How to Cite this Article: Derwińska K, Mierzewska H, Goszczańska A, Szczepanik E, Xia Z, Kuśmierska K, Tryfon J, Kutkowska-Kaźmierczak A, Bocian E, Mazurczak T, Obersztyn E, Stankiewicz P. 2012. Clinical Improvement of the Aggressive Neurobehavioral Phenotype in a Patient With a Deletion of PITX3 and the Absence of L-DOPA in the Cerebrospinal Fluid. Am J Med Genet Part B 159B:236–242.
Clinical improvement of the aggressive neurobehavioral phenotype in a patient with a deletion of PITX3 and the absence of L-DOPA in the cerebrospinal fluid†
Article first published online: 5 JAN 2012
Copyright © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume 159B, Issue 2, pages 236–242, March 2012
How to Cite
Derwińska, K., Mierzewska, H., Goszczańska, A., Szczepanik, E., Xia, Z., Kuśmierska, K., Tryfon, J., Kutkowska-Kaźmierczak, A., Bocian, E., Mazurczak, T., Obersztyn, E. and Stankiewicz, P. (2012), Clinical improvement of the aggressive neurobehavioral phenotype in a patient with a deletion of PITX3 and the absence of L-DOPA in the cerebrospinal fluid. Am. J. Med. Genet., 159B: 236–242. doi: 10.1002/ajmg.b.32020
- Issue published online: 12 JAN 2012
- Article first published online: 5 JAN 2012
- Manuscript Accepted: 9 DEC 2011
- Manuscript Received: 18 JUL 2011
- Polish Ministry of Science and Higher Education. Grant Number: R13-0005-04/2008
- Dopamine metabolism;
- array CGH;
- copy-number variation;
- Smith-Magenis syndrome
The development of midbrain dopamine (DA) neurons is regulated by several transcription factors, including Nurr1, Wnt1, Lmx1a/1b, En1, En2, Foxa1, Foxa2, and Pitx3. PITX3 is an upstream co-activator of the TH (tyrosine hydroxylase) promoter. Pitx3-/- mice have a selective loss of dopaminergic neurons in the substantia nigra and ventral tegmental area, leading to the significantly reduced DA levels in the nigrostriatal pathway and in the dorsal striatum and manifest anomalous striatum-dependent cognitive impairment and neurobehavioral activity. Treatment with L-DOPA, dopamine, or dopamine receptor agonists in these mice reversed several of their sensorimotor impairments. Heterozygous missense mutations in PITX3 have been reported in patients with autosomal dominant congenital cataract and anterior segment (ocular) mesenchymal dysgenesis (ASMD) whereas homozygous missense mutations have been found in patients with microphthalmia and neurological impairment. Using a clinical oligonucleotide array comparative genomic hybridization (aCGH), we have identified an ∼317 kb hemizygous deletion in 10q24.32, involving PITX3 in a 17-year-old male with a Smith–Magenis syndrome-like phenotype, including mild intellectual impairment, sleep disturbance, hyperactivity, and aggressive and self-destructive behavior. Interestingly, no eye anomalies were found in our patient. Analysis of neurotransmitters in his cerebrospinal fluid revealed an absence of L-DOPA and significantly decreased levels of catecholamine metabolites. Importantly, L-DOPA treatment of our patient has led to mild mitigation of his aggressive behavior and mild improvement of his attention span, extended time periods of concentration, and better sleep. © 2012 Wiley Periodicals, Inc.