Early-onset Disorder Research Articles

Clinical Characteristics of Bipolar vs. Unipolar Depression in Preschool Children

Despite retrospective reports of the onset of childhood bipolar disorder during the preschool period, few studies have investigated whether mania symptoms can be identified in preschoolers. A group of children with a cluster of mania symptoms that showed discriminant validity from other disruptive disorders was identified in a large preschool sample. These empirical data add to descriptive studies of mania in clinical preschool populations. An investigation of the characteristics of depression among putative bipolar preschoolers may inform the controversial nosologic questions that surround the diagnosis in this young age group. This study, conducted from 2002 to 2007, investigated major depressive disorder (MDD) symptoms and severity in preschoolers with a bipolar syndrome in comparison to those with unipolar MDD, identified by an age-appropriate structured psychiatric interview, the Preschool Age Psychiatric Assessment (based on DSM-IV). Twenty-one preschoolers were identified who met DSM-IV symptom criteria for bipolar I disorder and MDD and were compared to 54 preschoolers with unipolar MDD. The bipolar depressed preschoolers had significantly higher depression severity (p < .0001) and higher rates of comorbidity than did those with unipolar depression. The study is limited by the exploratory nature of clinical mania characteristics in preschoolers as well as reliance on parent reports of these symptoms. These findings suggest that, similar to adult bipolar patients, preschoolers with a putative bipolar syndrome experience clinically significant and severe depression. Symptom characteristics and comorbidity patterns also distinguished this group from the unipolar depressed preschoolers. Our findings underscore the marked depression that characterizes this putative bipolar syndrome and suggest that further investigation of this domain may clarify the nosology of this early-onset disorder.

Genetic assessment and management of dementia

Dementia in lata life is common, usually with a multifactorial aetiology. Early-onset dementy is very rare but much more likely to be Mendelian in origin children of someone with the common, late-onest form of Alzheimer's disease (AD) have a risk of developing AD themselves three to four times greater than the general population risk at the same age. However, this is not much more than above 10% as the corrent average life expectancy Most of the inherited, early-onset disorders causing dementia follow autosomal dominant inheritance with a 50% risk for children and siblings Genetic testing is available for Huntington's disease and for a few of the mutations associated with autosomal dominant disorders causing early-onset dementia, but remains a research activity for other forms of dementia Predictive genetic testing of individuals at risk for Huntington's disease or other inherited dementias shoul be carried out only in regional genetic centres following accepted genetic counselling protocols

Marked Neurocognitive Deficits Apparent In Early-Onset Psychotic Disorders

Marked Neurocognitive Deficits Apparent In Early-Onset Psychotic Disorders

The functional MAOA‐uVNTR promoter polymorphism in patients with frontotemporal dementia

The genetic underpinnings of frontotemporal dementia (FTD), a rare yet early onset disorder still remains elusive. As FTD is characterized by a serotonergic deficit in the frontal lobe, and as some symptoms of FTD resemble conditions of monoamino oxidase A (MAO-A) deficiency, MAO-A is an attractive candidate gene for case-control association studies of FTD. We have thus ascertained 62 Italian FTD patients and 151 controls matched to age and genotyped them for a functional promoter polymorphism, termed MAOA-uVNTR. However, no significant differences were observed between patients and controls. Bearing in mind the caveat of the small patient sample size, our data nevertheless argue against a major genetic role of MAO-A polymorphism in FTD.

Disorders of Childhood and Adolescence: Gender and Psychopathology

Early-onset disorders (e.g., conduct problems, autism) show a marked male preponderance, whereas adolescent-onset disorders (e.g., depression, anxiety) show a marked female preponderance. A developmental psychopathology framework provides a means to investigate complex gender-related etiologies of these different disorders. This review focuses on biological and environmental factors implicated in the development of conduct problems and depression in boys and girls. Boys and girls showed certain differences in types, rates, comorbidities, antecedents, correlates, and trajectories of these problems. Origins of male and female preponderant problems are likely to be rooted, in part, in biological, physical, cognitive, and social-emotional differences in boys and girls that can precede the expression of clinical problems. These male-like and female-like characteristics are considered regarding conduct problems and depression to explore how they inform biological and environmental theories about gender and psychopathology. At the same time, because boys and girls also show many similarities, it is important to avoid sex-stereotyping mental health problems.

“Pseudodominant inheritance” of ataxia with ocular apraxia type 2 (AOA2)

Ataxia with ocular apraxia type 2 (AOA2) is an autosomal recessive, early onset ataxia caused by mutations in the senataxin (SETX) gene. Ocular apraxia and increased levels of alpha-fetoprotein are characteristic but not obligate markers of the disease. AOA2 is allelic with ALS4, a motor neuron disorder of early onset and autosomal dominant inheritance. We observed a two generation family with ataxia which started at age 14 and 17 in two sibs and at age 23 in their paternal uncle.Oculomotor disturbances included strabismus, saccadic pursuit and gaze evoked nystagmus. MRI revealed severe cerebellar atrophy. All patients presented pronounced peripheral neuropathy with wasting of hand and leg muscles resembling distal motor neuronopathy. Increased alphafetoprotein levels triggered genetic analyses of SETX. We found the sib pair to be compound heterozygous for a single base deletion c.2835delC, resulting in a frameshift mutation and causing nonsense related mRNA decay, and a base exchange c.6106G > A, resulting in abnormal splicing and skipping of exon 15. The similarly affected uncle was homozygous for the c.6106G > A mutation probably due to distant consanguinity in the paternal branch of the family. Pseudodominant occurrence in two generations has not been described before in AOA2 and led, in this family, to false categorization as dominant ataxia before SETX mutations were detected. Clinically this family presented with a phenotype combining typical features of AOA2 and ALS4; thus extending the phenotypic spectrum of SETX mutations.

Genetik depressiver Störungen

Among the most common severe psychiatric disorders worldwide, depressive disorders are a leading cause of morbidity, the onset usually occurring during childhood or adolescence. Symptomatology, prevalence, outcome and treatment differentiate depressive disorder nosologically as being either unipolar depression or bipolar disorder, which is characterized by one or more episodes of mania with or without episodes of depression. Genetic factors decisively influence the susceptibility to depressive disorders. Family studies and twin studies have been essential in defining the magnitude of familial risk and liability to heritability, particularly in the case of bipolar disorder. In recent years, linkage and association studies have made great strides towards identifying candidate genes. Particularly the s-allele of the serotonin transporter has been repeatedly confirmed to be a risk factor. Meta-analyses suggest, however, that the genetic contributions of the ascertained loci are relatively small. Along with genetic factors, environmental factors are heavily involved. Gene-environment action plays a pivotal role, particularly in unipolar depression. The genetic disposition seems to be modulated by a protective or pathogenic environment. Early-onset disorders must be further investigated in future as studies to date are somewhat limited.

Targeting Early-Onset Conduct Disorder

Targeting Early-Onset Conduct Disorder

Functional characterization of a novel mutation in TITF-1 in a patient with benign hereditary chorea

Benign hereditary chorea (BHC) is an autosomal dominant disorder of early onset characterised by non progressive choreic movements with normal cognitive function occasionally associated with hypothyroidism and respiratory problems. Numerous pieces of evidence link BHC with TITF-1/NKX2.1 gene mutations. We studied a patient with a familial benign hereditary chorea and normal thyroid and respiratory function. Sequence analysis of TITF-1 revealed the presence of a heterozygous C>T substitution at nucleotide 532, predicted to change an arginine (CGA) with a stop codon (TGA) at position 178 (R178X). A functional analysis shows that the mutated TTF-1 is not binding DNA, nor activating the canonical thyroid target gene promoter or interfering with the ability of wild type TTF-1 to activate transcription. In addition, the mutated protein is predominantly cytoplasmic, rather than nuclear as in the case of the wild type TTF-1. Thus, we have identified a new mutation in the TTF-1 coding gene in a patient with benign hereditary chorea. The results show that the mutation leads to a haploinsufficiency of TITF-1 and opens the question of genotype/phenotype correlation.

History of illness prior to a diagnosis of bipolar disorder or schizoaffective disorder

Background There are obstacles to early identification of bipolar disorder. Identifying and treating illness early in its time course may be associated with a better prognosis. Methods A questionnaire was administered at interview, when the participant was euthymic, to participants ( n = 240) enrolled in the Bipolar Comprehensive Outcomes Study (BCOS). Information was collected about the sequential timeline of specific symptoms of mental illness up to when they first received a diagnosis of Bipolar Disorder or Schizoaffective Disorder. Results Any symptoms of mental illness were first experienced at 17.5 years (median; Inter Quartile Range (IQR) 13.8–24.3; n = 216) and mood swings at 18.0 years (IQR 14–25; n = 197). Symptoms of depression were experienced at 18.0 years (IQR 14–25; n = 197), a full episode of depression at 21.2 years (IQR 17–28.5; n = 200), symptoms of mania at 21.0 years (IQR 16.8–29.5; n = 212) and a full episode of mania at 24.1 years (IQR 19–30.5; n = 205). Medical treatment was sought at 24.0 years (IQR 19–31.5; n = 217). Participants received a diagnosis of Bipolar Disorder or Schizoaffective Disorder at 30.0 years (IQR 23–37.3; n = 215). Having had a previous diagnosis other than Bipolar Disorder or Schizoaffective Disorder was reported by 120 of 216 participants who answered this question, most commonly unipolar depression (26.6%). Diagnostic delay was greater in individuals with early onset disorder. Conclusions Participants typically experience a long sequential course of symptoms, episodes, treatments and diagnosis. The polarity of onset is most commonly depressive, and subthreshold symptoms tend to precede threshold symptoms of both polarities. Limitations Data were collected retrospectively.

Relationship between Thrombophilic Disorders and Type of Severe Early-Onset Hypertensive Disorder of Pregnancy

Objective: To determine whether specific subtypes of early-onset hypertensive disorders of pregnancy (haemolysis, elevated liver enzymes, low platelets [HELLP] syndrome; severe preeclampsia; eclampsia; and fetal growth restriction) differ in increased prevalences of thrombophilic disorders. Design: Cohort study. Setting: Two university hospitals in Amsterdam, the Netherlands. Population: 216 patients participating in a randomized clinical trial with severe and early-onset hypertensive disorders of pregnancy. Methods: More than 3 months after delivery, all patients were invited for a thrombophilia screening protocol, including hereditary thrombophilic disorders (Factor II or V-Leiden mutation, APC-resistance, protein S deficiency), antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant activity), and hyperhomocysteinemia (before and after methionin challenge). Disease expression was classified by HELLP syndrome, severe preeclampsia, or neonatal birth weight ratio below the median (0.65). Univariate and multinomial regression analyses examined the association of disease expression with thrombophilic disorders, and other associated factors (chronic hypertension, smoking, body mass index, positive family history of cardiovascular morbidity, and demographic parameters). Main outcome measures: incidence of thrombophilic disorders in different subtypes of disease. Results: Overall prevalence of thrombophilic disorders in 206 (95%) screened women was 36%. Chronic hypertension was present in 32%, and 34% had a positive family history of cardiovascular morbidity. Multinomial regression analysis showed that hereditary thrombophilia was more frequent among women with infants with a birth weight ratio <0.65 than in women with HELLP syndrome or severe preeclampsia (p = 0.01, OR 5.1 (1.5 to 7.3) and OR 3.4 (1.1 to 10.6), respectively). High body mass index was less frequent in women with HELLP syndrome than in those with severe preeclampsia or fetal growth restriction (p = 0.06, OR 0.5 (0.3 to 0.9) and OR 0.4 (0.2 to 1.0), respectively). Conclusion: In this population, the high prevalence of thrombophilic factors and chronic hypertension was confirmed. There were small differences between groups. Hereditary thrombophilic disorders were associated with fetal growth restriction but not with type of maternal disease, suggesting an effect on placental function. Maternal body mass index was lower in women with HELLP syndrome.

Risperidone in adolescent schizophrenic psychoses: A retrospective study

Objective. The aim of the study was to assess the therapeutic effect and tolerability of risperidone in patients with early-onset schizophrenia and other related psychotic disorders. Methods. Our retrospective study included 47 schizophrenic patients (27 boys, 20 girls) with an average age of 16.5±1.3 years. The patients were evaluated based on their medical records prior to being started on risperidone, and then after 1, 3 and 6 weeks of risperidone administration. Efficacy of treatment was evaluated using the first item on the CGI scale. Survivors analysis was used. Results. After week 6, the average dose of risperidone was 3.8±1.4 mg. Eighty-two percent of the patients were evaluated as responders, 64% as full responders and 18% as partial responders. There were eight patients who dropped out of the study during treatment. The initial inclusion score on the CGI was 5.8±0.7. This score showed a steady decrease at each evaluation point during the treatment. At week 1 the score was 4.5±1.1 (P<0.001), at week 3, 3.4±1.2 (P<0.001), and at week 6 it was 2.6±1.2 (P<0.001). The medication was well tolerated. Less than half of the patients (46%) reported any side effects, according to their medical records. Parkinsonism (19%), sedation (8.5%) and hypersalivation (8.5%) were the most commonly reported side effects. The mean weight of the participants increased from 61.2±10.0 kg to 64.7±10.0 kg between baseline and week 6 (P=0.002). Conclusion. Our experience supports the use of risperidone in the treatment of schizophrenic disorders in adolescence.

Pharmacological treatment options for panic disorder in children and adolescents

Although panic disorder usually emerges in early to middle adulthood, adults with panic disorder often retrospectively report that their panic symptoms began in childhood or early adolescence. The majority of these juvenile cases are being misdiagnosed, and/or do not come to clinical attention. Awareness of early-onset panic disorder, as well as a more precise definition of early signs and possible clinical subtypes, can favour timely diagnosis and treatment, reduce clinical impairment and improve the prognosis of these patients. In the context of a multimodal approach, pharmacological treatment can be helpful. This review focuses on the empirical evidence of pharmacotherapy in early-onset panic disorder, including selective serotonin re-uptake inhibitors, benzodiazepines and tricyclics. The data supporting efficacy are still limited, and no controlled studies are available. Practical guidelines for the management of these patients are provided, including treatment of the most frequent psychiatric comorbidities.

Systematic re-examination of carriers of balanced reciprocal translocations: a strategy to search for candidate regions for common and complex diseases

Balanced reciprocal translocations associated with genetic disorders have facilitated the identification of a variety of genes for early-onset monogenic disorders, but only rarely the genes associated with common and complex disorders. To assess the potential of chromosomal breakpoints associated with common/ complex disorders, we investigated the full spectrum of diseases in 731 carriers of balanced reciprocal translocations without known early-onset disorders in a nation-wide questionnaire-based re-examination. In 42 families, one of the breakpoints at the cytogenetic level concurred with known linkage data and/or the translocation co-segregated with the reported phenotype, for example, we found a significant linkage (lod score=2.1) of dyslexia and a co-segregating translocation with a breakpoint in a previously confirmed locus for dyslexia. Furthermore, we identified 441 instances of at least two unrelated carriers with concordant breakpoints and traits. If applied to other populations, re-examination of translocation carriers may identify additional genotype-phenotype associations, some of which may be novel and others that may coincide with and provide additional support of data presented here.

Increased Sympathetic Activity Present in Early Hypertensive Pregnancy is Not Lowered by Plasma Volume Expansion

Objective: To evaluate whether sympathetic activity is increased in early-onset hypertensive pregnancy and whether this can be influenced by management with plasma volume expansion. Methods: The study group consisted of 74 subjects, of which 37 had early-onset hypertensive disorders of pregnancy (preeclampsia or gestational hypertension with fetal growth restriction), who were included at 24 to 34 weeks in a randomized controlled trial of management with (n = 18) or without (n = 19) plasma volume expansion. Heart rate and blood pressure variabilities, LF/HF ratio for heart rate, baroreflex sensitivity, and phase difference at low frequency (LF≈0.1 Hz) were calculated by spectral analysis from continuous heart rate and blood pressure recordings of the finger pulse wave (Portapres™, TNO). Measurements were performed at inclusion, after 20 to 40 hours and after 65 to 100 hours. The control group consisted of 29 women with a normal pregnancy and 8 women who had late-onset preeclampsia after 34 weeks. Controls were measured at 32 weeks. All controls had a normal blood pressures at that time. Results: LF variability of heart rate and blood pressure were significantly higher and baroreflex sensitivity was significantly lower in early-onset patients compared with normal controls. A significant trend towards higher LF variability of blood pressure and lower baroreflex sensitivity was found from normal controls to late-onset controls to early-onset patients. Parameters of sympathetic activity were not influenced by plasma volume expansion. Conclusion: Sympathetic activity was increased in early-onset hypertensive pregnancy. However, this was not affected by management with plasma volume expansion, suggesting that hypovolaemia in preeclampsia is a secondary phenomenon.

Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea

Benign hereditary chorea (BHC) is an autosomaldominant disorder of early onset characterized by a slowly progressing or nonprogressing chorea, without cognitive decline or other progressive neurologic dysfunction, but also by the existence of heterogeneity of the clinical presentation within and among families. The genetic cause of BHC is the presence of either point mutations or deletions in the thyroid transcription factor 1 gene (TITF1). We studied a Portuguese BHC family composed of two probands: a mother and her only son. The patients were identified in a neurology out-patient clinic showing mainly involuntary choreiform movements since childhood, myoclonic jerks, falls, and dysarthria. We performed magnetic resonance imaging (MRI), electroencephalogram (EEG), nerve conduction studies, thyroid ultrasound scan, biochemical thyroid tests, and electrocardiogram (ECG). We excluded Huntington disease by appropriate genetic testing and sequenced the entire TITF1 gene for both patients. The patients showed MRI alterations: (1) in the mother, abnormal hyperintense pallida and cortical cerebral/cerebellar atrophy; and (2) in the son, small hyperintense foci in the cerebellum and subtle enlargement of the fourth ventricle. Sequence analysis of the TITF1 gene in these patients revealed the presence of a heterozygous C > T substitution at nucleotide 745, leading to the replacement of a glutamine at position 249 for a premature stop codon. A previously undescribed nonsense mutation in the TITF1 gene was identified as being the genetic cause of BHC in this family.

Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression

Hippocampal volume reduction has been reported inconsistently in people with major depression. To evaluate the interrelationships between hippocampal volumes, memory and key clinical, vascular and genetic risk factors. Totals of 66 people with depression and 20 control participants underwent magnetic resonance imaging and clinical assessment. Measures of depression severity, psychomotor retardation, verbal and visual memory and vascular and specific genetic risk factors were collected. Reduced hippocampal volumes occurred in older people with depression, those with both early-onset and late-onset disorders and those with the melancholic subtype. Reduced hippocampal volumes were associated with deficits in visual and verbal memory performance. Although reduced hippocampal volumes are most pronounced in late-onset depression, older people with early-onset disorders also display volume changes and memory loss. No clear vascular or genetic risk factors explain these findings. Hippocampal volume changes may explain how depression emerges as a risk factor to dementia.

Amygdala and nucleus accumbens in responses to receipt and omission of gains in adults and adolescents

Adolescents' propensity for risk-taking and reward-seeking behaviors suggests a heightened sensitivity for reward, reflected by greater feedback-related activity changes in reward circuitry (e.g., nucleus accumbens), and/or a lower sensitivity to potential harm reflected by weaker feedback-related activity changes in avoidance circuitry (e.g., amygdala) relative to adults. Responses of nucleus accumbens and amygdala to valenced outcomes (reward receipt and reward omission) were assayed using an event-related functional magnetic resonance imaging procedure paired with a monetary reward task in 14 adults and 16 adolescents. Bilateral amygdala and nucleus accumbens showed significantly greater activation when winning than when failing to win in both groups. Group comparisons revealed stronger activation of left nucleus accumbens by adolescents, and of left amygdala by adults. When examining responses to reward receipts and to reward omissions separately, the most robust group difference was within the amygdala during reward omission. The reduction of the fMRI BOLD signal in the amygdala in response to reward omission was larger for adults than for adolescents. Correlations showed a close link between negative emotion and amygdala decreased BOLD signal in adults, and between positive emotion and nucleus accumbens activation in adolescents. Overall, these findings support the notion that the signal differences between positive and negative outcomes involve the nucleus accumbens more in adolescents than in adults, and the amygdala more in adults than in adolescents. These developmental differences, if replicated, may have important implications for the development of early-onset disorders of emotion and motivation.

Functional imaging of neurocognitive dysfunction in attention deficit hyperactivity disorder

Attention Deficit Hyperactivity Disorder (ADHD) is a neurobiological disorder of early childhood onset. Defining symptoms are chronic impairments of attention, impulse control and motor hyperactivity that frequently persist until adulthood. Miscellaneous causes of the disorder have been discussed. Accumulating evidence from imaging- and molecular genetic studies strengthened the theory of ADHS being a predominantly inherited disorder of neurobiological origin. In the last 15 years, non-invasive brain imaging methods were successfully implemented in pediatric research. Functional magnetic resonance imaging studies gave major insight into the neurobiological correlates of executive malfunction, inhibitory deficits and psychomotoric soft signs. These findings are in good accordance with brain morphometric data indicating a significant volumetric decrease of major components of striato-thalamo-cortical feedback loops, primarily influencing prefrontal executive functioning (e.g. basal ganglia). Empirical evidence points to a broad array of associated behavioral disturbances like deficient visuomotor abilities and oculomotor dysfunctions. This paper reviews the current empirical evidence derived from prior imaging studies. Special emphasis is given to the relevance of oculomotor dysfunctions in clinical and research settings, as well as their assessment in the MR environment.

Inherited eye disease: cause and late effect

Molecular genetics has provided relatively few insights into late-onset eye disorders, but epidemiological data indicate that genetic factors are important in some late-onset eye disorders that cause major health burdens. Much clinical genetic research is based on the belief that developmental and late-onset disorders are not necessarily the result of defects in different genes, but are often caused by different mutations in the same collection of genes. Thus, mutations that either abolish or radically change gene function might cause early-onset disorders, whereas more-subtle changes in gene expression might underlie late-onset diseases. We present arguments and examples that indicate that this principle might be a fruitful guide to investigating the causes of late-onset eye disorders.