The effect of intrathecal recombinant arylsulfatase A therapy on structural brain magnetic resonance imaging in children with metachromatic leukodystrophy.

This study aimed to evaluate the effect of intrathecal (IT) recombinant human arylsulfatase A (rhASA) on magnetic resonance imaging (MRI)-assessed brain tissue changes in children with metachromatic leukodystrophy (MLD). In total, 510 MRI scans were collected from 12 intravenous (IV) rhASA-treated children with MLD, 24 IT rhASA-treated children with MLD, 32 children with untreated MLD, and 156 normally developing children. Linear mixed models were fitted to analyze the time courses of gray matter (GM) volume and fractional anisotropy (FA) in the posterior limb of the internal capsule. Time courses for demyelination load and FA in the centrum semiovale were visualized using locally estimated scatterplot smoothing regression curves. All assessed imaging parameters demonstrated structural evidence of neurological deterioration in children with MLD. GM volume was significantly lower at follow-up (median duration, 104 weeks) in IV rhASA-treated versus IT rhASA-treated children. GM volume decline over time was steeper in children receiving low-dose (10 or 30 mg) versus high-dose (100 mg) IT rhASA. Similar effects were observed for demyelination. FA in the posterior limb of the internal capsule showed a higher trend over time in IT rhASA-treated versus children with untreated MLD, but FA parameters were not different between children receiving the low doses versus those receiving the high dose. GM volume in IT rhASA-treated children showed a strong positive correlation with 88-item Gross Motor Function Measure score over time. In some children with MLD, IT administration of high-dose rhASA may delay neurological deterioration (assessed using MRI), offering potential therapeutic benefit.

Spatially regularized low-rank tensor approximation for accurate and fast tractography.

Tractography based on diffusion Magnetic Resonance Imaging (dMRI) is the prevalent approach to the in vivo delineation of white matter tracts in the human brain. Many tractography methods rely on models of multiple fiber compartments, but the local dMRI information is not always sufficient to reliably estimate the directions of secondary fibers. Therefore, we introduce two novel approaches that use spatial regularization to make multi-fiber tractography more stable. Both represent the fiber Orientation Distribution Function (fODF) as a symmetric fourth-order tensor, and recover multiple fiber orientations via low-rank approximation. Our first approach computes a joint approximation over suitably weighted local neighborhoods with an efficient alternating optimization. The second approach integrates the low-rank approximation into a current state-of-the-art tractography algorithm based on the unscented Kalman filter (UKF). These methods were applied in three different scenarios. First, we demonstrate that they improve tractography even in high-quality data from the Human Connectome Project, and that they maintain useful results with a small fraction of the measurements. Second, on the 2015 ISMRM tractography challenge, they increase overlap, while reducing overreach, compared to low-rank approximation without joint optimization or the traditional UKF, respectively. Finally, our methods permit a more comprehensive reconstruction of tracts surrounding a tumor in a clinical dataset. Overall, both approaches improve reconstruction quality. At the same time, our modified UKF significantly reduces the computational effort compared to its traditional counterpart, and to our joint approximation. However, when used with ROI-based seeding, joint approximation more fully recovers fiber spread.

Clinical Significance of Diffusion Tensor Imaging in Metachromatic Leukodystrophy.

BACKGROUND: Metachromatic leukodystrophy (MLD) is a lysosomal enzyme deficiency disorder leading to progressive demyelination and, consecutively, to cognitive and motor decline. Brain magnetic resonance imaging (MRI) can detect affected white matter as T2 hyperintense areas but cannot quantify the gradual microstructural process of demyelination more accurately. Our study aimed to investigate the value of routine MR diffusion tensor imaging in assessing disease progression. METHODS: MR diffusion parameters (apparent diffusion coefficient [ADC] and fractional anisotropy [FA]) were in the frontal white matter, central region (CR), and posterior limb of the internal capsule in 111 MR datasets from a natural history study of 83 patients (age: 0.5-39.9 years; 35 late-infantile, 45 juvenile, 3 adult, with clinical diffusion sequences of different scanner manufacturers) as well as 120 controls. Results were correlated with clinical parameters reflecting motor and cognitive function. RESULTS: ADC values increase and FA values decrease depending on disease stage/severity. They show region-specific correlations with clinical parameters of motor and cognitive symptoms, respectively. Higher ADC levels in CR at diagnosis predicted a disease course with more rapid motor deterioration in juvenile MLD patients. In highly organized tissues such as the corticospinal tract, in particular, diffusion MR parameters were highly sensitive to MLD-associated changes and did not correlate with the visual quantification of T2 hyperintensities. CONCLUSION: Our results show that diffusion MRI can deliver valuable, robust, clinically meaningful, and easily obtainable/accessible/available parameters in the assessment of prognosis and progression of MLD. Therefore, it provides additional quantifiable information to established methods such as T2 hyperintensity.

Human COQ4 deficiency: delineating the clinical, metabolic and neuroimaging phenotypes.

BACKGROUND: Human coenzyme Q4 (COQ4) is essential for coenzyme Q10 (CoQ10) biosynthesis. Pathogenic variants in COQ4 cause childhood-onset neurodegeneration. We aimed to delineate the clinical spectrum and the cellular consequences of COQ4 deficiency. METHODS: Clinical course and neuroradiological findings in a large cohort of paediatric patients with COQ4 deficiency were analysed. Functional studies in patient-derived cell lines were performed. RESULTS: We characterised 44 individuals from 36 families with COQ4 deficiency (16 newly described). A total of 23 different variants were identified, including four novel variants in COQ4. Correlation analyses of clinical and neuroimaging findings revealed three disease patterns: type 1: early-onset phenotype with neonatal brain anomalies and epileptic encephalopathy; type 2: intermediate phenotype with distinct stroke-like lesions; and type 3: moderate phenotype with non-specific brain pathology and a stable disease course. The functional relevance of COQ4 variants was supported by in vitro studies using patient-derived fibroblast lines. Experiments revealed significantly decreased COQ4 protein levels, reduced levels of cellular CoQ10 and elevated levels of the metabolic intermediate 6-demethoxyubiquinone. CONCLUSION: Our study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of COQ4 variants. Due to the insufficient clinical response to oral CoQ10 supplementation, alternative treatment strategies are warranted.

Predicting clinical phenotypes of metachromatic leukodystrophy based on the arylsulfatase A activity and the ARSA genotype? - Chances and challenges.

OBJECTIVES: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficiency of arylsulfatase A (ARSA). Subsequent accumulation of sulfatides leads to demyelination and neurodegeneration in the central and peripheral nervous system. To date MLD is classified based on the age at onset, however, especially for late onset forms this classification provides only limited projection regarding the clinical disease course. Moreover, evolving newborn screening approaches raise the need to predict the disease onset and course in pre-symptomatic individuals. Here, we correlate the ARSA activity and the ARSA-genotype with clinical parameters in a large cohort of 96 affected individuals. MATERIALS AND METHODS: Clinical data of 96 affected individuals with genetically and/or biochemically confirmed MLD were collected from a national database. Leukocyte samples from 69 affected individuals were re-analyzed for the ARSA activity using p-nitrocatecholsulfate as substrate with a refined ARSA assay towards the lower limit of detection. For 84 individuals genetic sequencing was conducted by Sanger or next generation sequencing (NGS). RESULTS: The adapted ARSA assay revealed the discriminatory power to differentiate MLD subtypes as the residual enzyme activity was low in late infantile and early juvenile forms, and clearly higher in late juvenile and adult MLD (p < 0.001). A residual enzyme activity below 1% compared to controls predicted an early onset (late-infantile or early-juvenile) and rapid disease progression. A firm genotype-phenotype correlation was proven as reliable for bi-allelic protein-truncating variants in the ARSA gene resulting in minimal residual ARSA activity, an early onset of the disease and initial decline of motor functions. Although the impact of missense variants was equivocal, few variants with a recognizable clinical spectrum were identified. DISCUSSION: ARSA activity in leukocytes as well as the ARSA genotype can predict the age of disease onset and the dynamic of disease progression for most of the early onset forms. This knowledge is relevant for patient counseling and to guide treatment decisions, especially when identifying pre-symptomatic individuals, e.g., in newborn screening. However, due to the high cumulative frequency of rare disease-causing missense variants in the ARSA gene that lead to highly variable residual enzyme activity, reiterated biochemical and genetic studies are needed to improve disease course prediction.

Natural history of multiple sulfatase deficiency: Retrospective phenotyping and functional variant analysis to characterize an ultra-rare disease.

Multiple sulfatase deficiency (MSD) is an ultra-rare neurodegenerative disorder caused by pathogenic variants in SUMF1. This gene encodes formylglycine-generating enzyme (FGE), a protein required for sulfatase activation. The clinical course of MSD results from additive effect of each sulfatase deficiency, including metachromatic leukodystrophy (MLD), several mucopolysaccharidoses (MPS II, IIIA, IIID, IIIE, IVA, VI), chondrodysplasia punctata, and X-linked ichthyosis. While it is known that affected individuals demonstrate a complex and severe phenotype, the genotype-phenotype relationship and detailed clinical course is unknown. We report on 35 cases enrolled in our retrospective natural history study, n = 32 with detailed histories. Neurologic function was longitudinally assessed with retrospective scales. Biochemical and computational modeling of novel SUMF1 variants was performed. Genotypes were classified based on predicted functional change, and each individual was assigned a genotype severity score. The median age at symptom onset was 0.25 years; median age at diagnosis was 2.7 years; and median age at death was 13 years. All individuals demonstrated developmental delay, and only a subset of individuals attained ambulation and verbal communication. All subjects experienced an accumulating systemic symptom burden. Earlier age at symptom onset and severe variant pathogenicity correlated with poor neurologic outcomes. Using retrospective deep phenotyping and detailed variant analysis, we defined the natural history of MSD. We found that attenuated cases can be distinguished from severe cases by age of onset, attainment of ambulation, and genotype. Results from this study can help inform prognosis and facilitate future study design.

Comparative Analysis of Cerebral Magnetic Resonance Imaging Changes in Nontreated Infantile, Juvenile and Adult Patients with Niemann-Pick Disease Type C.

AIM: The study aims to describe cerebral MRI in different onset forms of Niemann-Pick type C (NPC). Systematic MRI analyses in this rare lysosomal storage disease are lacking in the infantile and juvenile onset forms. METHODS: Thirty-two cerebral MRI scans from 19 patients with NPC were assessed using a newly established and validated scoring system which addresses white matter changes and supratentorial versus infratentorial atrophy. RESULTS: Seven scans were from six NPC patients with early infantile onset (<2 years of age), six scans were from three patients with late infantile onset (2-6 years), six scans from four with juvenile onset (6-15 years), and 13 from six with adult onset (>15 years). While supratentorial atrophy was the leading sign in the infantile groups, the juvenile and adult forms were characterized by both, infra- and supratentorial atrophy. White matter changes were found in nearly every patient; they increased with the disease duration in the earlier forms and were prominent in the later forms already early in the disease course. CONCLUSION: This is the first systematic and comparative MRI analysis in the different onset groups of NPC using a scoring system. Early during disease course, MRI showed different patterns in infantile compared with juvenile and adult onset NPC patients, for example, only supratentorial atrophy in juvenile versus global atrophy in adult onset patients. MRI changes provide an additional, early biomarker for NPC.

SHORE-based detection and imputation of dropout in diffusion MRI.

PURPOSE: In diffusion MRI, dropout refers to a strong attenuation of the measured signal that is caused by bulk motion during the diffusion encoding. When left uncorrected, dropout will be erroneously interpreted as high diffusivity in the affected direction. We present a method to automatically detect dropout, and to replace the affected measurements with imputed values. METHODS: Signal dropout is detected by deriving an outlier score from a simple harmonic oscillator-based reconstruction and estimation (SHORE) fit of all measurements. The outlier score is defined to detect measurements that are substantially lower than predicted by SHORE in a relative sense, while being less sensitive to measurement noise in cases of weak baseline signal. A second SHORE fit is based on detected inliers only, and its predictions are used to replace outliers. RESULTS: Our method is shown to reliably detect and accurately impute dropout in simulated data, and to achieve plausible results in corrupted in vivo dMRI measurements. Computational effort is much lower than with previously proposed alternatives. CONCLUSIONS: Deriving a suitable outlier score from SHORE results in a fast and accurate method for detection and imputation of dropout in diffusion MRI. It requires measurements with multiple b values (such as multi-shell or DSI), but is independent from the models used for analysis (such as DKI, NODDI, deconvolution, etc.).

Role of presurgical functional MRI and diffusion MR tractography in pediatric low-grade brain tumor surgery: a single-center study.

PURPOSE: Presurgical functional MRI (fMRI) and diffusion MRI tractography (dMRI tractography) are widely employed to delineate eloquent brain regions and their connections prior to brain tumor resection in adults. However, such studies are harder to perform in children, resulting in suboptimal neurosurgical care in pediatric brain tumor surgery as compared to adults. Thus, our objective was to assess the feasibility and the influence of presurgical advanced MR imaging on neurosurgical care in pediatric brain tumor surgery. METHODS: Retrospective analyses of 31 presurgical fMRI/dMRI tractography studies were performed in children with low-grade tumors near eloquent brain regions at our site between 2005 and 2017. RESULTS: In only 3/31 cases, imaging results were not interpretable (10%). All 28 successful imaging sessions were used for neurosurgical risk assessment. Based on this, surgery was canceled in 2/28 patients, and intention to treat was changed in 5/28 patients. In 4/28 cases, the surgical approach was changed and in 10/28, electrode placement for intraoperative neurophysiological monitoring was guided by imaging results. Gross total resection (GTR) was planned in 21/28 cases and could be achieved in 15/21 (71%). Despite highly eloquent tumor location, only four children suffered from a mild permanent neurological deficit after the operation. CONCLUSIONS: We demonstrate that presurgical fMRI/dMRI tractography can have a profound impact on pediatric brain tumor management, optimizing preoperative risk-assessment and pre- as well as intraoperative decision-making. We believe that these tools should be offered to children suffering from eloquent brain tumors as part of a comprehensive operative work-up.

Predicting hand function after hemidisconnection.

Hemidisconnections (i.e. hemispherectomies or hemispherotomies) invariably lead to contralateral hemiparesis. Many patients with a pre-existing hemiparesis, however, experience no deterioration in motor functions, and some can still grasp with their paretic hand after hemidisconnection. The scope of our study was to predict this phenomenon. Hypothesizing that preserved contralateral grasping ability after hemidisconnection can only occur in patients controlling their paretic hands via ipsilateral corticospinal projections already in the preoperative situation, we analysed the asymmetries of the brainstem (by manual magnetic resonance imaging volumetry) and of the structural connectivity of the corticospinal tracts within the brainstem (by magnetic resonance imaging diffusion tractography), assuming that marked hypoplasia or Wallerian degeneration on the lesioned side in patients who can grasp with their paretic hands indicate ipsilateral control. One hundred and two patients who underwent hemidisconnections between 0.8 and 36 years of age were included. Before the operation, contralateral hand function was normal in 3/102 patients, 47/102 patients showed hemiparetic grasping ability and 52/102 patients could not grasp with their paretic hands. After hemidisconnection, 20/102 patients showed a preserved grasping ability, and 5/102 patients began to grasp with their paretic hands only after the operation. All these 25 patients suffered from pre- or perinatal brain lesions. Thirty of 102 patients lost their grasping ability. This group included all seven patients with a post-neonatally acquired or progressive brain lesion who could grasp before the operation, and also all three patients with a preoperatively normal hand function. The remaining 52/102 patients were unable to grasp pre- and postoperatively. On magnetic resonance imaging, the patients with preserved grasping showed significantly more asymmetric brainstem volumes than the patients who lost their grasping ability. Similarly, these patients showed striking asymmetries in the structural connectivity of the corticospinal tracts. In summary, normal preoperative hand function and a post-neonatally acquired or progressive lesion predict a loss of grasping ability after hemidisconnection. A postoperatively preserved grasping ability is possible in hemiparetic patients with pre- or perinatal lesions, and this is highly likely when the brainstem is asymmetric and especially when the structural connectivity of the corticospinal tracts within the brainstem is asymmetric.

Association of transcallosal motor fibres with function of both hands after unilateral neonatal arterial ischemic stroke.

AIM: The objective of this study was to investigate the involvement of the motor fibres of the corpus callosum after unilateral neonatal arterial ischemic stroke (NAIS) of the middle cerebral artery territory and the relationship to both ipsilesional and contralesional hand function. METHOD: Using high-resolution structural magnetic resonance imaging (MRI), functional MRI, and magnetic resonance diffusion-tractography, we compared the midsagittal area of the motor part of the corpus callosum (defined by the fibres connecting the precentral gyri) between 33 7-year-old children after unilateral NAIS and 31 typically developing 7-year-old children. Hand motor performance was assessed by the box and blocks test. RESULTS: Children after NAIS showed on average significantly smaller motor corpus callosum area compared to typically developing children (p<0.001, without differences of the non-motor corpus callosum area). In addition, there was a significant positive association between the motor part of the corpus callosum and both contralesional (Pr(>|t|)=0.034) and ipsilesional hand motor performance (Pr(>|t|)=0.006) after controlling for lesion volume and sex. In a post-hoc analysis the additional contribution of corticospinal tract damage was evaluated. INTERPRETATION: Compared to typically developing children, children after NAIS exhibited a smaller motor part of their corpus callosum associated with reduced contralesional but also ipsilesional manual dexterity. These results indicate that the affection of transcallosal motor fibres in unilateral NAIS might be of functional relevance and an important part of the involved structural network that should be elucidated in further studies.

Does Contralesional Hand Function After Neonatal Stroke Only Depend on Lesion Characteristics?

BACKGROUND AND PURPOSE: In children having suffered from neonatal arterial ischemic stroke, the relationship between contralesional hand performance and structural changes in brain areas remote from the infarct site was examined. METHODS: Using voxel-based morphometry, we correlated contralesional gross manual dexterity assessed by the box and block test and whole-brain gray and white-matter volume changes on high-resolution magnetic resonance imaging in 37 7-year-old post-neonatal arterial ischemic stroke children. We also compared the volume of the identified structures with magnetic resonance imaging data of 10 typically developing age-matched children. RESULTS: Areas showing the highest positive correlation with the box and block test scores were ipsilesional mediodorsal thalamus, contralesional cerebellar lobule VIIa Crus I, and ipsilesional corticospinal tract at the level of superior corona radiata, the posterior limb of the internal capsule, and the cerebral peduncle and the ipsilesional body of corpus callosum. When compared with typically developing age-matched children, post-neonatal arterial ischemic stroke children with severe contralesional hand motor deficit exhibited significant volume reductions in these structures (except the cerebellum), whereas no differences were found with those with good manual dexterity. No negative correlation was found between box and block test scores and brain areas. CONCLUSIONS: Contralesional hand performance after neonatal arterial ischemic stroke is correlated with atrophy in brain areas directly or functionally connected but anatomically remote from the infarct. Our study suggests a role of the cerebellar lobule VIIa Crus I and mediodorsal thalamus in manual dexterity. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02511249.

Long term motor function after neonatal stroke: Lesion localization above all.

Motor outcome is variable following neonatal arterial ischemic stroke (NAIS). We analyzed the relationship between lesion characteristics on brain MRI and motor function in children who had suffered from NAIS. Thirty eight full term born children with unilateral NAIS were investigated at the age of seven. 3D T1- and 3D FLAIR-weighted MR images were acquired on a 3T MRI scanner. Lesion characteristics were compared between patients with and without cerebral palsy (CP) using the following approaches: lesion localization either using a category-based analysis, lesion mapping as well as voxel-based lesion-symptom mapping (VLSM). Using diffusion-weighted imaging the microstructure of the cortico-spinal tract (CST) was related to the status of CP by measuring DTI parameters. Whereas children with lesions sparing the primary motor system did not develop CP, CP was always present when extensive lesions damaged at least two brain structures involving the motor system. The VLSM approach provided a statistical map that confirmed the cortical lesions in the primary motor system and revealed that CP was highly correlated with lesions in close proximity to the CST. In children with CP, diffusion parameters indicated microstructural changes in the CST at the level of internal capsule and the centrum semiovale. White matter damage of the CST in centrum semiovale was a highly reproducible marker of CP. This is the first description of the implication of this latter region in motor impairment after NAIS. In conclusion, CP in childhood was closely linked to the location of the infarct in the motor system.

Comparison of different tractography algorithms and validation by intraoperative stimulation in a child with a brain tumor.

BACKGROUND: Advanced modalities such as functional magnetic resonance imaging (MRI) and diffusion MR tractography offer in vivo information about brain networks and are therefore increasingly used for neurosurgical planning in children also. AIM: This study aims to study the application of routine and advanced tractography algorithms and its comparison with intraoperative subcortical electrical stimulation. METHOD: Presurgical functional MRI and MR diffusion tractography were performed on a 6-year-old patient presenting with seizures, but no motor symptoms, due to a neuroectodermal tumor in the left central region. Three different tractography algorithms were compared: deterministic diffusion tensor imaging (DTI)-tracking, probabilistic DTI-tracking, and probabilistic constrained spherical deconvolution tracking (pCSD). RESULTS: All three tractography algorithms could localize the core of the corticospinal tract with good agreement. The pCSD-tracking algorithm was more sensitive in revealing the anatomically most realistic fiber distribution and a proportion of fibers traversing a solid part of the tumor. Intraoperative stimulation confirmed these fibers close to the tumor. As a result, only a subtotal resection was performed, preventing postoperative sensorimotor deficits. CONCLUSION: Although, all tractography algorithms successfully identified the core of the corticospinal pathway, deterministic DTI-tractography, as widely used in clinical neuronavigation software, only insufficiently visualized critical fibers here. We believe these results argue for a stronger consideration of advanced tractography approaches in neurosurgical planning.

Identification and interpretation of microstructural abnormalities in motor pathways in adolescents born preterm.

There has been extensive interest in assessing the long-term effects of preterm birth on brain white matter microstructure using diffusion MRI. Our aim in this study is to explore diffusion MRI differences between adolescents born preterm and term born controls, with a specific interest in characterising how such differences are manifested in white matter regions containing predominantly single or crossing fibre populations. Probabilistic high angular resolution tractography together with large deformation spatial normalisation were used to objectively investigate diffusion tensor parameters at regular intervals along fibre tracts of 45 adolescents born before 33 weeks of gestation and 30 term-born typically developing adolescents. Diffusion parameters were significantly different between preterms and controls at several levels along the cortico-spinal, thalamo-cortical and transcallosal pathways. Within the predominantly single fibre regions of the corpus callosum and internal capsule, in the preterms mean diffusivity (MD) was found to be increased while fractional anisotropy (FA) was decreased compared to controls. In contrast, however, where these pathways traversed the centrum semiovale, FA and MD were both significantly increased. The major contributor to reduced FA in preterms in predominantly single fibre regions was the increased radial eigenvalue (i.e. increased radial diffusivity). In predominantly crossing-fibre regions, the tensor eigenvalues are not meaningful, and the observed increase in FA is likely to be due to a decrease in anisotropy in one of the contributing fibre bundles. Similar differences (although less pronounced) were observed after excluding preterms with radiological signs of preterm brain injury from the sample. In summary, white matter microstructure was found to be altered in motor pathways in adolescents born preterm. Disruption of white matter (WM) microstructure in a single fibre region with resulting higher radial diffusivity leads to lower FA, whereas selective disruption of one fibre population in a crossing fibre region is observed to lead to higher FA. These findings challenge the common simplistic interpretation of FA as a measure of WM tract integrity.

Late-onset Krabbe disease presenting as spastic paraplegia - implications of GCase and CTSB/D.

OBJECTIVE: Krabbe disease (KD) is a multisystem neurodegenerative disorder with severe disability and premature death, mostly with an infancy/childhood onset. In rare cases of late-onset phenotypes, symptoms are often milder and difficult to diagnose. We here present a translational approach combining diagnostic and biochemical analyses of a male patient with a progressive gait disorder starting at the age of 44 years, with a final diagnosis of late-onset KD (LOKD). METHODS: Additionally to cerebral MRI, protein structural analyses of the ß-galactocerebrosidase protein (GALC) were performed. Moreover, expression, lysosomal localization, and activities of ß-glucocerebrosidase (GCase), cathepsin B (CTSB), and cathepsin D (CTSD) were analyzed in leukocytes, fibroblasts, and lysosomes of fibroblasts. RESULTS: Exome sequencing revealed biallelic likely pathogenic variants: GALC exons 11-17: 33 kb deletion; exon 4: missense variant (c.334A>G, p.Thr112Ala). We detected a reduced GALC activity in leukocytes and fibroblasts. While histological KD phenotypes were absent in fibroblasts, they showed a significantly decreased activities of GCase, CTSB, and CTSD in lysosomal fractions, while expression levels were unaffected. INTERPRETATION: The presented LOKD case underlines the age-dependent appearance of a mildly pathogenic GALC variant and its interplay with other lysosomal proteins. As GALC malfunction results in reduced ceramide levels, we assume this to be causative for the here described decrease in CTSB and CTSD activity, potentially leading to diminished GCase activity. Hence, we emphasize the importance of a functional interplay between the lysosomal enzymes GALC, CTSB, CTSD, and GCase, as well as between their substrates, and propose their conjoined contribution in KD pathology.

Clinical, Imaging, Genetic, and Disease Course Characteristics in Patients With GM2 Gangliosidosis: Beyond Age of Onset

BACKGROUND AND OBJECTIVES: GM2 gangliosidoses, a group of autosomal-recessive neurodegenerative lysosomal storage disorders, result from ß-hexosaminidase (HEX) deficiency with GM2 ganglioside as its main substrate. Historically, GM2 gangliosidoses have been classified into infantile, juvenile, and late-onset forms. With disease-modifying treatment trials now on the horizon, a more fine-grained understanding of the disease course is needed. METHODS: We aimed to map and stratify the clinical course of GM2 gangliosidoses in a multicenter cohort of pediatric and adult patients. Patients were stratified according to age at onset and age at diagnosis. The 2 resulting GM2 disease clusters were characterized in-depth for respective disease features (detailed standardized clinical, laboratory, and MRI assessments) and disease evolution. RESULTS: In 21 patients with GM2 gangliosidosis (17 Tay-Sachs, 2 GM2 activator deficiency, 2 Sandhoff disease), 2 disease clusters were discriminated: an early-onset and early diagnosis cluster (type I; n = 8, including activator deficiency and Sandhoff disease) and a cluster with very variable onset and long interval until diagnosis (type II; n = 13 patients). In type I, rapid onset of developmental stagnation and regression, spasticity, and seizures dominated the clinical picture. Cherry red spot, startle reactions, and elevated AST were only seen in this cluster. In type II, problems with balance or gait, muscle weakness, dysarthria, and psychiatric symptoms were specific and frequent symptoms. Ocular signs were common, including supranuclear vertical gaze palsy in 30%. MRI involvement of basal ganglia and peritrigonal hyperintensity was seen only in type I, whereas predominant infratentorial atrophy (or normal MRI) was characteristic in type II. These types were, at least in part, associated with certain genetic variants. DISCUSSION: Age at onset alone seems not sufficient to adequately predict different disease courses in GM2 gangliosidosis, as required for upcoming trial planning. We propose an alternative classification based on age at disease onset and dynamics, predicted by clinical features and biomarkers, into type I-an early-onset, rapid progression cluster-and type II-a variable onset, slow progression cluster. Specific diagnostic workup, including GM2 gangliosidosis, should be performed in patients with combined ataxia plus lower motor neuron weakness to identify type II patients.

Effects of sulfatide on peripheral nerves in metachromatic leukodystrophy.

OBJECTIVE: To evaluate the longitudinal correlations between sulfatide/lysosulfatide levels and central and peripheral nervous system function in children with metachromatic leukodystrophy (MLD) and to explore the impact of intravenous recombinant human arylsulfatase A (rhASA) treatment on myelin turnover. METHODS: A Phase 1/2 study of intravenous rhASA investigated cerebrospinal fluid (CSF) and sural nerve sulfatide levels, 88-item Gross Motor Function Measure (GMFM-88) total score, sensory and motor nerve conduction, brain N-acetylaspartate (NAA) levels, and sural nerve histology in 13 children with MLD. Myelinated and unmyelinated nerves from an untreated MLD mouse model were also analyzed. RESULTS: CSF sulfatide levels correlated with neither Z-scores for GMFM-88 nor brain NAA levels; however, CSF sulfatide levels correlated negatively with Z-scores of nerve conduction parameters, number of large (≥7 µm) myelinated fibers, and myelin/fiber diameter slope, and positively with nerve g-ratios and cortical latencies of somatosensory-evoked potentials. Quantity of endoneural litter positively correlated with sural nerve sulfatide/lysosulfatide levels. CSF sulfatide levels decreased with continuous high-dose treatment; this change correlated with improved nerve conduction. At 26 weeks after treatment, nerve g-ratio decreased by 2%, and inclusion bodies per Schwann cell unit increased by 55%. In mice, abnormal sulfatide storage was observed in non-myelinating Schwann cells in Remak bundles of sciatic nerves but not in unmyelinated urethral nerves. INTERPRETATION: Lower sulfatide levels in the CSF and peripheral nerves correlate with better peripheral nerve function in children with MLD; intravenous rhASA treatment may reduce CSF sulfatide levels and enhance sulfatide/lysosulfatide processing and remyelination in peripheral nerves.