A randomised clinical pilot trial to test the effectiveness of parent training with video modelling to improve functioning and symptoms in children with autism spectrum disorders and intellectual disability.

BACKGROUND: Poor eye contact and joint attention are early signs of autism spectrum disorder (ASD) and important prerequisites for developing other socio-communicative skills. Teaching parents evidence-based techniques to improve these skills can impact the overall functioning of children with ASD. We aimed to analyse the impact of conducting a group parent-training intervention with video modelling to improve the intelligent quotient (IQ), social and communication functioning and to minimise symptoms in children with ASD and intellectual disability (ID). METHODS: Study design: A multicentre, single-blinded, randomised clinical pilot trial of parent training using video modelling was conducted. SAMPLE: Sixty-seven parents of children with ASD, aged between 3 and 6 years and with IQs between 50 and 70, were randomised: 34 to the intervention group and 33 to the control group. Intervention program: The intervention group received parent training over 22 sessions, and the control group received the standard community treatment. INSTRUMENTS: Pre-evaluation and post-evaluation (week 28), the following were used: Autism Diagnostic Interview, Vineland Adaptive Behaviour Scale I, Snijders-Oomen Nonverbal Intelligence Test, Autism Behaviour Checklist and Hamilton Depression Rating Scale. DATA ANALYSIS: Intention to treat and complier-average causal effect (CACE) were used to estimate the effects of the intervention. RESULTS: There was a statistically significant improvement in the Vineland standardized communication scores in CACE (Cohen's d = 0.260). There was a non-statistically significant decrease in autism symptomatology (Autism Behaviour Checklist total scores) and a significant increase in the non-verbal IQ in the intervention group. After the false discovery rate correction was applied, IQ remained statistically significant under both paradigms. The effect size for this adjusted outcome under the intention-to-treat paradigm was close to 0.4, and when considering adherence (CACE), the effect sizes were more robust (IQ's Cohen's d = 0.433). CONCLUSIONS: Parent training delivered by video modelling can be a useful technique for improving the care given to children with ASD and ID, particularly in countries that lack specialists.

Impact of 5-HTTLPR and BDNF polymorphisms on response to sertraline versus transcranial direct current stimulation: implications for the serotonergic system.

Transcranial direct current stimulation (tDCS) has been intensively investigated as a non-pharmacological treatment for major depressive disorder (MDD). While many studies have examined the genetic predictors of antidepressant medications, this issue remains to be investigated for tDCS. In the current study, we evaluated whether the BDNF Val66Met and the 5-HTT (5-HTTLPR) polymorphisms were associated with tDCS antidepressant response. We used data from a factorial trial that evaluated the efficacy of tDCS and sertraline and enrolled 120 moderate-to-severe, antidepressant-free participants. In the present study, we used analyses of variance to evaluate whether the BDNF (Val/Val vs. Met-carries) and 5-HTTLPR alleles (long/long vs short-carriers) were predictors of tDCS (active/sham) and sertraline (sertraline/placebo) response. Analyses were conducted on the polymorphisms separately and also on their interaction. Genotype frequencies were in Hardy-Weinberg equilibrium. BDNF polymorphism was not associated with treatment response. We found that 5-HTTLPR predicted tDCS effects as long/long homozygotes displayed a larger improvement comparing active vs. sham tDCS, while short-allele carriers did not. A dose-response relationship between active-sham differences with the long allele was also suggested. These results strengthen the role of the serotonergic system in the tDCS antidepressant effects and expand previous findings that reported that tDCS mechanisms of action partially involve serotonergic receptors. Therefore, we hypothesize that tDCS is a neuromodulation technique that acts over depression through the modulation of serotonergic system and that tDCS "top-down" antidepressant effects might not be optimal in brain networks with a hyperactive amygdala inducing bottom-up effects, such as occurs in short-carriers.

Subtelomeric rearrangements and copy number variations in people with intellectual disabilities.

BACKGROUND: The most prevalent type of structural variation in the human genome is represented by copy number variations that can affect transcription levels, sequence, structure and function of genes. METHOD: In the present study, we used the multiplex ligation-dependent probe amplification (MLPA) technique and quantitative PCR for the detection of copy number variation in 132 intellectually disabled male patients with normal karyotypes and negative fragile-X-testing. RESULTS: Ten of these patients (7.6%) showed copy number variation in the subtelomeric regions, including deletions and duplications. DISCUSSION: Duplications of the SECTM1 gene, located at 17q25.3, and of the FLJ22115 gene, located at 20p13, could be associated with phenotype alterations. This study highlights the relevance in the aetiology of intellectual disability of subtelomeric rearrangements that can be screened by MLPA and other molecular techniques.

Ring chromosome instability evaluation in six patients with autosomal rings.

Ring chromosomes are often associated with abnormal phenotypes due to loss of genomic material and also because of ring instability at mitosis after sister chromatid exchange events. We investigated ring chromosome instability in six patients with ring chromosomes 4, 14, 15, and 18 by examining 48- and 72-h lymphocyte cultures at the first, second and subsequent cell divisions after bromodeoxyuridine incorporation. Although most cells from all patients showed only one monocentric ring chromosome, ring chromosome loss and secondary aberrations were observed both in 48- and 72-h lymphocyte cultures and in metaphase cells of the different cell generations. We found no clear-cut correlation between ring size and ring instability; we also did not find differences between apparently complete rings and rings with genetic material loss. The cytogenetic findings revealed secondary aberrations in all ring chromosome patients. We concluded that cells with ring chromosome instability can multiply and survive in vivo, and that they can influence the patient's phenotype.

Pseudoaminopterin syndrome: clinical report with new characteristics.

Fetuses exposed to aminopterin during the 8th-9th week of development may show aminopterin embryophathy (AE). Surviving children have a specific phenotype that includes unusual face, skull, and skeletal abnormalities. Fraser et al. [Fraser et al. (1987); Clin Genet 32:28-34] described two children with multiple malformations characteristic of the aminopterin syndrome but without history of exposure to aminopterin in the mothers and suggested that this represents a new syndrome, the aminopterin syndrome-like sine aminopterin (ASSA) syndrome. Here we describe a 9-year-old girl, born to unaffected first cousin parents. She has short stature, microcephaly, broad forehead with high hair implantation; sparse and fine hair, areas of alopecia; arched eyebrows with upturned hair, synophris; ocular hypertelorism, epicanthal folds, palpebral ptosis; oligodontia; low-set and small ears with hypoplasia of antihelices; brachydactyly, clinodactyly of both 4th and 5th fingers; hypoplasia of the 4th metacarpal and clinodactyly of the 4th and 5th toes; overlap of the second over the third toe; bilateral hip luxation; patent foramen ovale; left posterior diaphragmatic hernia, absence of spleen and horseshoe kidney. She, her mother and her brother have a karyotype of 46,XX, with an inv(9)(p12q13) polymorphism. Although this patient has some characteristics did not described before in patients with ASSA such as, palpebral ptosis, oligodontia, left posterior diaphragmatic hernia, absence of spleen, and horseshoe kidney, her phenotype strongly suggest she has the pseudoaminopterin syndrome. However, we do not exclude the possibility that this is a different condition not described previously.

Screening for fragile X syndrome among Brazilian mentally retarded male patients using PCR from buccal cell DNA.

Fragile X syndrome is one of the most frequent causes of mental retardation. Since the phenotype in this syndrome is quite variable, clinical diagnosis is not easy and molecular laboratory diagnosis is necessary. Usually DNA from blood cells is used in molecular tests to detect the fragile X mutation which is characterized by an unstable expansion of a CGG repeat in the fragile X mental retardation gene (FMR1). In the present study, blood and buccal cells of 53 mentally retarded patients were molecularly analyzed for FMR1 mutation by PCR. Our data revealed that DNA extraction from buccal cells is a useful noninvasive alternative in the screening of the FMR1 mutation among mentally retarded males.

Avaliação genético-clínica do recém-nascido

Apresenta uma avaliação dos recém-nascidos que têm indicação para avaliação genética. Informações para estabelecer prognóstico clínico e reprodutivo da família e definir os recém-nascidos com sinais e sintomas que sugerem doenças metabólicas hereditárias. Documento em formato PDF, requer Acrobat Reader.

Screening for fragile X syndrome among Brazilian mentally retarded male patients using PCR from buccal cell DNA

Fragile X syndrome is one of the most frequent causes of mental retardation. Since the phenotype in this syndrome is quite variable, clinical diagnosis is not easy and molecular laboratory diagnosis is necessary. Usually DNA from blood cells is used in molecular tests to detect the fragile X mutation which is characterized by an unstable expansion of a CGG repeat in the fragile X mental retardation gene (FMR1). In the present study, blood and buccal cells of 53 mentally retarded patients were molecularly analyzed for FMR1 mutation by PCR. Our data revealed that DNA extraction from buccal cells is a useful noninvasive alternative in the screening of the FMR1 mutation among mentally retarded males.

Duplication 4p and deletion 4p (Wolf-Hirschhorn syndrome) due to complementary gametes from a 3:1 segregation of a maternal balanced t(4;13)(p16;q11) translocation.

We present clinical and cytogenetic data on a family with a t(4;13)(p16;q11) translocation present in four generations. The balanced translocation resulted in one individual with monosomy 4p and one individual with trisomy 4p, due to 3:1 segregation. The male patient with trisomy 4p was fertile and transmitted the extra chromosome to his daughter.

Absence of 12q21.2q22 deletions and subtelomeric rearrangements in cardiofaciocutaneous (CFC) syndrome patients.

Recent publications described two patients with a CFC-like phenotype and the same deletion of chromosome region 12q21.2q22 [Rauen et al., 2000, 2002]. The patients did not have the classical CFC phenotype and presented other signs not usually seen in CFC patients: the first patient had hydrocephalus, and the second, a history of olygohydramnios, normal stature, pyloric stenosis, cutaneous syndactyly of toes and bilateral transverse palmar creases. In order to verify if classic CFC patients with normal chromosomes in conventional preparations have microdeletions within the 12q21.2q22 chromosome region, we performed FISH analysis using 12 BAC probes to screen this area. The average interval between the probes was of approximately 1 Mb. No deletions were found in any of the 17 classical CFC patients we examined. We conclude that the region 12q21.2q22 is not a candidate region for CFC syndrome and that the patients described by Rauen et al. [2000, 2002] probably have a different condition, i.e., an aneuploidy syndrome, with some phenotypic resemblance to the CFC syndrome. To further evaluate the possibility of other chromosome imbalances, we performed a subtelomeric analysis, by FISH technique, of all chromosomes, and did not find any subtelomeric rearrangements.

PTPN11 mutations are not responsible for the Cardiofaciocutaneous (CFC) syndrome.

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomalies/mental retardation syndrome characterized by congenital heart defects, characteristic facial appearance, short stature, ectodermal abnormalities and mental retardation. It was described in 1986, and to date is of unknown genetic etiology. All reported cases are sporadic, born to non-consanguineous parents and have apparently normal chromosomes. Noonan and Costello syndromes remain its main differential diagnosis. The recent finding of PTPN11 missense mutations in 45-50% of the Noonan patients studied with penetrance of almost 100% and the fact that in animals mutations of this gene cause defects of semilunar valvulogenesis, made PTPN11 mutation screening in CFC patients a matter of interest. We sequenced the entire coding region of the PTPN11 gene in ten well-characterised CFC patients and found no base changes. We also studied PTPN11 cDNA in our patients and demonstrated that there are no interstitial deletions either. The genetic cause of CFC syndrome remains unknown, and PTPN11 can be reasonably excluded as a candidate gene for the CFC syndrome, which we regard as molecular evidence that CFC and Noonan syndromes are distinct genetic entities.

CFC index for the diagnosis of cardiofaciocutaneous syndrome.

Controversy exists concerning the delineation of cardiofaciocutaneous syndrome (CFC). Many authors have attempted to establish syndrome traits for CFC, but to date none are pathognomonic or obligatory. We have created a clinical and objective method, called the CFC index, for CFC diagnosis. This method also differentiates CFC from Noonan syndrome and Costello syndrome, CFC's main differential diagnosis. We propose the use of the CFC index for the confirmation of CFC diagnosis and to differentiate CFC from other phenotypically similar genetic conditions, while molecular studies are still in progress.

Identification of a novel cathepsin C mutation (p.W185X) in a Brazilian kindred with Papillon-Lefèvre syndrome.

Papillon-Lefèvre syndrome (PLS) is an autosomal recessive palmoplantar keratoderma caused by cathepsin C (CTSC) gene mutations. This study reports CTSC mutational and enzyme analyses in a consanguineous Brazilian family with PLS, representing the first enzymatic analysis of a Brazilian kinship with PLS. This family segregates a novel PLS-related mutation, p.W185X, that is associated with a complete loss of enzymatic activity.

Ocular and clinical manifestations of Möbius' syndrome.

PURPOSE: To assess ocular and otorhinolaryngologic manifestations and intellectual ability in patients with Möbius' syndrome. METHODS: Patients with Möbius' syndrome underwent prospective ophthalmic, genetic-clinical, and otorhinolaryngologic examinations as well as psychological evaluation. RESULTS: Sixteen patients with Möbius' syndrome between the ages of 8 months and 10.6 years underwent ocular examination. Esotropia was present in 12 (75%) patients and V-pattern in 8 (50%). Limited abduction was present in 30 (93.8%) eyes, and limited adduction was present in 21 (65.6%) eyes. The most frequent refractive error was compound hyperopic astigmatism (13 [40.6%] eyes). Eleven (68.8%) patients had lagophthalmos and 12 (75%) patients had bilateral epicanthus. Unilateral amblyopia was present in 2 (12.5%) patients. Clubfoot was the most common lower limb defect (7 [43.8%] patients). Cranial nerve impairments included paralysis of 7th nerve in all patients, paralysis of the 12th nerve in 13 patients, and paralysis of the 9th and 10th nerves in 3 patients. Evaluation of intellectual ability showed that 4 (25%) patients had normal intelligence. The mothers of 3 (18.8%) patients used misoprostol during the first trimester of pregnancy. CONCLUSION: Prominent ophthalmic features of Möbius' syndrome in this series were esotropia, V-pattern, abduction limitation, and compound hyperopic astigmatism. Intellectual assessment showed some degree of mental retardation in 75% of patients. Möbius' syndrome is associated with prenatal exposure to misoprostol.

Novel COL1A1 mutation (G559C) [correction of G599C] associated with mild osteogenesis imperfecta and dentinogenesis imperfecta.

A genotype-phenotype analysis of a three-generation family segregating for an autosomal-dominant osteogenesis imperfecta (OI) variant is reported here. The family was ascertained through the presentation of a proband concerned about discoloration of her teeth, found to be dentinogenesis imperfecta (DGI). Examination of 36 family members identified 15 individuals with DGI. Linkage studies were performed for genetic markers from candidate intervals known to contain genes responsible for DGI on chromosomes 4q, 7q, and 17q. Conclusive evidence for linkage of DGI was obtained to genetic markers on chromosome 17q21-q22 (DLX-3, Z(max) = 5.34, theta = 0.00). All DGI-affected family members shared a common haplotype, which was not present in individuals without DGI. Haplotype analysis sublocalized the gene to a 5-cM genetic interval that contained the collagen 1 alpha 1 (COL1A1) gene. More than 150 different COL1A1 gene mutations have been associated with various forms of OI, and five of these have been associated with DGI and type IV OI. After excluding these five mutations, mutational analysis was performed on the remaining exons including intron--exon boundaries, which resulted in identification of a Gly559Cys mutation in exon 32, present in all DGI-affected family members. Clinical features segregating with this G559C mutation included hyperextensible joints, joint pain and an increased propensity for bone fractures with moderate trauma. This is the first report of joint pain associated with a COL1A1 mutation and DGI. The mild skeletal features and reduced penetrance of the non-dental findings illustrate the importance of genetic evaluations for families with a history of DGI.

High mutation detection rate in TCOF1 among Treacher Collins syndrome patients reveals clustering of mutations and 16 novel pathogenic changes.

Twenty-eight families with a clinical diagnosis of Treacher Collins syndrome were screened for mutations in the 25 coding exons of TCOF1 and their adjacent splice junctions through SSCP and direct sequencing. Pathogenic mutations were detected in 26 patients, yielding the highest detection rate reported so far for this disease (93%) and bringing the number of known disease-causing mutations from 35 to 51. This is the first report to describe clustering of pathogenic mutations. Thirteen novel polymorphic alterations were characterized, confirming previous reports that TCOF1 has an unusually high rate of single-nucleotide polymorphisms (SNPs) within its coding region. We suggest a possible different mechanism leading to TCS or genetic heterogeneity for this condition, as we identified two families with no apparent pathogenic mutation in the gene. Furthermore, our data confirm the absence of genotype-phenotype correlation and reinforce that the apparent anticipation often observed in TCS families is due to ascertainment bias.

Prenatal exposure to misoprostol and vascular disruption defects: a case-control study.

Prenatal exposure to misoprostol has been associated with Moebius and limb defects. Vascular disruption has been proposed as the mechanism for these teratogenic effects. The present study is a multicenter, case-control study that was designed to compare the frequency of prenatal misoprostol use between mothers of Brazilian children diagnosed with vascular disruption defects and matched control mothers of children diagnosed with other types of defects. A total of 93 cases and 279 controls were recruited in eight participating centers. Prenatal exposure was identified in 32 infants diagnosed with vascular disruption defects (34.4%) compared with only 12 (4.3%) in the control group (P<0.0000001). Our data suggest that prenatal exposure to misoprostol is associated to the occurrence of vascular disruption defects in the newborns.

CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome.

Altered growth and function of synoviocytes, the intimal cells which line joint cavities and tendon sheaths, occur in a number of skeletal diseases. Hyperplasia of synoviocytes is found in both rheumatoid arthritis and osteoarthritis, despite differences in the underlying aetiologies of the two disorders. We have studied the autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP; MIM 208250) to identify biological pathways that lead to synoviocyte hyperplasia, the principal pathological feature of this syndrome. Using a positional-candidate approach, we identified mutations in a gene (CACP) encoding a secreted proteoglycan as the cause of CACP. The CACP protein, which has previously been identified as both 'megakaryocyte stimulating factor precursor' and 'superficial zone protein', contains domains that have homology to somatomedin B, heparin-binding proteins, mucins and haemopexins. In addition to expression in joint synovium and cartilage, CACP is expressed in non-skeletal tissues including liver and pericardium. The similarity of CACP sequence to that of other protein families and the expression of CACP in non-skeletal tissues suggest it may have diverse biological activities.

Blomstrand chondrodysplasia: a lethal sclerosing skeletal dysplasia. Case report and review.

We report a female stillborn with typical clinical, radiological, and anatomopathological features of Blomstrand chondrodysplasia. The main findings in this lethal osteochondrodysplasia are osteosclerosis and advanced skeletal maturation. Autosomal recessive inheritance has been proposed because of parental consanguinity of affected siblings in all reported cases, including this one. Histopathological study of the bones confirmed the advanced skeletal maturation radiological features. We also review this rare lethal osteochondrodysplasia.