Stefano D'Arrigo

Consensus Paper: The Cerebellum's Role in Movement and Cognition

While the cerebellums role in motor function is well recognized, the nature of its concurrent role in cognitive function remains considerably less clear. The current consensus paper gathers diverse views on a variety of important roles played by the cerebellum across a range of cognitive and emotional functions. This paper considers the cerebellum in relation to neurocognitive development, language function, working memory, executive function, and the development of cerebellar internal control models and reflects upon some of the ways in which better understanding the cerebellums status as a “supervised learning machine” can enrich our ability to understand human function and adaptation. As all contributors agree that the cerebellum plays a role in cognition, there is also an agreement that this conclusion remains highly inferential. Many conclusions about the role of the cerebellum in cognition originate from applying known information about cerebellar contributions to the coordination and quality of movement. These inferences are based on the uniformity of the cerebellums compositional infrastructure and its apparent modular organization. There is considerable support for this view, based upon observations of patients with pathology within the cerebellum.

Molecular mechanisms generating and stabilizing terminal 22q13 deletions in 44 subjects with Phelan/McDermid syndrome

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.

Duplications of FOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment

Genome-wide high-resolution array analysis is rapidly becoming a reliable method of diagnostic investigation in individuals with mental retardation and congenital anomalies, leading to the identification of several novel microdeletion and microduplication syndromes. We have identified seven individuals with duplication on chromosome 14q11.2q13.1, who exhibited idiopathic developmental delay and cognitive impairment, severe speech delay, and developmental epilepsy. Among these cases, the minimal common duplicated region on chromosome 14q11.2q13.1 includes only three genes, FOXG1, C14orf23, and PRKD1. We propose that increased dosage of Forkhead Box G1 (FOXG1) is the best candidate to explain the abnormal neurodevelopmental phenotypes observed in our patients. Deletions and inactivating mutations of FOXG1 have been associated with a Rett-like syndrome characterized by hypotonia, irritability, developmental delay, hand stereotypies, and deceleration of head growth. FOXG1, encoding a brain-specific transcription factor, has an important role in the developing brain. In fact, in vivo studies in chicken brain demonstrated that overexpression of FOXG1 results in thickening of the neuroepithelium and outgrowth of the telencephalon and mesencephalum, secondary to a reduction in neuroepithelial cell apoptosis.

MKS3/TMEM67 Mutations Are a Major Cause of COACH Syndrome, a Joubert Syndrome Related Disorder with Liver Involvement

The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the “molar tooth sign”, a midbrain‐hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel‐like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene‐phenotype correlates in JSRDs.

Delineation and Diagnostic Criteria of Oral-Facial-Digital Syndrome Type VI

Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of one or more hands or feet; 3) hypothalamic hamartoma.

Functional genome-wide siRNA screen identifies KIAA0586 as mutated in Joubert syndrome.

Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome-wide small interfering RNA (siRNA) screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised-learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586. A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3, required for ciliogenesis and Sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies. DOI: http://dx.doi.org/10.7554/eLife.06602.001

Personality traits in childhood and adolescent headache

We evaluate personality traits, anxiety and depression in a population of paediatric and adolescent patients, correlating personality characteristics with headache and sociodemographic variables. The clinical features of headache include specific personality traits. We report a clinical study of 57 patients (age 8–18 years), divided up as follows: 12 migraine with aura, 29 migraine without aura and 16 tension-type headache. One of Cattels tests was administered to every patient; the Childrens Depression Inventory test was administered to 53 patients and the Test Anxiety Inventory test to 43 subjects. The scores obtained by every patient in each test were correlated with the characteristics of headache and with sociodemographic data. We found that patients affected by idiopathic headache share some personality traits, mainly emotional rigidity and tendency to repress anger and aggression. These traits do not seem to be correlated with sociodemographic data and the duration of headache: we considered these as characteristic of migrainous patients.

Cognitive and behavioural effects of migraine in childhood and adolescence

Since cognitive and behavioural characteristics of paediatric migraineurs have yet to be adequately defined, in this study we assessed the effect of migraine on the interictal functioning of children and adolescents by comparing the performance of two patient groups, 17 migraineurs with aura (MA) and 31 without aura (MoA) and by correlating the duration of the disorder, the frequency of attacks and interictal period with neuropsychological and behavioural findings. Both patient groups had cognitive performance within normal range except for a significant delay in the reaction time (RT) task. Both MA and MoA revealed a behavioural phenotype characterized by internalizing problems on Child Behaviour Check List (CBCL) scales. Slower RT to simple visual stimuli may be an early sign of a subclinical neuropsychological dysfunction, significantly correlated with the frequency of headache attacks and interictal period. The lack of a control group and other methodological limitations, such as patient selection bias and unadjusted P-value for multiple testing, make it difficult to give this finding a clearcut meaning. Further studies are needed on larger samples compared with a control group.

Verbal dichotic listening performance and its relationship with EEG features in benign childhood epilepsy with centrotemporal spikes

PURPOSE Benign epilepsy of childhood with centrotemporal spikes (BECTS) is the most common form of idiopathic partial epilepsy in children from 3 to 12 years old. Little and far from conclusive information is available on its chronic impact on the organization of higher cognitive functions during development. The aim of this study was to assess the effect of interictal EEG discharges in the peri-sylvian regions on language lateralization in BECTS. METHODS Twenty-four 7-12-year-old children with BECTS were compared with a control group of 16 healthy children matched for age, gender and schooling. Hemispheric speech lateralization was determined with the vowel-consonant dichotic listening (DL) test. RESULTS DL data showed that BECTS children lacked the typical right ear/left hemisphere functional advantage. The side of the interictal spikes had no specific influence on DL performance, while a multifocal location of the discharges had a particularly significant effect on the laterality index, as shown by the complete loss of the right-ear advantage in favor of a symmetrical performance with the overall level of accuracy remaining constant. No correlation was found between spike frequency and DL data. CONCLUSIONS BECTS coincides with an atypical performance in DL test with the loss of the usual right ear/left hemisphere advantage, suggesting that interictal activity may induce a reorganization of speech perception lateralization, with a bilateral representation of the phonological processing of auditory and verbal stimuli. This was particularly evident in the group with multifocal spikes, which may mean that a widespread hyperexcitability can affect the network underlying DL performance more severely.

Band‐like intracranial calcification with simplified gyration and polymicrogyria: A distinct “pseudo‐TORCH” phenotype

The combination of intracranial calcification and polymicrogyria is usually seen in the context of intrauterine infection, most frequently due to cytomegalovirus. Rare familial occurrences have been reported. We describe five patients—two male–female sibling pairs, one pair born to consanguineous parents, and an unrelated female—with a distinct pattern of band‐like intracranial calcification associated with simplified gyration and polymicrogyria. Clinical features include severe post‐natal microcephaly, seizures and profound developmental arrest. Testing for infectious agents was negative. We consider that these children have the same recognizable “pseudo‐TORCH” phenotype inherited as an autosomal recessive trait.