Magdalena Budisteanu

Use of early intervention for young children with autism spectrum disorder across Europe

Little is known about use of early interventions for autism spectrum disorder in Europe. Parents of children with autism spectrum disorder aged 7 years or younger (N = 1680) were recruited through parent organisations in 18 European countries and completed an online survey about the interventions their child received. There was considerable variation in use of interventions, and in some countries more than 20% of children received no intervention at all. The most frequently reported interventions were speech and language therapy (64%) and behavioural, developmental and relationship-based interventions (55%). In some parts of Europe, use of behavioural, developmental and relationship-based interventions was associated with higher parental educational level and time passed since diagnosis, rather than with child characteristics. These findings highlight the need to monitor use of intervention for children with autism spectrum disorder in Europe in order to contrast inequalities.

Autism and the Grand Challenges in Global Mental Health

There is increasing recognition of the global burden related to mental and neurological conditions greatly surpassing many health conditions such as cardiovascular disease and cancer. Recently, partnership among leading funders and academics has given rise to the grand challenges in global mental health initiative, aiming to reduce the global burden associated with mental and neurological conditions [Collins et al., 2011]. Among the actions of this initiative was a priority-setting exercise to articulate the most pressing challenges research in this area needs to address. Representing a diverse group of researchers and practitioners, we collectively considered progress and barriers in these priorities as they apply to autism research. In this editorial, we describe, based on our knowledge of and direct experience with autism in lowand middle-income countries (LMICs), the state of the science corresponding to the grand challenges and offer suggestions for how a truly global approach to autism research can bridge knowledge gaps leading to substantive improvements in quality of life for those affected wherever they may be.

3p Interstitial Deletion Novel Case Report and Review

3p interstitial deletions have emerged in recent years as a new cause of neurodevelopmental delay and intellectual disability. Since the first report of this condition in 1979, 16 cases have been described in the literature, delineating it as a presumptive syndrome. Here, we add a novel case presenting severely delayed neurodevelopment and psychomotor development; facial dysmorphism (square facies, broad forehead, short palpebral fissures, epicanthic folds, broad nasal bridge, and low-set malformed ears); cerebral, cardiac, and genital malformations; hand and feet anomalies; sacral sinus; and hearing impairment. Genetic investigations revealed a del(3)(p12.3p14.1) of 12.5 Mb, including 31 ORFs, among which ROBO2, PDZRN3, MITF, and FOXP1 are known to act in neurodevelopment. The clinical features of our patient are compared with those previously reported in the literature, thus providing further support for the delineation of the 3p interstitial deletion syndrome.

Haploinsufficiency of BAZ1B contributes to Williams syndrome through transcriptional dysregulation of neurodevelopmental pathways

Williams syndrome (WS) is a neurodevelopmental disorder caused by a genomic deletion of ∼28 genes that results in a cognitive and behavioral profile marked by overall intellectual impairment with relative strength in expressive language and hypersocial behavior. Advancements in protocols for neuron differentiation from induced pluripotent stem cells allowed us to elucidate the molecular circuitry underpinning the ontogeny of WS. In patient-derived stem cells and neurons, we determined the expression profile of the Williams-Beuren syndrome critical region-deleted genes and the genome-wide transcriptional consequences of the hemizygous genomic microdeletion at chromosome 7q11.23. Derived neurons displayed disease-relevant hallmarks and indicated novel aberrant pathways in WS neurons including over-activated Wnt signaling accompanying an incomplete neurogenic commitment. We show that haploinsufficiency of the ATP-dependent chromatin remodeler, BAZ1B, which is deleted in WS, significantly contributes to this differentiation defect. Chromatin-immunoprecipitation (ChIP-seq) revealed BAZ1B target gene functions are enriched for neurogenesis, neuron differentiation and disease-relevant phenotypes. BAZ1B haploinsufficiency caused widespread gene expression changes in neural progenitor cells, and together with BAZ1B ChIP-seq target genes, explained 42% of the transcriptional dysregulation in WS neurons. BAZ1B contributes to regulating the balance between neural precursor self-renewal and differentiation and the differentiation defect caused by BAZ1B haploinsufficiency can be rescued by mitigating over-active Wnt signaling in neural stem cells. Altogether, these results reveal a pivotal role for BAZ1B in neurodevelopment and implicate its haploinsufficiency as a likely contributor to the neurological phenotypes in WS.

Novel clinical finding in MECP2 duplication syndrome

MECP2 duplication syndrome (MECP2 DS) is a newly described genetic condition, with approximately 120 affected males being reported in so far [1–11]. The clinical features of this syndrome are hypotonia with feeding difficulties in the first month of life followed by spasticity in childhood, delayed motor developmental milestones, severe speech delay, dysmorphic features (brachycephaly, midfacial hypoplasia, large ears, and flat nasal bridge), moderate to severe intellectual disability, autistic features, seizures, recurrent respiratory infections, hypoplasia of the corpus callosum, severe constipation, and less frequent bladder dysfunction (urinary retention, bladder dilatation) [8]. Movement disorders (i.e., choreiform movements, stereotypies, and repetitive behaviors—especially, midline hand movements) were reported in various percentages of patients; rocking, spinning, and self-injurious behavior were also reported [11]. Most females heterozygous for MECP2 duplication are asymptomatic, but can exhibit features of the broad autism phenotype or other symptoms like anxiety, depression, and compulsions [11]. These patients’ management is multidisciplinary, including the treatment of feeding difficulties and of respiratory infection, physical therapy, speech therapy, ergotherapy, and specific behavioral therapy. We report on a 6-year-old boy, the first child of healthy nonconsanguineous parents, born after an uneventful pregnancy with a birth weight 2,500 g, Apgar score 10. No movement disorders or attention disorders in the family history were reported. Shortly after birth, the boy presented hypotonia with delayed psychomotor development; he held his head at 10 months, sat at 15 months, walked alone at 36 months, and spoke first words at 40 months. In the first year of life, the patient had feeding difficulties and recurrent respiratory infections. The clinical examination showed: weight 23 kg (Pc 75), height 115 cm (Pc 50), occipitofrontal circumference 48 cm (\2 DS); facial dysmorphism (hypertelorism; partial palpebral ptosis; open, carp-shaped mouth; micrognathia) (Fig. 1); cryptorchidism; bilateral pyramidal syndrome; severe intellectual disability; severe speech delay; autistic features; drooling. A prominent feature of the clinical picture was severe hyperkinesis, manifested as random non-purposeful movements, occurring throughout the day, in any environment (at home, in kindergarten, and in other public spaces), more prominent during the morning and in the afternoon impairing daily activities (the child was not able to play or to stay at the table to do a task for more than 5 min, thus not being able to participate in different activities together with other children). The patient presented also stereotyped movements (hand-flapping movements) and agitation during sleep. Hyperkinesis was, actually, the main reason for referral to our Department. The patient had not chorea, tremor, or epileptic seizures. To our knowledge, this is the first case with confirmed MECP2 duplication and hyperkinesis and the MECP2 duplication syndrome patients being considered rather hypoactive [12]. Biological tests, EEG and cerebral MRI were normal. M. Budisteanu, S. M. Papuc and A. Arghir equally contributed to this paper.

FOXP1-related intellectual disability syndrome: a recognisable entity

Background Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far. Methods We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting. Results Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability. Conclusions FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype–phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.

Oculocutaneous albinism associated with multiple malformations and psychomotor retardation

Abstract:  We present a case of oculocutaneous albinism in a child associating multiple malformations (preaxial polydactyly, small penis, cardiac malformation) and psychomotor retardation. To our knowledge, this association has not been previously described.

Angelman syndrome patient management: 5 years of clinical experience

Abstract Angelman syndrome (AS) is a genetic condition characterized by severe mental retardation, ataxic gait, severe speech delay, dysmorphic features, abnormal behavior, and movement disorder. It is caused by a variety of genetic mechanisms that all interfere with the expression of the UBE3A gene on chromosome 15q11-13. The management of AS patients is complex and involves a multidisciplinary approach. Here, we present our experience in the diagnosis and treatment of children with AS.

Atypical presentations of 22q11.2 deletion syndrome: explaining the genetic defects and genome architecture

22q11.2 deletion syndrome, the most common microdeletion syndrome, exhibits a broad range of phenotypes, implying a cumbersome diagnosis due to atypical or paucisymptomatic presentations. We present two atypical cases of 22q11.2 deletion syndrome and suggest a preferential occurrence of the breakpoints in regions poor in repetitive elements of SINE/Alu family.

P131 Challenges in clinical interpretation of gfap gene variant in a child with alexander disease

Objective We report on a case with clinical phenotype suggesting Alexander disease in which the genetic testing – sequencing of the GFAP gene – provided no definitive conclusions. Case presentation The proband is a 3 years-old boy who was referred to our department for epileptic seizures and psychomotor delay. The personal history revealed a normal psychomotor development till the age of 13 months when epileptic seizures occurred with partial response to antiepileptic drugs. A psychomotor regression was also observed, at actual presentation the boy presenting a development quotient of around 2 months. The clinical examination revealed also macrocephaly. Two cerebral MRI exams showed diffuse demyelization in fronto-insular white matter and striate nucleus bilaterally, with progressive aspect. The clinical and neuroimaging features are suggestive for Alexander disease and genetic testing (sequencing of GFAP gene) was indicated. Results the genetic testing revealed a heterozygous variant in exon 1 of the GFAP gene, c.292G>C (p.Ala98Pro), previously unreported, which was interpreted as being of uncertain significance. Conclusions In this case, the gene sequencing, although identified a variant of the gene, could not offer a clear result. New data (genetic testing of the parents, other cases with similar variant, functional studies) could bring further information about the clinical impact of this variant.