Efficacy of risperidone and behavioral delineation in METTL5-related syndrome: a pooled analysis of literature and report of a novel variant.

Primary hereditary microcephaly (MCPH) comprises a group of genetically heterogeneous disorders characterized by severe microcephaly and mild intellectual disability. It differs from syndromic primary microcephaly (PM) by the lack of syndromic features and major brain malformations. We evaluated the genetic diagnostic yield, pathogenic mechanisms, and clinical features of these two PM groups in 87 patients from 64 families. Exome sequencing was performed on probands, 52 of whom had consanguineous parents. The diagnostic yield was 53.1%. Of the 34 disease-causing variants identified, 15 were novel, with 83.7% being biallelic. MCPH-associated genes were found in 17.2% of families, while syndromic PM accounted for 35.9%. Most patients in both groups had speech delay. In the MCPH group, borderline to mild intellectual disability, independent of microcephaly severity, and behavioral abnormalities were prominent, whereas severe intellectual disability was more common in the syndromic group. Notably, most genes associated with MCPH are involved in mitotic division and DNA repair pathways, while those in syndromic PM are involved in transcription regulation and cell trafficking pathways. A bird-like facial gestalt was observed in patients from both groups with genes related to mitotic division and DNA repair. In addition, we expanded the genetic heterogeneity to include a potential candidate gene, KNTC1.

BackgroundDYRK1A plays different functions during development, with an important role in controlling brain growth through neuronal proliferation and neurogenesis. It is expressed in a gene dosage dependent manner since dyrk1a...

Autosomal recessive primary microcephaly (MCPH) is a rare condition characterized by a reduced cerebral cortex accompanied with intellectual disability. Mutations in 17 genes have been shown to cause this phenotype. Recently, mutations in CIT, encoding CRIK (citron rho-interacting kinase)-a component of the central spindle matrix-were added. We aimed at identifying novel MCPH-associated genes and exploring their functional role in pathogenesis. Linkage analysis and whole exome sequencing were performed in consanguineous and nonconsanguineous MCPH families to identify disease-causing variants. Functional consequences were investigated by RNA studies and on the cellular level using immunofluorescence and microscopy. We identified homozygous mutations in KIF14 (NM_014875.2;c.263T>A;pLeu88*, c.2480_2482delTTG; p.Val827del, and c.4071G>A;p.Gln1357=) as the likely cause in 3 MCPH families. Furthermore, in a patient presenting with a severe form of primary microcephaly and short stature, we identified compound heterozygous missense mutations in KIF14 (NM_014875.2;c.2545C>G;p.His849Asp and c.3662G>T;p.Gly1221Val). Three of the 5 identified mutations impaired splicing, and 2 resulted in a truncated protein. Intriguingly, Kif14 knockout mice also showed primary microcephaly. Human kinesin-like protein KIF14, a microtubule motor protein, localizes at the midbody to finalize cytokinesis by interacting with CRIK. We found impaired localization of both KIF14 and CRIK at the midbody in patient-derived fibroblasts. Furthermore, we observed a large number of binucleated and apoptotic cells-signs of failed cytokinesis that we also observed in experimentally KIF14-depleted cells. Our data corroborate the role of an impaired cytokinesis in the etiology of primary and syndromic microcephaly, as has been proposed by recent findings on CIT mutations. Ann Neurol 2017;82:562-577.

Primary microcephaly (MCPH) is a rare developmental defect characterized by impaired cognitive functions, retarded neurodevelopment and reduced brain size. It is genetically heterogeneous and so far more than 17 genes associated with this disease have been identified. Primary microcephaly type 1 (MCPH1) gene encodes a protein called microcephalin, which is implicated in chromosome condensation and DNA damage induced cellular responses. It is suggested to play a role in neurogenesis and regulation of the size of the cerebral cortex. Whole exome sequencing revealed a novel, homozygous frameshift mutation (c.373_374delAA) in MCPH1 gene in exon 5 resulting in frameshift change from p.Lys125Glusfs*7. Our report presents the results of the simultaneous analysis of the trio exome data of both unaffected parents and their affected son. A homozygous frameshift variant in the MCPH1 gene was identified as a plausible candidate causal variant for the clinical phenotype in this family.

Sorting Nexin 27 (SNX27), a key regulator of synaptic receptor trafficking and endosomal recycling, has been implicated in maintaining synaptic homeostasis and cognitive function. To date, variants in SNX27 have been reported in a small number of patients across three publications with severe neurodevelopmental phenotypes. However, the genetic and functional landscape of SNX27-related disorders remains poorly understood, and further evidence is needed to confirm its association with disease and to better delineate the associated phenotype. Two unrelated Pakistani families with a total of five affected individuals segregating a neurodevelopmental disorder were investigated via exome or genome sequencing. This revealed a novel homozygous frameshift variant in family I [NM_001330723.2: c.75dup; p. (Ser26Valfs*85)], predicted to be targeted by nonsense-mediated decay. In family II, a novel homozygous missense variant [NM_001330723.2: c.929 T>C; p. (Met310Thr)] was found within the FERM-like region of the SNX27 protein, which is critical for retromer complex interaction. Comparison of five cases described in this study with previously reported six cases reinforces the presence of consistent "core" clinical features-global developmental delay, intellectual disability, speech delay, behavioral abnormalities, seizures, and motor dysfunction in all assessed cases. Other features such as dental anomalies, failure to thrive, and dysmorphisms occurred variably in few. Affected individuals with predicted loss-of-function variants typically presented with a more severe phenotype. Thus, core features of SNX27-related neurodevelopmental disorders (NDDs) are intellectual disability, developmental, and speech delays. This study, alongside prior reports, augments the genetic and phenotypic spectrum of SNX27-associated NDDs. The novel frameshift variant p.(Ser26Valfs*85) is predicted to severely disrupt SNX27 function, causing profound neurodevelopmental impairment, whereas the missense p.(Met310Thr) in the FERM-like region is associated with a milder phenotype. Comparative analyses with previous reports reveal a spectrum from early lethality to long-term survival with intellectual disability in SNX27-linked families. These findings underscore the importance of SNX27 in neurodevelopment and further validate its link to a neurodevelopmental disorder.

Microcephaly, a commonly documented finding in paediatric neurological practice, confers little diagnostic specificity. Defined by a significant decrease in head circumference, it does not do much to discriminate between the many processes that result in reduced cranial capacity. Given that reduced skull volume reflects the size of the underlying brain, microcephaly is either the consequence of impaired cerebral growth during development or destructive neurological insults. It may be the consequence of environmental, maternal, or genetic aetiologies that include birth asphyxia, intrauterine infections, teratogen exposure, metabolic disease, chromosomal abnormalities, and single gene disorders. Frequently, associated developmental anomalies or neurological findings assist to make specific diagnoses. However, microcephaly may occur in isolation, and when this is extreme (4 or more standard deviations below the population mean), a diagnosis of primary microcephaly (MCPH) is likely. Surprisingly, despite marked reduction in cerebral cortical volume, such patients have mild/moderate intellectual disability without additional neurological deficits. As an autosomal recessive genetic disorder, this condition has been extensively studied in recent years yielding significant insight into the cellular and regulatory mechanisms governing brain growth. Brain volume is reduced to as little as a third of normal in primary microcephaly. This is accompanied by simplified cortical gyration with an otherwise structurally normal brain on neuroimaging. Over the last 3 million years our brains have seen a three-fold increase in size1 and 100-fold increase in surface area through cortical folding (gyrification).2 Evolutionary parallels have consequently been drawn with the expectation that genes identified may provide insight into human brain evolution. Over the last decade seven genes have been identified:3MCPH1, WDR62, CDK5RAP2, CEP152, ASPM, CENPJ (CPAP), and STIL. All are expressed in the neuroepithelium during embryonic neurogenesis and localize to the centrosomes and mitotic spindle poles. It is therefore thought that primary microcephaly is a disorder of neurogenic mitosis,4 where impaired proliferation of neural progenitor cells results in reduced numbers of neurons and a smaller brain. By determining the orientation of the mitotic spindle, these centrosomal proteins may influence the mode of stem cell division, augmenting the stem cell pool and consequently, brain size. This could provide an explanation for how neurogenesis has been modified during primate evolution to achieve expansion of the cerebral cortex. Intriguingly, comparative genomic sequencing has detected adaptive sequence changes in some of the MCPH genes.5 This raises the possibility that changes in these genes have directly contributed to increasing brain size, though this conjecture remains to be proven. In the last 2 years, the phenotypes associated with the MCPH genes have been substantially extended. Firstly, exome sequencing has identified mutations in WDR62 in a range of severe brain malformations.6,7 These include phenotypes usually thought of as distinct diagnostic entities, such as pachygyria, lissencephaly, schizencephaly, polymicrogyria, and cerebellar hypoplasia. Furthermore, the association of mutations in WDR62 with asymmetric polymicrogyria, unilateral cerebrellar hypoplasia, or open-lipped schizencephaly, suggests that such lesions should not be automatically attributed to vascular-disruptive aetiologies. Secondly, MCPH genes have also been associated with microcephalic primordial dwarfism, a group of autosomal recessive disorders with global growth failure.8 Here, prenatal growth restriction is followed by a marked reduction in postnatal height as well as brain size. Mutations in both CEP152 and CENPJ have been reported9,10 but why mutations in the same genes should cause localized reduction in brain size or global growth failure remains unclear. Maintaining the centrosomal theme, pericentrin is also an established and major disease gene for microcephalic dwarfism. However, centrosomes are not the whole story; the recent identification of multiple genes encoding components of the DNA replication machinery11–13 and an RNA splicing gene14,15 have demonstrated that at least for microcephalic primordial dwarfism other mechanisms are in play. Lastly, progress been made on the most extreme microcephaly phenotype in which profound intellectual disability is accompanied by brain size a tenth of its normal weight. Mutations in the NDE1 gene have been reported by two groups.16,17 This gene encodes a centrosomal protein involved in neuronal migration, as well as mitotic spindle formation, these functions respectively explaining the observed partial deficiency in cortical lamination and extreme microcephaly with grossly simplified cortical gyral structure (microlissencephaly). As well as affording insight into neurobiology and evolution, the burgeoning list of disease genes will have diagnostic utility. Comprehensive molecular testing should soon be a realistic possibility, informing diagnosis and patient management as well as permitting families to make informed reproductive choices. Though screening these large genes with established sequencing technologies has been cumbersome, the advent of next-generation sequencing technologies in diagnostic laboratories will provide the realistic prospect of efficient and cost-effective testing to assist the clinician in dissecting the heterogeneous entity that is microcephaly.

Primary microcephaly is a rare neurogenic and genetically heterogeneous disorder characterized by significant brain size reduction that results in numerous neurodevelopmental disorders (NDD) problems, including mild to severe intellectual disability (ID), global developmental delay (GDD), seizures and other congenital malformations. This disorder can arise from a mutation in genes involved in various biological pathways, including those within the brain. We characterized a recessive neurological disorder observed in nine young adults from five independent consanguineous Pakistani families. The disorder is characterized by microcephaly, ID, developmental delay (DD), early-onset epilepsy, recurrent infection, hearing loss, growth retardation, skeletal and limb defects. Through exome sequencing, we identified novel homozygous variants in five genes that were previously associated with brain diseases, namely CENPJ (NM_018451.5: c.1856A > G; p.Lys619Arg), STIL (NM_001048166.1: c.1235C > A; p.(Pro412Gln), CDK5RAP2 (NM_018249.6 c.3935T > G; p.Leu1312Trp), RBBP8 (NM_203291.2 c.1843C > T; p.Gln615*) andCEP135(NM_025009.5 c.1469A > G; p.Glu490Gly). These variants were validated by Sanger sequencing across all family members, and in silico structural analysis. Protein 3D homology modeling of wild-type and mutated proteins revealed substantial changes in the structure, suggesting a potential impact on function. Importantly, all identified genes play crucial roles in maintaining genomic integrity during cell division, with CENPJ, STIL, CDK5RAP2, and CEP135 being involved in centrosomal function. Collectively, our findings underscore the link between erroneous cell division, particularly centrosomal function, primary microcephaly and ID.

Primary microcephaly (MCPH) is a prenatal condition of small brain size with a varying degree of intellectual disability. It is a heterogeneous genetic disorder with 28 associated genes reported so far. Most of these genes encode centrosomal proteins. Recently, AKNA was recognized as a novel centrosomal protein that regulates neurogenesis via microtubule organization, making AKNA a likely candidate gene for MCPH. Using linkage analysis and whole-exome sequencing, we found a frameshift variant in exon 12 of AKNA (NM_030767.4: c.2737delG) that cosegregates with microcephaly, mild intellectual disability and speech impairment in a consanguineous family from Pakistan. This variant is predicted to result in a protein with a truncated C-terminus (p.(Glu913Argfs*42)), which has been shown to be indispensable to AKNA’s localization to the centrosome and a normal brain development. Moreover, the amino acid sequence is altered from the beginning of the second of the two PEST domains, which are rich in proline (P), glutamic acid (E), serine (S), and threonine (T) and common to rapidly degraded proteins. An impaired function of the PEST domains may affect the intracellular half-life of the protein. Our genetic findings compellingly substantiate the predicted candidacy, based on its newly ascribed functional features, of the multifaceted protein AKNA for association with MCPH.

Primary microcephaly (PM) is a highly heterogeneous neurodevelopmental disorder with many contributing risk genes and loci identified to date. We report a consanguineous family with PM, intellectual disability and short stature. Using whole exome sequencing, we identified a homozygous frameshift variant in programmed cell death 6 interacting protein (PDCD6IP, c.154_158dup; p.Val54Profs*18). This gene, PDCD6IP, plays an important role in the endosomal sorting complexes required for transport (ESCRT) pathway in the abscission stage of cytokinesis and apoptosis, and is required for normal brain development in mice. The clinical features observed in our patient were similar to the phenotypes observed in mouse and zebrafish models of PDCD6IP mutations in previous studies. This study provides evidence that clinical manifestations of PDCD6IP mutations as seen in our patients with PM and ID may be a novel cause for neurodevelopmental disorders.

BackgroundPrimary autosomal recessive microcephaly (MCPH) is a rare neurodevelopmental disorder that results in severe microcephaly at birth with pronounced reduction in brain volume, particularly of the neocortex, simplified cortical gyration and intellectual disability. Homozygous mutations in the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 are the cause of MCPH3. Despite considerable interest in MCPH as a model disorder for brain development, the underlying pathomechanism has not been definitively established and only four pedigrees with three CDK5RAP2 mutations have been reported. Specifically for MCPH3, no detailed radiological or histological descriptions exist.Methods/ResultsWe sought to characterize the clinical and radiological features and pathological cellular processes that contribute to the human MCPH3 phenotype. Haplotype analysis using microsatellite markers around the MCPH1-7 and PNKP loci in an Italian family with two sons with primary microcephaly, revealed possible linkage to the MCPH3 locus. Sequencing of the coding exons and exon/intron splice junctions of the CDK5RAP2 gene identified homozygosity for the novel nonsense mutation, c.4441C > T (p.Arg1481*), in both affected sons. cMRI showed microcephaly, simplified gyral pattern and hypogenesis of the corpus callosum. The cellular phenotype was assessed in EBV-transformed lymphocyte cell lines established from the two affected sons and compared with healthy male controls. CDK5RAP2 protein levels were below detection level in immortalized lymphocytes from the patients. Moreover, mitotic spindle defects and disrupted γ-tubulin localization to the centrosome were apparent.ConclusionThese results suggest that spindle defects and a disruption of centrosome integrity play an important role in the development of microcephaly in MCPH3.

The first case of CDK5RAP2-related primary microcephaly in a non-consanguineous patient identified by next generation sequencing

Open Trial of Risperidone in 24 Young Children With Pervasive Developmental Disorders

P-12-8 - A review of the psychomotor effects of paroxetine

Skin picking disorder (SPD) has frequently been reported to start before the age of 10; but “very-early onset” type was not defined before in the literature. Also research on the treatment of SPD in childhood is limited. We presented a “very-early onset” SPD case whose symptoms have started on the age of 4 and escalated with her comorbid oppositional defiant disorder diagnosis. Patient was successfully treated with low dose (0.25 mg/day) risperidone and proper psychoeducational interventions. Identifying SPD in very early childhood is hard cause; criterion of SPD might not capture all the specific features which very young children manifest and clinicians might overlook their complaints. Efficacy of risperidone might reflect a shared psychopathological etiology between impulse control and SPD, and lead future research on treatment of SPD with atypical anti-psychotics.

Individuals with repetitive or impulsive aggression in the absence of other disorders may be diagnosed with intermittent explosive disorder according to DSM-IV, but no such diagnostic category exists in ICD-10. Mood stabilisers are often used off-license for the treatment of aggression associated with a variety of psychiatric conditions, but their efficacy in these and in idiopathic aggression is not known. To summarise and evaluate the evidence for the efficacy of mood stabilisers (anticonvulsants/lithium) in the treatment of impulsive or repetitive aggression in adults. A meta-analysis of randomised controlled trials that compared a mood stabiliser with placebo in adults without intellectual disability, organic brain disorder or psychotic illness, identified as exhibiting repetitive or impulsive aggression. Ten eligible trials (489 participants) were identified A pooled analysis showed an overall significant reduction in the frequency/severity of aggressive behaviour (standardised mean difference (SMD) = -1.02, 95% CI -1.54 to -0.50), although heterogeneity was high (I(2) = 84.7%). When analysed by drug type, significant effects were found in the pooled analysis of three phenytoin trials (SMD = -1.34, 95% CI -2.16 to -0.52), one lithium trial (SMD = -0.81, 95% CI -1.35 to -0.28), and two oxcarbazepine/carbamazepine trials (SMD = -1.20, 95% CI -1.83 to -0.56). However, when the results of only those studies that had a low risk of bias were pooled (347 participants), there was no significant reduction in aggression (SMD = -0.28, 95% CI -0.73 to 0.17, I(2) = 71.4%). There is evidence that mood stabilisers as a group are significantly better than placebo in reducing aggressive behaviour, but not all mood stabilisers appear to share this effect. There is evidence of efficacy for carbamazepine/oxcarbazepine, phenytoin and lithium. Many studies, however, were at risk of bias and so further randomised controlled trials are recommended.