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

Abstract

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.

Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics

“…To challenge this assumption, we first assessed if HDAC4 , MBD5 , and PITX3 , three genes previously reported to be associated with SMS phenotypes [13, 14, 16], BRD2 and ZBTB17 (a.k.a. MIZ1 ), two genes encoding high-confidence RAI1 interactors we identified by two-hybrid assay (see “Methods”) and JAKMIP1 , ZEB2 , CASK , KMT2D , GLDC , MECP2 , MAP2K2 , POGZ , and KDM5C , the nine genes identified here, were part of a RAI1 functional network.…”

“…Similarly, PITX3 was proposed to be responsible for the SMS-like neurobehavioral abnormalities observed in an individual [16]. …”

Noninvasive sleep monitoring in large-scale screening of knock-out mice reveals novel sleep-related genes

“…We identified several genes that had significant effect on sleep only during a specific Although little is known about the role of Pitx3 in sleep, Pitx3 is well known for its role in regulating lens development and is therefore associated with ocular abnormalities as seen in a range of animals including xenopus, zebrafish, humans as well as mice where its deficiency is reflected as a form of aphakia (52)(53)(54). A case study by Derwinska et al has reported that a hemizygous deletion on chromosome 10 including Pitx3 resulted in sleep disturbances beginning in early childhood in a Caucasian boy (55). In the KOMP2 pipeline, Pitx3 is associated with a multitude of additional outlier phenotypes including vision/eye, neurological/behavior, growth/size, homeostasis/metabolism, cardiovascular and skeletal assessments.…”

Novel and recurrent PITX3 mutations in Belgian families with autosomal dominant congenital cataract and anterior segment dysgenesis have similar phenotypic and functional characteristics

“…The patient also presented with intellectual disability and dysmorphic features but, surprisingly, lacked an eye phenotype. Analysis of neurotransmitters in his cerebrospinal fluid revealed an absence of L-DOPA and L-DOPA treatment led to mild improvement of his behavior [41]. Based on these observations and the selective loss of dopaminergic neurons in the Pitx3 mutant mice, it might be interesting to assess the dopaminergic function of patients with PITX3 mutations.…”