Recessively Inherited Parkinsonism Effect of ATP13A2 Mutations on the Clinical and Neuroimaging Phenotype

ArticleinArchives of neurology 67(11):1357-63 · November 2010with93 Reads
Impact Factor: 7.42 · DOI: 10.1001/archneurol.2010.281 · Source: PubMed
Abstract

To determine clinical features and to identify changes in brain structure and function in compound heterozygous and heterozygous ATP13A2 mutation carriers. Prospective multimodal clinical and neuroimaging study. University of Lübeck, Lübeck, Germany. Eight family members of a large Chilean pedigree with Kufor-Rakeb syndrome (KRS). Clinical characterization, dopamine transporter (DAT) imaging, voxel-based morphometry (VBM), and transcranial sonography (TCS). Frequency of parkinsonian signs, brain structure, and functional alterations. The only available patient with compound heterozygous KRS showed a markedly reduced striatal DAT density bilaterally. Magnetic resonance imaging revealed severe global brain atrophy as well as iron deposition in the basal ganglia. The heterozygous mother had definite parkinsonism with reduced DAT density in both putamina. While all asymptomatic heterozygous siblings displayed subtle extrapyramidal signs, DAT imaging revealed striatal tracer uptake within physiological levels. Voxel-based morphometry revealed an increase in gray matter volume in the right putamen and a decrease in the cerebellum of the heterozygous carriers. In all mutation carriers, the substantia nigra had a normal appearance on TCS. Single ATP13A2 heterozygous mutations may be associated with clinical signs of parkinsonism and contribute to structural and functional brain changes. Lack of hyperechogenicity in the substantia nigra may be a distinctive feature of this form of genetic parkinsonism. This, along with the finding of iron in the basal ganglia in our patient with KRS, implies a different underlying pathophysiology compared with other monogenic forms of parkinsonism and idiopathic PD and may place KRS among the syndromes of neurodegeneration with brain iron accumulation (NBIA).

    • "...rkinsonism and obvious iron accumulation in the basal ganglia, but display normal SN echogenicity [16]. From our study, we would like to propose a further hypothesis: that a poorer response to medical t..."
      For example, patients with LRRK2-mutations may present with clinical features that are typical of PD, but display a rather moderate SNþ [15]. Another example is some patients with the ATP13A2 mutation may develop severe parkinsonism and obvious iron accumulation in the basal ganglia, but display normal SN echogenicity [16]. From our study, we would like to propose a further hypothesis: that a poorer response to medical therapy in patients with a larger echogenic size in their SN might contribute to the correlation between the UPDRS part II and SN echogenicity.
    [Show abstract] [Hide abstract] ABSTRACT: Background: Transcranial sonography can display structural alterations in the substantia nigra (SN) of patients with Parkinson's disease (PD), and is considered to be a potential useful tool for the diagnosis of PD. The aim of this study was to assess the correlation between SN echogenicity and clinical features in Chinese patients with PD. Methods: A total of 420 subjects including 290 patients with PD and 130 controls were recruited from the neurological clinic or the community. Transcranial sonographic evaluations of the SN were performed in all subjects, and motor and non-motor symptoms were thoroughly assessed by a series of rating scales in PD patients. Results: Two hundred and one patients were successfully assessed by transcranial sonography. SN hyperechogenicity was found to be associated with male sex (p = 0.004), higher scores on the Unified Parkinson's Disease Rating Scale (UPDRS) part II (p = 0.001) and autonomic symptoms scores (p = 0.003). Moreover, regression analysis revealed that UPDRS part II scores (odds ratio = 1.141, p < 0.001) and gender (odds ratio = 2.409, p = 0.007) could be the independent predictors for SN hyperechogenicity; in addition, among all items of UPDRS part II, speech, dressing, hygiene, and turning in bed and adjusting bed clothes significantly correlated with SN hyperechogenicity. Conclusions: This is the first report suggesting the correlation between SN echogenicity and UPDRS part II, and we conclude that increased SN echogenicity might reflect more severe disease disability or poorer medical response.
    Full-text · Article · Jan 2016 · Parkinsonism & Related Disorders
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    • "...., 2009; Kong et al., 2014) and in KRS patients iron deposits in the brain are observed (Bruggemann et al., 2010; Schneider et al., 2010). The prevailing hypothesis is therefore that ATP13A2 is a lysosomal cation..."
      ATP13A2 causes protection toward several heavy metals (Gitler et al., 2009; Schmidt et al., 2009; Kong et al., 2014) and in KRS patients iron deposits in the brain are observed (Bruggemann et al., 2010; Schneider et al., 2010). The prevailing hypothesis is therefore that ATP13A2 is a lysosomal cation pump (Gitler et al., 2009).
    [Show abstract] [Hide abstract] ABSTRACT: Mutations in ATP13A2 lead to Kufor-Rakeb syndrome, a parkinsonism with dementia. ATP13A2 belongs to the P-type transport ATPases, a large family of primary active transporters that exert vital cellular functions. However, the cellular function and transported substrate of ATP13A2 remain unknown. To discuss the role of ATP13A2 in neurodegeneration, we first provide a short description of the architecture and transport mechanism of P-type transport ATPases. Then, we briefly highlight key P-type ATPases involved in neuronal disorders such as the copper transporters ATP7A (Menkes disease), ATP7B (Wilson disease), the Na(+)/K(+)-ATPases ATP1A2 (familial hemiplegic migraine) and ATP1A3 (rapid-onset dystonia parkinsonism). Finally, we review the recent literature of ATP13A2 and discuss ATP13A2's putative cellular function in the light of what is known concerning the functions of other, better-studied P-type ATPases. We critically review the available data concerning the role of ATP13A2 in heavy metal transport and propose a possible alternative hypothesis that ATP13A2 might be a flippase. As a flippase, ATP13A2 may transport an organic molecule, such as a lipid or a peptide, from one membrane leaflet to the other. A flippase might control local lipid dynamics during vesicle formation and membrane fusion events.
    Full-text · Article · May 2014 · Frontiers in Molecular Neuroscience
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    • "...al neuroimaging as a tool to detect other non-dopaminergic abnormalities in patients with PD [23] [24], showing promising application in the investigation of a multitude of pathophysiological aspects re..."
      Another application for such neuroimaging methods is to grade the intensity of the loss of the striatal dopaminergic innervation and monitor the progression of the neurodegenerative process [22]. Currently, increasing number of studies have also used functional neuroimaging as a tool to detect other non-dopaminergic abnormalities in patients with PD [23] [24], showing promising application in the investigation of a multitude of pathophysiological aspects related to the disease.
    [Show abstract] [Hide abstract] ABSTRACT: The pathophysiology of Parkinson's disease (PD) has not yet been completely elucidated. However, during the past few years, significant progress has been made in understanding the intra- and extracellular mechanisms by which proteins such as alpha-synuclein and neuroinflammatory molecules may display impaired function and/or expression in PD. Recent developments in imaging techniques based on positron emission tomography (PET) and single photon emission computed tomography (SPECT) now allow the non-invasive tracking of such molecular targets of known relevance to PD in vivo. This article summarizes recent PET and SPECT studies of new radiopharmaceuticals and discusses their potential role and perspectives for use in the fields of new drug development and early diagnosis for PD, as well to aid in differential diagnosis and monitoring of the progression of PD.
    Full-text · Article · Aug 2013
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    • "...., 2009; Martin et al., 2009; Wattendorf et al., 2009; Agosta et al., 2010a,b; Bruggemann et al., 2010; Hamasaki et al., 2010; Focke et al., 2011). Over the past decade, the voxel-based morphometry (VBM..."
      However, these two diseases involve different internal mechanisms and therefore require different clinical treatments (Draganski and Bhatia, 2010; Watts et al., 2011). Numerous studies have utilized brain imaging to probe alterations in the structural and functional organization of patients with PD (Kassubek et al., 2002; Brenneis et al., 2003; Burton et al., 2004; Price et al., 2004; Chebrolu et al., 2006; Beyer et al., 2007; Ramirez-Ruiz et al., 2007; Bouchard et al., 2008; Feldmann et al., 2008; Ibarretxe-Bilbao et al., 2008, 2009a, 2011a,b; Benninger et al., 2009; Camicioli et al., 2009; Cardoso et al., 2009; Jubault et al., 2009; Martin et al., 2009; Wattendorf et al., 2009; Agosta et al., 2010a,b; Bruggemann et al., 2010; Hamasaki et al., 2010; Focke et al., 2011). Over the past decade, the voxel-based morphometry (VBM) technique has been applied often for studying brain volume changes in PD and other degenerative brain diseases.
    [Show abstract] [Hide abstract] ABSTRACT: Symptoms of essential tremor (ET) are similar to those of Parkinson's disease (PD) during their initial stages. Presently, there are few stable biomarkers available on a neuroanatomical level for distinguishing between these two diseases. However, few investigations have directly compared the changes in brain volume and assessed the compensatory effects of a change in the parts of the brain associated with PD and with ET. To determine the compensatory and/or degenerative anatomical changes in the brains of PD and ET patients, the present study tested, via two voxel-based morphometry (VBM) approaches (Basic vs. DARTEL VBM processing), the anatomical brain images of 10 PD and 10 ET patients, as well as of 13 age-matched normal controls, obtained through a 3T magnetic resonance scanner. These findings indicate that PD and ET caused specific patterns of brain volume alterations in the brains examined. In addition, our observations also revealed compensatory effects, or self-reorganization, occurring in the thalamus and the middle temporal gyrus in the PD and ET patients, due perhaps in part to the enhanced thalamocortical sensorimotor interaction and the head-eye position readjustment, respectively, in these PD and ET patients. Such a distinction may lend itself to use as a biomarker for differentiating between these two diseases.
    Full-text · Article · Jun 2013 · Frontiers in Human Neuroscience
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    • "...results in neurodegenerative diseases with brain iron accumulation (Behrens et al. 2010; Bruggemann et al. 2010; Schneider et al. 2010). However, the iron accumulation is not a characteristic feature of all pati..."
      The results suggest that PD-associated ATP13A2 mutation results in neurodegenerative diseases with brain iron accumulation (Behrens et al. 2010; Bruggemann et al. 2010; Schneider et al. 2010). However, the iron accumulation is not a characteristic feature of all patients with ATP13A2 mutation, and the role of iron accumulation in the development of KRS is unknown.
    [Show abstract] [Hide abstract] ABSTRACT: J. Neurochem. (2012) 122, 251–259. Parkinson’s disease (PD) is the second most common neurodegenerative disorders with a variable combination of motor and non-motor symptoms. Mutations in several genes including ATP13A2 (PARK9) are reported to be associated with PD. The underlying mechanism of PD is not well defined, however, both genetic and environmental causes contribute to it. ATP13A2 gene locates in chromosome 1 and contains 29 exons encoding for a protein of 1180 amino acids with 10 transmembrane domains. Abnormal gene expression has been implicated in neurodegenerative disorders. The transcriptional regulation of the ATP13A2 gene is unknown. In this report, we cloned and functionally characterized the human ATP13A2 gene promoter. We showed that the promoter region of the human ATP13A2 gene contains hypoxia response elements which can bind to transcription factor hypoxia-inducible factor 1α (HIF-1α). Hypoxia up-regulated ATP13A2 transcription via HIF-1α in HEK293 and dopaminergic MN9D cells. Our study indicates that hypoxia signaling plays a very important role in the regulation of human ATP13A2 gene expression. Further study is needed to determine the role of hypoxia in the pathogenesis of PD and its interaction with other PD causative genes, which will provide insights to the role of hypoxia and dysregulation of gene expression in Parkinson’s disease.
    Preview · Article · Jan 2012 · Journal of Neurochemistry
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    • "...position (but which awaits neuropathological confirmation). In a recently-reported Chilean family [78], a 45 year-old mother with compound heterozygosity for mutant ATP13A2 exhibited parkinsonism (Hoehn..."
      Brain MRI in KRD reveals generalized cortical and subcortical atrophy and hypointensities of the caudate and putamen on T2* sequences (Fig. 6) compatible with augmented iron deposition (but which awaits neuropathological confirmation). In a recently-reported Chilean family [78], a 45 year-old mother with compound heterozygosity for mutant ATP13A2 exhibited parkinsonism (Hoehn and Yahr stage 2), dementia, symmetrically reduced putaminal tracer uptake on dopamine transporter (DAT) imaging, global brain atrophy, and T2/T2* hypointensities in caudate and putamen consistent with abundant iron. Children heterozygous for mutant ATP13A2 all manifested subtle signs of parkinsonism (reduced arm swing, limb rigidity, mild postural tremor), but T2/T2* imaging, TS and DAT single photon emission computed tomography scans of the basal ganglia were within normal limits.
    [Show abstract] [Hide abstract] ABSTRACT: Iron participates in a wide array of cellular functions and is essential for normal neural development and physiology. However, if inappropriately managed, the transition metal is capable of generating neurotoxic reactive oxygen species. A number of hereditary conditions perturb body iron homeostasis and some, collectively referred to as neurodegeneration with brain iron accumulation (NBIA), promote pathological deposition of the metal predominantly or exclusively within the central nervous system (CNS). In this article, we discuss seven NBIA disorders with emphasis on the clinical syndromes and neuroimaging. The latter primarily entails magnetic resonance scanning using iron-sensitive sequences. The conditions considered are Friedreich ataxia (FA), pantothenate kinase 2-associated neurodegeneration (PKAN), PLA2G6-associated neurodegeneration (PLAN), FA2H-associated neurodegeneration (FAHN), Kufor-Rakeb disease (KRD), aceruloplasminemia, and neuroferritinopathy. An approach to differential diagnosis and the status of iron chelation therapy for several of these entities are presented. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.
    Full-text · Article · Jul 2011 · Biochimica et Biophysica Acta
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