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

Schilling Section of Clinical and Molecular Neurogenetics and Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Archives of neurology (Impact Factor: 7.42). 11/2010; 67(11):1357-63. DOI: 10.1001/archneurol.2010.281
Source: PubMed


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).

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    • "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). "
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    Frontiers in Molecular Neuroscience 05/2014; 7:48. DOI:10.3389/fnmol.2014.00048 · 4.08 Impact Factor
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    • "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. "
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    08/2013; 3(3). DOI:10.3233/JPD-130207
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    • "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. "
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