The spectrum of neurological presentation in individuals affected by TBL1XR1 gene defects.

BACKGROUND: TBL1XR1 encodes a F-box-like/WD40 repeat-containing protein that plays a role in transcription mediated by nuclear receptors and is a known genetic cause of neurodevelopmental disease of childhood (OMIM# 608628). Yet the developmental trajectory and progression of neurologic symptoms over time remains poorly understood. METHODS: We developed and distributed a survey to two closed Facebook groups devoted to families of patients with TBL1XR1-related disorder. The survey consisted of 14 subsections focused upon the developmental trajectories of cognitive, behavioral, motor, and other neurological abnormalities. Data were collected and managed using REDCap electronic data capture tools. RESULTS: Caregivers of 41 patients with a TBL1XR1-related disorder completed the cross-sectional survey. All reported variants affecting a single amino acid, including missense mutations and in-frame deletions, were found in the WD40 repeat regions of Tbl1xr1. These are domains considered important for protein-protein interactions that may plausibly underlie disease pathology. The majority of patients were diagnosed with a neurologic condition before they received their genetic diagnosis. Language appeared most significantly affected with only a minority of the cohort achieving more advanced milestones in this domain. CONCLUSION: TBL1XR1-related disorder encompasses a spectrum of clinical presentations, marked by early developmental delay ranging in severity, with a subset of patients experiencing developmental regression in later childhood.

Restless Legs Syndrome in X-linked adrenoleukodystrophy.

OBJECTIVE/BACKGROUND: X-linked adrenoleukodystrophy (ALD) is a neurodegenerative disease that causes progressive gait and balance problems. Leg discomfort, sleep disturbances, and pain contribute to daily disability. We sought to investigate the prevalence and severity of Restless Legs Syndrome (RLS) in patients with ALD. PATIENTS/METHODS: We administered questionnaires and conducted diagnostic telephone interviews to assess RLS severity. We retrospectively extracted data from neurological examinations, functional gait measures, and laboratory assessments. RESULTS AND CONCLUSIONS: Thirty-two adults with ALD (21 female, 11 male) were recruited to participate. Thirteen patients (40.6%) had RLS (10/21 females and 3/11 males). The median age of RLS onset was 35 years [IQR = 22-54]. Patients with RLS had more signs and symptoms related to myelopathy, but not the brain demyelination seen in ALD. This pilot study suggests a high prevalence of RLS in adults with ALD, which may contribute to sleep problems and impair quality of life.

Linkage disequilibrium mapping of the chromosome 6q21-22.31 bipolar I disorder susceptibility locus.

We previously reported genome-wide significant evidence for linkage between chromosome 6q and bipolar I disorder (BPI) by performing a meta-analysis of original genotype data from 11 genome scan linkage studies. We now present follow-up linkage disequilibrium mapping of the linked region utilizing 3,047 single nucleotide polymorphism (SNP) markers in a case-control sample (N = 530 cases, 534 controls) and family-based sample (N = 256 nuclear families, 1,301 individuals). The strongest single SNP result (rs6938431, P = 6.72 x 10(-5)) was observed in the case-control sample, near the solute carrier family 22, member 16 gene (SLC22A16). In a replication study, we genotyped 151 SNPs in an independent sample (N = 622 cases, 1,181 controls) and observed further evidence of association between variants at SLC22A16 and BPI. Although consistent evidence of association with any single variant was not seen across samples, SNP-wise and gene-based test results in the three samples provided convergent evidence for association with SLC22A16, a carnitine transporter, implicating this gene as a novel candidate for BPI risk. Further studies in larger samples are warranted to clarify which, if any, genes in the 6q region confer risk for bipolar disorder.

Fear of harm, a possible phenotype of pediatric bipolar disorder: a dimensional approach to diagnosis for genotyping psychiatric syndromes.

BACKGROUND: In a prior concordance study of affected sibling pairs with a community diagnosis of pediatric bipolar disorder (PBD) a behavioral phenotype termed Fear of Harm (FOH) was found to have one of the strongest concordance coefficients (rho) between probands and siblings, and the widest contrasts between the rho-estimates for the proband/sibling vs. proband/comparison pairs [Papolos, D., Hennen, J., Cockerham, M.S, Lachman, H., 2007]. A strategy for identifying phenotypic subtypes: concordance of symptom dimensions between sibling pairs who met screening criteria for a genetic linkage study of childhood-onset bipolar disorder using the Child Bipolar Questionnaire (CBQ) was employed. J. Affect. Disord. 99, 27-36.]. We used the Child Bipolar Questionnaire (OUT) (CBQ) to further elucidate this behavioral phenotype of PBD. We hypothesized that selective factors including parent reported symptoms of mania and depression, would be distinguishing features of impairment between groups defined by 1) the magnitude of their score on a continuous measure of FOH, and 2) the high FOH group would have significantly greater levels of severity on course of illness variables. These measures included earlier age of onset of first psychiatric symptoms, first hospitalization, and frequency of psychiatric hospitalizations, as well as, degree of social impairment as determined by exposure to the juvenile justice system and school performance problems. METHODS: The sample was comprised of children with community diagnoses of bipolar disorder or at risk for the illness based on enriched family history with multiple first degree relatives diagnosed with BPD (N=5335). Included were all subjects who had >40 positively endorsed CBQ symptom items at frequencies of very often, almost always, and always. This group was divided randomly into two groups, the exploratory group (N=2668) and the hypothesis testing (study) group (N=2666). The exploratory group was used for the development of hypotheses and the study group was used to test these hypotheses on a new set of data. All results reported here derive from the latter group. In subsequent analyses, we classified each child as having a high degree of FOH, low FOH, or no FOH. We examined a subset of the sample for differences in age of onset of first psychiatric symptoms, course of illness and measures of symptom severity. These groups were compared using the chi-square procedure for categorical data and the Analysis of Variance (ANOVA) with Scheffe pair wise tests for continuous variables. The Child Bipolar Questionnaire V.2.0, the Yale-Brown Obsessive Compulsive Scale (YBOCS) and the Overt Aggression Scale (OAS) were the principal instruments used to obtain diagnostic information for this study. RESULTS: We found that children representative of the FOH phenotype when compared to children with PBD who lack this trait had higher indices of severity of mania and depression, as well as other indices that reflect severity and course of illness. Trait factors were derived from a factor analysis of CBQ in a large population of children diagnosed with or at risk for PBD, and used to further elucidate trait features of children with FOH. Children with the FOH traits were also more likely to be defined by six CBQ factors; Sleep/Arousal, Harm to Self and Others, Territorial Aggression, Anxiety, Self-esteem, Psychosis/Parasomnias/Sweet Cravings/Obsessions (PPSO). LIMITATIONS: This data is derived from samples enriched with bipolar disorder cases. Further validation is needed with samples in which childhood-onset BD is rarer and diagnoses more diverse. Clinician diagnosis was not validated via research interview. CONCLUSIONS: The FOH phenotype, as defined by a metric derived from combining items from the YBOCS/OAS, is a clinically homogeneous behavioral phenotype of PBD with early age of onset, severe manic and depressive symptoms, and significant social impairment that is strongly associated with 6 CBQ factors and can be easily identified using the CBQ. Through the examination of dimensional features of PBD in an enriched sample of large size, we were able to further refine a phenotype and identify clinical dimensions potentially linked to endophenotypic markers that may prove fruitful in differential diagnosis, treatment and etiological studies of PBD. The nature of the sets of specific symptoms that comprise the FOH factors enabled us to propose a biological model for the phenotype (OUT) that involves a complex orexigenic circuit which links hypothalamic, limbic, and other brain nuclei primarily responsible for the regulation of behavioral and proposed physiological features of the FOH phenotype.

Longitudinal follow-up of reproductive and metabolic features of valproate-associated polycystic ovarian syndrome features: A preliminary report.

BACKGROUND: In the Systematic Treatment Enhancement Program for Bipolar Disorder, we showed that valproate is associated with new-onset menstrual-cycle irregularities and hyperandrogenism in 10.5% of 86 women. We now determine whether polycystic ovarian syndrome (PCOS) features reverse on valproate discontinutation. METHODS: Women with valproate-associated PCOS and those at risk for PCOS (valproate use < or =6 months) were re-evaluated for PCOS. RESULTS: Follow-up (mean 17 months) assessments were completed in 14 women (5 with treatment-emergent PCOS, 9 on valproate < or =6-month). Of seven women who developed valproate-associated PCOS, PCOS reproductive features remitted in three of four discontinuing valproate and persisted in all 3 continuing valproate. Menstrual-cycle irregularities improved among valproate-discontinuers whose PCOS features remitted (p = 0.01). There was a trend toward lower serum testosterone (p = 0.06). Body-weight and polycystic ovarian morphology did not change. CONCLUSIONS: In the first longitudinal bipolar-disorder study of valproate-associated PCOS, most valproate-discontinuers had improved reproductive features of PCOS despite static body-weight.