Recessively inherited parkinsonism: effect of ATP13A2 mutations on the clinical and neuroimaging phenotype

TY - JOUR

T1 - Recessively inherited parkinsonism

T2 - effect of ATP13A2 mutations on the clinical and neuroimaging phenotype

AU - Brüggemann, Norbert

AU - Hagenah, Johann

AU - Reetz, Kathrin

AU - Schmidt, Alexander

AU - Kasten, Meike

AU - Buchmann, Inga

AU - Eckerle, Susanne

AU - Bähre, Manfred

AU - Münchau, Alexander

AU - Djarmati, Ana

AU - van der Vegt, Joyce

AU - Siebner, Hartwig

AU - Binkofski, Ferdinand

AU - Ramirez, Alfredo

AU - Behrens, Maria I

AU - Klein, Christine

PY - 2010/11/1

Y1 - 2010/11/1

N2 - Objective: To determine clinical features and to identify changes in brain structure and function in compound heterozygous and heterozygous ATP13A2 mutation carriers. Design: Prospective multimodal clinical and neuroimaging study. Setting: University of Lübeck, Lübeck, Germany. Participants: Eight family members of a large Chilean pedigree with Kufor-Rakeb syndrome (KRS). Interventions: Clinical characterization, dopamine transporter (DAT) imaging, voxel-based morphometry (VBM), and transcranial sonography (TCS). Main Outcome Measures: 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).

AB - Objective: To determine clinical features and to identify changes in brain structure and function in compound heterozygous and heterozygous ATP13A2 mutation carriers. Design: Prospective multimodal clinical and neuroimaging study. Setting: University of Lübeck, Lübeck, Germany. Participants: Eight family members of a large Chilean pedigree with Kufor-Rakeb syndrome (KRS). Interventions: Clinical characterization, dopamine transporter (DAT) imaging, voxel-based morphometry (VBM), and transcranial sonography (TCS). Main Outcome Measures: 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).

KW - Aged

KW - Brain

KW - Brain Mapping

KW - Color Perception

KW - Discrimination (Psychology)

KW - Female

KW - Genetic Predisposition to Disease

KW - Heterozygote

KW - Humans

KW - Magnetic Resonance Imaging

KW - Male

KW - Middle Aged

KW - Mutation

KW - Nerve Degeneration

KW - Olfactory Perception

KW - Parkinsonian Disorders

KW - Pedigree

KW - Phenotype

KW - Prospective Studies

KW - Proton-Translocating ATPases

U2 - 10.1001/archneurol.2010.281

DO - 10.1001/archneurol.2010.281

M3 - Journal article

C2 - 21060012

SN - 2168-6149

VL - 67

SP - 1357

EP - 1363

JO - JAMA Neurology

JF - JAMA Neurology

IS - 11

ER -