DAT Function Links Parkinsonism, ADHD

Pauline Anderson

July 14, 2014

Danish researchers believe they are the first to identify a genetic connection between parkinsonism manifesting in early adulthood and specific mutations in the presynaptic sodium-coupled dopamine transporter (DAT) gene.

Their research suggests that 2 mutations in the DAT gene (SLC6A3) may be involved not only in early-onset parkinsonism but also in attention-deficit/hyperactivity disorder (ADHD), bipolar disorder, and autism.

"This is sort of a missing link" connecting altered DAT function and early-onset parkinsonism, later-onset parkinsonism, and a host of psychiatric illnesses, said lead author Freja H. Hansen, PhD, postdoctoral fellow, University of Copenhagen, Denmark.

"We believe that these mutations can cause or contribute to a spectrum of diseases where pathological outcome is determined by the nature and severity of the mutations," said Dr. Hansen. "On the milder end would be psychiatric disorders and in very severe cases where patients have no functional transporter, you will see infantile parkinsonism."

Dr. Freja H. Hansen

DAT controls the effect of dopamine by mediating reuptake of released dopamine from the synaptic cleft to the nerve cell. Mutations in this gene have already been identified and linked to movement disorders in infancy. ADHD also involves disturbances of dopaminergic signaling.

The paper was published in the July 1 issue of the Journal of Clinical Investigation.

Genetic Testing

The investigators sequenced coding exons of SLC6A3 in 91 unrelated patients referred because of early-onset parkinsonism or a related atypical movement disorder.

One patient had also been diagnosed with ADHD. This 40-year-old man had no family history of movement disorders or psychiatric disease. He had experienced unspecified failure to thrive in infancy and learning problems in school. At age 28 years, he had insidious onset of right-sided hand tremor with normal findings on biochemistry, computed tomography, and electroencephalography. At age 35, he had severe course tremor in all extremities and his head, during action and at rest, accompanied by rigidity and bradykinesia. At age 39, ADHD was diagnosed according to Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria.

At the time of the current study, this patient had universal tremor as well as bradykinesia and rigidity in the upper and lower limbs.

DAT single-photon emission computed tomography (DAT-SPECT) scanning and fluorodeoxyglucose PET-MRI confirmed that the patient had progressive dopaminergic neurodegeneration.

Genetic testing revealed that this patient is compound heterozygous for 2 SLC6A3 missense mutations: One coding variant (DAT-1321F) was transmitted from his deceased father, and the other variant (DAT-D421N) is the result of a presumed de novo mutation.

"This patient had these novel mutations on 2 alleles," said Dr. Hansen. "So he doesn't have any normal transporter; they're all mutated in some way."

The mutations severely reduce dopamine uptake capacity but preserve membrane targeting. For DAT-D421N, uptake is almost eliminated, probably because of disrupted binding of sodium to a sodium site in DAT, said the authors.

Although the reduced uptake capacity of both DAT-1312F and DAT-D421N is likely key to the dopaminergic dysfunction in the patient (because the DAT-431N phenotype was much more pronounced), most of the alterations underlying his clinical presentation might be due to this particular mutation, said the authors.

And because both mutations, but particularly DAT-D421N, have deleterious consequences for the transporter function, researchers believe that both might be a rare monogenetic cause of early-onset atypical parkinsonism.

Monogenetic Causes

In general, 5% to 10% of parkinsonism cases can be attributed to monogenetic causes, giving rise to both dominant and recessive modes of inheritance, said the authors. The most common cause of early-onset parkinsonism is a mutation in parkin, which is estimated to account for 1.4% to 8.2% of earl-onset cases.

According to Dr. Hansen, the patient in question had only about 25% DAT function, whereas children with the previously described DAT mutations have less dopamine function. The study results, she said, suggest that DAT deficiency is not just a childhood disease.

"What we see here is that the dopamine transporter mutations can cause parkinsonism in adults as well as in children, whereas dopamine transporter mutations have previously been described as a childhood disease."

There's increasing awareness that de novo mutations may make up a considerable segment of the etiology of complex brain disorders. This case of a patient who is compound heterozygous for DAT mutations and has neuropsychiatric comorbidity suggests that DAT -coding variants are risk factors in ADHD, said the authors.

"To our knowledge, this patient represents the first case of parkinsonism as well as ADHD, in which a de novo mutation has been identified in DAT."

Dr. Hansen stressed, however, that the DAT mutations are rare and would not explain a large percentage of ADHD or autism cases. A causal relationship to psychiatric disorders "needs further investigation," she said.

Researchers hope to develop a mouse model with the same genetic deficiencies to further investigate the pathologic mechanisms that underlie the genetic-driven development of parkinsonism and mental disorders, said Dr. Hansen.

As for treating patients with these mutations, gene therapy is "somewhat down the road," she said. It might also be possible to "rescue" some function by getting the transporter that is retained inside cells onto the cell surface, she said. "If you can get just a little bit out, you can alleviate symptoms."

The work was supported by grants from the National Institutes of Health, the Danish Medical Research Council, the University of Copenhagen BioScaRT Program of Excellence, the Lundbeck Foundation Center for Biomembranes in Nanomedicine, the Lundbeck Foundation, the Novo Nordisk Foundation, Fabrikant Vilhelm Pedersen og Hustrus Mindelegat, the Austrian Science Fund, and the Canadian Institutes of Health Research (CIHR) Postdoctoral Fellowship.The authors have disclosed no relevant financial relationships.

J Clin Invest. 2014;124:3107-3120. Abstract

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