Increased symptoms of attention deficit hyperactivity disorder and major depressive disorder symptoms in nail‐patella syndrome: Potential association with LMX1B loss‐of‐function

Abstract

Nail-Patella syndrome (NPS) is an autosomal dominant disorder that is the result of heterozygous loss-of-function mutations in LMX1B, coding for a LIM homeobox (LIM-HD) transcription factor. Analyses of lmx1b mutant mice have revealed the role of Lmx1b in the development of mesencephalic dopaminergic neurons and the serotonergic system; these areas have been linked with symptoms of attention deficit hyperactivity disorder (ADHD) and major depressive disorder (MDD). Fifty adults (38 females, 12 males) with NPS completed the Conners’ Adult ADHD Rating Scales—Self-report: Long Version (CAARS) and Beck Depression Inventory-II (BDI-II). The objective was to describe the neurobehavioral phenotype of these subjects and examine possible relationships between neurobehavioral symptoms and NPS. Elevated levels of DSM-IV-TR ADHD Inattentive symptoms were reported on the CAARS by 22% of the NPS sample. The BDI-II Total score was elevated for 40% of the NPS sample. There was a significant increase in the odds of an elevated BDI-II Total score when any of the three CAARS scales were elevated (odds ratios ranging from 11.455 to 15.615). The CAARS and BDI-II did not significantly differ with gender, age, or education level. There was no significant association between genetic mutation-predicted protein status and elevations on CAARS or BDI-II. Individuals with NPS reported co-occurring symptoms of ADHD and MDD, with higher levels of co-occurrence than reported in the literature for the general population. The co-occurrence of these symptoms may be related to mesencephalic dopaminergic neurologic pathway abnormalities that are a consequence of LMX1B loss of function.

Self-Reported ADHD Symptoms and Interhemispheric Interaction in Adults: A Dimensional Approach

“…The latter measures the overall level of ADHD related symptoms. The ADHD index subscale score is seen to be the most reliable and valid estimate of self-reported overall ADHD symptomatology [ 27 , 56 , 57 ]. From the CAARS, an inconsistency index may be calculated that indicates inconsistent responding based on eight pairs of items has similar content; the score is computed by summing the difference scores on each pair.…”

Serotonergic transcriptional networks and potential importance to mental health

“…Given its place, functionally in the serotonergic regulatory network we imagine altered network function in at least some NPS individuals. Although not yet studied in sufficient depth to establish a clear link to neuropsychiatric disease, disrupted LMX1B binding may promote susceptibility to ADHD and major depressive disorder in NPS cases 91 . Further study of this important possibility, including quantitative analysis of disease–associated serotonergic biomarker indices in NPS individuals, is of significant interest in the search for the genetic basis of serotonergic dysfunction in neuropsychiatric disorders.…”

Opposite Control of Excitatory and Inhibitory Synapse Formation by Slitrk2 and Slitrk5 on Dopamine Neurons Modulates Hyperactivity Behavior

“…These proteins are also required for mDA neuron survival, and specific inactivation of Lmx1a/b in adult mDA neurons results in dopamine neuron degeneration and parkinsonism Laguna et al, 2015). Previous studies have shown that a heterozygous loss-of-function mutation in Lmx1b, a LIM homeobox transcription factor, predisposes individuals to exhibit ADHD symptoms (Ló pez-Arvizu et al, 2011). Although animal models cannot fully replicate complex human neuropsychiatric diseases such as ADHD, the specific and conditional knockout (cKO) of the Lmx1a and Lmx1b genes in postmitotic dopaminergic neurons during development results in increased locomotor activity (Doucet-Beaupré et al, 2015).…”