Cerebellum (2011) 10:245–253 DOI 10.1007/s12311-010-0239-9
Spinocerebellar Ataxia Type 2 (SCA2): Identification of Early Brain Degeneration in One Monozygous Twin in the Initial Disease Stage Franziska Hoche & Laszlo Balikó & Wilfred den Dunnen & Katalin Steinecker & Laszlo Bartos & Eniko Sáfrány & Georg Auburger & Thomas Deller & Horst-Werner Korf & Thomas Klockgether & Udo Rüb & Bela Melegh
Published online: 3 December 2010 # Springer Science+Business Media, LLC 2010
Abstract Spinocerebellar ataxia type 2 (SCA2) is a progressive autosomal dominantly inherited cerebellar ataxia and is assigned to the CAG repeat or polyglutamine diseases. Recent morphological studies characterized the pathoanatomical features in heterozygous SCA2 patients Franziska Hoche and Laszlo Balikó are joint first authors. Udo Rüb and Bela Melegh are joint senior authors. F. Hoche : T. Deller : U. Rüb (*) Institute of Clinical Neuroanatomy, Dr. Senckenberg Anatomy, Goethe-University, 60590 Frankfurt am Main, Germany e-mail:
[email protected] L. Balikó : K. Steinecker : L. Bartos Department of Neurology and Stroke, County Hospital, Veszprém, Hungary W. den Dunnen Department of Pathology and Laboratory Medicine, University Medical Center Groningen, University of Groningen, 5970 RB Groningen, The Netherlands E. Sáfrány : B. Melegh Department of Medical Genetics, University of Pécs, Pécs, Hungary G. Auburger Department of Neurology, Molecular Neurogenetics, Goethe-University, 60590 Frankfurt am Main, Germany H.-W. Korf Dr. Senckenberg Chronomedical Institute, Goethe-University, 60590 Frankfurt am Main, Germany T. Klockgether Department of Neurology, University Hospital of Bonn, 53105 Bonn, Germany
and revealed severe neuronal loss in a large variety of cerebellar and extra-cerebellar brain sites. In the present study, we examined the brain pathoanatomy of a monozygous twin of a large Hungarian SCA2 family with pathologically extended CAG repeats in both SCA2 alleles. This unique patient was in the initial clinical stage of SCA2 and died almost 3 years after SCA2 onset. Upon pathoanatomical investigation, we observed loss of giant Betz pyramidal cells in the primary motor cortex, degeneration of sensory thalamic nuclei, the Purkinje cell layer, and deep cerebellar nuclei, as well as select brainstem nuclei (i.e., substantia nigra, oculomotor nucleus, reticulotegmental nucleus of the pons, facial, lateral vestibular, and raphe interpositus nuclei, inferior olive). All of these degenerated brain gray matter structures are known as consistent targets of the underlying pathological process in heterozygous SCA2 patients. Since they were already involved in our patient within 3 years after disease onset, we think that we were for the first time able to identify the early brain targets of the pathological process of SCA2. Keywords ADCA . Ataxia . Polyglutamine . SCA2 . Spinocerebellar ataxia
Introduction Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited progressive ataxic disorder. It commonly begins in adulthood and belongs to the group of CAG repeat or polyglutamine diseases. These neurological disorders share expanded and meiotically unstable CAG trinucleotide repeats at specific gene loci, which are translated into elongated polyglutamine tracts of the disease
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specific proteins [1–7]. The locus of the SCA2 gene was identified in families of the Holguín province of Cuba and the SCA2 gene has been mapped to chromosome 12q23– 24.1 in 1998. It includes 14–31 CAG repeats in healthy individuals, is expanded to sequences of 35–59 CAG triplets in SCA2 patients, and encodes the disease protein ataxin-2 [2–11]. Recent pathoanatomical studies revealed the widespread and consistent degeneration of a variety of brain structures in clinically diagnosed and genetically confirmed heterozygous SCA2 patients [1, 2, 4, 5, 12–20]. These studies were confined to brains of SCA2 patients in the advanced clinical stages and with disease durations of more than 10 years. Therefore, the initial sites of the SCA2 brain pathology remained unclear and the spatiotemporal spread of the neurodegenerative process could not be reconstructed up to now. In the present study, we report the brain pathoanatomy of a monozygous twin of a large Hungarian SCA2 family. This patient suffered from initial SCA2 and owing to a concomitant cancer died approximately within 3 years after SCA2 onset. Since neuronal loss in this SCA2 patient was restricted to brain gray matter areas known to be affected in advanced heterozygous SCA2 patients, these early affected gray matter areas most likely represent the initial brain targets of the disease process of SCA2.
Patients and Methods Pedigree of the Hungarian SCA2 Family The SCA2 family was originally situated in Bakonyszentiván in the country Veszprém, Hungary. Subsequent to the first clinical diagnosis of an autosomal dominantly inherited ataxia in a patient of this family in 1988, 19 of the 33 affected family members could be clinically investigated and genetically confirmed up to now (Figs. 1 and 2; Table 1). For molecular genetical investigation, genomic DNA was obtained from peripheral blood leucocytes according a standard salting out method. The CAG repeat lengths in the SCA2 genes were determined by direct sequencing using two independent sets of primers. The examined parts of the DNA were amplified with polymerase chain reactions using the following forward and reverse primers: method 1— SCA-2F: GGCGTGCGAGCCGGTGTA and SCA-2R: AGCCGTGGCCGAGGACGA; method 2—SCA2-F1: GTATGGGCCCCTCACCAT and SCA2-R2: AGGACGAG GAGACCGAGGAC. A unique feature of the pedigree of this large SCA2 family is the inclusion of two monozygous twins (patients V/44 and V/45) (Figs. 1 and 2; Table 1). While one of the affected twin brothers (V/44) is still living (Figs. 1 and 2;
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Table 1), the brain of the other twin brother (patient V/45) (Figs. 1 and 2; Table 1) was subject to the present postmortem study. In this family, age at disease onset was significantly correlated with the length of the CAG repeat (Spearman’s rho −0.76; p
