Maternal polycystic ovary syndrome and risk of neuropsychiatric disorders in offspring: prenatal androgen exposure or genetic confounding?

BACKGROUND: Maternal polycystic ovary syndrome (PCOS) has been proposed as a model for investigating the role of prenatal androgen exposure in the development of neuropsychiatric disorders. However, women with PCOS are at higher risk of developing psychiatric conditions and previous studies are likely confounded by genetic influences. METHODS: A Swedish nationwide register-based cohort study was conducted to disentangle the influence of prenatal androgen exposure from familial confounding in the association between maternal PCOS and offspring attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and Tourette's disorder and chronic tic disorders (TD/CTD). PCOS-exposed offspring (n = 21 280) were compared with unrelated PCOS-unexposed offspring (n = 200 816) and PCOS-unexposed cousins (n = 17 295). Associations were estimated with stratified Cox regression models. RESULTS: PCOS-exposed offspring had increased risk of being diagnosed with ADHD, ASD, and TD/CTD compared with unrelated PCOS-unexposed offspring. Associations were stronger in girls for ADHD and ASD but not TD/CTD [ADHD: adjusted hazard ratio (aHR) = 1.61 (95% confidence interval (CI) 1.31-1.99), ASD: aHR = 2.02 (95% CI 1.45-2.82)] than boys [ADHD: aHR = 1.37 (95% CI 1.19-1.57), ASD: aHR = 1.46 (95% CI 1.21-1.76)]. For ADHD and ASD, aHRs for girls were stronger when compared with PCOS-unexposed cousins, but slightly attenuated for boys. CONCLUSIONS: Estimates were similar when accounting for familial confounding (i.e. genetics and environmental factors shared by cousins) and stronger in girls for ADHD and ASD, potentially indicating a differential influence of prenatal androgen exposure v. genetic factors. These results strengthen evidence for a potential causal influence of prenatal androgen exposure on the development of male-predominant neuropsychiatric disorders in female offspring of women with PCOS.

Perinatal risk factors in Tourette's and chronic tic disorders: a total population sibling comparison study.

Adverse perinatal events may increase the risk of Tourette's and chronic tic disorders (TD/CTD), but previous studies have been unable to control for unmeasured environmental and genetic confounding. We aimed to prospectively investigate potential perinatal risk factors for TD/CTD, taking unmeasured factors shared between full siblings into account. A population-based birth cohort, consisting of all singletons born in Sweden in 1973-2003, was followed until December 2013. A total of 3 026 861 individuals were identified, 5597 of which had a registered TD/CTD diagnosis. We then studied differentially exposed full siblings from 947 942 families; of these, 3563 families included siblings that were discordant for TD/CTD. Perinatal data were collected from the Medical Birth Register and TD/CTD diagnoses were collected from the National Patient Register, using a previously validated algorithm. In the fully adjusted models, impaired fetal growth, preterm birth, breech presentation and cesarean section were associated with a higher risk of TD/CTD, largely independent from shared family confounders and measured covariates. Maternal smoking during pregnancy was associated with risk of TD/CTD in a dose-response manner but the association was no longer statistically significant in the sibling comparison models or after the exclusion of comorbid attention-deficit/hyperactivity disorder. A dose-response relationship between the number of adverse perinatal events and increased risk for TD/CTD was also observed, with hazard ratios ranging from 1.41 (95% confidence interval (CI): 1.33-1.50) for one event to 2.42 (95% CI: 1.65-3.53) for five or more events. These results pave the way for future gene by environment interaction and epigenetic studies in TD/CTD.

Cystic cerebellar dysplasia and biallelic LAMA1 mutations: a lamininopathy associated with tics, obsessive compulsive traits and myopia due to cell adhesion and migration defects.

BACKGROUND: Laminins are heterotrimeric complexes, consisting of α, ß and γ subunits that form a major component of basement membranes and extracellular matrix. Laminin complexes have different, but often overlapping, distributions and functions. METHODS: Under our clinical protocol, NCT00068224, we have performed extensive clinical and neuropsychiatric phenotyping, neuroimaging and molecular analysis in patients with laminin α1 (LAMA1)-associated lamininopathy. We investigated the consequence of mutations in LAMA1 using patient-derived fibroblasts and neuronal cells derived from neuronal stem cells. RESULTS: In this paper we describe individuals with biallelic mutations in LAMA1, all of whom had the cerebellar dysplasia, myopia and retinal dystrophy, in addition to obsessive compulsive traits, tics and anxiety. Patient-derived fibroblasts have impaired adhesion, reduced migration, abnormal morphology and increased apoptosis due to impaired activation of Cdc42, a member of the Rho family of GTPases that is involved in cytoskeletal dynamics. LAMA1 knockdown in human neuronal cells also showed abnormal morphology and filopodia formation, supporting the importance of LAMA1 in neuronal migration, and marking these cells potentially useful tools for disease modelling and therapeutic target discovery. CONCLUSION: This paper broadens the phenotypes associated with LAMA1 mutations. We demonstrate that LAMA1 deficiency can lead to alteration in cytoskeletal dynamics, which may invariably lead to alteration in dendrite growth and axonal formation. Estimation of disease prevalence based on population studies in LAMA1 reveals a prevalence of 1-20 in 1 000 000. TRIAL REGISTRATION NUMBER: NCT00068224.

The DRD4 gene and severity of tics and comorbid symptoms: main effects and interactions with delivery complications.

In this study, we investigated the role of the dopamine receptor D4 (DRD4) 48-base pairs (bp) variable number of tandem repeats (VNTR) and perinatal adversities regarding severity of tics and comorbid symptoms in children with tic disorders. We genotyped 110 children with tics with regard to the 48-bp VNTR and assessed presence of prenatal smoking exposure, and pregnancy and delivery complications by parent questionnaires. We examined associations between 2, 3, 4, and 7 repeat (R) alleles and severity of tics and comorbid obsessive-compulsive, depressive, anxious, and autistic symptoms. Through linear regressions, we investigated whether perinatal adversities and the 2R, 3R, 4R, and 7R alleles would interact with severity ratings of tics or comorbid symptoms as outcome. Presence of a 2R allele was related to more severe obsessive-compulsive symptoms, and presence of a 3R allele to increased severity of autistic features. Pregnancy complications were associated with decreased obsessive-compulsive symptom severity, and prenatal smoking exposure to more severe depressive and autistic symptoms. In children without a 3R allele delivery complications were associated with more severe tics, but in children with a 3R variant an inverse relation between delivery complications and tic severity was found. Moreover, the relation between delivery complications and internalizing symptom severity appeared to be most pronounced in children with a 2R allele. In conclusion, this study provides evidence for a role of the 48-bp VNTR in the etiology of tic and associated disorders, and for interactions with delivery complications regarding severity of tics and co-occurring internalizing symptoms.

The Autism--Tics, AD/HD and other Comorbidities (A-TAC) telephone interview: convergence with the Child Behavior Checklist (CBCL).

OBJECTIVE: To compare telephone interview screening for child psychiatric/neuropsychiatric disorders using the inventory of Autism-Tics, Attention deficit/hyperactivity disorder (AD/HD) and other Comorbidities (A-TAC) with results from the Child Behavior Checklist (CBCL). BACKGROUND: The A-TAC is a parent telephone interview focusing on autism spectrum disorders (ASDs) and co-existing problems, developed for lay interviewers. SUBJECTS AND METHODS: A-TAC telephone interviews and CBCL questionnaires were obtained from parents of 106 Swedish twin pairs aged 9 and 12 years. RESULTS: Correlations between A-TAC modules and CBCL scales aimed at measuring similar concepts were generally significant albeit modest, with correlation coefficients ranging from 0.30 through 0.55. CONCLUSION: The A-TAC has convergent validity with the CBCL in several problem areas, but the A-TAC also provides more detailed and specific assessments of ASD symptoms and related neuropsychiatric problems.

Candidate locus for chorea and tic disorders at 15q?

Cases of chromosomal aberrations are known to be associated with specific phenotypic abnormalities, including tics and chorea. We report the case of a 10-year-old caucasian boy with tics, chorea, and a de novo chromosome 15 paracentric inversion, 46,XY,inv(15) (q13;q22.3) identified with G-banding chromosome analysis (trypsin-Giemsa staining). Subsequent fluorescence in situ hybridization with locus-specific small nuclear ribonucleoprotein polypeptide N gene probe confirmed that the breakpoints of the inversion were distal to 15q12. Mutation analysis showed no mutation or polymorphism in the thyroid transcription factor 1 gene (TITF1). The results suggest that 15q is a region to explore for candidate genes of etiologic importance in the development of tics and chorea.

Psychopathology in tuberous sclerosis: an overview and findings in a population-based sample of adults with tuberous sclerosis.

BACKGROUND: Tuberous sclerosis (TS) is a multi- system disorder with complex genetics. The neurodevelopmental manifestations of TS are responsible for considerable morbidity. The prevalence of epilepsy and intellectual disabilities among individuals with TS have been well described. Ours is the first study that explores the prevalence and pattern of psychopathology in a population-based sample of adults with TS. METHODS: Sixty subjects were identified through a capture-recapture analysis of TS. Information was gathered as to seizure history, cognitive functioning (WISC-III) and psychopathology (SADS-L, SAPPA). Lifetime psychopathology was categorized according to Research Diagnostic Criteria. The overall pattern of mental illness (MI) was examined as well as how this varied with IQ and seizure history. RESULTS: Twenty-four (40.0%) subjects had a history of MI. The most common diagnosis was that of an affective disorder [18 (30.0%)], the majority of which were major depressive episodes. Alcoholism [4 (6.7%)] and anxiety disorders [3 (5.0%)] were the next most common diagnoses. Two (3.3%) subjects had had a tic disorder. Only one individual had a diagnosis of schizophrenia. MI was found in 75.0% of those with a history of epilepsy and 37.5% of those without epilepsy. MI was significantly more prevalent in those with a full-scale IQ above 70. CONCLUSIONS: A significant proportion of adult with TS experience MI. MI was significantly more [corrected] prevalent in subjects with a full-scale IQ above 70. Reasons for such a finding are explored, and related methodological considerations for future research outlined.

Doença dos tiques: aspectos genéticos e neuroquímicos atuais / Tic disease: current genetic and neurochemical factors

Após breve revisão dos dados históricos, do conceito, do quadro clínico e dos critérios para o diagnóstico, analisamos os principais aspectos genéticos e neuroquímicos atuais dos tiques e da síndrome de Gilles de La Tourette. Dados epidemiológicos sugerem que todo tique seja de natureza orgânica, a maioria de origem genética, e que obedecem a transmissão autossômica dominante com penetrância aproximada de 100 por cento. Ressaltamos, ainda, os recentes estudos imuno-histoquímicos, particularmente os que se referem aos sistemas dopaminérgico, noradrenérgico e serotoninérgico, que modulam a atividade dos circuitos córtico-estriato-talâmico-cortical, envolvidos na gênese dos tiques e dos transtornos obsessivos-compulsivos.

Investigation of dopamine system genes in obsessive-compulsive disorder.

Evidence from anatomical, pharmacological, and animal studies on the involvement of the dopamine system in obsessive-compulsive disorder (OCD) is mounting. This, along with evidence for a genetic diathesis provided by family and twin studies, prompted us to conduct genetic association studies of dopamine system genes in OCD. We genotyped OCD patients (n > 100) and matched controls for four loci: (1) a 40-base-pair repeat in the dopamine transporter gene; (2) the TaqIA polymorphism and the serine/cysteine variation in the D2 dopamine receptor gene; (3) an MscI polymorphism in the D3 dopamine receptor gene; and (4) a 48-base-pair repeat in the D4 dopamine receptor gene. Significant differences in allele frequencies were found between patients and controls for the D4 receptor gene, although replication is required with family-based controls before any conclusions can be entertained. This study represents the first comprehensive assessment of the roles of dopamine system genes in OCD.

Familial tic disorder, parkinsonism, motor neuron disease, and acanthocytosis: a new syndrome.

We report two brothers who were of consanguineous parents and who displayed a unique association of motor and vocal tics, parkinsonism, distal muscular atrophy, and acanthocytosis. In the older brother, leg weakness and muscle wasting started at age 13, and he became wheelchair bound at 40. Electrophysiologic studies and muscle biopsy confirmed diffuse denervation. Involuntary vocalizations and facial tics began at age 36, but within 5 years the tics were replaced by progressive parkinsonism with supranuclear ophthalmoparesis. CSF studies implied impaired central dopamine and serotonin turnover. In the younger brother, orofacial tics started at age 36, vocalizations and fasciculations in the legs began 1 year later, and parkinsonian findings were present at age 40. This is the first report of an association of Tourettism, parkinsonism, motor neuron disease, and acanthocytosis occurring as an autosomal recessive syndrome.