder is characterized by leukodystrophy and neuroregression. Currently, most of the reported patients are from Saudi Arabia. All these patients carry a homozygous founder variant (NM_194279.2:c.229G>A:p.Gly77Ser) in ISCA2.MethodsWe describe a patient who underwent full clinical evaluation, including metabolic, neurological, and radiological examinations. Standard genetic testing, including whole exome sequencing coupled with autozygome analysis, was undertaken, as were assessments of mitochondrial DNA (mtDNA) copy number and mtDNA sequencing on DNA extracted from blood and cultured fibroblasts. Functional workup consisted of splicing assessment of ISCA2 using RT-PCR, biochemical assessment of complex I status using dipstick assays, and mitochondrial respiration measurements using a Seahorse XFp analyzer.ResultsWe present the clinical and functional characterization of a novel homozygous ISCA2 missense variant (NM_194279.3:c.70A>G:p.Arg24Gly), leading to aberrant splicing in a patient presenting with neuroregression, generalized spasticity with exaggerated deep tendon reflexes and head lag, and progressive loss of acquired milestones. The novel variant was fully segregated in a wider family and was absent in a large control cohort, ethnically matching in-house exomes, local databases such as CGMdb and Saudi Human Genome Program, and ClinVar.ConclusionsOur analyses revealed that the variant is pathogenic, disrupting normal ISCA2 splicing and presumably leading to a truncated protein that disturbs metabolic pathways in patient-derived cells.

BACKGROUND: Globoid cell leukodystrophy (GCL) is a fatal autosomal recessive disease caused by variants in the galactosylceramidase (GALC) gene. Two dog breed-specific variants are reported. OBJECTIVES: Characterize the putatively causative GALC variant for GCL in a family of dogs and determine population allele frequency. ANIMALS: Four related mixed-breed puppies with signs of neurologic disease were evaluated. Subsequently, 33 related dogs were tested for genetic markers for parentage and the identified GALC variant. Additional GALC genotyping was performed on 278 banked samples from various breeds. METHODS: The 4 affected puppies had neurological exams and necropsies. DNA was isolated from blood samples. Variants in GALC were identified via Sanger sequencing. Parentage testing was performed using short tandem repeat markers. Prevalence of the GALC variant of interest was investigated in other breeds. RESULTS: GCL was confirmed histopathologically. A novel missense variant in GALC (NC_006590.4:g.58893972G>A) was homozygous in all affected animals (n = 4). A recessive mode of inheritance was confirmed by parentage testing as was variant linkage with the phenotype (LOD = 3.36). Among the related dogs (n = 33), 3 dogs were homozygous and 7 heterozygous. The variant allele was not detected in screening 278 dogs from 5 breeds. The novel variant is either unique to this family or has an extremely low allele frequency in the general population. CONCLUSIONS AND CLINICAL IMPORTANCE: A novel GALC variant was identified that likely explains GCL in this cohort. The identification of multiple causal variants for GCL in dogs is consistent with findings in humans.