Recessively inherited parkinsonism: effect of ATP13A2 mutations on the clinical and neuroimaging phenotype.
OBJECTIVE
To determine clinical features and to identify changes in brain structure and function in compound heterozygous and heterozygous ATP13A2 mutation carriers.


METHODS
Prospective multimodal clinical and neuroimaging study.


METHODS
University of Lübeck, Lübeck, Germany.


METHODS
Eight family members of a large Chilean pedigree with Kufor-Rakeb syndrome (KRS).


METHODS
Clinical characterization, dopamine transporter (DAT) imaging, voxel-based morphometry (VBM), and transcranial sonography (TCS).


METHODS
Frequency of parkinsonian signs, brain structure, and functional alterations.


RESULTS
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.


CONCLUSIONS
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).
Schilling Section of Clinical and Molecular Neurogenetics and Department of Neurology, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Norbert
N
Brüggemann
Johann
J
Hagenah
Kathrin
K
Reetz
Alexander
A
Schmidt
Meike
M
Kasten
Inga
I
Buchmann
Susanne
S
Eckerle
Manfred
M
Bähre
Alexander
A
Münchau
Ana
A
Djarmati
Joyce
J
van der Vegt
Hartwig
H
Siebner
Ferdinand
F
Binkofski
Alfredo
A
Ramirez
Maria I
MI
Behrens
Christine
C
Klein
D000368:Aged; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D001931:Brain Mapping; D003118:Color Perception / Q000502:physiology; D004192:Discrimination, Psychological / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D055696:Olfactory Perception / Q000502:physiology; D020734:Parkinsonian Disorders / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D011446:Prospective Studies; D006180:Proton-Translocating ATPases / Q000235:genetics*
C514983:ATP13A2 protein, human; D006180:Proton-Translocating ATPases