Mutations in ASH1L confer susceptibility to Tourette syndrome.

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by repetitive motor movements and vocal tics. The clinical manifestations of TS are complex and often overlap with other neuropsychiatric disorders. TS is highly heritable; however, the underlying genetic basis and molecular and neuronal mechanisms of TS remain largely unknown. We performed whole-exome sequencing of a hundred trios (probands and their parents) with detailed records of their clinical presentations and identified a risk gene, ASH1L, that was both de novo mutated and associated with TS based on a transmission disequilibrium test. As a replication, we performed follow-up targeted sequencing of ASH1L in additional 524 unrelated TS samples and replicated the association (P value = 0.001). The point mutations in ASH1L cause defects in its enzymatic activity. Therefore, we established a transgenic mouse line and performed an array of anatomical, behavioral, and functional assays to investigate ASH1L function. The Ash1l+/- mice manifested tic-like behaviors and compulsive behaviors that could be rescued by the tic-relieving drug haloperidol. We also found that Ash1l disruption leads to hyper-activation and elevated dopamine-releasing events in the dorsal striatum, all of which could explain the neural mechanisms for the behavioral abnormalities in mice. Taken together, our results provide compelling evidence that ASH1L is a TS risk gene.

Lack of association between SLC5A7 polymorphisms and Tourette syndrome in a Chinese Han population.

Although Tourette syndrome (TS) is a chronic neuropsychiatric disorder whose pathogenesis remains unclear, genetic factors play an important role in the occurrence and development. A variety of studies have been shown that the candidate genes related to cholinergic neurons may be associated with the onset of TS. To investigate the association between the SLC5A7 polymorphisms and Tourette syndrome (TS) in the Chinese Han population, the SNP rs1013940, rs2433718, and rs4676169 were genotyped in 401 TS trios and 400 controls. The transmission disequilibrium test (TDT) and haplotype relative risk (HRR) compared genetic distributions of trios, while the chi-square test compared patients and controls. However, no transmission disequilibrium was found between the three SLC5A7 SNPs and TS. Therefore, we think that this gene may not be the main risk factor on the onset of TS. However, these results should be further validated in different populations.

The role of GRIN2B in Tourette syndrome: Results from a transmission disequilibrium study.

BACKGROUND: Previous studies have indicated that dopamine interacts with glutamatergic projection neurons and that N-methyl-d-aspartate (NMDA) receptors might be involved in the pathogenesis of Tourette syndrome (TS). In this study, we examined whether two functional polymorphisms (rs1805476 and rs1805502) in the 3'UTR of the NMDA receptor 2B subunit gene (GRIN2B) were associated with TS in Chinese Han trios. METHODS: DNA samples collected from 261 TS nuclear families were genotyped by PCR and direct sequencing technology. Haplotype relative risk (HRR), transmission disequilibrium test (TDT) and Haplotype-based haplotype relative risk (HHRR) analyses were performed on the genotype data. RESULTS: We found an over-transmission of the A allele in rs1805476 and the T allele in rs1805502 from parents to their affected children, using the HRR (rs1805476: HRR=0.696, χ(2)=4.161, P=0.041, 95% CI: 0.491-0.986; rs1805502: HRR=0.697, χ(2)=3.954, P=0.047, 95% CI: 0.488-0.995). There was also strong evidence for a linkage between polymorphisms and TS using the TDT (rs1805476: TDT=5.447, df=1, P=0.024; rs1805502: TDT=5.233, df=1, P=0.027). LIMITATIONS: The sample is small and the current population is just limited to the Chinese Han population. CONCLUSIONS: These data support the hypothesis that GRIN2B might play a major role in the pathogenesis of TS in Chinese Han trios. However, these results need to be replicated using larger datasets collected from different populations.

[Association of serotonin transporter linked polymorphic region 44 bp variable number of tandem repeat polymorphism with Tourette syndrome].

OBJECTIVE: To assess the association between the serotonin transporter linked polymorphic region (5-HTTLPR) 44 bp variable number of tandem repeat (VNTR) polymorphism and Tourette syndrome (TS) in ethnic Han Chinese trios. METHODS: A total of 252 TS trios (patients and their parents) were recruited. Genetic contribution of the 5-HTTLPR 44 bp VNTR polymorphism was evaluated by genotyping, haplotype relative risk (HRR) analysis and transmission disequilibrium test (TDT) statistics. To enhance the efficiency of the test, haplotype-based HRR (HHRR) was also performed. RESULTS: The TDT, HRR and HHRR analyses have revealed a significant association of the 5-HTTLPR 44 bp VNTR polymorphism with TS, and provided a strong evidence for an over-transmission of L allele from parents to the affected children (TDT: χ² = 6.680, df= 1, P= 0.012; HRR: χ² = 9.345, P= 0.002, OR= 1.739, 95% CI for 1.218-2.483). For 204 male and 48 female TS trios, TDT and HRR were analyzed separately. The results showed a significant association between 5-HTTLPR and male TS (for males. TDT: χ² = 4.643, df= 1, P= 0.038; for females, TDT: χ² = 2.189, df= 1, P= 0.188). CONCLUSION: 5-HTTLPR may be the susceptibility gene for male TS patients among the Chinese Han population. However, the results need to be replicated in datasets collected from different populations.

Composition of long chain polyunsaturated fatty acids (LC-PUFAs) in different encephalic regions and its association with behavior in spontaneous hypertensive rat (SHR).

Long chain polyunsaturated fatty acids (LC-PUFAs) are hypothesized to play an important role in attention deficit/hyperactivity disorder (ADHD). This study evaluated LC-PUFAs composition in different encephalic regions by gas chromatography and its association with behavior on the attentional set-shifting task, open field test and the Morris water maze of spontaneous hypertensive rat (SHR)-a genetic animal model of ADHD. In behavioral tests, the SHRs exhibited deficiencies in attentional set-shifting, autonomic activities and spatial learning and memory. In all the studied encephalic regions, we observed higher concentration of docosahexaenoic acid (DHA) and arachidonic acid (AA) and higher AA/DHA ratio in the SHRs compared with the Wistar-Kyoto (WKY) and Sprague-Dawley (SD) rats (p<0.01), which was associated with abnormal behavior in the SHRs. This study provided an appropriate animal model for study on the relationship between LC-PUFAs and ADHD. Our results prove abnormal neurobehaviour associated with imbalance of AA/DHA ratio and highlights the significance of normal AA/DHA ratio in behavior.

Atomoxetine increases histamine release and improves learning deficits in an animal model of attention-deficit hyperactivity disorder: the spontaneously hypertensive rat.

Substantial development in the pharmacological treatment for attention-deficit hyperactivity disorder (ADHD) has been made recently including approval of new non-stimulant agents targeting noradrenergic, histaminergic and dopaminergic systems. Among such, atomoxetine has been widely used, although its mechanism of action is poorly understood. It is known that central nervous system histamine is closely associated with cognition and it was recently shown that both atomoxetine and methylphenidate enhance cortical histamine release in rats. To that end, the aim of our study was to investigate the effect of atomoxetine (2 mg/kg, intraperitoneally) on histamine release using the microdialysis technique in the spontaneously hypertensive rat (SHR), a suitable genetic model for ADHD. Our data confirmed that atomoxetine increases extracellular levels of histamine in the prefrontal cortex, a brain region that is implicated in the pathophysiology of ADHD. Given the tie between histamine neurotransmission and treatment of cognitive dysfunction, we also assessed the effects of atomoxetine on learning and memory as measured by the Morris water maze in SHR. The results indicated that atomoxetine significantly ameliorated performance in the Morris water maze, consistent with its histamine-enhancing profile. In conclusion, the current study provides further support for the notion that the therapeutic effect of atomoxetine could involve activation of histamine neurotransmission within the prefrontal cortex.

[Successful treatment of agammaglobulinemia by HLA-mismatched unrelated cord blood stem cell transplantation--the first case report].

OBJECTIVE: To evaluate cord blood stem cell transplantation (CBT) in the treatment of X-linked agammaglobulinemia, and observe the courses of the hematopoietic and immune reconstitution. METHODS: A 14-year-old male patient with agammaglobulinemia received CBT from a 1/6 HLA-mismatched unrelated cord blood. The conditioning regimen was Bu/Cy/anti-CD3 antibody. CsA was given together with MMF and MTX for prophylaxis of GVHD. The patient received 0.42 x 10(8) nucleated cells/kg, containing 0.35 x 10(6) CD34(+) cells/kg. RESULTS: The recipient showed hematopoietic reconstitution on day 30 post-transplantation when ANC was 0.5 x 10(9)/L and BPC 20 x 10(9)/L. Sex chromosome analysis showed engraftment (donor 46, XX/recipient 46, XY = 4:1) on day 45. The recipient's blood group changed from AB to O, IgG from 1.1 g/L to 3.5 g/L, sex chromosome from 46, XY to full 46, XX, and mature B cells in peripheral blood from 0 to 5% on day 100, indicating immune reconstitution. At the last follow-up of 360 days, the patient without acute or chronic GVHD showed normal hemogram and myelogram, IgG 13.5 g/L and 10% mature B cells in peripheral blood, indicating the hematopoiesis and immune persistent reconstitution. No acute or chronic GVHD was developed. CONCLUSION: This is the first case report of successful treatment of X-linked agammaglobulinemia by HLA-mismatched unrelated CBT.

[Clinical features of hematological abnormality in systemic lupus erythematosus-related hematological disorders].

In order to investigate the clinical characteristics of hematological abnormality in patients with systemic lupus erythematosus (SLE) and inquire into the basis for differential diagnosis, the hematological data of 92 cases with lupus erythematosus-related hematological disorder (SLERHD) were retrospectively analyzed by use of SPSS/PC software. The results showed that these patients were short of specificity in clinical manifestation and hemogram, however, all cases possessed multiple SLE-related autoantibodies, increase of serum globulin level and varying extent dermal and arthral signs. The incidence of primary or initial symptom in the 92 cases was as follow: 65 anemia (72.8%), 39 purpura (42.4%), 17 hemolytic anemia (18.5%), 56 leukopenia (60.9%), 54 thrombocytopenia (58.7%), and 41 pancytopenia (44.6%). The bone marrow examinations showed that the cellularity of nucleated cells was mostly normal, and active proliferation in 57 cases (61.9%) and hypercellularity in 35 cases (38.1%); the G/E ratio was normal in majority, and G/E ratio > 3 in 59 cases (64.1%) and < 3 in 33 cases (35.9%) and G/E < 1 in 17 cases with hemolytic anemia Coombs' test positive; megakaryocyte counts were normal in 11 cases (11.9%), increase in 80 cases (86.9%) and lower than 7/marrow smear in 1 case (1.1%). Neutrophil alkaline phosphatase staining was negative in all of the cases. From above data it is concluded that patients with SLERHD are varied in clinical and blood pictures, but all patients are provided with multiple SLE-related autoantibodies, globulinemia and dermal and arthral signs. It is easy to identify SLERHD from aplastic anemia, myelodysplastic syndrome, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia and Evans' syndrome by comprehensive and detailed clinical and laboratory examinations.

[Analysis of Clinical and Hematologic Features in 22 Patients with Metastatic Carcinoma of Bone Marrow]

The clinical and hematologic features in 22 patients with metastatic carcinoma of bone marrow were observed and analyzed. Morphology of bone marrow cells, bone marrow biopsy and other accessory examinations were performed. The primary or cardinal symptoms of metastatic carcinoma of bone marrow included anemia (17 cases, 77.3%), ostealgia (10 cases, 45.5%), fever (8 cases, 36.4%), hemorrhage (4 cases, 18.2%) and complicated hemolytic anemia (4 cases, 18.2%). The primary carcinomas, diagnosed by pathologic and accessory examinations, include gastric carcinoma (6 cases, 27%), lung cancer (3 cases, 13.6%), ovarian cancer (2 cases, 9%), mammary cancer, prostatic carcinoma, osteocarcinoma and metastatic malignant melanoma (1 case, respectively), and unknown primary lesion (7 cases, 31.8%). The hematologic features were decrease of hemoglobin (17 cases, 77.3%) and blood plate count (16 cases, 72.7%), leukocytosis (11 cases, 50%), immature leukocytes (14 cases, 63.6%) and erythrocytes (9 cases, 40.9%) seen on the peripheral blood smear, and reticulocytosis (4 cases, 18.2%). Masses of metastatic carcinoma cells can be frequently seen at two sides and tail of bone marrow smear. Bone marrow biopsy of 8 cases demonstrated the infiltration of carcinoma cells with nest-like distribution in the bone marrow cavity. Examination of MRI in 6 case showed destruction of bone and corpus vertebra and abnormal signal focus. Bone marrow biopsy could contribute to improve the accuracy of diagnosis and determine the origin of primary carcinoma. MRI plays an important role in diagnosis of metastatic carcinoma in bone marrow.