In vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia: a [11C](R)-PK11195 positron emission tomography study.

Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO) has been used to investigate whether microglial activation, an indication of neuroinflammation, is evident in the brain of adults with schizophrenia. Interpretation of these studies is confounded by potential modulatory effects of antipsychotic medication on microglial activity. In the first such study in antipsychotic-free schizophrenia, we have used [11C](R)-PK11195 PET to compare TSPO availability in a predominantly antipsychotic-naive group of moderate-to-severely symptomatic unmedicated patients (n=8), similarly symptomatic medicated patients with schizophrenia taking risperidone or paliperidone by regular intramuscular injection (n=8), and healthy comparison subjects (n=16). We found no evidence for increased TSPO availability in antipsychotic-free patients compared with healthy controls (mean difference 4%, P=0.981). However, TSPO availability was significantly elevated in medicated patients (mean increase 88%, P=0.032) across prefrontal (dorsolateral, ventrolateral, orbital), anterior cingulate and parietal cortical regions. In the patients, TSPO availability was also strongly correlated with negative symptoms measured using the Positive and Negative Syndrome Scale across all the brain regions investigated (r=0.651-0.741). We conclude that the pathophysiology of schizophrenia is not associated with microglial activation in the 2-6 year period following diagnosis. The elevation in the medicated patients may be a direct effect of the antipsychotic, although this study cannot exclude treatment resistance and/or longer illness duration as potential explanations. It also remains to be determined whether it is present only in a subset of patients, represents a pro- or anti-inflammatory state, its association with primary negative symptoms, and whether there are significant differences between antipsychotics.

A novel trinucleotide repeat expansion at chromosome 3q26.2 identified by a CAG/CTG repeat expansion detection array.

CAG/CTG repeat expansions cause at least 12 different neurological disorders, and additional disorders of this type probably exist. Using the repeat expansion detection (RED) assay, we identified an expanded CAG/CTG repeat in a 50-year-old woman with an autosomal dominant syndrome with prominent progressive sensory neuropathy. The expansion could not be accounted for by any of the CAG/CTG repeats known to undergo expansion. To identify the locus of the expansion, we created a PCR array to assess the repeat length of all repeats of eight or more CAG or CTG triplets in the human genome. The expansion was localized to a repeat contained in an intron of a Genscan-predicted gene, 185 nt downstream of a predicted exon that is conserved through mouse. The closest experimentally verified gene in the region (TNIK, encoding a serine/threonine kinase) occurs approximately 63 Kb downstream from the repeat. The length of the expansion in the proband is 98 triplets. This repeat is not expanded in the proband's cousin (the only other affected family member for whom DNA is currently available) and no expansions were detected in a set of 230 patients with movement disorders of unknown cause. An expanded allele containing 58 triplets was detected in a single control individual, and no other expansions were detected in a set of 255 controls. The normal repeat length ranges from 5 to 30 triplets, with 8 triplets the most common allele. Our results suggest that this new repeat expansion is probably not the direct cause of the phenotype in the proband. Whether the repeat contributes to the patient's phenotype, or is associated with another phenotype, remains to be determined.

Evidence of a common founder for SCA12 in the Indian population.

Spinocerebellar ataxia type 12 (SCA12) is an autosomal dominant cerebellar ataxia associated with the expansion of an unstable CAG repeat in the 5' region of the PPP2R2B gene on chromosome 5q31-5q32. We found that it accounts for approximately 16% (20/124) of all the autosomal dominant ataxia cases diagnosed in AIIMS, a major tertiary referral centre in North India. The length of the expanded allele in this population ranges from 51-69 CAG triplets. Interestingly, all the affected families belong to an endogamous population, which originated in the state of Haryana, India. We identified four novel SNPs and a dinucleotide marker spanning approximately 137 kb downstream of CAG repeat in the PPP2R2B gene. Analysis of 20 Indian SCA12 families and ethnically matched normal unrelated individuals revealed one haplotype to be significantly associated with the affected alleles (P= 0.000), clearly indicating the presence of a common founder for SCA12 in the Indian population. This haplotype was not shared by the American pedigree with SCA12. Therefore, the SCA12 expansion appears to have originated at least twice.

A frameshift mutation in Disrupted in Schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder.

In a large Scottish pedigree, a balanced translocation t(1;11)(q42.1;q14.3) segregates with major mental illness, including schizophrenia, bipolar disorder, and recurrent major depression. The translocation is predicted to result in the loss of the C-terminal region of the protein product of Disrupted In SChizophrenia 1 (DISC1), a gene located on 1q42.1. Since this initial discovery, DISC1 has been functionally implicated in several processes, including neurodevelopment. Based on the genetic and functional evidence that DISC1 may be associated with schizophrenia, we sequenced portions of DISC1 in 28 unrelated probands with schizophrenia and six unrelated probands with schizoaffective disorder, ascertained as part of a large sibpair study. We detected a 4 bp deletion at the extreme 3' end of exon 12 in a proband with schizophrenia. The mutation was also present in a sib with schizophrenia, a sib with schizoaffective disorder, and the unaffected father, while the mutation was not detected in 424 control individuals. The mutation is predicted to cause a frameshift and encode a truncated protein with nine abnormal C-terminal amino acids. The truncated transcript is detectable, but at a reduced level, in lymphoblastoid cell lines from three of four mutation carriers. These findings are consistent with the possibility that mutations in the DISC1 gene can increase the risk for schizophrenia and related disorders.

Novel CAG/CTG repeat expansion mutations do not contribute to the genetic risk for most cases of bipolar disorder or schizophrenia.

The possible presence of anticipation in bipolar affective disorder and schizophrenia has led to the hypothesis that repeat expansion mutations could contribute to the genetic etiology of these diseases. Using the repeat expansion detection (RED) assay, we have systematically examined genomic DNA from 100 unrelated probands with schizophrenia and 68 unrelated probands with bipolar affective disorder for the presence of CAG/CTG repeat expansions. Our results show that 28% of the probands with schizophrenia and 30% of probands with bipolar disorder have a CAG/CTG repeat in the expanded range, but that each expansion could be explained by one of three nonpathogenic repeat expansions known to exist in the general population. We conclude that novel CAG/CTG repeat expansions are not a common genetic risk factor for bipolar disorder or schizophrenia.

Huntington's disease--like 2 can present as chorea-acanthocytosis.

Three patients from a previously described family with autosomal dominant chorea-acanthocytosis were found to have the CTG trinucleotide repeat expansion mutation of the junctophilin-3 gene associated with Huntington's disease-like 2 (HDL2). One of six previously identified patients with HDL2 had acanthocytosis on peripheral blood smear, suggesting that HDL2 should be considered in the differential of chorea-acanthocytosis.

Why is SCA12 different from other SCAs?

Spinocerebellar ataxia type 12 (SCA12), now described in European-American and Asian (Indian) pedigrees, is unique among the SCAs from clinical, pathological, and molecular perspectives. Clinically, the distinguishing feature is early and prominent action tremor with variability in other signs. Pathologically, brain MRIs also suggest variability, with prominent cortical as well as cerebellar atrophy. Genetically, SCA12 is caused by a CAG repeat expansion that does not encode polyglutamine; we speculate that the mutation may affect expression of the gene PPP2R2B, which encodes a brain-specific regulatory subunit of the protein phosphatase PP2A.

Trinucleotide repeats in 202 families with ataxia: a small expanded (CAG)n allele at the SCA17 locus.

BACKGROUND: Ten neurodegenerative disorders characterized by spinocerebellar ataxia (SCA) are known to be caused by trinucleotide repeat (TNR) expansions. However, in some instances the molecular diagnosis is considered indeterminate because of the overlap between normal and affected allele ranges. In addition, the mechanism that generates expanded alleles is not completely understood. OBJECTIVE: To examine the clinical and molecular characteristics of a large group of Portuguese and Brazilian families with ataxia to improve knowledge of the molecular diagnosis of SCA. PATIENTS AND METHODS: We have (1) assessed repeat sizes at all known TNR loci implicated in SCA; (2) determined frequency distributions of normal alleles and expansions; and (3) looked at genotype-phenotype correlations in 202 unrelated Portuguese and Brazilian patients with SCA. Molecular analysis of TNR expansions was performed using polymerase chain reaction amplification. RESULTS: Patients from 110 unrelated families with SCA showed TNR expansions at 1 of the loci studied. Dominantly transmitted cases had (CAG)(n) expansions at the Machado-Joseph disease gene (MJD1) (63%), at SCA2 (3%), the gene for dentatorubropallidoluysian atrophy (DRPLA) (2%), SCA6 (1%), or SCA7 (1%) loci, or (CTG)(n) expansions at the SCA8 (2%) gene, whereas (GAA)(n) expansions in the Freidreich ataxia gene (FRDA) were found in 64% of families with recessive ataxia. Isolated patients also had TNR expansions at the MJD1 (6%), SCA8 (6%), or FRDA (8%) genes; in addition, an expanded allele at the TATA-binding protein gene (TBP), with 43 CAGs, was present in a patient with ataxia and mental deterioration. Associations between frequencies of SCA2 and SCA6 and a frequency of large normal alleles were found in Portuguese and Brazilian individuals, respectively. Interestingly, no association between the frequencies of DRPLA and large normal alleles was found in the Portuguese group. CONCLUSIONS: Our results show that (1) a significant number of isolated cases of ataxia are due to TNR expansions; (2) expanded DRPLA alleles in Portuguese families may have evolved from an ancestral haplotype; and (3) small (CAG)(n) expansions at the TBP gene may cause SCA17.

CAG/CTG repeat expansions at the Huntington's disease-like 2 locus are rare in Huntington's disease patients.

The authors report a large series of patients with Huntington disease (HD)-like phenotype without CAG repeat expansions in the IT15 gene that were screened for the newly identified CAG/CTG expansion in the gene encoding junctophilin-3. Normal alleles in controls had from 8 to 28 repeats. A single patient of North African origin with typical HD carried an allele with 50 uninterrupted repeats, representing approximately 2% of the non-IT15 HD patients tested. Therefore, further genetic heterogeneity is expected in HD.

A repeat expansion in the gene encoding junctophilin-3 is associated with Huntington disease-like 2.

We recently described a disorder termed Huntington disease-like 2 (HDL2) that completely segregates with an unidentified CAG/CTG expansion in a large pedigree (W). We now report the cloning of this expansion and its localization to a variably spliced exon of JPH3 (encoding junctophilin-3), a gene involved in the formation of junctional membrane structures.

SCA12: an unusual mutation leads to an unusual spinocerebellar ataxia.

Spinocerebellar ataxia type 12 (SCA12) is an autosomal dominant neurodegenerative disorder which has been described in pedigrees of German American and Indian descent. The phenotype typically begins with tremor in the fourth decade, progressing to include ataxia and other cerebellar and cortical signs. SCA12 is associated with an expansion of a CAG repeat in the 5' region of the gene PPP2R2B which encodes a brain-specific regulatory subunit of the protein phosphatase PP2A. The repeat size ranges from 55 to 78 triplets in the mutant allele of affected individuals, and from 9 to 28 triplets in normal alleles. It is possible that an expansion mutation in PPP2R2B may influence PPP2R2B expression, perhaps altering the activity of PP2A, an enzyme implicated in multiple cellular functions, including cell cycle regulation, tau phosphorylation, and apoptosis.

A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion.

Huntington's disease (HD) is an autosomal dominant disorder characterized by abnormalities of movement, cognition, and emotion and selective atrophy of the striatum and cerebral cortex. While the etiology of HD is known to be a CAG trinucleotide repeat expansion, the pathways by which this mutation causes HD pathology remain unclear. We now report a large pedigree with an autosomal dominant disorder that is clinically similar to HD and that arises from a different CAG expansion mutation. The disorder is characterized by onset in the fourth decade, involuntary movements and abnormalities of voluntary movement, psychiatric symptoms, weight loss, dementia, and a relentless course with death about 20 years after disease onset. Brain magnetic resonance imaging scans and an autopsy revealed marked striatal atrophy and moderate cortical atrophy, with striatal neurodegeneration in a dorsal to ventral gradient and occasional intranuclear inclusions. All tested affected individuals, and no tested unaffecteds, have a CAG trinucleotide repeat expansion of 50 to 60 triplets, as determined by the repeat expansion detection assay. Tests for the HD expansion, for all other known CAG expansion mutations, and for linkage to chromosomes 20p and 4p were negative, indicating that this mutation is novel. Cloning the causative CAG expansion mutation for this new disease, which we have termed Huntington's disease-like 2, may yield valuable insight into the pathogenesis of HD and related disorders.

Prevalence, clinical manifestations, etiology, and treatment of depression in Parkinson's disease.

To determine the extent to which depression complicates Parkinson's disease (PD), the authors analyzed the literature on depression in PD in order to report on its prevalence, clinical manifestations, and treatment. By means of MEDLINE literature searches, the analysis focused on 45 PD depression studies conducted from 1922 through 1998. The results indicate that the prevalence of depression is 31% for all PD patients. The clinical manifestations of PD depression include apathy, psychomotor retardation, memory impairment, pessimism, irrationality, and suicidal ideation without suicidal behavior. PD depression is effectively treated with a variety of antidepressants, most commonly at present the selective serotonin reuptake inhibitors. Anecdotal evidence supports the use of sertraline to treat PD depression.

SCA12 is a rare locus for autosomal dominant cerebellar ataxia: a study of an Indian family.

Spinocerebellar ataxia 12 (SCA12) is an autosomal dominant cerebellar ataxia (ADCA) described in a single family with a CAG repeat expansion in the PPP2R2B gene. We screened 247 index cases, including 145 families with ADCA, for this expansion. An expanded repeat ranging from 55 to 61 triplets was detected in 6 affected and 3 unaffected individuals at risk in a single family from India. The association of the PPP2R2B CAG repeat expansion with disease in this new family provides additional evidence that the mutation is causative.

Risk factors in childhood that lead to the development of conduct disorder and antisocial personality disorder.

With juvenile crime on the rise, understanding and preventing juvenile delinquency is one of the greatest challenges facing mental health professionals today. Recognizing early signs of conduct disorder (CD) can be difficult, but identifying risk factors is an important step in preventing a child's progression to CD or Antisocial Personality Disorder (APD). This paper focuses on various risk factors for CD and APD, such as intrinsic individual differences, psychosocial/environmental factors, genetic and neurochemical factors. Early recognition and intervention may prevent the progression from aggressive and maladaptive behaviors to CD and later APD.

SCA-12: Tremor with cerebellar and cortical atrophy is associated with a CAG repeat expansion.

OBJECTIVE: To characterize the clinical and neuroradiologic features of a new spinocerebellar ataxia, SCA-12, in the index family. BACKGROUND: The authors recently linked SCA-12 to a novel CAG repeat expansion on chromosome 5q31-33 that is located within the 5' region of PPP2R2B, a gene encoding a brain-specific regulatory subunit of protein phosphatase 2A. METHODS: Neurologic features of the proband and nine symptomatic relatives in the first SCA-12 family were compiled and, in some individuals, related to changes found on brain MRI or CT. RESULTS: SCA-12 typically presented in the 4th decade of life with action tremor of the head or arms (present in 10/10 of the affected individuals). Hyperreflexia (8/10) was a common feature, and cerebellar signs (8/10), including ataxia, dysmetria, and dysarthria, developed gradually but were less prominent and disabling than cerebellar dysfunction in other SCA. Subtle parkinsonian features (9/10) and dementia (2/10) were observed in later stages of SCA-12, and psychiatric symptoms, including depression, anxiety, or delusions, were present in some affected family members (4/10). Two individuals studied had nondisabling neurologic signs neonatally, including nystagmus and lower extremity dystonia. Brain images of affected individuals revealed cerebral and cerebellar atrophy. CONCLUSIONS: SCA-12 is a slowly progressive, autosomal dominant, neurodegenerative disorder that differs from other SCA in that it typically presents with action tremor in patients in their mid 30s and usually includes hyperreflexia and subtle parkinsonian signs. Cerebellar dysfunction, including gait ataxia, is relatively nondisabling, and cognitive or psychiatric disorders may occur. Neuroradiologic studies reveal atrophy of the cerebellum and cerebral cortex.

A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion.

Huntington's disease (HD) is an autosomal dominant disorder characterized by abnormalities of movement, cognition, and emotion and selective atrophy of the striatum and cerebral cortex. While the etiology of HD is known to be a CAG trinucleotide repeat expansion, the pathways by which this mutation causes HD pathology remain unclear. We now report a large pedigree with an autosomal dominant disorder that is clinically similar to HD and that arises from a different CAG expansion mutation. The disorder is characterized by onset in the fourth decade, involuntary movements and abnormalities of voluntary movement, psychiatric symptoms, weight loss, dementia, and a relentless course with death about 20 years after disease onset. Brain magnetic resonance imaging scans and an autopsy revealed marked striatal atrophy and moderate cortical atrophy, with striatal neurodegeneration in a dorsal to ventral gradient and occasional intranuclear inclusions. All tested affected individuals, and no tested unaffecteds, have a CAG trinucleotide repeat expansion of 50 to 60 triplets, as determined by the repeat expansion detection assay. Tests for the HD expansion, for all other known CAG expansion mutations, and for linkage to chromosomes 20p and 4p were negative, indicating that this mutation is novel. Cloning the causative CAG expansion mutation for this new disease, which we have termed Huntington's disease-like 2, may yield valuable insight into the pathogenesis of HD and related disorders.

Assessing parental utilization of the poison center: an emergency center-based survey.

The purpose of this study was to identify and characterize caretakers who fail to utilize the poison center for unintentional poisonings involving children. We interviewed 210 caretakers of children evaluated for unintentional poisoning in the emergency center of an urban, university-based teaching hospital to determine (1) whether demographic differences exist between those caretakers who contacted a poison center prior to the emergency center visit and those who did not and (2) whether differences exist in prevalence of poison prevention knowledge and behaviors between the two groups. Ninety-six (46%) of caretakers did not contact the poison center prior to the emergency center visit. Significant differences were found between the two groups for the following caretaker variables: race/ethnicity, language preference, age, level of education, country in which schooling occurred, and type of insurance coverage for the child. When logistic regression was used to control for confounding, the two variables associated with failure to use the poison center were black race and schooled outside the United States (primarily in Mexico). Poison center callers reported a higher prevalence of poison prevention knowledge and behaviors than noncallers. Educational interventions should be targeted to the groups of caretakers identified who do not use the poison center.

Disruption of the clathrin heavy chain-like gene (CLTCL) associated with features of DGS/VCFS: a balanced (21;22)(p12;q11) translocation.

The smallest region of deletion overlap in the patients we have studied defines a DIGeorge syndrome/velocardiofacial syndrome (DGS/VCFS) minimal critical region (MDGCR) of approximately 250 kb within 22q11. A de novo constitutional balanced translocation has been identified within the MDGCR. The patient has some features which have been reported in individuals with DGS/VCFS, including: facial dysmorphia, mental retardation, long slender digits and genital anomalies. We have cloned the breakpoint of his translocation and shown that it interrupts the clathrin heavy chain-like gene (CLTCL) within the MDGCR. The breakpoint of the translocation partner is in a repeated region telomeric to the rDNA cluster on chromosome 21p. Therefore, it is unlikely that the patient's findings are caused by interruption of sequences on 21p. The chromosome 22 breakpoint disrupts the 3' coding region of the CLTCL gene and leads to a truncated transcript, strongly suggesting a role for this gene in the features found in this patient. Further, the patient's partial DGS/VCFS phenotype suggests that additional features of DGS/VCFS may be attributed to other genes in the MDGCR. Thus, haploinsufficiency for more than one gene in the MDGCR may be etiologic for DGS/VCFS.