28 results on '"von Au K"'
Search Results
2. Diagnostic algorithms in Charcot-Marie-Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients
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Rudnik-Schöneborn, S., primary, Tölle, D., additional, Senderek, J., additional, Eggermann, K., additional, Elbracht, M., additional, Kornak, U., additional, von der Hagen, M., additional, Kirschner, J., additional, Leube, B., additional, Müller-Felber, W., additional, Schara, U., additional, von Au, K., additional, Wieczorek, D., additional, Bußmann, C., additional, and Zerres, K., additional
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- 2015
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3. Recessive truncating IGHMBP2 mutations presenting as axonal sensorimotor neuropathy
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Schottmann, G., primary, Jungbluth, H., additional, Schara, U., additional, Knierim, E., additional, Morales Gonzalez, S., additional, Gill, E., additional, Seifert, F., additional, Norwood, F., additional, Deshpande, C., additional, von Au, K., additional, Schuelke, M., additional, and Senderek, J., additional
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- 2015
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4. G.P.192
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Radke, J., primary, von Au, K., additional, Dreesmann, M., additional, von Pein, H., additional, Stenzel, W., additional, and Goebel, H.H., additional
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- 2014
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5. Muscle and nerve pathology in spinal muscular atrophy with respiratory distress (SMARD1). Comparison of human and murine SMARD
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Stoltenburg-Didinger, G, Jablonka, S, Kaindl, A, von Au, K, Stoltenburg-Didinger, G, Jablonka, S, Kaindl, A, and von Au, K
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- 2012
6. L’amyotrophie spinale distale de type 1 (DSMA1 ou SMARD1)
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Kaindl, A.M., primary, Guenther, U.-P., additional, Rudnik-Schöneborn, S., additional, Varon, R., additional, Zerres, K., additional, Gressens, P., additional, Schuelke, M., additional, Hubner, C., additional, and von Au, K., additional
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- 2008
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7. NMP05 Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1) associated with delayed CNS myelination and novel mutation in IGHMBP2 gene
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Barisic, N., primary, von Au, K., additional, Rados, M., additional, Pazanin, L., additional, Galic, S., additional, Cvitkovic, M., additional, Novak, M., additional, Lochmüller, H., additional, Sperling, K., additional, Lehman, I., additional, and Varon, R., additional
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- 2007
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8. Comparison of the disease course of two patients with SMARD1
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Schlicke, M, primary, Polster, T, additional, Albani, M, additional, Huebner, C, additional, and von Au, K, additional
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- 2006
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9. G.P.192: Muscle heart brain disease in 3 of 4 siblings
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Radke, J., von Au, K., Dreesmann, M., von Pein, H., Stenzel, W., and Goebel, H.H.
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- 2014
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10. N.P.2 08 Infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1) associated with delayed CNS myelination and novel mutation in the IGHMBP2 gene
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Barisic, N., von Au, K., Rados, M., Pazanin, L., Galic, S., Cvitkovic, M., Novak, M., Lochmueller, H., Sperling, K., Lehman, I., and Varon, R.
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- 2006
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11. Retrospective Pediatric Cohort Study Validates NEOS Score and Demonstrates Applicability in Children With Anti-NMDAR Encephalitis.
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Nikolaus M, Rausch P, Rostásy K, Bertolini A, Wickström R, Johannsen J, Denecke J, Breu M, Schimmel M, Diepold K, Haeusler M, Quade A, Berger A, Rosewich H, Steen C, von Au K, Dreesmann M, Finke C, Bartels F, Kaindl AM, Schuelke M, and Knierim E
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- Adult, Child, Humans, Cohort Studies, Retrospective Studies, Prospective Studies, Receptors, N-Methyl-D-Aspartate, Anti-N-Methyl-D-Aspartate Receptor Encephalitis drug therapy, Encephalitis, Herpes Simplex complications
- Abstract
Background and Objectives: Anti-N-methyl-D-aspartate receptor encephalitis (NMDARE) is the most common form of autoimmune encephalitis in children and adults. Although our understanding of the disease mechanisms has progressed, little is known about estimating patient outcomes. Therefore, the NEOS (anti- N MDAR E ncephalitis O ne-Year Functional S tatus) score was introduced as a tool to predict disease progression in NMDARE. Developed in a mixed-age cohort, it currently remains unclear whether NEOS can be optimized for pediatric NMDARE., Methods: This retrospective observational study aimed to validate NEOS in a large pediatric-only cohort of 59 patients (median age of 8 years). We reconstructed the original score, adapted it, evaluated additional variables, and assessed its predictive power (median follow-up of 20 months). Generalized linear regression models were used to examine predictability of binary outcomes based on the modified Rankin Scale (mRS). In addition, neuropsychological test results were investigated as alternative cognitive outcome., Results: The NEOS score reliably predicted poor clinical outcome (mRS ≥3) in children in the first year after diagnosis ( p = 0.0014) and beyond ( p = 0.036, 16 months after diagnosis). A score adapted to the pediatric cohort by adjusting the cutoffs of the 5 NEOS components did not improve predictive power. In addition to these 5 variables, further patient characteristics such as the " Herpes simplex virus encephalitis (HSE) status" and "age at disease onset" influenced predictability and could potentially be useful to define risk groups. NEOS also predicted cognitive outcome with higher scores associated with deficits of executive function ( p = 0.048) and memory ( p = 0.043)., Discussion: Our data support the applicability of the NEOS score in children with NMDARE. Although not yet validated in prospective studies, NEOS also predicted cognitive impairment in our cohort. Consequently, the score could help identify patients at risk of poor overall clinical outcome and poor cognitive outcome and thus aid in selecting not only optimized initial therapies for these patients but also cognitive rehabilitation to improve long-term outcomes., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2023
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12. Effect and safety of treatment with ACE-inhibitor Enalapril and β-blocker metoprolol on the onset of left ventricular dysfunction in Duchenne muscular dystrophy - a randomized, double-blind, placebo-controlled trial.
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Dittrich S, Graf E, Trollmann R, Neudorf U, Schara U, Heilmann A, von der Hagen M, Stiller B, Kirschner J, Pozza RD, Müller-Felber W, Weiss K, von Au K, Khalil M, Motz R, Korenke C, Lange M, Wilichowski E, Pattathu J, Ebinger F, Wiechmann N, and Schröder R
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- Adolescent, Cardiomyopathies prevention & control, Child, Double-Blind Method, Enalapril adverse effects, Female, Humans, Kaplan-Meier Estimate, Male, Metoprolol adverse effects, Treatment Outcome, Adrenergic beta-1 Receptor Antagonists therapeutic use, Angiotensin-Converting Enzyme Inhibitors therapeutic use, Enalapril therapeutic use, Metoprolol therapeutic use, Muscular Dystrophy, Duchenne drug therapy, Ventricular Dysfunction, Left prevention & control
- Abstract
Background: X-linked Duchenne muscular dystrophy (DMD), the most frequent human hereditary skeletal muscle myopathy, inevitably leads to progressive dilated cardiomyopathy. We assessed the effect and safety of a combined treatment with the ACE-inhibitor enalapril and the β-blocker metoprolol in a German cohort of infantile and juvenile DMD patients with preserved left ventricular function., Methods Trial Design: Sixteen weeks single-arm open run-in therapy with enalapril and metoprolol followed by a two-arm 1:1 randomized double-blind placebo-controlled treatment in a multicenter setting., Inclusion Criteria: DMD boys aged 10-14 years with left ventricular fractional shortening [LV-FS] ≥ 30% in echocardiography. Primary endpoint: time from randomization to first occurrence of LV-FS < 28%. Secondary: changes of a) LV-FS from baseline, b) blood pressure, c), heart rate and autonomic function in ECG and Holter-ECG, e) cardiac biomarkers and neurohumeral serum parameters, f) quality of life, and g) adverse events., Results: From 3/2010 to 12/2013, 38 patients from 10 sites were centrally randomized after run-in, with 21 patients continuing enalapril and metoprolol medication and 17 patients receiving placebo. Until end of study 12/2015, LV-FS < 28% was reached in 6/21 versus 7/17 patients. Cox regression adjusted for LV-FS after run-in showed a statistically non-significant benefit for medication over placebo (hazard ratio: 0.38; 95% confidence interval: 0.12 to 1.22; p = 0.10). Analysis of secondary outcome measures revealed a time-dependent deterioration of LV-FS with no statistically significant differences between the two study arms. Blood pressure, maximal heart rate and mean-NN values were significantly lower at the end of open run-in treatment compared to baseline. Outcome analysis 19 months after randomization displayed significantly lower maximum heart rate and higher noradrenalin and renin values in the intervention group. No difference between treatments was seen for quality of life. As a single, yet important adverse event, the reversible deterioration of walking abilities of one DMD patient during the run-in period was observed., Conclusions: Our analysis of enalapril and metoprolol treatment in DMD patients with preserved left ventricular function is suggestive to delay the progression of the intrinsic cardiomyopathy to left ventricular failure, but did not reach statistical significance, probably due to insufficient sample size., Clinical Trial Registration: DRKS-number 00000115, EudraCT-number 2009-009871-36.
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- 2019
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13. Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy.
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Schottmann G, Seelow D, Seifert F, Morales-Gonzalez S, Gill E, von Au K, von Moers A, Stenzel W, and Schuelke M
- Abstract
Objective: To identify the underlying genetic cause of a congenital neuropathy in a 5-year-old boy as part of a cohort of 32 patients from 23 families with genetically unresolved neuropathies., Methods: We used autozygosity mapping coupled with next-generation sequencing to investigate a consanguineous family from Lebanon with 1 affected and 2 healthy children. Variants were investigated for segregation in the family by Sanger sequencing. A splice site mutation was further evaluated on the messenger RNA level by quantitative reverse transcription PCR. Subsequently, a larger cohort was specifically screened for receptor expression-enhancing protein 1 (REEP1) gene mutations., Results: We detected a homozygous splice donor mutation in REEP1 (c.303+1-7GTAATAT>AC, p.F62Kfs23*; NM_022912) that cosegregated with the phenotype in the family, leading to complete skipping of exon 4 and a premature stop codon. The phenotype of the patient is similar to spinal muscular atrophy with respiratory distress type 1 (SMARD1) with additional distal arthrogryposis and involvement of the upper motor neuron manifested by pronounced hyperreflexia., Conclusion: To date, only dominant REEP1 mutations have been reported to be associated with a slowly progressive hereditary spastic paraplegia. The findings from our patient expand the phenotypical spectrum and the mode of inheritance of REEP1-associated disorders. Recessive mutations in REEP1 should be considered in the molecular genetic workup of patients with a neuromuscular disorder resembling SMARD1, especially if additional signs of upper motor neuron involvement and distal arthrogryposis are present.
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- 2015
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14. Corrigendum: Transcriptional regulator PRDM12 is essential for human pain perception.
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Chen YC, Auer-Grumbach M, Matsukawa S, Zitzelsberger M, Themistocleous AC, Strom TM, Samara C, Moore AW, Cho LT, Young GT, Weiss C, Schabhüttl M, Stucka R, Schmid AB, Parman Y, Graul-Neumann L, Heinritz W, Passarge E, Watson RM, Hertz JM, Moog U, Baumgartner M, Valente EM, Pereira D, Restrepo CM, Katona I, Dusl M, Stendel C, Wieland T, Stafford F, Reimann F, von Au K, Finke C, Willems PJ, Nahorski MS, Shaikh SS, Carvalho OP, Nicholas AK, Karbani G, McAleer MA, Cilio MR, McHugh JC, Murphy SM, Irvine AD, Jensen UB, Windhager R, Weis J, Bergmann C, Rautenstrauss B, Baets J, De Jonghe P, Reilly MM, Kropatsch R, Kurth I, Chrast R, Michiue T, Bennett DL, Woods CG, and Senderek J
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- 2015
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15. Transcriptional regulator PRDM12 is essential for human pain perception.
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Chen YC, Auer-Grumbach M, Matsukawa S, Zitzelsberger M, Themistocleous AC, Strom TM, Samara C, Moore AW, Cho LT, Young GT, Weiss C, Schabhüttl M, Stucka R, Schmid AB, Parman Y, Graul-Neumann L, Heinritz W, Passarge E, Watson RM, Hertz JM, Moog U, Baumgartner M, Valente EM, Pereira D, Restrepo CM, Katona I, Dusl M, Stendel C, Wieland T, Stafford F, Reimann F, von Au K, Finke C, Willems PJ, Nahorski MS, Shaikh SS, Carvalho OP, Nicholas AK, Karbani G, McAleer MA, Cilio MR, McHugh JC, Murphy SM, Irvine AD, Jensen UB, Windhager R, Weis J, Bergmann C, Rautenstrauss B, Baets J, De Jonghe P, Reilly MM, Kropatsch R, Kurth I, Chrast R, Michiue T, Bennett DL, Woods CG, and Senderek J
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- Animals, COS Cells, Carrier Proteins metabolism, Chlorocebus aethiops, Consanguinity, Female, Genetic Association Studies, Hereditary Sensory and Autonomic Neuropathies genetics, Humans, Male, Mutation, Nerve Tissue Proteins metabolism, Neurogenesis, Nociceptors metabolism, Pain Insensitivity, Congenital genetics, Pedigree, Polymorphism, Single Nucleotide, Xenopus laevis, Carrier Proteins genetics, Nerve Tissue Proteins genetics, Pain Perception
- Abstract
Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.
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- 2015
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16. Truncating and missense mutations in IGHMBP2 cause Charcot-Marie Tooth disease type 2.
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Cottenie E, Kochanski A, Jordanova A, Bansagi B, Zimon M, Horga A, Jaunmuktane Z, Saveri P, Rasic VM, Baets J, Bartsakoulia M, Ploski R, Teterycz P, Nikolic M, Quinlivan R, Laura M, Sweeney MG, Taroni F, Lunn MP, Moroni I, Gonzalez M, Hanna MG, Bettencourt C, Chabrol E, Franke A, von Au K, Schilhabel M, Kabzińska D, Hausmanowa-Petrusewicz I, Brandner S, Lim SC, Song H, Choi BO, Horvath R, Chung KW, Zuchner S, Pareyson D, Harms M, Reilly MM, and Houlden H
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- Adult, Base Sequence, Charcot-Marie-Tooth Disease pathology, Chromosome Mapping, Female, Haplotypes genetics, Humans, Molecular Sequence Data, Pedigree, Protein Interaction Mapping, Sequence Analysis, DNA, Sural Nerve pathology, Charcot-Marie-Tooth Disease genetics, Exome genetics, Models, Molecular, Mutation, Missense genetics, Phenotype
- Abstract
Using a combination of exome sequencing and linkage analysis, we investigated an English family with two affected siblings in their 40s with recessive Charcot-Marie Tooth disease type 2 (CMT2). Compound heterozygous mutations in the immunoglobulin-helicase-μ-binding protein 2 (IGHMBP2) gene were identified. Further sequencing revealed a total of 11 CMT2 families with recessively inherited IGHMBP2 gene mutations. IGHMBP2 mutations usually lead to spinal muscular atrophy with respiratory distress type 1 (SMARD1), where most infants die before 1 year of age. The individuals with CMT2 described here, have slowly progressive weakness, wasting and sensory loss, with an axonal neuropathy typical of CMT2, but no significant respiratory compromise. Segregating IGHMBP2 mutations in CMT2 were mainly loss-of-function nonsense in the 5' region of the gene in combination with a truncating frameshift, missense, or homozygous frameshift mutations in the last exon. Mutations in CMT2 were predicted to be less aggressive as compared to those in SMARD1, and fibroblast and lymphoblast studies indicate that the IGHMBP2 protein levels are significantly higher in CMT2 than SMARD1, but lower than controls, suggesting that the clinical phenotype differences are related to the IGHMBP2 protein levels., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2014
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17. Descemet membrane endothelial keratoplasty in a child with corneal endothelial dysfunction in Kearns-Sayre syndrome.
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Gonnermann J, Klamann MK, Maier AK, Bertelmann E, Schroeter J, von Au K, Joussen AM, and Torun N
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- Child, Corneal Diseases diagnosis, Endothelium, Corneal pathology, Follow-Up Studies, Humans, Kearns-Sayre Syndrome diagnosis, Male, Postoperative Complications, Visual Acuity physiology, Corneal Diseases surgery, Descemet Stripping Endothelial Keratoplasty, Endothelium, Corneal surgery, Kearns-Sayre Syndrome surgery
- Abstract
Purpose: To evaluate clinical outcomes and complications after Descemet membrane endothelial keratoplasty (DMEK) in a child., Methods: A 12-year-old boy with Kearns-Sayre syndrome (chronic progressive external ophthalmoplegia, cardiac conduction block, and pigmentary retinal degeneration) and corneal endothelial dysfunction was successfully treated with DMEK. Corneal transparency, central corneal thickness (CCT), endothelial cell density (ECD), visual outcomes, and complication rates were measured during the follow-up of 6 months., Results: Best spectacle-corrected visual acuity (BSCVA) improved from counting fingers at 4 feet preoperatively to 20/100, 1 week after surgery. The ECD of the graft was 2595 cells per square millimeter. The CCT diminished from 837 μm preoperatively to 735 μm 1 week after surgery. Six months postoperatively, the BSCVA was still 20/100, and the cornea remained clear and compact. The ECD was 2341 cells per square millimeter and CCT was almost normal with 583 μm. No postoperative complications were observed. Fundus examination showed atypical pigmentary retinal degeneration with arterial narrowing. Electroretinography with full-field flash stimulation showed bilaterally severe retinal dysfunction with absent photopic and scotopic amplitudes explaining the reduced BSCVA., Conclusions: Although DMEK has been used in adult populations, we are unaware of previous reports of DMEK in a child. DMEK should be considered as a feasible technique in pediatric patients with endothelial dysfunction.
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- 2014
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18. A paucisymptomatic neuromuscular disease mimicking type III 5q-SMA with complex rearrangements in the SMN gene.
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Lohkamp LN, von Au K, Goebel HH, Kress W, Grieben U, Drossel K, Garbes L, Wirth B, Heppner FL, and Stenzel W
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- Animals, Biopsy, Child, DNA Mutational Analysis, Diagnosis, Differential, Humans, Immunohistochemistry, Male, Mice, Muscular Atrophy metabolism, Muscular Atrophy pathology, Neuromuscular Diseases diagnosis, Neuromuscular Diseases metabolism, Neuromuscular Diseases pathology, Phenotype, Quadriceps Muscle metabolism, Quadriceps Muscle pathology, Sequence Deletion, Spinal Muscular Atrophies of Childhood genetics, Survival of Motor Neuron 1 Protein metabolism, Survival of Motor Neuron 2 Protein genetics, Survival of Motor Neuron 2 Protein metabolism, Muscular Atrophy genetics, Mutation, Neuromuscular Diseases genetics, Spinal Muscular Atrophies of Childhood diagnosis, Survival of Motor Neuron 1 Protein genetics
- Abstract
Spinal muscular atrophy is an autosomal-recessive neuromuscular disorder, causing progressive proximal weakness and atrophy of the voluntary muscles. More than 96% of the spinal muscular atrophy patients show a homozygous absence of exons 7 and 8, or exon 7 only, in SMN1, the telomeric copy of the SMN gene. We report a young male patient with neurogenic symptoms and sparse muscle fiber atrophy, suggestive of a mild form of type III spinal muscular atrophy. He was found to be a carrier of intragenic mutations in both copies of the SMN gene, exhibiting a homozygous duplication of exons 7 and 8 in SMN1 and a homozygous deletion of exon 8 as well as a heterozygous deletion of exon 7 in SMN2. However, an intact full-length SMN1 complementary deoxyribonucleic acid was identified, and SMN protein levels in a muscle specimen were identical to that of a healthy control, formally excluding the diagnosis of spinal muscular atrophy III.
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- 2014
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19. Growth and psychomotor development of patients with Duchenne muscular dystrophy.
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Sarrazin E, von der Hagen M, Schara U, von Au K, and Kaindl AM
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- Adolescent, Body Height physiology, Body Weight physiology, Child, Child, Preschool, Developmental Disabilities etiology, Developmental Disabilities genetics, Genotype, Head growth & development, Humans, Intellectual Disability etiology, Intellectual Disability genetics, Intellectual Disability physiopathology, Learning Disabilities etiology, Learning Disabilities genetics, Learning Disabilities physiopathology, Male, Muscular Dystrophy, Duchenne complications, Muscular Dystrophy, Duchenne pathology, Phenotype, Retrospective Studies, Developmental Disabilities physiopathology, Growth physiology, Growth and Development genetics, Muscular Dystrophy, Duchenne physiopathology
- Abstract
Duchenne muscular dystrophy (DMD) is one of the most common hereditary degenerative neuromuscular diseases and caused by mutations in the dystrophin gene. The objective of the retrospective study was to describe growth and psychomotor development of patients with DMD and to detect a possible genotype-phenotype correlation. Data from 263 patients with DMD (mean age 7.1 years) treated at the Departments of Pediatric Neurology in three German University Hospitals was assessed with respect to body measurements (length, weight, body mass index BMI, head circumference OFC), motor and cognitive development as well as genotype (site of mutation). Anthropometric measures and developmental data were compared to those of a reference population and deviations were analyzed for their frequency in the cohort as well as in relation to the genotypes. Corticosteroid therapy was implemented in 29 from 263 patients. Overall 30% of the patients exhibit a short statue (length < 3rd centile) with onset early in development at 2-5 years of age, and this is even more prevalent when steroid therapy is applied (45% of patients with steroid therapy). The BMI shows a rightwards shift (68% > 50th centile) and the OFC a leftwards shift (65% < 50th centile, 5% microcephaly). Gross motor development is delayed in a third of the patients (mean age at walking 18.3 months, 30% > 18 months, 8% > 24 months). Almost half of the patients show cognitive impairment (26% learning disability, 17% intellectual disability). Although there is no strict genotype-phenotype correlation, particularly mutations in the distal part of the dystrophin gene are frequently associated with short stature and a high rate of microcephaly as well as cognitive impairment., (Copyright © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2014
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20. 190 th ENMC international workshop: Spinal muscular atrophy with respiratory distress/distal spinal muscular atrophy type 1: 11-13 May 2012, Naarden, The Netherlands.
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van der Pol WL, Talim B, Pitt M, and von Au K
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- Animals, Disease Models, Animal, Education, Humans, Muscular Atrophy, Spinal metabolism, Netherlands, Respiratory Distress Syndrome, Newborn metabolism, Muscular Atrophy, Spinal diagnosis, Muscular Atrophy, Spinal therapy, Respiratory Distress Syndrome, Newborn diagnosis, Respiratory Distress Syndrome, Newborn therapy
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- 2013
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21. Angelman syndrome and severe infections in a patient with de novo 15q11.2-q13.1 deletion and maternally inherited 2q21.3 microdeletion.
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Neubert G, von Au K, Drossel K, Tzschach A, Horn D, Nickel R, and Kaindl AM
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- Adenosine Triphosphatases genetics, Adenosine Triphosphatases metabolism, Angelman Syndrome pathology, Chromosome Aberrations, Chromosomes, Human, Pair 15 genetics, Chromosomes, Human, Pair 15 metabolism, Female, Humans, Infant, Infections pathology, Intellectual Disability metabolism, Intellectual Disability pathology, Male, Membrane Transport Proteins genetics, Membrane Transport Proteins metabolism, Receptors, GABA-A genetics, Receptors, GABA-A metabolism, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Angelman Syndrome genetics, Infections genetics, Intellectual Disability genetics
- Abstract
Angelman syndrome is a neurodevelopmental disorder characterized by mental retardation, severe speech disorder, facial dysmorphism, secondary microcephaly, ataxia, seizures, and abnormal behaviors such as easily provoked laughter. It is most frequently caused by a de novo maternal deletion of chromosome 15q11-q13 (about 70-90%), but can also be caused by paternal uniparental disomy of chromosome 15q11-q13 (3-7%), an imprinting defect (2-4%) or in mutations in the ubiquitin protein ligase E3A gene UBE3A mostly leading to frame shift mutation. In addition, for patients with overlapping clinical features (Angelman-like syndrome), mutations in methyl-CpG binding protein 2 gene MECP2 and cyclin-dependent kinase-like 5 gene CDKL5 as well as a microdeletion of 2q23.1 including the methyl-CpG binding domain protein 5 gene MBD5 have been described. Here, we describe a patient who carries a de novo 5Mb-deletion of chromosome 15q11.2-q13.1 known to be associated with Angelman syndrome and a further, maternally inherited deletion 2q21.3 (~364kb) of unknown significance. In addition to classic features of Angelman syndrome, she presented with severe infections in the first year of life, a symptom that has not been described in patients with Angelman syndrome. The 15q11.2-q13.1 deletion contains genes critical for Prader-Willi syndrome, the Angelman syndrome causing genes UBE3A and ATP10A/C, and several non-imprinted genes: GABRB3 and GABRA5 (both encoding subunits of GABA A receptor), GOLGA6L2, HERC2 and OCA2 (associated with oculocutaneous albinism II). The deletion 2q21.3 includes exons of the genes RAB3GAP1 (associated with Warburg Micro syndrome) and ZRANB3 (not disease-associated). Despite the normal phenotype of the mother, the relevance of the 2q21.3 microdeletion for the phenotype of the patient cannot be excluded, and further case reports will need to address this point., (Copyright © 2012 Elsevier B.V. All rights reserved.)
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- 2013
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22. The natural course of infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1).
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Eckart M, Guenther UP, Idkowiak J, Varon R, Grolle B, Boffi P, Van Maldergem L, Hübner C, Schuelke M, and von Au K
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- Adolescent, Child, Child, Preschool, Disease Progression, Female, Humans, Male, Muscular Atrophy, Spinal genetics, Muscular Atrophy, Spinal physiopathology, Muscular Atrophy, Spinal therapy, Mutation, Prognosis, Respiration, Artificial, Respiratory Distress Syndrome, Newborn genetics, Respiratory Distress Syndrome, Newborn physiopathology, Respiratory Distress Syndrome, Newborn therapy, DNA-Binding Proteins genetics, Muscular Atrophy, Spinal diagnosis, Respiratory Distress Syndrome, Newborn diagnosis, Transcription Factors genetics
- Abstract
Background: Only scarce information is available on the long-term outcome and the natural course of children with infantile spinal muscular atrophy with respiratory distress type 1 (SMARD1) due to mutations in the IGHMBP2 gene., Objective: To describe the natural disease course, to systematically quantify the residual capacities of children with SMARD1 who survive on permanent mechanical respiration, and to identify markers predicting the disease outcome at the time of manifestation., Methods: We conducted a longitudinal study of 11 infantile SMARD1 patients over a mean observational period of 7.8 (SD 3.2) years. Disease-specific features were continuously assessed by using a semiquantitative scoring system. Additionally, we analyzed the residual enzymatic activity of 6 IGHMBP2 mutants in our patients., Results: After an initial rapid decline of the clinical score until the age of 2 years, residual capabilities reached a plateau or even improved. The overall clinical outcome was markedly heterogeneous, but clinical scores at the age of 3 months showed a positive linear correlation with the clinical outcome at 1 year and at 4 years of age. If expressed in an in vitro recombinant system, mutations of patients with more favorable outcomes retained residual enzymatic activity., Conclusions: Despite their severe disabilities and symptoms, most SMARD1 patients are well integrated into their home environment and two thirds of them are able to attend kindergarten or school. This information will help to counsel parents at the time of disease manifestation.
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- 2012
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23. IGHMBP2 is a ribosome-associated helicase inactive in the neuromuscular disorder distal SMA type 1 (DSMA1).
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Guenther UP, Handoko L, Laggerbauer B, Jablonka S, Chari A, Alzheimer M, Ohmer J, Plöttner O, Gehring N, Sickmann A, von Au K, Schuelke M, and Fischer U
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- Adenosine Triphosphatases metabolism, Adenosine Triphosphate metabolism, Animals, Cell Extracts, Cell Line, Tumor, DNA Helicases chemistry, DNA-Binding Proteins chemistry, Enzyme Activation, Humans, Mice, Mutant Proteins metabolism, Protein Binding, Ribonucleoproteins metabolism, Transcription Factors chemistry, DNA Helicases metabolism, DNA-Binding Proteins metabolism, Muscular Atrophy, Spinal enzymology, Ribosomes enzymology, Transcription Factors metabolism
- Abstract
Distal spinal muscular atrophy type 1 (DSMA1) is an autosomal recessive disease that is clinically characterized by distal limb weakness and respiratory distress. In this disease, the degeneration of alpha-motoneurons is caused by mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2). This protein has been implicated in DNA replication, pre-mRNA splicing and transcription, but its precise function in all these processes has remained elusive. We have purified catalytically active recombinant IGHMBP2, which has enabled us to assess its enzymatic properties and to identify its cellular targets. Our data reveal that IGHMBP2 is an ATP-dependent 5' --> 3' helicase, which unwinds RNA and DNA duplices in vitro. Importantly, this helicase localizes predominantly to the cytoplasm of neuronal and non-neuronal cells and associates with ribosomes. DSMA1-causing amino acid substitutions in IGHMBP2 do not affect ribosome binding yet severely impair ATPase and helicase activity. We propose that IGHMBP2 is functionally linked to translation, and that mutations in its helicase domain interfere with this function in DSMA1 patients.
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- 2009
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24. Clinical variability in distal spinal muscular atrophy type 1 (DSMA1): determination of steady-state IGHMBP2 protein levels in five patients with infantile and juvenile disease.
- Author
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Guenther UP, Handoko L, Varon R, Stephani U, Tsao CY, Mendell JR, Lützkendorf S, Hübner C, von Au K, Jablonka S, Dittmar G, Heinemann U, Schuetz A, and Schuelke M
- Subjects
- Adult, Age of Onset, DNA Mutational Analysis, Female, Humans, Infant, Infant, Newborn, Male, Pregnancy, Premature Birth, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Mutation, Missense, Spinal Muscular Atrophies of Childhood genetics, Spinal Muscular Atrophies of Childhood metabolism, Transcription Factors genetics, Transcription Factors metabolism
- Abstract
Distal spinal muscular atrophy type 1 (DSMA1) is caused by mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene. Patients with DSMA1 present between 6 weeks and 6 months of age with progressive muscle weakness and respiratory failure due to diaphragmatic palsy. Contrary to this "classic" infantile disease, we have previously described a DSMA1 patient with juvenile disease onset. In this paper, we present (1) a second juvenile case and (2) the first study of DSMA1 on protein level in patients with infantile (n = 3) as well as juvenile (n = 2) disease onset observing elevated residual steady-state IGHMBP2 protein levels in the patients with late onset DSMA1 as compared to those with classic DSMA1. Mutation screening in IGHMBP2 revealed two patients compound heterozygous for a novel missense mutation (c.1478C-->T; p.T493I) and another previously described mutation. In lymphoblastoid cells of both patients, steady-state IGHMBP2 protein levels were reduced. In comparison to wild-type IGHMBP2, the p.T493I variant protein had an increased tendency to aggregate and spontaneously degrade in vitro. We verified a change in the physicochemical properties of the p.T493I variant which may explain the pathogenicity of this mutation. Our data further suggest that the age of onset of DSMA1 is variable, and we discuss the effect of residual IGHMBP2 protein levels on the clinical course and the severity of the disease.
- Published
- 2009
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25. [Distal spinal-muscular atrophy 1 (DSMA1 or SMARD1)].
- Author
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Kaindl AM, Guenther UP, Rudnik-Schöneborn S, Varon R, Zerres K, Gressens P, Schuelke M, Hubner C, and von Au K
- Subjects
- Diagnosis, Differential, Female, Humans, Infant, Newborn, Muscular Atrophy, Spinal genetics, Pregnancy, Prenatal Diagnosis, Respiratory Distress Syndrome, Newborn etiology, Muscular Atrophy, Spinal diagnosis
- Abstract
In this article, we review the clinical, neuropathological and genetic aspects of distal spinal-muscular atrophy 1 (DSMA1; MIM#604320), formerly designated as autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1) and also known as distal hereditary-motor neuropathy type 6 (dHMN6 or HMN6).
- Published
- 2008
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26. Spinal muscular atrophy with respiratory distress type 1 (SMARD1).
- Author
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Kaindl AM, Guenther UP, Rudnik-Schöneborn S, Varon R, Zerres K, Schuelke M, Hübner C, and von Au K
- Subjects
- DNA-Binding Proteins genetics, Diagnosis, Differential, Humans, Infant, Infant, Newborn, Muscle Weakness diagnosis, Muscle Weakness physiopathology, Muscular Atrophy, Spinal diagnosis, Muscular Atrophy, Spinal genetics, Muscular Atrophy, Spinal physiopathology, Respiratory Distress Syndrome, Newborn diagnosis, Respiratory Distress Syndrome, Newborn genetics, Respiratory Distress Syndrome, Newborn physiopathology, Respiratory Paralysis diagnosis, Respiratory Paralysis genetics, Respiratory Paralysis physiopathology, Spinal Muscular Atrophies of Childhood diagnosis, Spinal Muscular Atrophies of Childhood genetics, Spinal Muscular Atrophies of Childhood physiopathology, Transcription Factors genetics, Muscular Atrophy, Spinal complications, Respiratory Distress Syndrome, Newborn complications, Respiratory Paralysis complications, Spinal Muscular Atrophies of Childhood complications
- Abstract
Autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1), recently referred to as distal spinal muscular atrophy 1 (DSMA1; MIM#604320) and also known as distal hereditary motor neuropathy type 6 (dHMN6 or HMN6), results from mutations in the IGHMBP2 gene on chromosome 11q13.3 encoding the immunoglobulin micro-binding protein 2. In contrast to the infantile spinal muscular atrophy type 1 (SMA1; Werdnig-Hoffmann disease) with weakness predominantly of proximal muscles and bell-shaped thorax deformities due to intercostal muscle atrophy, infants with distal spinal muscular atrophy 1 usually present with distal muscle weakness, foot deformities, and sudden respiratory failure due to diaphragmatic paralysis that often requires urgent intubation. In this article, the authors review the clinical, neuropathological, and genetic aspects of distal spinal muscular atrophy 1 and discuss differential diagnoses.
- Published
- 2008
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27. Clinical and mutational profile in spinal muscular atrophy with respiratory distress (SMARD): defining novel phenotypes through hierarchical cluster analysis.
- Author
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Guenther UP, Varon R, Schlicke M, Dutrannoy V, Volk A, Hübner C, von Au K, and Schuelke M
- Subjects
- Chi-Square Distribution, Cluster Analysis, Cohort Studies, DNA Mutational Analysis, DNA, Complementary, DNA-Binding Proteins genetics, Gene Expression Regulation, Humans, Infant, Infant, Newborn, Muscular Atrophy, Spinal pathology, Phenotype, Respiration Disorders pathology, Transcription Factors genetics, Muscular Atrophy, Spinal complications, Muscular Atrophy, Spinal genetics, Mutation genetics, Respiration Disorders complications, Respiration Disorders genetics
- Abstract
Autosomal recessive spinal muscular atrophy with respiratory distress (SMARD) is a heterogeneous disorder. Mutations in the immunoglobulin micro-binding protein gene (IGHMBP2) lead to SMARD1, but clinical criteria that delineate SMARD1 from other SMARD syndromes are not well established. Here we present a retrospective clinical and genetic study to determine the criteria that would predict the presence or absence of IGHMBP2 mutations. From 141 patients with respiratory distress and a spinal muscular atrophy phenotype we recorded the clinical features through a questionnaire and sequenced the entire coding region of IGHMBP2. In 47 (33%) patients we identified IGHMBP2 mutations, 14 of which were not described before. Clinical features and combinations thereof associated with the presence of IGHMBP2 mutations were discovered through hierarchical cluster analysis. This method detects common traits not evident at first sight by grouping items according to their similarity. The combination of "manifestation of respiratory failure between 6 weeks and 6 months" AND ("presence of diaphragmatic eventration" OR "preterm birth") predicted the presence of IGHMBP2 mutations with 98% sensitivity and 92% specificity. Non-SMARD1 patients fell into two different symptom clusters, mainly separated by the age at respiratory failure and the presence of multiple congenital contractures. The 14 novel IGHMBP2 mutations comprised missense, frameshift, splice-site, and nonsense mutations. All missense mutations altered conserved residues within or adjacent to the putative DNA helicase domain. The c.1235+3A>G splice-site mutation did not entirely suppress correct splicing and we found a residual wild-type IGHMBP2 mRNA steady-state level of 24.4+/-6.9%, which was, however, not sufficient to avert SMARD1 in this patient., ((c) 2007 Wiley-Liss, Inc.)
- Published
- 2007
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28. Distinct and overlapping alterations in motor and sensory neurons in a mouse model of spinal muscular atrophy.
- Author
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Jablonka S, Karle K, Sandner B, Andreassi C, von Au K, and Sendtner M
- Subjects
- Actins metabolism, Animals, Cell Survival, Cells, Cultured, Cyclic AMP Response Element-Binding Protein deficiency, Cyclic AMP Response Element-Binding Protein metabolism, Embryo, Mammalian metabolism, Foot pathology, Ganglia, Spinal pathology, Growth Cones metabolism, Heterogeneous-Nuclear Ribonucleoproteins metabolism, Mice, Mice, Knockout, Motor Neurons metabolism, Muscular Atrophy, Spinal metabolism, Nerve Tissue Proteins deficiency, Nerve Tissue Proteins metabolism, Neurites metabolism, Neurons, Afferent metabolism, Protein Transport, RNA, Messenger genetics, RNA-Binding Proteins metabolism, SMN Complex Proteins, Sensory Receptor Cells pathology, Disease Models, Animal, Motor Neurons pathology, Muscular Atrophy, Spinal pathology, Neurons, Afferent pathology
- Abstract
Motor neuron degeneration is the predominant pathological feature of spinal muscular atrophy (SMA). In patients with severe forms of the disease, additional sensory abnormalities have been reported. However, it is not clear whether the loss of sensory neurons is a common feature in severe forms of the disease, how many neurons are lost and how loss of sensory neurons compares with motor neuron degeneration. We have analysed dorsal root ganglionic sensory neurons in Smn-/-;SMN2 mice, a model of type I SMA. In contrast to lumbar motor neurons, no loss of sensory neurons in the L5 dorsal root ganglia is found at post-natal days 3-5 when these mice are severely paralyzed and die from motor defects. Survival of cultured sensory neurons in the presence of NGF and other neurotrophic factors is not reduced in comparison to wild-type controls. However, isolated sensory neurons have shorter neurites and smaller growth cones, and beta-actin protein and beta-actin mRNA are reduced in sensory neurite terminals. In footpads of Smn-deficient mouse embryos, sensory nerve terminals are smaller, suggesting that Smn deficiency reduces neurite outgrowth during embryogenesis. These data indicate that pathological alterations in severe forms of SMA are not restricted to motor neurons, but the defects in the sensory neurons are milder than those in the motor neurons.
- Published
- 2006
- Full Text
- View/download PDF
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