Aurora Arghir

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.

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.

Molecular characterization of complex chromosomal changes in de novo acute myeloid leukemia: a case report

Abstract De novo acute myeloid leukemias (AML) represent a heterogeneous group of clonal hematopoietic disorders in which chromosomal abnormalities are detected in a majority of patients. At present, cytogenetic changes are recognized as important diagnostic markers and prognosis determinants. Complex karyotype changes are associated with resistance to treatment and unfavorable evolution. We report on an AML case with complex karyotype changes characterized by molecular genetic techniques (fluorescence in situ hybridization - FISH and array-based comparative genomic hybridization - array-CGH) and an extremely poor outcome. A 72 year-old female patient was admitted for genetic investigations with a clinical diagnosis of AML. Classical and molecular cytogenetic tests as well as array-CGH were performed. Complex chromosomal abnormalities were identified at diagnosis, consisting of genomic imbalances involving chromosomes 6, 7, 9, and 17. AML with complex karyotype changes is a heterogeneous disease, as a variety of genomic abnormalities are detected, involving virtually all chromosomes. The pathogenesis of AML with complex karyotype is poorly understood. The complexity of karyotypic changes in our case highlights the importance of using complementary genetic investigation in order to obtain a comprehensive view of AML genome. Rezumat Leucemiile mieloide acute de novo (LAM) reprezintă un grup heterogen de afecţiuni hematopoietice clo- nale, majoritatea pacienţilor prezentând anomalii cromozomiale. Modificările citogenetice sunt considerate în momentul actual factori importanţi de diagnostic şi prognostic. Modificările complexe ale cariotipului sunt aso- ciate cil rezistenţa la tratament şi evoluţie nefavorabilă. Raportăm cazul unei paciente cu AML şi modificări complexe de cariotip identificate prin tehnici citogenetice şi moleculare (hibridizare in situ fluorescentă - FISH şi hibridizare comparativa genomică bazata pe microarray - array-CGH) la care evoluţia a fost extrem de nefa- vorabila. Pacientei, în vârsta de 72 de ani, i-aufost recomandate investigaţii citogenetice în contextul unui diag- nostic clinic şi hematologic de LAM. Au fost efectuate teste citogenetice şi moleculare, incluzând array-C.GH. Au fost identificate modificări cromozomiale complexe reprezentate de dezechilibre genomice implicând cromozomii 6, 7, 9 şi 17. Pacienţii cu LAM cu modificări complexe de cariotip reprezintă un grup heterogen, la care sunt de- tectate numeroase anomalii genomice ce pot afecta practic orice cromozom. Patogeneza LAM cu cariotip com- plex este incomplet înţeleasă. Complexitatea modificărilor genetice la pacienta noastră subliniază importanţa utilizării de investigaţii genetice complementare pentru a obţine o imagine cât mai comprehensivă a anomaliilor genomice la pacienţii cu LAM.

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.

PP11.11 – 2673: Phelan-McDermid syndrome in two siblings with complex phenotype

Objective Array based comparative genomic hybridization (aCGH) stands as the first tier approach in a wide range of human conditions including developmental delay and autism spectrum disorders. In this paper we present two siblings (sister-brother) with complex phenotype and the same genomic variation revealed by aCGH. Methods Two siblings (brother and sister) were referred to our hospital for psychomotor retardation and behaviour problems. The clinical evaluation revealed: the 4-year old brother presented facial and limb dysmorphisms, severe psychomotor delay, severe speech delay, autistic behaviour, hyperkinesia and heteroaggressivity; the 2-year old sister presented facial and limb dysmorphisms, moderate psychomotor delay, speech delay, autistic behaviour. Both children were complex evaluated, including psychiatric and psychologic examinations, biological tests, EEG, heart and abdominal ultrasound, cerebral MRI. Array-CGH investigation (180K platform, Agilent Technologies) was performed in both siblings. Results aCGH investigation revealed a complex abnormality of chromosome 22q13.3: a 1.5 Mb deletion, including SHANK3 gene, and a 1.3 Mb duplication, without pathogenic OMIM genes, proximal to the deletion. In both siblings the 22q13.3 deletion was confirmed by FISH. Conclusion SHANK3 gene haploinsufficiency is reported in 22q13.3 deletion syndrome (Phelan-McDermid syndrome, PMDS). Clinical manifestations characteristic for this syndrome include neonatal hypotonia, global developmental delay, severe speech delay, autistic behaviour and dysmorphic features. PMDS is underdiagnosed and patients with autistic features associated with psychomotor retardation and severe speech delay should be considered for evaluation for SHANK3 defects.