[Show abstract][Hide abstract] ABSTRACT: Rare copy number variants (CNVs) disrupting ASTN2 or both ASTN2 and TRIM32 have been reported at 9q33.1 by genome-wide studies in a few individuals with neurodevelopmental disorders. The vertebrate-specific astrotactins, ASTN2 and its paralog ASTN1, have key roles in glial-guided neuronal migration during brain development. To determine the prevalence of astrotactin mutations and delineate their associated phenotypic spectrum, we screened ASTN2/TRIM32 and ASTN1 (1q25.2) for exonic CNVs in clinical microarray data from 89,985 individuals across 10 sites, including 64,114 neurodevelopmental disorder subjects. In this clinical dataset, we identified 46 deletions and 12 duplications affecting ASTN2. Deletions of ASTN1 were much rarer. Deletions near the 3' terminus of ASTN2, which would disrupt all transcript isoforms (a subset of these deletions also included TRIM32), were significantly enriched in the neurodevelopmental disorder subjects (p=0.002) compared with 44,085 population-based controls. Frequent phenotypes observed in individuals with such deletions included Autism Spectrum Disorders (ASD), Attention Deficit Hyperactivity Disorder (ADHD), speech delay, anxiety and Obsessive Compulsive Disorder (OCD). The 3'-terminal ASTN2 deletions were significantly enriched compared with controls in males with neurodevelopmental disorders, but not in females. Upon quantifying ASTN2 human brain RNA, we observed shorter isoforms expressed from an alternative transcription start site of recent evolutionary origin near the 3' end. Spatiotemporal expression profiling in the human brain revealed consistently high ASTN1 expression while ASTN2 expression peaked in the early embryonic neocortex and postnatal cerebellar cortex. Our findings shed new light on the role of the astrotactins in psychopathology and their interplay in human neurodevelopment.
Full-text · Article · Dec 2013 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: The term "position effect" is used when the expression of a gene is deleteriously affected by an alteration in its chromosomal environment even though the integrity of the protein coding sequences is maintained. We describe a patient affected by epilepsy and severe neurodevelopment delay carrying a balanced translocation t(15;16)(p11.2;q12.1)dn that we assume caused a position effect as a result of the accidental juxtaposition of heterochromatin in the euchromatic region.
FISH mapped the translocation breakpoints (bkps) to 15p11.2 within satellite III and the 16q12.1 euchromatic band within the ITFG1 gene. The expression of the genes located on both sides of the translocation were tested by means of real-time PCR and three, all located on der(16), were found to be variously perturbed: the euchromatic gene NETO2/BTCL2 was silenced, whereas VPS35 and SHCBP1, located within the major heterochromatic block of chromosome 16q11.2, were over-expressed. Pyrosequencing and chromatin immunoprecipitation of NETO2/BTCL2 and VPS35 confirmed the expression findings. Interphase FISH analysis showed that der(16) localised to regions occupied by the beta satellite heterochromatic blocks more frequently than der(15).
To the best of our knowledge, this is the first report of a heterochromatic position effect in humans caused by the juxtaposition of euchromatin/heterochromatin as a result of chromosomal rearrangement. The overall results are fully in keeping with the observations in Drosophila and suggest the occurrence of a human heterochromatin position effect associated with the nuclear repositioning of the der(16) and its causative role in the patient's syndromic phenotype.
[Show abstract][Hide abstract] ABSTRACT: Genomic imbalances are considered the most frequent causes of mental retardation (MR). Although widespread screening with novel molecular karyotyping methods, such as multiplex ligation-dependent probe amplification (MLPA) and array-based comparative genomic hybridization (Array-CGH) might be desirable, effective clinical preselection is essential because of the technical complexities and cost of testing. This study focuses on a retrospective analysis of clinical features in patients with MR of unknown etiology, thereby assessing the sensitivity of a six item checklist in identifying rearranged subjects. The diagnostic powers of single techniques were also evaluated. We studied 164 subjects with MR who had completed the follow diagnostic process: karyotype and eventually fluorescence in situ hybridization (FISH) in case of suspected microdeletion syndrome, specific analysis in case of suspected X-linked or monogenic disease, MLPA for subtelomeric rearrangements in patients negative to previous tests, Array-CGH in patients negative to MLPA. A six items checklist based on relevant clinical signs was retrospectively applied. 5 patients were carrier of chromosomal abnormalities (3 detected by karyotype and 2 by FISH), 3 were affected by X-fragile syndrome, 6 had mutations, and 33 were carriers of genomic imbalances (9 detected by MLPA and 24 by Array-CGH), while 117 resulted negative to any tests. In patients with genomic imbalances and in subjects without rearrangements the median score of the checklist was 6 (range 3-9) and 4 (range 0-8), respectively (P <0,0001). The ROC analysis for the diagnostic accuracy of our checklist showed an area under the curve of 0.74 (95% confidence interval: 0.65-0.83). Using a cut-off for the score of U3, 24% of patients could have been excluded without missing any genomic imbalances. This study supports the evidence that the application of a clinical checklist may improve the rate of pathological findings in patients with MR.
No preview · Article · Jan 2012 · Biochimica clinica
[Show abstract][Hide abstract] ABSTRACT: In this study, we used deletions at 22q13, which represent a substantial source of human pathology (Phelan/McDermid syndrome), as a model for investigating the molecular mechanisms of terminal deletions that are currently poorly understood. We characterized at the molecular level the genomic rearrangement in 44 unrelated patients with 22q13 monosomy resulting from simple terminal deletions (72%), ring chromosomes (14%), and unbalanced translocations (7%). We also discovered interstitial deletions between 17-74 kb in 9% of the patients. Haploinsufficiency of the SHANK3 gene, confirmed in all rearrangements, is very likely the cause of the major neurological features associated with PMS. SHANK3 mutations can also result in language and/or social interaction disabilities. We determined the breakpoint junctions in 29 cases, providing a realistic snapshot of the variety of mechanisms driving non-recurrent deletion and repair at chromosome ends. De novo telomere synthesis and telomere capture are used to repair terminal deletions; non-homologous end-joining or microhomology-mediated break-induced replication is probably involved in ring 22 formation and translocations; non-homologous end-joining and fork stalling and template switching prevail in cases with interstitial 22q13.3. For the first time, we also demonstrated that distinct stabilizing events of the same terminal deletion can occur in different early embryonic cells, proving that terminal deletions can be repaired by multistep healing events and supporting the recent hypothesis that rare pathogenic germline rearrangements may have mitotic origin. Finally, the progressive clinical deterioration observed throughout the longitudinal medical history of three subjects over forty years supports the hypothesis of a role for SHANK3 haploinsufficiency in neurological deterioration, in addition to its involvement in the neurobehavioral phenotype of PMS.
[Show abstract][Hide abstract] ABSTRACT: The safety and effectiveness of psychotropic drug use in the paediatric population is widely debated, in particular because of the lack of data concerning long term effects.In Italy the prevalence of psychotropic drug prescriptions increased in the early 2000s and decreased afterwards. In such a context, a study with the aim to estimate the incidence and prevalence of psychotropic drug prescription in the paediatric population and to describe diagnostic and therapeutic approaches was performed.
The study population was composed of 76,000 youths less than 18 years and living in the area covered by the local health unit of Verona, Italy. The data source was the Verona local health unit's administrative prescription database. Prevalence and incidence of antidepressant and/or antipsychotic drug prescriptions in the 2004-2008 period were estimated. Children and adolescents receiving antidepressant and/or antipsychotic drug prescriptions between 1 January 2005 and 31 December 2006 were identified and questionnaires were sent to the prescribers with the aim to collect data concerning diagnostic and therapeutic approaches, and care strategies.
The prevalence of psychotropic drug prescriptions did not change in the 2004-2008 period, while incidence slightly increased (from 7.0 in 2005 to 8.3 per 10,000 in 2008). Between 1 January 2005 and 31 December 2006, 111 youths received at least one psychotropic drug prescription, 91 of whom received antidepressants. Only 28 patients attended child and adolescent psychiatry services. Information concerning diagnostic and therapeutic approaches, and care strategies was collected for 52 patients (47%). Anxiety-depressive syndrome and attention disorders were the diseases for which psychotropic drugs were most commonly prescribed. In all, 75% youths also received psychological support and 20% were prescribed drugs for 2 or more years.
Despite the low drug prescription prevalence, the finding that most children were not cared for by child and adolescent psychiatric services is of concern and calls for a systematic, continuous monitoring of psychopharmacological treatments.
[Show abstract][Hide abstract] ABSTRACT: To investigate the efficacy of cochlear implants (CIs) in infants versus children operated at later age in term of spoken language skills and cognitive performances.
The present prospective cohort study focuses on 19 children fitted with CIs between 2 and 11 months (X=6.4 months; SD=2.8 months). The results were compared with two groups of children implanted at 12-23 and 24-35 months. Auditory abilities were evaluated up to 10 years of CI use with: Category of Auditory Performance (CAP); Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS); Peabody Picture Vocabulary Test (PPVT-R); Test of Reception of Grammar (TROG) and Speech Intelligibility Rating (SIR). Cognitive evaluation was performed using selected subclasses from the Griffiths Mental Development Scale (GMDS, 0-8 years of age) and Leiter International Performance Scale-Revised (LIPS-R, 8-13 years of age).
The infant group showed significantly better results at the CAP than the older children from 12 months to 36 months after surgery (p<.05). Infants PPVT-R outcomes did not differ significantly from normal hearing children, whereas the older age groups never reached the values of normal hearing peers even after 10 years of CI use. TROG outcomes showed that infants developed significantly better grammar skills at 5 and 10 years of follow up (p<.001). Scores for the more complex subtests of the GMDS and LIPS-R were significantly higher in youngest age group (p<.05).
This study demonstrates improved auditory, speech language and cognitive performances in children implanted below 12 months of age compared to children implanted later.
No preview · Article · Apr 2011 · International journal of pediatric otorhinolaryngology
[Show abstract][Hide abstract] ABSTRACT: The neural basis of language and motor deficits in autism is still not completely clear. The aim of this study was to explore the involvement of the parietal lobe in language and motor development in autism, in view of the recognized role of this region in language and imitation functions. Twenty-eight autistic children underwent an extensive clinical assessment and an MRI examination. A significant direct correlation between age at first word and left parietal gray matter volumes was found (r=0.50, p=0.007). Conversely, age at reaching milestones of motor development, such as the ability to sit and to walk unaided, was not significantly associated with parietal size, after correcting for chronological age and for gender. To the best of our knowledge, this is the first structural MRI report demonstrating a role of left parietal gray matter volumes in delayed language development in autistic children representative of the 'real world' autistic population.
Full-text · Article · Jan 2010 · Functional neurology
[Show abstract][Hide abstract] ABSTRACT: Background. Subtelomeric rearrangements have been reported to be an important cause of mental retardation. These aberrations may remain undetected by routine conventional cytogenetic analysis because of limited resolution in light microscopy. Increased detection of cryptic subtelomeric abnormalities may be achieved by Fluorescence In Situ Hybridization (FISH) which is the most widely used technique in cytogenetic laboratories. However, this assay is expensive and time consuming, because metaphase spreads are needed. Accordingly, FISH is not indicated for broad screening. Multiplex Ligation-dependent Probe Amplification (MLPA) is a new reliable, sensitive and inexpensive technique, which can be used as a high throughput prospective screening tool for subtelomeric rearrangements. The aim of this study was to introduce a novel strategy for the screening of subtelomeric rearrangements in routine diagnosis which consists in a first screening with MLPA then followed by FISH analysis. Methods. We tested 70 children with idiopathic mental retardation both severe and mild, often associated with congenital malformations, growth retardation and/or dysmorphic features. MLPA was performed using SALSA P036E human telomere kit (MRC-Holland, Amsterdam, The Netherlands). If an aberrant MLPA result was observed, FISH with a probe specific for the region of interest was performed to validate the result. Results. Among 70 patients tested, 5 were carriers of unbalanced rearrangements. 3 patients had deletion of 6pter, 2qter and 6qter respectively, one showed a double aneusomy: a distal 21q deletion and 7q duplication and the other one showed a duplication of 13qter. Conclusions. Our preliminary data show a high degree of agreement between MLPA and FISH suggesting that MLPA might be a rapid, accurate, reliable and cost-effective technique for the screening of subtelomeric rearrangements in routine diagnostics.
Full-text · Article · Jan 2010 · Rivista Italiana della Medicina di Laboratorio
[Show abstract][Hide abstract] ABSTRACT: Six submicroscopic deletions comprising chromosome band 2q23.1 in patients with severe mental retardation (MR), short stature, microcephaly and epilepsy have been reported, suggesting that haploinsufficiency of one or more genes in the 2q23.1 region might be responsible for the common phenotypic features in these patients. In this study, we report the molecular and clinical characterisation of nine new 2q23.1 deletion patients and a clinical update on two previously reported patients. All patients were mentally retarded with pronounced speech delay and additional abnormalities including short stature, seizures, microcephaly and coarse facies. The majority of cases presented with stereotypic repetitive behaviour, a disturbed sleep pattern and a broad-based gait. These features led to the initial clinical impression of Angelman, Rett or Smith–Magenis syndromes in several patients. The overlapping 2q23.1 deletion region in all 15 patients comprises only one gene, namely, MBD5. Interestingly, MBD5 is a member of the methyl CpG-binding domain protein family, which also comprises MECP2, mutated in Rett's syndrome. Another gene in the 2q23.1 region, EPC2, was deleted in 12 patients who had a broader phenotype than those with a deletion of MBD5 only. EPC2 is a member of the polycomb protein family, involved in heterochromatin formation and might be involved in causing MR. Patients with a 2q23.1 microdeletion present with a variable phenotype and the diagnosis should be considered in mentally retarded children with coarse facies, seizures, disturbed sleeping patterns and additional specific behavioural problems.Keywords: 2q23.1, Angelman, EPC2, MBD5, microdeletion, Rett
Full-text · Article · Oct 2009 · European Journal of HumanGenetics
[Show abstract][Hide abstract] ABSTRACT: Aims. The safety and effectiveness of psychotropic drug use in the paediatric population are widely debated, in particular because of the lack of data concerning the long term effects. In Italy the prevalence of psychotropic drug prescriptions increased in the 2000-2002 period and decreased afterwards. In such a context, a study with the aim to estimate the prevalence of psychotropic drug prescription in the paediatric population and to describe diagnostic and therapeutic approaches was performed. Methods. The study population was composed by 76,000 youths <18 years of age living in the Local Health Unit of Verona, Italy. Children and adolescents receiving psychotropic drug prescriptions were identified. Questionnaires were sent to the prescribers with the aim to collect data concerning diagnostic and therapeutic approaches, and care strategies. Results. Between 1 January 2005 and 31 December 2006, 111 youths (0.8 per 1,000) received at least one psychotropic drug prescription. Ninty one youths received antidepressants and 25 received antipsychotics. Only 29 patients were in charge to child and adolescent outpatient psychiatric services. Information concerning diagnostic and therapeutic approaches, and care strategies were collected for 52 patients (47%). Anxiety-depressive syndrome and attention disorders were the diseases for which psychotropic drugs were most commonly prescribed. In all, 85% youths received also psychological support and 20% were prescribed drugs for 2 or more years. Child psychiatrists made the first diagnosis in 50% of the cases, but in 1/3 of the cases the parents attended 2 or more physicians before the diagnostic procedure was completed. Conclusions. Despite the low prevalence of drug prescription, the finding that most children were not cared for by child and adolescent psychiatric services is of concern and calls for a systematic continuous monitoring of psychopharmacological treatments.
No preview · Article · Sep 2009 · Ricerca e Pratica
[Show abstract][Hide abstract] ABSTRACT: Auditory brainstem implants (ABIs) can provide excellent open set speech recognition in adults without auditory tumors. These favorable results prompted us to extend ABI indications to children with profound hearing loss (HL) who are not candidates for a cochlear implant (CI). This article reports on the auditory performance and cognitive development measured in children with ABIs.
This study quantifies the development of auditory perceptual and nonverbal cognitive abilities of children with profound HL undergoing ABI. From 2000 to 2006, 17 children aged 14 months to 16 years received an ABI for different tumor and nontumor diseases in our department in Verona, and nine children were operated in other countries. Six of the children had been previously fitted elsewhere with a CI with no auditory results. Fourteen children had multiple associated psychomotor handicaps.
The retrosigmoid approach was used in all children. Intraoperative and postoperative electrically evoked auditory brainstem responses were performed in all children. Perceptual auditory abilities were evaluated with the Evaluation of Auditory Responses to Speech battery and the Category of Auditory Performance test. Cognitive evaluation was performed on 10 children using the Leiter International Performance Scale-Revised test.
All children consistently use their devices for 8 h/d at average and have environmental sound awareness and utterance of words and simple sentences. Their category of auditory performance test scores increased significantly with ABI use. Scores on two of the four subtests considered for cognitive evaluation in this study increased significantly (P < .05) during the first year of ABI use. Postimplant cognitive outcomes were positively related to the auditory results.
The present investigation clearly indicates that children who are not candidates for CI fitted with ABI obtain significant development of their hearing ability and a significant improvement in some cognitive parameters. The outcomes of the present study suggest that children with cochlear or cochlear nerve abnormalities with associated cognitive deficits should not be excluded from ABI implantation.
No preview · Article · May 2008 · The Laryngoscope
[Show abstract][Hide abstract] ABSTRACT: The authors describe two unrelated individuals with fragile X syndrome (FXS) due to marked expansion and instability of the CGG trinucleotide repeats within the fragile X mental retardation 1 gene (FMR1) and periventricular heterotopia (PH). This observation suggests that the FMR1 gene is involved in neuronal migration and that abnormal neuronal migration, even beyond the resolution of MRI, contributes to the neurologic phenotype of FXS.
[Show abstract][Hide abstract] ABSTRACT: Benign myoclonic epilepsy in infancy (BMEI) is a nosologically well-defined entity, characterized by myoclonic seizures (MS) in normal children younger than 3 years and by a good long term prognosis. In some cases the seizures are reflex. We studied 22 cases to better define the electroclinical semeiology and evolution of the disorder.
Serial electroclinical and neuropsychological assessments, both during wakefulness and during sleep, were performed in 22 otherwise healthy children with spontaneous (17) or reflex (5) MS, recorded by video-EEG-polygraphy since clinical onset.
Seizure onset was between 3 months and 4 years 10 months (50% during first year, 86% before the third year); in reflex cases onset, was earlier than the 14th month. MS recurred during wakefulness and slow sleep in all cases and during REM sleep in reflex cases. MS and related EEG discharges were synchronous or asynchronous. Often ictal EEG discharges were limited to the rolandic and vertex regions (falsely focal paroxysms). Several seizures were subtle and could have escaped recognition. Unusually frequent sleep startles were recorded mostly in reflex cases. MS were well controlled by treatment. At follow-up, between ages 3 and 19 years, four patients had occasional seizures; two had cognitive impairment and three had learning difficulties. No other seizures or cognitive deficits were observed in reflex cases.
Seizures associated with BMEI are rarely truly generalized and are often so subtle and related to falsely focal paroxysms that their frequency can be underestimated. The reflex form is a well-defined variant with an early onset, peculiar electroclinical features, and a good prognosis.
[Show abstract][Hide abstract] ABSTRACT: We report the case of a child with partial biotinidase deficiency and autistic developmental disorder. We arrived at the diagnosis of biotinidase deficiency when the child was almost 4 years of age. Consequently, he began cofactor biotin treatment (10 mg daily) which did not resolve his autistic behavior. His younger brother was affected by partial biotinidase deficiency diagnosed at birth through our neonatal screening program. He was precociously treated with cofactor biotin therapy (10 mg daily) and did not show any behavioral abnormality or developmental delay. Since the brain is quite vulnerable to biotin deficiency, delayed biotin therapy could result in neurological damage. Our patient is the first case of partial biotinidase deficiency associated with autism. We hypothesize that the low biotinidase activity could have caused biotin deficiency in his brain and cerebrospinal fluids and consequently serious neurological problems, such as stereotyped and autistic behaviors, which were irreversible in spite of biotin supplementation.
No preview · Article · Oct 2003 · Child Neuropsychology