Browsing by Author "Groeschel, Samuel"

Background: Metachromatic leukodystrophy (MLD) is a rare, genetic neurodegenerative disease. It leads to progressive demyelination resulting in regression of development and early death. With regard to experimental therapies, knowledge of the natural course of the disease is highly important. We aimed to analyse onset and character of first symptoms in MLD and to provide detailed natural course data concerning language and cognition. Methods: Patients with MLD were recruited nationwide within the scope of the German research network LEUKONET. 59 patients' questionnaires (23 late-infantile, 36 juvenile) were analysed. Results: Time from first symptoms (at a median age of 1.5 years in late-infantile and 6 years in juvenile MLD) to diagnosis took one year in late-infantile and two years in juvenile patients on average. Gait disturbances and abnormal movement patterns were first signs in all patients with late-infantile and in most with juvenile MLD. Onset in the latter was additionally characterized by problems in concentration, behaviour and fine motor function (p = 0.0011, p < 0.0001, and p = 0.0012). Half of late-infantile patients did not learn to speak in complete sentences after an initially normal language acquisition. They showed a rapid language decline with first language difficulties at a median age of 2.5 years and complete loss of expressive language within several months (median age 32, range 22-47 months). This was followed by total loss of communication at a median age of around four years. In juvenile patients, language decline was more protracted, and problems in concentration and behaviour were followed by decline in skills for reading, writing and calculating around four years after disease onset. Conclusions: Our data reflect the natural course of decline in language and cognition in late-infantile and juvenile MLD in a large cohort over a long observation period. This is especially relevant to juvenile patients where the disease course is protracted and prospective studies are hardly feasible. Knowledge of first symptoms may lead to earlier diagnosis and subsequently to a better outcome following therapeutic intervention. Our data may serve as a reference for individual treatment decisions and for evaluation of clinical outcome after treatment intervention.

Abstract 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 β‐galactocerebrosidase protein (GALC) were performed. Moreover, expression, lysosomal localization, and activities of β‐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.

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

Background: Perivascular spaces of the brain, also known as Virchow-Robin spaces (VRS), are of immunological and neuropathological relevance and can be observed in magnetic resonance images (MRI). Their histopathological significance in X-linked adrenoleukodystrophy (ALD) has been reported. Aim of this study was to elucidate the prognostic or diagnostic value of VRS on MRI of the brain in the evaluation of onset or severity of the clinical course in ALD. Methods: Clinical data and MRI from 35 patients with the cerebral form of X-ALD, 29 with the asymptomatic form (including those with adrenal insufficiency), and 36 control patients were studied retrospectively. Results: VRS could be visualised by MRI in 87% of patients with asymptomatic ALD, in 80% of control patients, and in 47% of patients with cerebral ALD. None of them were found to be dilated. The number of visible VRS correlated negatively with the degree of demyelination both in patients with the cerebral and the asymptomatic form. Furthermore, in the group of patients with cerebral ALD the number of visible VRS correlated positively with a milder course of the disease. Conclusion: VRS on MRI of patients with ALD seem to reflect the perivascular inflammatory component of this disease. it is possible to speculate that the appearance or a higher number of visible VRS in ALD is associated with an earlier stage of the disease, or even a more benign clinical course. (c) 2006 Published by Elsevier Ltd. on behalf of European Paediatric Neurology Society.

Introduction Virchow-Robin spaces (VRS) are perivascular spaces in the brain and can be visualized on magnetic resonance images (MRI). We attempt to provide a better understanding of the significance of VRS for pathological and physiological processes by reviewing the literature, presenting normative data for the first time, and proposing a definition for the dilatation of the VRS on MRI that is based on shape rather than size. Methods We evaluated the VRS in 125 healthy subjects (age range 1-30 years) using high-resolution 3D images, and in 36 patients (age range 2-16 years) with normal MRI, using routine clinical sequences. Results VRS were visible in all high-resolution images of the 125 healthy subjects. Two of them revealed dilated VRS, giving a prevalence of 1.6%. VRS could be visualized in 29 (80%) of the 36 paediatric clinical scans; none was dilated. It was demonstrated that the visibility of VRS on MRI is sequence-dependent. Conclusion From the results of this study and the literature on the nature and pathology of VRS, we conclude that VRS on MR images of healthy individuals are normal findings, even if they are dilated. A judgement on whether dilated VRS in an individual patient is a normal variant or part of a disease process can be made by taking into account the appearance of the adjacent tissue on MRI and the clinical context.