Jutta Gärtner

Georg-August-Universität Göttingen, Göttingen, Lower Saxony, Germany

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Publications (216)854.16 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The mechanisms behind CSF flow in humans are still not fully known. CSF circulates from its primary production sites at the choroid plexus through the brain ventricles to reach the outer surface of the brain in the subarachnoid spaces from where it drains into venous bloodstream and cervical lymphatics. According to a recent concept of brain fluid transport, established in rodents, CSF from the brain surface also enters the brain tissue along para-arterial routes and exits through paravenous spaces again into subarachnoid compartments. This unidirectional flow is mainly driven by arterial pulsation. To investigate how CSF flow is regulated in humans, we applied a novel real-time magnetic resonance imaging technique at high spatial (0.75 mm) and temporal (50 ms) resolution in healthy human subjects. We observed significant CSF flow exclusively with inspiration. In particular, during forced breathing, high CSF flow was elicited during every inspiration, whereas breath holding suppressed it. Only a minor flow component could be ascribed to cardiac pulsation. The present results unambiguously identify inspiration as the most important driving force for CSF flow in humans. Inspiratory thoracic pressure reduction is expected to directly modulate the hydrostatic pressure conditions for the low-resistance paravenous, venous, and lymphatic clearance routes of CSF. Furthermore, the experimental approach opens new clinical opportunities to study the pathophysiology of various forms of hydrocephalus and to design therapeutic strategies in relation to CSF flow alterations. Copyright © 2015 the authors 0270-6474/15/352485-07$15.00/0.
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    ABSTRACT: Currently, it is unclear whether pediatric multiple sclerosis (PMS) is a pathoetiologically homogeneous disease phenotype due to clinical and epidemiological differences between early and late onset PMS (EOPMS and LOPMS). Consequently, the question was raised whether diagnostic guidelines need to be complemented by spe-cific EOPMS markers. To search for such markers, we analyzed cerebral MRI images acquired with standard pro-tocols using computer-based classification techniques. Specifically, we applied classification algorithms to gray (GM) and white matter (WM) tissue probability parameters of small brain regions derived from T2-weighted MRI images of EOPMS patients (onset b12 years), LOPMS patients (onset ≥12 years), and healthy controls (HC). This was done for PMS subgroups matched for disease duration and participant age independently. As ex-pected, maximal diagnostic information for distinguishing PMS patients and HC was found in a periventricular WM area containing lesions (87.1% accuracy, p b 2.2 × 10 −5). MRI-based biomarkers specific for EOPMS were identified in prefrontal cortex. Specifically, a coordinate in middle frontal gyrus contained maximal diagnostic in-formation (77.3%, p = 1.8 × 10 −4). Taken together, we were able to identify biomarkers reflecting pathognomon-ic processes specific for MS patients with very early onset. Especially GM involvement in the separation between PMS subgroups suggests that conventional MRI contains a richer set of diagnostically informative features than previously assumed.
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    ABSTRACT: Objective Axonal damage occurs early in multiple sclerosis (MS) and contributes to the degree of clinical disability. Children with MS more often show disabling and polyfocal neurological symptoms at disease onset than adults with MS. Thus, axonal damage may differ between pediatric and adult MS patients.Methods We analyzed axonal pathology in archival brain biopsy and autopsy samples from 19 children with early MS. Lesions were classified according to demyelinating activity and presence of remyelination. Axonal density and extent of acute axonal damage were assessed using Bielschowsky silver impregnation and immunohistochemistry for amyloid precursor protein (APP), respectively. Axonal injury was correlated with the inflammatory infiltrate as well as clinical characteristics. Results were compared with data from adult MS patients.ResultsAcute axonal damage was most extensive in early active demyelinating (EA) lesions of pediatric patients and correlated positively with the Expanded Disability Status Scale at attack leading to biopsy/autopsy. Comparison with 12 adult patients showed a 50% increase in the extent of acute axonal damage in EA lesions from children compared to adults, with the highest number of APP-positive spheroids found prior to puberty. The extent of acute axonal damage correlated positively with the number of lesional macrophages. Axonal density was reduced in pediatric lesions irrespective of the demyelinating activity or the presence of remyelination. Axonal reduction was similar between children and adults.InterpretationOur results provide evidence for more pronounced acute axonal damage in inflammatory demyelinating lesions from children compared to adults. Ann Neurol 2015;77:655–667
    Annals of Neurology 01/2015; 77(4). DOI:10.1002/ana.24364 · 11.91 Impact Factor
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    ABSTRACT: The apoptosis-inducing factor (AIF) functions as a FAD-dependent NADH oxidase in mitochondria. Upon apoptotic stimulation it is released from mitochondria and migrates to the nucleus where it induces chromatin condensation and DNA fragmentation. So far mutations in AIFM1, a X-chromosomal gene coding for AIF, have been described in three families with 11 affected males. We report here on a further patient thereby expanding the clinical and mutation spectrum. In addition, we review the known phenotypes related to AIFM1 mutations. The clinical course in the male patient described here was characterized by phases with rapid deterioration and long phases without obvious progression of disease. At age 2.5 years he developed hearing loss and severe ataxia and at age 10 years muscle wasting, swallowing difficulties, respiratory insufficiency and external opthamoplegia. By next generation sequencing of whole exome we identified a hemizygous missense mutation in the AIFM1 gene, c.727G > T (p.Val243Leu) affecting a highly conserved residue in the FAD-binding domain. Summarizing what is known today, mutations in AIFM1 are associated with a progressive disorder with myopathy, ataxia and neuropathy. Severity varies greatly even within one family with onset of symptoms between birth and adolescence. 3 of 12 patients died before age 5 years while others were still able to walk during young adulthood. Less frequent symptoms were hearing loss, seizures and psychomotor regression. Results from clinical chemistry, brain imaging and muscle biopsy were unspecific and inconsistent.
    Mitochondrion 01/2015; 21. DOI:10.1016/j.mito.2015.01.001 · 3.52 Impact Factor
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    ABSTRACT: Rett syndrome, one of the most common causes of mental retardation in females, is caused by mutations in the X chromosomal gene MECP2. Mice deficient for MeCP2 recapitulate some of the symptoms seen in patients with Rett syndrome. It has been shown that reactivation of silent MECP2 alleles can reverse some of the symptoms in these mice. We have generated a knockin mouse model for translational research that carries the most common nonsense mutation in Rett syndrome, R168X. In this article we describe the phenotype of this mouse model. In male MeCP2R168X mice life span was reduced to 12-14 weeks and bodyweight was significantly lower than in wild type littermates. First symptoms including tremor, hind limb clasping and inactivity occurred at age 27 days. At age 6 weeks nest building, rotarod, open-field and elevated plus maze experiments showed impaired motor performance, reduced activity and decreased anxiety-like behavior. Plethysmography at the same time showed apneas and irregular breathing with reduced frequency. Female MeCP2R168X mice showed no significant abnormalities except decreased performance on the rotarod at age 9 months. In conclusion we show that the male MeCP2R168X mice have a phenotype similar to that seen in MECP2 knockout mouse models and are therefore well suited for translational research. The female mice, however, have a much milder and less constant phenotype making such research with this mouse model more challenging.
    PLoS ONE 12/2014; 9(12):e115444. DOI:10.1371/journal.pone.0115444 · 3.53 Impact Factor
  • European journal of human genetics: EJHG 11/2014; DOI:10.1038/ejhg.2014.250 · 4.23 Impact Factor
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    ABSTRACT: eLife digest Amino acids are the building blocks of proteins, and the order of the amino acids in a protein is determined by the order in which ‘codons’ appear in a messenger RNA molecule. Most codons represent a specific amino acid, but there are also three stop codons that are used to mark the end of a protein. When the cellular machinery that ‘translates’ the messenger RNA molecule into a protein encounters a stop codon, it stops and releases the completed protein. Sometimes, however, the stop codon is not interpreted as a stop signal, and the translation of the messenger RNA molecule continues until another stop codon is encountered. This process is known as readthrough. Some organisms, in particular viruses and fungi, use readthrough to produce a wider range of proteins than their genomes would otherwise allow. While readthrough also occurs in higher organisms such as mammals, it is not known if the resulting proteins perform extra functions that the original protein does not perform. A number of factors affect whether readthrough occurs when an mRNA template is being translated. For example, each of the three stop codons has a different likelihood of having its stop signal misinterpreted, and the mRNA sequence that surrounds the stop codon can also affect the likelihood of readthrough. Schueren et al. have developed a computational model that estimates how common this form of translational readthrough is in the human genome. The model was based on the identity of the stop codons themselves and the surrounding mRNA sequence. This model was then combined with another model that identifies proteins that are targeted to a structure inside a cell called the peroxisome, which is where a number of essential energy-releasing reactions take place. The combined model enabled Schueren et al. to identify proteins that both perform functions in the peroxisome and are likely to be formed by readthrough. The combined model suggested a protein that is a part of lactate dehydrogenase: an enzyme that speeds up chemical reactions that are important for the cell to produce energy. Low levels of lactate dehydrogenase had previously been found in the peroxisome, despite it apparently lacking a specific sequence of amino acids that proteins need to have to enter the peroxisome. However, Schueren et al. confirmed experimentally that readthrough does occur for the lactate dehydrogenase component identified by the model, revealing that it contains a ‘hidden’ peroxisome-targeting region. Furthermore, when more translational readthrough occurred, more lactate dehydrogenase was found in the peroxisomes. This unusual way that lactate dehydrogenase enters the peroxisome is an example of how the cell optimizes the used of the genetic information encoded in the genome and in messenger RNA. Translational readthrough always ensures that a certain proportion of lactate dehydrogenase will be brought to the peroxisome. The computational model developed here will be a valuable tool to identify other such proteins produced from genomes, including the human genome and those of other species. DOI: http://dx.doi.org/10.7554/eLife.03640.002
    eLife Sciences 09/2014; 3. DOI:10.7554/eLife.03640 · 8.52 Impact Factor
  • Neuropediatrics 09/2014; 45(S 01). DOI:10.1055/s-0034-1390657 · 1.10 Impact Factor
  • Neuropediatrics 09/2014; 45(S 01). DOI:10.1055/s-0034-1390522 · 1.10 Impact Factor
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    ABSTRACT: So far very few patients with sequence variants in the closely related tectonic genes TCTN1-3 have been described. By multi-gene panel next-generation sequencing (NGS) in patients with Joubert syndrome, we identified two more patients and summarize what is currently known about the phenotypes associated with sequence variants in these genes. In a boy aged 12 years with intellectual disability and the classical molar tooth sign on MRI, a homozygous splice-site sequence variant in TCTN3 leading to in-frame skipping of exon 7 was detected. A previously described non-truncating sequence variant in TCTN3 was also associated with Joubert syndrome, whereas four truncating sequence variants were detected in patients with Meckel-Gruber or Mohr-Majewski syndrome. The second patient, a boy aged 7 years with severe psychomotor retardation, was found to carry a homozygous canonic splice-site sequence variant in TCTN2. So far, only three sequence variants associated with Joubert syndrome and two with Meckel-Gruber syndrome have been described in this gene. Reviewing the clinical data on patients with sequence variants in the tectonic genes TCTN1-3 reveals that all of them have a neurological phenotype with vermis hypoplasia or occipital encephalocele associated with severe intellectual disability in the surviving patients. In contrast, other features frequently seen in patients with ciliopathies such as nephronophthisis, liver fibrosis, retinal dystrophy or coloboma have not been reported. Our patients emphasize the usefulness and efficacy of a comprehensive NGS panel approach. A concise genetic diagnosis may help to prevent unnecessary investigations and improve the clinical management of these patients.European Journal of Human Genetics advance online publication, 13 August 2014; doi:10.1038/ejhg.2014.160.
    European journal of human genetics: EJHG 08/2014; DOI:10.1038/ejhg.2014.160 · 4.23 Impact Factor
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    ABSTRACT: Because of the emergence of novel therapies for multiple sclerosis (MS) and the associated increased risk of progressive multifocal leukoencephalopathy, John Cunningham (JC) virus infection has become a focus of interest for neurologists. However, little is known about JC virus infection in pediatric MS to date.
    Multiple Sclerosis 07/2014; DOI:10.1177/1352458514543340 · 4.86 Impact Factor
  • Neurology 07/2014; DOI:10.1212/WNL.0000000000000735 · 8.30 Impact Factor
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    ABSTRACT: Mutations in the ATP1A3 gene are associated with rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) as well as RDP/AHC intermediate presentations. Phenotypic diversity is being recognized. In order to identify ATP1A3-related phenotypes not meeting the classical criteria for RDP or AHC we lowered the threshold for mutation analysis in clinical presentations resembling AHC or RDP. A novel heterozygous ATP1A3 missense mutation c.2600G > A (p.Gly867Asp, G867D) was detected in a 15-year-old girl. Her clinical phenotype is partially consistent with an intermediate presentation between alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism and comprises additional yet unreported features. With onset at 4½ years of age recurrent paroxysmal flaccid hemiplegia alternating in laterality was triggered by watching television or playing computer games. Occlusion of both eyes reliably stopped the plegic attacks with the patient remaining awake. Our observation further widens the phenotypic spectrum associated with ATP1A3 mutations.
    Journal of the neurological sciences 06/2014; 341(1-2). DOI:10.1016/j.jns.2014.03.034 · 2.26 Impact Factor
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    ABSTRACT: Mucopolysaccharidosis type IIIA (Sanfilippo A syndrome), a fatal childhood-onset neurodegenerative disease with mild facial, visceral and skeletal abnormalities, is caused by an inherited deficiency of the enzyme N-sulfoglucosamine sulfohydrolase (SGSH; sulfamidase). More than 100 mutations in the SGSH gene have been found to reduce or eliminate its enzymatic activity. However, the molecular understanding of the effect of these mutations has been confined by a lack of structural data for this enzyme. Here, the crystal structure of glycosylated SGSH is presented at 2 Å resolution. Despite the low sequence identity between this unique N-sulfatase and the group of O-sulfatases, they share a similar overall fold and active-site architecture, including a catalytic formylglycine, a divalent metal-binding site and a sulfate-binding site. However, a highly conserved lysine in O-sulfatases is replaced in SGSH by an arginine (Arg282) that is positioned to bind the N-linked sulfate substrate. The structure also provides insight into the diverse effects of pathogenic mutations on SGSH function in mucopolysaccharidosis type IIIA and convincing evidence for the molecular consequences of many missense mutations. Further, the molecular characterization of SGSH mutations will lay the groundwork for the development of structure-based drug design for this devastating neurodegenerative disorder.
    Acta Crystallographica Section D Biological Crystallography 05/2014; 70(Pt 5):1321-35. DOI:10.1107/S1399004714002739 · 7.23 Impact Factor
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    ABSTRACT: Peroxisomes are ubiquitous and dynamic organelles that house many important pathways of cellular metabolism. In recent years it has been demonstrated that mitochondria are tightly connected with peroxisomes and are defective in several peroxisomal diseases. Indeed, these two organelles share metabolic routes as well as resident proteins and, at least in mammals, are connected via a vesicular transport pathway. However the exact extent of cross-talk between peroxisomes and mitochondria remains unclear. Here we used a combination of high throughput genetic manipulations of yeast libraries alongside high content screens to systematically unravel proteins that affect the transport of peroxisomal proteins and peroxisome biogenesis. Follow up work on the effector proteins that were identified revealed that peroxisomes are not randomly distributed in cells but are rather localized to specific mitochondrial subdomains such as mitochondria-ER junctions and sites of acetyl-CoA synthesis. Our approach highlights the intricate geography of the cell and suggests an additional layer of organization as a possible way to enable efficient metabolism. Our findings pave the way for further studying the machinery aligning mitochondria and peroxisomes, the role of the juxtaposition, as well as its regulation during various metabolic conditions. More broadly, the approaches used here can be easily applied to study any organelle of choice, facilitating the discovery of new aspects in cell biology.
    Molecular BioSystems 04/2014; 10(7). DOI:10.1039/c4mb00001c · 3.18 Impact Factor
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    ABSTRACT: We aimed to delineate the clinical and genetic spectrum of ATP1A3-related disorders and recognition of a potential genotype-phenotype correlation. We identified 16 new patients with alternating hemiplegia of childhood (AHC) and 3 new patients with rapid-onset dystonia-parkinsonism (RDP) and included these as well as the clinical and molecular findings of all previously reported 164 patients with mutation-positive AHC and RDP in our analyses. Major clinical characteristics shared in common by AHC and RDP comprise a strikingly asymmetric, predominantly dystonic movement disorder with rostrocaudal gradient of involvement and physical, emotional, or chemical stressors as triggers. The clinical courses include an early-onset polyphasic for AHC, a later-onset mono- or biphasic for RDP, as well as intermediate forms. Meta-analysis of the 8 novel and 38 published ATP1A3 mutations shows that the ones affecting transmembrane and functional domains tend to be associated with AHC as the more severe phenotype. The majority of mutations are located in exons 8, 14, 17, and 18. AHC and RDP constitute clinical prototypes in a continuous phenotypic spectrum of ATP1A3-related disorders. Intermediate phenotypes combining criteria of both conditions are increasingly recognized. Efficient stepwise mutation analysis of the ATP1A3 gene may prioritize those exons where current state of knowledge indicates mutational clusters.
    Neurology 02/2014; 82(11). DOI:10.1212/WNL.0000000000000212 · 8.30 Impact Factor
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    ABSTRACT: Pediatric multiple sclerosis (MS) clinical and incidence data have been reported for several countries but valid age dependent incidence data are not yet available. The true incidence of pediatric MS in Germany was estimated and the clinical characteristics at diagnosis according to the 2005 McDonald criteria are described. Between 2009 and 2011 active prospective nationwide surveillance for MS in children and adolescents ≤15 years included all pediatric hospitals, MS centers and private practices specialized in MS. Data were adjusted for under-reporting by capture-recapture from an independent second source. The estimated incidence of pediatric MS was 0.64 per 100 000 person-years with clear increase from age group ≤10 (0.09/100 000) to 2.64 per 100 000 in age group 14-15 years. All had relapsing-remitting disease with polysymptomatic onset in half of the cases. Spinal MRI with positive findings in two-thirds of patients contributed to diagnosis. Using an active prospective surveillance system and the McDonald criteria for first MS diagnosis the age-related incidence of pediatric MS in Germany was uncovered and is more common than in previous estimates. Thorough application of McDonald criteria and inclusion of spinal MRI data allowed for early diagnosis in almost 90% of cases.
    European Journal of Neurology 01/2014; 21(4). DOI:10.1111/ene.12371 · 3.85 Impact Factor
  • 01/2014; 1(Suppl 1):A15. DOI:10.1186/2194-7791-1-S1-A15
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    ABSTRACT: Multiple sclerosis (MS) onset before puberty is extremely rare and establishment of diagnosis is often difficult due to atypical presentation. The study aims to identify the typical presentation of MS in this age group. Pediatric MS patients were identified from the database of the Center for Multiple Sclerosis in Childhood and Adolescence at the University Medical Center Göttingen, Germany. Inclusion criteria were a relapsing-remitting initial disease course and minimum disease duration of 4 years. Forty-seven pre-pubertal (<11 years) and 41 post-pubertal (14-16 years) MS patients were compared. Before puberty an even gender ratio was found. The pre-pubertal patients were more likely to have a polysymptomatic severe first attack with motor and brainstem involvement, sphincter dysfunction, cognitive disturbances and milder residual neurological sequelae after the first episode whilst the post-pubertal patients predominantly presented with optic neuritis and sensory symptoms. The initial symptom pattern prevailed over the first 2 years of disease. Presentation of pre-pubertal boys and girls did not differ significantly. To facilitate early diagnosis it is important to recognize that pre-pubertal MS presents with a specific pattern of symptoms that is maintained over the first two disease years.
    European Journal of Neurology 12/2013; 21(3). DOI:10.1111/ene.12327 · 3.85 Impact Factor
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    ABSTRACT: X-linked creatine transport (CRTR) deficiency, caused by mutations in the SLC6A8 gene, leads to intellectual disability, speech delay, epilepsy, and autistic behavior in hemizygous males. Additional diagnostic features are depleted brain creatine levels and increased creatine/creatinine ratio (cr/crn) in urine. In heterozygous females the phenotype is highly variable and diagnostic hallmarks might be inconclusive. This survey aims to explore the intrafamilial variability of clinical and brain proton Magnetic Resonance Spectroscopy (MRS) findings in males and females with CRTR deficiency. X-chromosome exome sequencing identified a novel missense mutation in the SLC6A8 gene (p.G351R) in a large family with X-linked intellectual disability. Detailed clinical investigations including neuropsychological assessment, measurement of in vivo brain creatine concentrations using quantitative MRS, and analyses of creatine metabolites in urine were performed in five clinically affected family members including three heterozygous females and one hemizygous male confirming the diagnosis of CRTR deficiency. The severe phenotype of the hemizygous male was accompanied by most distinct aberrations of brain creatine concentrations (-83% in gray and -79% in white matter of age-matched normal controls) and urinary creatine/creatinine ratio. In contrast, the heterozygous females showed varying albeit generally milder phenotypes with less severe brain creatine (-50% to -33% in gray and -45% to none in white matter) and biochemical urine abnormalities. An intrafamilial correlation between female phenotype, brain creatine depletion, and urinary creatine abnormalities was observed. The combination of powerful new technologies like exome-next-generation sequencing with thorough systematic evaluation of patients will further expand the clinical spectrum of neurometabolic diseases.
    11/2013; DOI:10.1007/8904_2013_261

Publication Stats

3k Citations
854.16 Total Impact Points


  • 2003–2015
    • Georg-August-Universität Göttingen
      • • Faculty of Medicine
      • • Department of Plant Biochemistry
      Göttingen, Lower Saxony, Germany
  • 2013
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem, Israel
  • 2006–2013
    • Universitätsmedizin Göttingen
      • Division of Neuropediatrics
      Göttingen, Lower Saxony, Germany
  • 2012
    • Universität zu Lübeck
      • Department of Paediatrics
      Lübeck, Schleswig-Holstein, Germany
    • Universitätsklinikum Freiburg
      Freiburg an der Elbe, Lower Saxony, Germany
  • 1994–2007
    • Heinrich-Heine-Universität Düsseldorf
      • Institut für Diagnostische und Interventionelle Radiologie
      Düsseldorf, North Rhine-Westphalia, Germany
  • 1997
    • Universitätsklinikum Düsseldorf
      Düsseldorf, North Rhine-Westphalia, Germany
  • 1993
    • Johns Hopkins Medicine
      • Department of Pediatrics
      Baltimore, MD, United States
  • 1991–1993
    • Johns Hopkins University
      • Department of Pediatrics
      Baltimore, Maryland, United States