Ludger Schöls

Hertie-Institute for Clinical Brain Research, Tübingen, Baden-Württemberg, Germany

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Publications (295)1524.52 Total impact

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    ABSTRACT: The genetic diagnosis in inherited optic neuropathies often remains challenging, and the emergence of complex neurological phenotypes that involve optic neuropathy is puzzling. Here we unravel two novel principles of genetic mechanisms in optic neuropathies: deep intronic OPA1 mutations, which explain the disease in several so far unsolved cases; and an intralocus OPA1 modifier, which explains the emergence of syndromic 'optic atrophy plus' phenotypes in several families. First, we unravelled a deep intronic mutation 364 base pairs 3' of exon 4b in OPA1 by in-depth investigation of a family with severe optic atrophy plus syndrome in which conventional OPA1 diagnostics including gene dosage analyses were normal. The mutation creates a new splice acceptor site resulting in aberrant OPA1 transcripts with retained intronic sequence and subsequent translational frameshift as shown by complementary DNA analysis. In patient fibroblasts we demonstrate nonsense mediated messenger RNA decay, reduced levels of OPA1 protein, and impairment of mitochondrial dynamics. Subsequent site-specific screening of >360 subjects with unexplained inherited optic neuropathy revealed three additional families carrying this deep intronic mutation and a base exchange four nucleotides upstream, respectively, thus confirming the clinical significance of this mutational mechanism. Second, in all severely affected patients of the index family, the deep intronic mutation occurred in compound heterozygous state with an exonic OPA1 missense variant (p.I382M; NM_015560.2). The variant alone did not cause a phenotype, even in homozygous state indicating that this long debated OPA1 variant is not pathogenic per se, but acts as a phenotypic modifier if it encounters in trans with an OPA1 mutation. Subsequent screening of whole exomes from >600 index patients identified a second family with severe optic atrophy plus syndrome due to compound heterozygous p.I382M, thus confirming this mechanism. In summary, we provide genetic and functional evidence that deep intronic mutations in OPA1 can cause optic atrophy and explain disease in a substantial share of families with unsolved inherited optic neuropathies. Moreover, we show that an OPA1 modifier variant explains the emergence of optic atrophy plus phenotypes if combined in trans with another OPA1 mutation. Both mutational mechanisms identified in this study-deep intronic mutations and intragenic modifiers-might represent more generalizable mechanisms that could be found also in a wide range of other neurodegenerative and optic neuropathy diseases.
    Brain 06/2014; · 9.92 Impact Factor
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    ABSTRACT: Mutations in the gene coding for Sequestosome 1 (SQSTM1) have been genetically associated with amyotrophic lateral sclerosis (ALS) and Paget disease of bone. In the present study, we analyzed the SQSTM1 coding sequence for mutations in an extended cohort of 1,808 patients with frontotemporal lobar degeneration (FTLD), ascertained within the European Early-Onset Dementia consortium. As control dataset, we sequenced 1,625 European control individuals and analyzed whole-exome sequence data of 2,274 German individuals (total n = 3,899). Association of rare SQSTM1 mutations was calculated in a meta-analysis of 4,332 FTLD and 10,240 control alleles. We identified 25 coding variants in FTLD patients of which 10 have not been described. Fifteen mutations were absent in the control individuals (carrier frequency <0.00026) whilst the others were rare in both patients and control individuals. When pooling all variants with a minor allele frequency <0.01, an overall frequency of 3.2 % was calculated in patients. Rare variant association analysis between patients and controls showed no difference over the whole protein, but suggested that rare mutations clustering in the UBA domain of SQSTM1 may influence disease susceptibility by doubling the risk for FTLD (RR = 2.18 [95 % CI 1.24-3.85]; corrected p value = 0.042). Detailed histopathology demonstrated that mutations in SQSTM1 associate with widespread neuronal and glial phospho-TDP-43 pathology. With this study, we provide further evidence for a putative role of rare mutations in SQSTM1 in the genetic etiology of FTLD and showed that, comparable to other FTLD/ALS genes, SQSTM1 mutations are associated with TDP-43 pathology.
    Acta Neuropathologica 06/2014; · 9.73 Impact Factor
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    ABSTRACT: To identify a novel disease gene in 2 families with autosomal recessive hereditary spastic paraplegia (HSP). We used whole-exome sequencing to identify the underlying genetic disease cause in 2 families with apparently autosomal recessive spastic paraplegia. Endogenous expression as well as subcellular localization of wild-type and mutant protein were studied to support the pathogenicity of the identified mutations. In 2 families, we identified compound heterozygous or homozygous mutations in the kinesin gene KIF1C to cause hereditary spastic paraplegia type 58 (SPG58). SPG58 can be complicated by cervical dystonia and cerebellar ataxia. The same mutations in a heterozygous state result in a mild or subclinical phenotype. KIF1C mutations in SPG58 affect the domains involved in adenosine triphosphate hydrolysis and microtubule binding, key functions for this microtubule-based motor protein. KIF1C is the third kinesin gene involved in the pathogenesis of HSPs and is characterized by a mild dominant and a more severe recessive disease phenotype. The identification of KIF1C as an HSP disease gene further supports the key role of intracellular trafficking processes in the pathogenesis of hereditary axonopathies.
    Neurology 05/2014; · 8.25 Impact Factor
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    ABSTRACT: Hereditary spastic paraplegias (HSP) constitute a rare and highly heterogeneous group of neurodegenerative disorders, defined clinically by progressive lower limb spasticity and pyramidal weakness. Autosomal recessive HSP as well as sporadic cases present a significant diagnostic challenge. Mutations in AP5Z1, a gene playing a role in intracellular membrane trafficking, have been recently reported to be associated with spastic paraplegia type 48 (SPG48). Our objective was to determine the relative frequency and clinical relevance of AP5Z1 mutations in a large cohort of 127 HSP patients. We applied a targeted next-generation sequencing approach to analyze all coding exons of the AP5Z1 gene. With the output of high-quality reads and a mean coverage of 51-fold, we demonstrated a robust detection of variants. One 43-year-old female with sporadic complicated paraplegia showed two heterozygous nonsynonymous variants of unknown significance (VUS3; p.[R292W];[(T756I)]). Thus, AP5Z1 gene mutations are rare, at least in Europeans. Due to its low frequency, systematic genetic testing for AP5Z1 mutations is not recommended until larger studies are performed to add further evidence. Our findings demonstrate that amplicon-based deep sequencing is technically feasible and allows a compact molecular characterization of multiple HSP patients with high accuracy.
    Molecular Genetics & Genomic Medicine. 05/2014;
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    Journal of neurology, neurosurgery, and psychiatry 04/2014; · 4.87 Impact Factor
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    ABSTRACT: Mutations in the gene STUB1, encoding the protein CHIP (C-terminus of HSC70-interacting protein), have recently been suggested as a cause of recessive ataxia based on the findings in few Chinese families. Here we aimed to investigate the phenotypic and genotypic spectrum of STUB1 mutations, and to assess their frequency in different Caucasian disease cohorts. 300 subjects with degenerative ataxia (n = 167) or spastic paraplegia (n = 133) were screened for STUB1 variants by whole-exome-sequencing (n = 204) or shotgun-fragment-library-sequencing (n = 96). To control for the specificity of STUB1 variants, we screened an additional 1707 exomes from 891 index families with other neurological diseases. We identified 3 ataxia patients (3/167 = 1.8%) with 4 novel missense mutations in STUB1, including 3 mutations in its tetratricopeptide-repeat domain. All patients showed evidence of pyramidal tract damage. Cognitive impairment was present only in one and hypogonadism in none of them. Ataxia did not start before age 48 years in one subject. No recessive STUB1 variants were identified in families with other neurological diseases, demonstrating that STUB1 variants are not simply rare polymorphisms ubiquitous in neurodegenerative disease. STUB1-disease occurs also in Caucasian ataxia populations (1.8%). Our results expand the genotypic spectrum of STUB1-disease, showing that pathogenic mutations affect also the tetratricopeptide-repeat domain, thus providing clinical evidence for the functional importance of this domain. Moreover, they further delineate the phenotypic core features of STUB1-ataxia. Pyramidal tract damage is a common accompanying feature and can include lower limb spasticity, thus adding STUB1-ataxia to the differential diagnosis of "spastic ataxias". However, STUB1 is rare in subjects with predominant spastic paraplegia (0/133). In contrast to previous reports, STUB1-ataxia can start even above age 40 years, and neither hypogonadism nor prominent cognitive impairment are obligatory features.
    Orphanet Journal of Rare Diseases 04/2014; 9(1):57. · 4.32 Impact Factor
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    ABSTRACT: Background and purposeIn chronic progressive spasticity of the legs many rare causes have to be considered, including leukodystrophies due to neurometabolic disorders. To determine the frequency of leukodystrophies and the phenotypic spectrum patients with cryptic spasticity of the legs were screened for underlying neurometabolic abnormalities.Methods Seventy-six index patients presenting with adult-onset lower limb spasticity of unknown cause consistent with autosomal recessive inheritance were included in this study. Screening included serum levels of very long chain fatty acids for X-linked adrenoleukodystrophy/adrenomyeloneuropathy and lysosomal enzyme activities in leukocytes for metachromatic leukodystrophy, GM1-gangliosidosis, Tay−Sachs, Sandhoff and Krabbe disease. If clinical evidence was indicative of other types of leukodystrophies, additional genetic testing was conducted. Clinical characterization included neurological and psychiatric features and magnetic resonance imaging.ResultsBasic screening detected one index patient with metachromatic leukodystrophy, two patients with Krabbe disease and four patients with adrenoleukodystrophy/adrenomyeloneuropathy. Additional genetic testing revealed one patient with vanishing white matter disease. These patients accounted for an overall share of 11% of leukodystrophies. One patient with Krabbe disease and three patients with adrenoleukodystrophy/adrenomyeloneuropathy presented with pure spasticity of the lower limbs, whilst one patient each with Krabbe disease, metachromatic leukodystrophy and adrenoleukodystrophy/adrenomyeloneuropathy showed additional complicating symptoms.Conclusions Adult patients presenting with cryptic spasticity of the legs should be screened for underlying X-linked adrenoleukodystrophy/adrenomyeloneuropathy and lysosomal disorders, irrespective of the presence of additional complicating symptoms. Leukodystrophies may manifest as late as the sixth decade and hyperintensity of cerebral white matter on magnetic resonance FLAIR images is not obligatory.
    European Journal of Neurology 04/2014; · 4.16 Impact Factor
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    ABSTRACT: Sanfilippo syndrome type A (mucopolysaccharidosis IIIA - MPS IIIA) is an autosomal recessive lysosomal storage disorder caused by a deficiency in sulfamidase. Two daughters (13 and 11 years old) of a consanguineous Palestinian family from the Israeli Arab community were investigated clinically and genetically for the presence of progressive neurodegenerative disease, psychomotor retardation and behavioral abnormalities. Development was normal up to one year of age. Thereafter, progressive motor and speech delay started. Metabolic screening including glycosaminoglycans, karyotype testing and magnetic resonance imaging were normal. Later in the disease, they developed severe spasticity and intellectual disability with autistic features and incontinence. Magnetic resonance imaging revealed diffuse hypomyelination with thinning of the corpus callosum. Genetic examination through whole exome sequencing revealed a homozygous mutation c.416C >T (p.T139M) in the N-sulfoglucosamine sulfohydrolase (SGSH) gene. Repeated biochemical testing at age 11 and 13 revealed increased levels of glycosaminoglycans confirming the diagnosis of Sanfilippo syndrome type A. These cases were considered to be the first report of Sanfilippo syndrome in Israel. We recommend that if similar clinical features are present during childhood, it is preferred to go directly and primarily for a genetic diagnosis of Sanfilippo syndrome, then secondarily for other lysosomal storage disorders that may also be involved.
    Journal of Medical Case Reports 02/2014; 8(1):78.
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    ABSTRACT: X-linked Charcot-Marie-Tooth disease type 5 (CMTX5), Arts syndrome, and non-syndromic sensorineural deafness (DFN2) are allelic syndromes, caused by reduced activity of phosphoribosylpyrophosphate synthetase 1 (PRS-I) due to loss-of-function mutations in PRPS1. As only few families have been described, knowledge about the relation between these syndromes, the phenotypic spectrum in patients and female carriers, and the relation to underlying PRS-I activity is limited. We investigated a family with a novel PRPS1 mutation (c.830A > C, p.Gln277Pro) by extensive phenotyping, MRI, and genetic and enzymatic tests. The male index subject presented with an overlap of CMTX5 and Arts syndrome features, whereas his sister presented with prelingual DFN2. Both showed mild parietal and cerebellar atrophy on MRI. Enzymatically, PRS-I activity was undetectable in the index subject, reduced in his less affected sister, and normal in his unaffected mother. Our findings demonstrate that CMTX5, Arts syndrome and DFN2 are phenotypic clusters on an intrafamilial continuum, including overlapping phenotypes even within individuals. The respective phenotypic presentation seems to be determined by the exact PRPS1 mutation and the residual enzyme activity, the latter being largely influenced by the degree of skewed X-inactivation. Finally, our findings show that brain atrophy might be more common in PRPS1-disorders than previously thought.
    Orphanet Journal of Rare Diseases 02/2014; 9(1):24. · 4.32 Impact Factor
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    ABSTRACT: Erythropoietin (EPO) derivatives have been found to increase frataxin levels in Friedreich's ataxia (FRDA) in vitro. This multicenter, double-blind, placebo-controlled, phase II clinical trial aimed to evaluate the safety and tolerability of Lu AA24493 (carbamylated EPO; CEPO). Thirty-six ambulatory FRDA patients harboring >400 GAA repeats were 2:1 randomly assigned to either CEPO in a fixed dose (325 µg thrice-weekly) or placebo. Safety and tolerability were assessed up to 103 days after baseline. Secondary outcome measures of efficacy (exploration of biomarkers and ataxia ratings) were performed up to 43 days after baseline. All patients received six doses of study medication. Adverse events were equally distributed between CEPO and placebo. There was no evidence for immunogenicity of CEPO after multiple dosing. Biomarkers, such as frataxin, or measures for oxidative stress and ataxia ratings did not differ between CEPO and placebo. CEPO was safe and well tolerated in a 2-week treatment phase. Secondary outcome measures remained without apparent difference between CEPO and placebo. © 2014 International Parkinson and Movement Disorder Society.
    Movement Disorders 02/2014; · 5.63 Impact Factor
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    ABSTRACT: Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are allelic disorders of the gene CACNA1A encoding the P/Q subunit of a voltage gated calcium channel. While SCA6 is related to repeat expansions affecting the C-terminal part of the protein, EA2 and FHM phenotypes are usually associated with nonsense and missense mutations leading to impaired channel properties. In three unrelated families with dominant cerebellar ataxia, symptoms cosegregated with CACNA1A missense mutations of evolutionary highly conserved amino acids (exchanges p.E668K, p.R583Q and p.D302N). To evaluate pathogenic effects, in silico, protein modeling analyses were performed which indicate structural alterations of the novel mutation p.E668K within the homologous domain 2 affecting CACNA1A protein function.The phenotype is characterised by a very slowly progressive ataxia, while ataxic episodes or migraine are uncommon. These findings enlarge the phenotypic spectrum of CACNA1A mutations.
    European journal of medical genetics 01/2014; · 1.57 Impact Factor
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    ABSTRACT: Background We describe the clinical characteristics of a Swedish family with autosomal dominant cerebellar ataxia, sensory and autonomic neuropathy, additional neurological features and unknown genetic cause. Methods Fourteen affected family members were identified. Their disorder was characterized by neurological examination, MRI, electroneurography, electromyography, MIBG-scintigraphy, and tilt-testing. Results The disorder presented as a balance and gait disturbance starting between 16 and 47 years of age. Cerebellar ataxia progressed slowly over the course of decades, and MRI showed mild to moderate cerebellar atrophy. Sensory axonal polyneuropathy was the most prominent additional feature and occurred in all patients examined. Autonomic neuropathy caused pronounced orthostatic dysregulation in at least four patients. Several affected members showed muscle wasting, and mild upper or lower motor neuron signs were documented. Patients had no nystagmus but slow or hypometric horizontal saccades and ocular motor apraxia. Cognition remained unimpaired, and there were no non-neurological disease manifestations. The disorder affected men and women in successive generations in a pattern compatible with autosomal dominant inheritance without evidence of anticipation. A second family where 7 members had very similar symptoms was identified and its origin traced back to the same village in southern Sweden as that of the first family’s ancestors. All relevant known genetic causes of cerebellar ataxia were excluded by a novel next-generation sequencing approach. Conclusion We present two probably related Swedish families with a characteristic and novel clinical syndrome of cerebellar ataxia and sensory polyneuropathy. The study serves as a basis for the mapping of the underlying genetic cause.
    Parkinsonism & Related Disorders 01/2014; · 3.27 Impact Factor
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    ABSTRACT: Background In Friedreich’s ataxia (FA) the genetically decreased expression of the mitochondrial protein frataxin leads to disturbance of the mitochondrial iron metabolism. Within the cerebellum the dentate nuclei (DN) are primarily affected. Histopathological studies show atrophy and accumulation of mitochondrial iron in DN. Dentate iron content has been suggested as a biomarker to measure the effects of siderophores/antioxidant treatment of FA. We assessed the iron content and the volume of DN in FA patients and controls based on ultra-high-field MRI (7 Tesla) images. Methods Fourteen FA patients (mean age 38.1 yrs) and 14 age- and gender-matched controls participated. Multi-echo gradient echo and susceptibility weighted imaging (SWI) sequences were acquired on a 7 T whole-body scanner. For comparison SWI images were acquired on a 1.5 T MR scanner. Volumes of the DN and cerebellum were assessed at 7 and 1.5 T, respectively. Parametric maps of T2 and T2* sequences were created and proton transverse relaxation rates were estimated as a measure of iron content. Results In FA, the DN and the cerebellum were significantly smaller compared to controls. However, proton transverse relaxation rates of the DN were not significantly different between both groups. Conclusions Applying in vivo MRI methods we could demonstrate significant atrophy of the DN in the presence of normal iron content. The findings suggest that relaxation rates are not reliable biomarkers in clinical trials evaluating the potential effect of FA therapy.
    NeuroImage: Clinical. 01/2014;
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    ABSTRACT: We previously localized a new form of recessive ataxia with generalized tonic-clonic epilepsy and mental retardation to a 19 Mb interval in 16q21-q23 by homozygosity mapping of a large consanguineous Saudi Arabian family. We now report the identification by whole exome sequencing of the missense mutation changing proline 47 into threonine in the first WW domain of the WW domain containing oxidoreductase gene, WWOX, located in the linkage interval. Proline 47 is a highly conserved residue that is part of the WW motif consensus sequence and is part of the hydrophobic core that stabilizes the WW fold. We demonstrate that proline 47 is a key amino acid essential for maintaining the WWOX protein fully functional, with its mutation into a threonine resulting in a loss of peptide interaction for the first WW domain. We also identified another highly conserved homozygous WWOX mutation changing glycine 372 to arginine in a second consanguineous family. The phenotype closely resembled the index family, presenting with generalized tonic-clonic epilepsy, mental retardation and ataxia, but also included prominent upper motor neuron disease. Moreover, we observed that the short-lived Wwox knock-out mouse display spontaneous and audiogenic seizures, a phenotype previously observed in the spontaneous Wwox mutant rat presenting with ataxia and epilepsy, indicating that homozygous WWOX mutations in different species causes cerebellar ataxia associated with epilepsy.
    Brain 12/2013; · 9.92 Impact Factor
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    ABSTRACT: Boucher-Neuhäuser and Gordon Holmes syndromes are clinical syndromes defined by early-onset ataxia and hypogonadism plus chorioretinal dystrophy (Boucher-Neuhäuser syndrome) or brisk reflexes (Gordon Holmes syndrome). Here we uncover the genetic basis of these two syndromes, demonstrating that both clinically distinct entities are allelic for recessive mutations in the gene PNPLA6. In five of seven Boucher-Neuhäuser syndrome/Gordon Holmes syndrome families, we identified nine rare conserved and damaging mutations by applying whole exome sequencing. Further, by dissecting the complex clinical presentation of Boucher-Neuhäuser syndrome and Gordon Holmes syndrome into its neurological system components, we set out to analyse an additional 538 exomes from families with ataxia (with and without hypogonadism), pure and complex hereditary spastic paraplegia, and Charcot-Marie-Tooth disease type 2. We identified four additional PNPLA6 mutations in spastic ataxia and hereditary spastic paraplegia families, revealing that Boucher-Neuhäuser and Gordon Holmes syndromes in fact represent phenotypic clusters on a spectrum of neurodegenerative diseases caused by mutations in PNPLA6. Structural analysis indicates that the majority of mutations falls in the C-terminal phospholipid esterase domain and likely inhibits the catalytic activity of PNPLA6, which provides the precursor for biosynthesis of the neurotransmitter acetylcholine. Our findings show that PNPLA6 influences a manifold of neuronal systems, from the retina to the cerebellum, upper and lower motor neurons and the neuroendocrine system, with damage of this protein causing an extraordinarily broad continuous spectrum of associated neurodegenerative disease.
    Brain 12/2013; · 9.92 Impact Factor
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    Journal of neurology, neurosurgery, and psychiatry 12/2013; · 4.87 Impact Factor
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    ABSTRACT: Hereditary spastic paraplegias (HSPs) are characterized by progressive weakness and spasticity of the legs because of the degeneration of cortical motoneuron axons. SPG15 is a recessively inherited HSP variant caused by mutations in the ZFYVE26 gene and is additionally characterized by cerebellar ataxia, mental decline, and progressive thinning of the corpus callosum. ZFYVE26 encodes the FYVE domain-containing protein ZFYVE26/SPASTIZIN, which has been suggested to be associated with the newly discovered adaptor protein 5 (AP5) complex. We show that Zfyve26 is broadly expressed in neurons, associates with intracellular vesicles immunopositive for the early endosomal marker EEA1, and co-fractionates with a component of the AP5 complex. As the function of ZFYVE26 in neurons was largely unknown, we disrupted Zfyve26 in mice. Zfyve26 knockout mice do not show developmental defects but develop late-onset spastic paraplegia with cerebellar ataxia confirming that SPG15 is caused by ZFYVE26 deficiency. The morphological analysis reveals axon degeneration and progressive loss of both cortical motoneurons and Purkinje cells in the cerebellum. Importantly, neuron loss is preceded by accumulation of large intraneuronal deposits of membrane-surrounded material, which co-stains with the lysosomal marker Lamp1. A density gradient analysis of brain lysates shows an increase of Lamp1-positive membrane compartments with higher densities in Zfyve26 knockout mice. Increased levels of lysosomal enzymes in brains of aged knockout mice further support an alteration of the lysosomal compartment upon disruption of Zfyve26. We propose that SPG15 is caused by an endolysosomal membrane trafficking defect, which results in endolysosomal dysfunction. This appears to be particularly relevant in neurons with highly specialized neurites such as cortical motoneurons and Purkinje cells.
    PLoS Genetics 12/2013; 9(12):e1003988. · 8.52 Impact Factor
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    ABSTRACT: Treatment of motor symptoms of degenerative cerebellar ataxia remains difficult. Yet there are recent developments that are likely to lead to significant improvements in the future. Most desirable would be a causative treatment of the underlying cerebellar disease. This is currently available only for a very small subset of cerebellar ataxias with known metabolic dysfunction. However, increasing knowledge of the pathophysiology of hereditary ataxia should lead to an increasing number of medically sensible drug trials. In this paper, data from recent drug trials in patients with recessive and dominant cerebellar ataxias will be summarized. There is consensus that up to date, no medication has been proven effective. Aminopyridines and acetazolamide are the only exception, which are beneficial in patients with episodic ataxia type 2. Aminopyridines are also effective in a subset of patients presenting with downbeat nystagmus. As such, all authors agreed that the mainstays of treatment of degenerative cerebellar ataxia are currently physiotherapy, occupational therapy, and speech therapy. For many years, well-controlled rehabilitation studies in patients with cerebellar ataxia were lacking. Data of recently published studies show that coordinative training improves motor function in both adult and juvenile patients with cerebellar degeneration. Given the well-known contribution of the cerebellum to motor learning, possible mechanisms underlying improvement will be outlined. There is consensus that evidence-based guidelines for the physiotherapy of degenerative cerebellar ataxia need to be developed. Future developments in physiotherapeutical interventions will be discussed including application of non-invasive brain stimulation.
    The Cerebellum 11/2013; · 2.60 Impact Factor
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    ABSTRACT: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is caused by autosomal-dominantly inherited mutations in the colony stimulating factor 1 receptor (CSF1R) gene, and is clinically characterized by a progressive cognitive and motor decline leading to death within several years. In a continuous series of 25 patients with adult-onset leukoencephalopathy of unknown cause, we genetically confirmed HDLS in 6 families. Affected and nonaffected individuals were examined clinically and by brain MRI studies. HDLS presented as prominent dementia and apraxia, often with extrapyramidal and pyramidal signs, rarely with ataxia. White matter MRI changes were detectable early in the disease course. Family history was negative in 4 of 6 index patients. In 2 of 6 index patients, we could confirm the occurrence of de novo mutations in the CSF1R gene. One family showed possible incomplete penetrance: the 69-year-old father of the index patient carried a CSF1R mutation but was clinically unaffected. In one family, the parents were apparently unaffected and not available for genetic testing. Typical clinical phenotype and early brain MRI alterations can help to guide the diagnosis of HDLS. Because we confirmed de novo mutations in one-third of patients with CSF1R mutations, this diagnosis should be considered even in the absence of a family history. Furthermore, we present evidence for reduced penetrance of a CSF1R mutation. These results have substantial impact for genetic counseling of asymptomatic individuals at risk and should foster research into disease-modifying factors.
    Neurology 11/2013; · 8.25 Impact Factor
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    ABSTRACT: Targeted high-throughput sequencing of many amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) genes in parallel has the potential to reveal novel ALS- and/or FTD-phenotypes and to provide missing links on the ALS-FTD continuum. For example, although the 43-kDa transactive response DNA binding protein is the major pathologic hallmark linking ALS and FTD, mutations in the gene encoding 43-kDa transactive response DNA binding protein (TARDBP) have been appreciated only as a cause of ALS-phenotypes, but not yet of pure FTD. Thus, the genetic link is not yet well substantiated that TARDBP mutations can cause the full spectrum of the ALS-FTD continuum. High-throughput sequencing of 18 ALS and FTD genes in an index patient presenting with early-onset pure (behavioral) FTD and a positive family history for ALS revealed an established TARDBP mutation, A382T. This finding demonstrates that a TARDPB mutation can cause early-onset pure FTD without evidence for ALS even in advanced FTD disease stages. Moreover, it indicates that TARDPB screening might be considered even in young patients with "pure" neuropsychiatric disturbances and without evidence of neurodegenerative disease in the parental generation.
    Neurobiology of aging 10/2013; · 5.94 Impact Factor

Publication Stats

7k Citations
1,524.52 Total Impact Points

Institutions

  • 2005–2014
    • Hertie-Institute for Clinical Brain Research
      Tübingen, Baden-Württemberg, Germany
  • 1996–2014
    • University of Tuebingen
      • • Hertie Institute for Clinical Brain Research
      • • Institute for Medical Genetics and Applied Genomics
      • • Department of Neurology
      • • Department of Psychiatry and Psychotherapy
      Tübingen, Baden-Württemberg, Germany
  • 2013
    • University of Bonn - Medical Center
      Bonn, North Rhine-Westphalia, Germany
  • 2006–2013
    • Goethe-Universität Frankfurt am Main
      • Dr. Senckenbergische Anatomie
      Frankfurt am Main, Hesse, Germany
  • 2012
    • University of Duisburg-Essen
      • Erwin L. Hahn Institute for Magnetic Resonance Imaging
      Essen, North Rhine-Westphalia, Germany
    • University of Miami Miller School of Medicine
      Miami, Florida, United States
  • 2002–2012
    • University of Bonn
      • Department of Neurobiology
      Bonn, North Rhine-Westphalia, Germany
  • 2011
    • Johannes Gutenberg-Universität Mainz
      • Neurobiology
      Mainz, Rhineland-Palatinate, Germany
  • 2010
    • Center for Human Genetics and Laboratory Medicine
      Planeck, Bavaria, Germany
    • University of Barcelona
      • Department of Basic Psychology
      Barcelona, Catalonia, Spain
    • Universität Bern
      Berna, Bern, Switzerland
    • Deutsches Zentrum für Neurodegenerative Erkrankungen
      Bonn, North Rhine-Westphalia, Germany
  • 2008–2010
    • Otto-von-Guericke-Universität Magdeburg
      Magdeburg, Saxony-Anhalt, Germany
  • 2007–2010
    • Technische Universität Dresden
      • Abteilung Neuroradiologie
      Dresden, Saxony, Germany
  • 2009
    • Danube University Krems
      Krems, Lower Austria, Austria
    • University of Oslo
      • Faculty of Medicine
      Oslo, Oslo, Norway
    • University Medical Center Hamburg - Eppendorf
      Hamburg, Hamburg, Germany
  • 1991–2008
    • Ruhr-Universität Bochum
      • Neurologische Klinik
      Bochum, North Rhine-Westphalia, Germany
  • 2004
    • St. Vincenz-Krankenhaus Paderborn
      Paderborn, North Rhine-Westphalia, Germany
    • Hannover Medical School
      • Institute for Human Genetics
      Hanover, Lower Saxony, Germany
  • 2002–2003
    • University of Rostock
      • Klinik und Poliklinik für Neurologie
      Rostock, Mecklenburg-Vorpommern, Germany
  • 1995–2003
    • St. Josef-Hospital
      Bonn, North Rhine-Westphalia, Germany
  • 1994–2000
    • University of Wuerzburg
      • Department of Neurology
      Würzburg, Bavaria, Germany
  • 1999
    • Ludwig-Maximilian-University of Munich
      • Department of Neurology
      München, Bavaria, Germany