Publications by authors named "Jasper E Visser"

21 Publications

  • Page 1 of 1

Induced pluripotent stem cells from subjects with Lesch-Nyhan disease.

Sci Rep 2021 Apr 19;11(1):8523. Epub 2021 Apr 19.

Department of Neurology, Emory University School of Medicine, 101 Woodruff Circle, 6305 Woodruff Memorial Building, Atlanta, GA, 30322, USA.

Lesch-Nyhan disease (LND) is an inherited disorder caused by pathogenic variants in the HPRT1 gene, which encodes the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt). We generated 6 induced pluripotent stem cell (iPSC) lines from 3 individuals with LND, along with 6 control lines from 3 normal individuals. All 12 lines had the characteristics of pluripotent stem cells, as assessed by immunostaining for pluripotency markers, expression of pluripotency genes, and differentiation into the 3 primary germ cell layers. Gene expression profiling with RNAseq demonstrated significant heterogeneity among the lines. Despite this heterogeneity, several anticipated abnormalities were readily detectable across all LND lines, including reduced HPRT1 mRNA. Several unexpected abnormalities were also consistently detectable across the LND lines, including decreases in FAR2P1 and increases in RNF39. Shotgun proteomics also demonstrated several expected abnormalities in the LND lines, such as absence of HGprt protein. The proteomics study also revealed several unexpected abnormalities across the LND lines, including increases in GNAO1 decreases in NSE4A. There was a good but partial correlation between abnormalities revealed by the RNAseq and proteomics methods. Finally, functional studies demonstrated LND lines had no HGprt enzyme activity and resistance to the toxic pro-drug 6-thioguanine. Intracellular purines in the LND lines were normal, but they did not recycle hypoxanthine. These cells provide a novel resource to reveal insights into the relevance of heterogeneity among iPSC lines and applications for modeling LND.
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http://dx.doi.org/10.1038/s41598-021-87955-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055678PMC
April 2021

Deep brain stimulation in Lesch-Nyhan disease: outcomes from the patient's perspective.

Dev Med Child Neurol 2021 Aug 10;63(8):963-968. Epub 2021 Mar 10.

Departments of Neurology and Human Genetics, Emory University School of Medicine, Atlanta.

Aim: To provide insight into outcome and long-term safety and efficacy of deep brain stimulation (DBS), from the perspective of individuals with Lesch-Nyhan disease (LND) and their families.

Method: We used patient-centered outcome measures to assess long-term outcomes of DBS for 14 individuals (mean [SD] age 10y 10mo [5y 6mo], range 5-23y, all males) with LND, after an average duration of 5y 6mo (range 11mo-10y 5mo) after surgery. We compared these results with a comprehensive review of previously published cases.

Results: Patients and their families reported that DBS of the globus pallidus can be effective both for motor and behavioral disturbances in LND. However, outcome measures were often not significantly changed owing to substantial variability among individuals, and were overall less positive than in previous reports based on clinician assessments. In addition, there was an unexpectedly high rate of adverse events, tempering overall enthusiasm for the procedure.

Interpretation: Although DBS might be an effective treatment for LND, more research is needed to understand the reasons for response variability and the unusually high rates of adverse events before DBS can be recommended for these patients. What this paper adds Individuals with Lesch-Nyhan disease and their families report variable efficacy of deep brain stimulation. Long-term outcomes are associated with a high adverse event rate.
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http://dx.doi.org/10.1111/dmcn.14852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350791PMC
August 2021

Physical Exercise Modulates L-DOPA-Regulated Molecular Pathways in the MPTP Mouse Model of Parkinson's Disease.

Mol Neurobiol 2018 Jul 10;55(7):5639-5657. Epub 2017 Oct 10.

Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), resulting in motor and non-motor dysfunction. Physical exercise improves these symptoms in PD patients. To explore the molecular mechanisms underlying the beneficial effects of physical exercise, we exposed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP)-treated mice to a four-week physical exercise regimen, and subsequently explored their motor performance and the transcriptome of multiple PD-linked brain areas. MPTP reduced the number of DA neurons in the SNpc, whereas physical exercise improved beam walking, rotarod performance, and motor behavior in the open field. Further, enrichment analyses of the RNA-sequencing data revealed that in the MPTP-treated mice physical exercise predominantly modulated signaling cascades that are regulated by the top upstream regulators L-DOPA, RICTOR, CREB1, or bicuculline/dalfampridine, associated with movement disorders, mitochondrial dysfunction, and epilepsy-related processes. To elucidate the molecular pathways underlying these cascades, we integrated the proteins encoded by the exercise-induced differentially expressed mRNAs for each of the upstream regulators into a molecular landscape, for multiple key brain areas. Most notable was the opposite effect of physical exercise compared to previously reported effects of L-DOPA on the expression of mRNAs in the SN and the ventromedial striatum that are involved in-among other processes-circadian rhythm and signaling involving DA, neuropeptides, and endocannabinoids. Altogether, our findings suggest that physical exercise can improve motor function in PD and may, at the same time, counteract L-DOPA-mediated molecular mechanisms. Further, we hypothesize that physical exercise has the potential to improve non-motor symptoms of PD, some of which may be the result of (chronic) L-DOPA use.
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http://dx.doi.org/10.1007/s12035-017-0775-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5994219PMC
July 2018

Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity.

Nat Genet 2016 08 11;48(8):877-87. Epub 2016 Jul 11.

Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, the Netherlands.

Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder (ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2) in individuals who, in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature. This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome. Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly. Intriguingly, in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain. Together, our data establish that haploinsufficiency of SIN3A is associated with mild syndromic intellectual disability and that SIN3A can be considered to be a key transcriptional regulator of cortical brain development.
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http://dx.doi.org/10.1038/ng.3619DOI Listing
August 2016

Validity of the MPTP-Treated Mouse as a Model for Parkinson's Disease.

Mol Neurobiol 2016 Apr 13;53(3):1625-1636. Epub 2015 Feb 13.

Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.

Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron death in the substantia nigra (SN) and subsequent striatal adaptations. Mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP) are widely used as a model for PD. To assess the validity of the MPTP mouse model for PD pathogenesis, we here identify the biological processes that are dysregulated in both human PD and MPTP-treated mice. Gene enrichment analysis of published differentially expressed messenger RNAs (mRNAs) in the SN of PD patients and MPTP-treated mice revealed an enrichment of gene categories related to motor dysfunction and neurodegeneration. In the PD striatum, a similar enrichment was found, whereas in the striatum of MPTP mice, acute processes linked to epilepsy were selectively enriched shortly following MPTP treatment. More importantly, we integrated the proteins encoded by the differentially expressed mRNAs into molecular landscapes showing PD pathogenesis-implicated processes only in the SN, including vesicular trafficking, exocytosis, mitochondrial apoptosis, and DA neuron-specific transcription, but not in the striatum. We conclude that the current use of the MPTP mouse as a model for studying the molecular processes in PD pathogenesis is more valid for SN than striatal mechanisms in PD. This novel insight has important practical implications for future studies using this model to investigate PD pathogenesis and evaluate the efficacy of new treatments.
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http://dx.doi.org/10.1007/s12035-015-9103-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789200PMC
April 2016

Loss of dopamine phenotype among midbrain neurons in Lesch-Nyhan disease.

Ann Neurol 2014 Jul 20;76(1):95-107. Epub 2014 Jun 20.

Department of Neurology, Emory University, Atlanta, GA.

Objective: Lesch-Nyhan disease (LND) is caused by congenital deficiency of the purine recycling enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt). Affected patients have a peculiar neurobehavioral syndrome linked with reductions of dopamine in the basal ganglia. The purpose of the current studies was to determine the anatomical basis for the reduced dopamine in human brain specimens collected at autopsy.

Methods: Histopathological studies were conducted using autopsy tissue from 5 LND cases and 6 controls. Specific findings were replicated in brain tissue from an HGprt-deficient knockout mouse using immunoblots, and in a cell model of HGprt deficiency by flow-activated cell sorting (FACS).

Results: Extensive histological studies of the LND brains revealed no signs suggestive of a degenerative process or other consistent abnormalities in any brain region. However, neurons of the substantia nigra from the LND cases showed reduced melanization and reduced immunoreactivity for tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis. In the HGprt-deficient mouse model, immunohistochemical stains for TH revealed no obvious loss of midbrain dopamine neurons, but quantitative immunoblots revealed reduced TH expression in the striatum. Finally, 10 independent HGprt-deficient mouse MN9D neuroblastoma lines showed no signs of impaired viability, but FACS revealed significantly reduced TH immunoreactivity compared to the control parent line.

Interpretation: These results reveal an unusual phenomenon in which the neurochemical phenotype of dopaminergic neurons is not linked with a degenerative process. They suggest an important relationship between purine recycling pathways and the neurochemical integrity of the dopaminergic phenotype.
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http://dx.doi.org/10.1002/ana.24191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4827147PMC
July 2014

Genotype-phenotype correlations in neurogenetics: Lesch-Nyhan disease as a model disorder.

Brain 2014 May 22;137(Pt 5):1282-303. Epub 2013 Aug 22.

1 Departments of Neurology, Human Genetics and Paediatrics; Emory University, Atlanta GA, USA.

Establishing meaningful relationships between genetic variations and clinical disease is a fundamental goal for all human genetic disorders. However, these genotype-phenotype correlations remain incompletely characterized and sometimes conflicting for many diseases. Lesch-Nyhan disease is an X-linked recessive disorder that is caused by a wide variety of mutations in the HPRT1 gene. The gene encodes hypoxanthine-guanine phosphoribosyl transferase, an enzyme involved in purine metabolism. The fine structure of enzyme has been established by crystallography studies, and its function can be measured with very precise biochemical assays. This rich knowledge of genetic alterations in the gene and their functional effect on its protein product provides a powerful model for exploring factors that influence genotype-phenotype correlations. The present study summarizes 615 known genetic mutations, their influence on the gene product, and their relationship to the clinical phenotype. In general, the results are compatible with the concept that the overall severity of the disease depends on how mutations ultimately influence enzyme activity. However, careful evaluation of exceptions to this concept point to several additional genetic and non-genetic factors that influence genotype-phenotype correlations. These factors are not unique to Lesch-Nyhan disease, and are relevant to most other genetic diseases. The disease therefore serves as a valuable model for understanding the challenges associated with establishing genotype-phenotype correlations for other disorders.
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http://dx.doi.org/10.1093/brain/awt202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3999711PMC
May 2014

Levodopa is not a useful treatment for Lesch-Nyhan disease.

Mov Disord 2011 Mar 31;26(4):746-9. Epub 2011 Jan 31.

Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Lesch-Nyhan disease (LND) is characterized by dystonia, cognitive abnormalities, and self-injurious behavior. No effective therapies are available. LND is associated with a presynaptic dopaminergic deficit, but the reported effects of dopamine replacement therapy are conflicting. The current prospective open-label study assesses the effects of levodopa on both neurological and behavioral features of LND. All 6 study participants discontinued levodopa early, due to lack of effect and sometimes worsening of motor function. The results provide important clues for pathophysiological mechanisms and suggestions for future treatment options.
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http://dx.doi.org/10.1002/mds.23478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523804PMC
March 2011

Attenuated variants of Lesch-Nyhan disease.

Brain 2010 Mar 22;133(Pt 3):671-89. Epub 2010 Feb 22.

Department of Neurology and Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.

Lesch-Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the classic disease, variant forms of the disease occur wherein some clinical features are absent or unusually mild. The current studies provide the results of a prospective and multi-centre international study focusing on neurological manifestations of the largest cohort of Lesch-Nyhan disease variants evaluated to date, with 46 patients from 3 to 65 years of age coming from 34 families. All had evidence for overproduction of uric acid. Motor abnormalities were evident in 42 (91%), ranging from subtle clumsiness to severely disabling generalized dystonia. Cognitive function was affected in 31 (67%) but it was never severe. Though none exhibited self-injurious behaviours, many exhibited behaviours that were maladaptive. Only three patients had no evidence of neurological dysfunction. Our results were compared with a comprehensive review of 78 prior reports describing a total of 127 Lesch-Nyhan disease variants. Together these results define the spectrum of clinical features associated with hypoxanthine-guanine phosphoribosyltransferase deficiency. At one end of the spectrum are patients with classic Lesch-Nyhan disease and the full clinical phenotype. At the other end of the spectrum are patients with overproduction of uric acid but no apparent neurological or behavioural deficits. Inbetween are patients with varying degrees of motor, cognitive, or behavioural abnormalities. Recognition of this spectrum is valuable for understanding the pathogenesis and diagnosis of all forms of hypoxanthine-guanine phosphoribosyltransferase deficiency.
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http://dx.doi.org/10.1093/brain/awq013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842514PMC
March 2010

Parkinson disease and comorbid cerebrovascular disease.

Nat Rev Neurol 2009 Oct 1;5(10):533-41. Epub 2009 Sep 1.

Donders Institute for Brain, Cognition and Behavior, Centre for Neuroscience, Department of Neurology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Optimal management of chronic diseases not only requires tackling of the primary disease processes, but also necessitates timely recognition and treatment of comorbid conditions. In this article, we illustrate this two-pronged approach for two common age-related disorders: Parkinson disease (PD) and cerebrovascular disease (CVD). We first discuss the pathophysiological mechanisms that could provide a link between PD and CVD. Patients with PD have a series of risk factors that could promote development of CVD, but also have several protective factors. We then review the available clinical, radiological and neuropathological evidence to support an association between these two conditions. We conclude by discussing the potential implications for clinical practice, highlighting how comorbid CVD could alter the clinical presentation of PD and reviewing the possibilities for prevention and secondary prophylaxis. Additional research will be needed to fully evaluate the prevalence and clinical relevance of comorbid CVD in PD. Pending further evidence, we recommend that cerebral neuroimaging should be considered if patients with initially uncomplicated PD develop-either acutely or chronically-prominent and/or treatment-resistant gait impairment, postural instability, depression, cognitive decline, or urinary incontinence. Finding comorbid CVD in such patients could have prognostic implications, and could necessitate treatment to arrest further progression of CVD.
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http://dx.doi.org/10.1038/nrneurol.2009.136DOI Listing
October 2009

The clinical utility of posturography.

Clin Neurophysiol 2008 Nov 12;119(11):2424-36. Epub 2008 Sep 12.

Department of Neurology, Parkinson Center Nijmegen (ParC), Donders Center for Neuroscience, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

Postural instability and falls are common and devastating features of ageing and many neurological, visual, vestibular or orthopedic disorders. Current management of these problems is hampered by the subjective and variable nature of the available clinical balance measures. In this narrative review, we discuss the clinical utility of posturography as a more objective and quantitative measure of balance and postural instability, focusing on several areas where clinicians presently experience the greatest difficulties in managing their patients: (a) to make an appropriate differential diagnosis in patients presenting with falls or balance impairment; (b) to reliably identify those subjects who are at risk of falling; (c) to objectively and quantitatively document the outcome of therapeutic interventions; and (d) to gain a better pathophysiological understanding of postural instability and falls, as a basis for the development of improved treatment strategies to prevent falling. In each of these fields, posturography offers several theoretical advantages and, when applied correctly, provides a useful tool to gain a better understanding of pathophysiological mechanisms in patients with balance disorders, at the group level. However, based on the available evidence, none of the existing techniques is currently able to significantly influence the clinical decision making in individual patients. We critically review the shortcomings of posturography as it is presently used, and conclude with several recommendations for future research.
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http://dx.doi.org/10.1016/j.clinph.2008.07.220DOI Listing
November 2008

Subthalamic nucleus stimulation and levodopa-resistant postural instability in Parkinson's disease.

J Neurol 2008 Feb 18;255(2):205-10. Epub 2008 Feb 18.

Dept. of Neurology (HP 935), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

We examined the effect of bilateral subthalamic nucleus stimulation on levodopa-resistant balance impairment in 14 patients with Parkinson's disease and 18 matched controls. Instability was quantitatively assessed using standardized multidirectional dynamic posturography. Patients were tested after taking a suprathreshold dose of levodopa, both with stimulators turned on and off. Patients with stimulators turned off were more unstable than controls following backward directed perturbations. Overall, patients' instability did not improve with STN stimulation, and considerable inter-individual variability was noted. Of note, marked levodopa- resistant axial motor symptoms before surgery correlated with an adverse treatment effect. We conclude that STN stimulation does not alleviate levodopa-resistant postural instability in Parkinson's disease.
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http://dx.doi.org/10.1007/s00415-008-0636-xDOI Listing
February 2008

Quantification of trunk rotations during turning and walking in Parkinson's disease.

Clin Neurophysiol 2007 Jul 23;118(7):1602-6. Epub 2007 Apr 23.

Department of Neurology, Radboud University Nijmegen Medical Centre, Parkinson Center Nijmegen, Nijmegen, The Netherlands.

Objective: To develop a reliable, objective and sensitive measure of axial trunk rotations in PD, which can be applied in an ambulatory setting.

Methods: To quantify turning motion, two angular velocity transducers attached to the lower back measured angular velocity of the trunk in the yaw plane (i.e., around the longitudinal axis) and the roll plane (i.e., medio-lateral movements) in freely moving subjects who were instructed to walk and make various types of turning movements.

Results: Turn duration was longer in PD patients compared to controls. Peak yaw and peak roll angular velocities were lower in PD patients compared to controls during all turning tasks.

Conclusions: This new approach to measure trunk sway during a simple turning task might serve as an instrument to objectively quantify turning while walking in PD.

Significance: It proves difficult to objectively assess turning performance based upon history taking or clinical examination alone. Objective and easy measurement of axial turning in PD might be used for clinical evaluation, but also in a domestic setting as outcome measure in intervention studies. Further research should focus on the clinical relevance of the new quantitative approach described in this paper, e.g., to detect freezing of gait episodes.
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http://dx.doi.org/10.1016/j.clinph.2007.03.010DOI Listing
July 2007

PRKCG mutation (SCA-14) causing a Ramsay Hunt phenotype.

Mov Disord 2007 May;22(7):1024-6

Department of Neurology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

Progressive myoclonic ataxia, also referred to as Ramsay Hunt syndrome, is characterized by a combination of myoclonus and cerebellar ataxia, infrequently accompanied by tonic-clonic seizures. Its differential diagnosis overlaps with progressive myoclonic epilepsy, a syndrome with myoclonus, tonic-clonic seizures, progressive ataxia and dementia. In patients with progressive myoclonic epilepsy, specific diseases can frequently be recognized, but the diagnostic yield in progressive myoclonic ataxia is much lower. We describe a patient who presented with multifocal myoclonus in his thirties and who later developed cerebellar ataxia and focal dystonia. His father was similarly affected. Genetic studies revealed a mutation in the protein kinase C gamma (PRKCG) gene, known to cause spinocerebellar ataxia type 14 (SCA-14). This case illustrates that both myoclonus and dystonia are part of the clinical spectrum in SCA-14 and that myoclonus can even be the presenting symptom. We suggest that SCA-14 should be considered in the differential diagnosis of progressive myoclonic ataxia.
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http://dx.doi.org/10.1002/mds.21414DOI Listing
May 2007

Postural responses to multidirectional stance perturbations in cerebellar ataxia.

Exp Neurol 2006 Nov 30;202(1):21-35. Epub 2006 Jun 30.

Department of ORL, University Hospital, Basel, Switzerland.

Previous studies of patients with focal cerebellar damage underscored the importance of the cerebellum for balance control. These studies were restricted to postural control in the pitch plane, and focused mainly on leg muscle responses. Here, we examined the effect of degenerative cerebellar lesions on postural control in multiple directions, and studied how such lesions affect intersegmental coordination of the legs, trunk and arms. We formulated two main questions. (a) Do patients with cerebellar ataxia predominantly have balance problems in the sagittal or frontal planes? (b) Is instability in cerebellar ataxia associated with increased joint motion or with reduced joint motion? We selected nine patients with autosomal dominant spinocerebellar ataxia (SCA)--three with pure ataxia and six with mild extra-cerebellar features--and 12 matched controls. Upright standing subjects received support surface rotations (7.5 degrees at 60 degrees /s) that were randomly delivered in eight different directions of pitch or roll. We used full body kinematics to determine displacements of the center of mass (COM) and of individual body segments. We also collected surface EMG from 10 leg, trunk and arm muscles. Primary variables of interest were COM displacement and trunk control (angles and muscle responses). Secondary analyses focused on angles and muscle responses of the legs and arms. COM analysis demonstrated that SCA patients had greatest instability following backward and laterally directed perturbations. Major factors in causing this instability were, first, a marked reduction of stimulus-induced knee flexion and, second, excessive "hypermetric" motion of the pelvis (in roll) and trunk (in pitch). Muscle responses of SCA patients were characterized by increased late balance correcting activity. Responses of patients with pure ataxia were comparable to those of patients with mild extra-cerebellar features. A main underlying cause of postural instability in SCA patients appears to be "locking" of the knees, which may reflect compensation (by reducing interaction between body links) or reduced vestibulocerebellar control over leg muscles. The observed pathophysiology is very different from that seen in other patient populations.
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http://dx.doi.org/10.1016/j.expneurol.2006.05.008DOI Listing
November 2006

Delineation of the motor disorder of Lesch-Nyhan disease.

Brain 2006 May 20;129(Pt 5):1201-17. Epub 2006 Mar 20.

Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.

Lesch-Nyhan disease (LND) is caused by deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Affected individuals exhibit over-production of uric acid, along with a characteristic neurobehavioural syndrome that includes mental retardation, recurrent self-injurious behaviour and motor disability. Prior studies involving relatively small numbers of patients have provided different conclusions on the nature of the motor disorder. The current study includes the results of a multi-centre international prospective study of the motor disorder in the largest cohort of patients studied to date. A total of 44 patients ranging from 2 to 38 years presented a characteristic motor syndrome that involved severe action dystonia superimposed on baseline hypotonia. Although some patients also displayed other extrapyramidal or pyramidal signs, these were always less prominent than dystonia. These results are compared with a comprehensive review of 122 prior reports that included a total of 254 patients. Explanations for the differing observations available in the literature are provided, along with a summary of how the motor disorder of LND relates to current understanding of its pathophysiology involving the basal ganglia.
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http://dx.doi.org/10.1093/brain/awl056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3508431PMC
May 2006

Role of the basal ganglia in balance control.

Neural Plast 2005 ;12(2-3):161-74; discussion 263-72

Department of Neurology, University Medical Center St Radboud, Nijmegen, The Netherlands.

In this review paper, we summarize the important contributions of the basal ganglia to the regulation of postural control. After a brief overview of basal ganglia circuitries, the emphasis is on clinical observations in patients with focal lesions in parts of the basal ganglia, as the impairments seen here can serve to highlight the normal functions of the basal ganglia nuclei in postural control. Two particularly relevant functions are discussed in detail: first, the contribution of the basal ganglia to flexibility and to gaining control of balance-correcting responses, including the ability to lend priority to the elements of a postural task; and second, processing afferent information by the basal ganglia, which is increasingly recognized as being highly relevant for postural control.
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http://dx.doi.org/10.1155/NP.2005.161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2565457PMC
September 2005

The motor disorder of classic Lesch-Nyhan disease.

Nucleosides Nucleotides Nucleic Acids 2004 Oct;23(8-9):1161-4

Department Neurology, University Hospital St. Radboud, Nijmegen, The Netherlands.

Reports describing the neurological features of Lesch-Nyhan disease (LND) vary widely, thereby implying the involvement of different neurological substrates. The movement abnormalities in 20 patients with LND were investigated. Dystonia was the most frequent and severe movement disorder. At rest, hypotonia was more frequent than hypertonia. These findings are compatible with basal ganglia dysfunction in LND.
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http://dx.doi.org/10.1081/NCN-200027432DOI Listing
October 2004

Falls and freezing of gait in Parkinson's disease: a review of two interconnected, episodic phenomena.

Mov Disord 2004 Aug;19(8):871-84

Department of Neurology, University Medical Centre St. Radboud, Nijmegen, The Netherlands.

Falls and freezing of gait are two "episodic" phenomena that are common in Parkinson's disease. Both symptoms are often incapacitating for affected patients, as the associated physical and psychosocial consequences have a great impact on the patients' quality of life, and survival is diminished. Furthermore, the resultant loss of independence and the treatment costs of injuries add substantially to the health care expenditures associated with Parkinson's disease. In this clinically oriented review, we summarise recent insights into falls and freezing of gait and highlight their similarities, differences, and links. Topics covered include the clinical presentation, recent ideas about the underlying pathophysiology, and the possibilities for treatment. A review of the literature and the current state-of-the-art suggests that clinicians should not feel deterred by the complex nature of falls and freezing of gait; a careful clinical approach may lead to an individually tailored treatment, which can offer at least partial relief for many affected patients.
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http://dx.doi.org/10.1002/mds.20115DOI Listing
August 2004

Oxidative stress and dopamine deficiency in a genetic mouse model of Lesch-Nyhan disease.

Brain Res Dev Brain Res 2002 Feb;133(2):127-39

Department of Neurology, Meyer 6-181, Johns Hopkins Hospital, Baltimore, MD 21287, USA.

Lesch-Nyhan disease, a neurogenetic disorder caused by congenital deficiency of the purine salvage enzyme hypoxanthine guanine phosphoribosyl transferase, is associated with a prominent loss of striatal dopamine. The current studies address the hypothesis that oxidant stress causes damage or dysfunction of nigrostriatal dopamine neurons in a knockout mouse model of the disease, by assessing several markers of oxidative damage and free radical scavenging systems. Some of these measures provided evidence for an increase in oxidative stress in the mutant mice (aconitase activity, oxidized glutathione, and lipid peroxides), but others did not (superoxide dismutase, protein thiol content, carbonyl protein content, total glutathione, glutathione peroxidase, catalase, and thiobarbituric reducing substances). Immunolocalization of heme-oxygenase 1 provided no evidence for oxidative stress restricted to specific elements of the striatum or midbrain in the mutants. Striatal dopamine systems of the mutant mice were more vulnerable to a challenge with the neurotoxin 6-hydroxydopamine, but they were not protected by cross-breeding the mutants with transgenic mice over-expressing superoxide dismutase. Overall, these data provide evidence for increased oxidative stress, but the failure to protect the knockout mice by over-expressing SOD1 argues that oxidative stress is not the sole process responsible for the loss of striatal dopamine.
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http://dx.doi.org/10.1016/s0165-3806(02)00280-8DOI Listing
February 2002
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