Smith-Magenis syndrome (SMS), linked to
(
) haploinsufficiency, is a unique model of the inversion of circadian melatonin secretion. In this regard, this model is a formidable approach to better ...understand circadian melatonin secretion cycle disorders and the role of the
gene in this cycle. Sleep-wake cycle disorders in SMS include sleep maintenance disorders with a phase advance and intense sleepiness around noon. These disorders have been linked to a general disturbance of sleep-wake rhythm and coexist with inverted secretion of melatonin. The exact mechanism underlying the inversion of circadian melatonin secretion in SMS has rarely been discussed. We suggest three hypotheses that could account for the inversion of circadian melatonin secretion and discuss them. First, inversion of the circadian melatonin secretion rhythm could be linked to alterations in light signal transduction. Second, this inversion could imply global misalignment of the circadian system. Third, the inversion is not linked to a global circadian clock shift but rather to a specific impairment in the melatonin secretion pathway between the suprachiasmatic nuclei (SCN) and pinealocytes. The development of diurnal SMS animal models that produce melatonin appears to be an indispensable step to further understand the molecular basis of the circadian melatonin secretion rhythm.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The
22q11.2 duplication
is a variably penetrant copy number variant (CNV) associated with a broad spectrum of clinical manifestations including autism spectrum disorders (ASD), and epilepsy. Here, we ...report on pathogenic
HUWE1
and
KIF1A
mutations in two severely affected ASD/ID participants carrying a 22q11.2 duplication. Based on previous studies, this CNV was originally considered as disease-causing. Yet, owing to their clinical severity, the participants were further investigated by next generation sequencing and eventually found to carry pathogenic mutations in
HUWE1
and
KIF1A
respectively. We suggest giving consideration to additive effect of 22q11.2 duplication and pathogenic mutations when clinical presentation is either unusually severe or associated with atypical features. Caution should be exercised when delivering genetic counseling for variably penetrant CNVs, as uncertain penetrance of this CNV may lead to ignore additive pathogenic mutations. Systematic panel or exome sequencing of known ASD genes should be recommended when counseling families of patients carrying variably penetrant CNV.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, ODKLJ, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Pathogenic variants of the AUTS2 (Autism Susceptibility candidate 2) gene predispose to intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, facial dysmorphism ...and short stature. This phenotype is therefore associated with neurocognitive disturbances and social cognition, indicating potential functional maladjustment in the affected subjects, and a potentially significant impact on quality of life. Although many isolated cases have been reported in the literature, to date no families have been described. This case reports on a family (three generations) with a frameshift variant in the AUTS2 gene.
The proband is 13 years old with short stature, dysmorphic features, moderate intellectual disability and autism spectrum disorder. His mother is 49 years old and also has short stature and similar dysmorphic features. She does not have autism disorder but presents an erotomaniac delusion. Her cognitive performance is heterogeneous. The two aunts are also of short stature. The 50-year-old aunt has isolated social cognition disorders. The 45-year-old aunt has severe cognitive impairment and autism spectrum disorder. The molecular analysis of the three sisters and the proband shows the same AUTS2 heterozygous duplication leading to a frame shift expected to produce a premature stop codon, p.(Met593Tyrfs*85). Previously reported isolated cases revealed phenotypic and cognitive impairment variability. In this case report, these variabilities are present within the same family, presenting the same variant.
The possibility of a phenotypic spectrum within the same family highlights the need for joint psychiatry and genetics research.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Comorbid psychiatric disorders are frequent in children with intellectual disability (ID). Given the limitations of drugs treatments, cognitive remediation could be a promising tool to reduce these ...challenging behaviors but evidence is still scarce. Our group recently developed the «COGNITUS & MOI» program that is designed to train the attentional and visuospatial skills in children with ID. This study investigates the efficiency of the «COGNITUS & MOI» program in this condition.
Children (age: 6.00-13.11) with mild to moderate ID and behavioral problems, will benefit from a therapy during a 16 week randomized controlled trial. One group will be randomly treated with the «COGNITUS & MOI» program and the other with a motor skill and video viewing intervention. All participants will undergo a behavioral, functional and neurocognitive assessment at baseline, post-intervention, and 6-month follow-up. Primary outcome will be the change from the baseline of the score on the "hyperactivity - noncompliance" subscale of the Aberrant Behavior Checklist.
If the results are conclusive, the «COGNITUS & MOI» program could be added to the therapeutic arsenal against challenging behavior in children with ID.
ClinicalTrials NCT02797418 . Date registered: 8th of June 2016.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Slowness of movement initiation is a cardinal motor feature of Parkinson’s disease (PD) and is not fully reverted by current dopaminergic treatments. This trouble could be due to the dysfunction of ...executive processes and, in particular, of inhibitory control of response initiation, a function possibly associated with the noradrenergic (NA) system. The implication of NA in the network supporting proactive inhibition remains to be elucidated using pharmacological protocols. For that purpose, we administered 150 μg of clonidine to 15 healthy subjects and 12 parkinsonian patients in a double-blind, randomized, placebo-controlled design. Proactive inhibition was assessed by means of a Go/noGo task, while pre-stimulus brain activity was measured by event-related functional MRI. Acute reduction in noradrenergic transmission induced by clonidine enhanced difficulties initiating movements reflected by an increase in omission errors and modulated the activity of the anterior node of the proactive inhibitory network (dorsomedial prefrontal and anterior cingulate cortices) in PD patients. We conclude that NA contributes to movement initiation by acting on proactive inhibitory control via the α2-adrenoceptor. We suggest that targeting noradrenergic dysfunction may represent a new treatment approach in some of the movement initiation disorders seen in Parkinson’s disease.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Smith-Magenis syndrome is a complex neurodevelopmental disorder that includes intellectual deficiency, speech delay, behavioral disturbance and typical sleep disorders. Ninety percent of the cases ...are due to a 17p11.2 deletion encompassing the RAI1 gene; other cases are linked to mutations of the same gene. Behavioral disorders often include outbursts, attention deficit/hyperactivity disorders, self-injury with onychotillomania and polyembolokoilamania (insertion of objects into body orifices), etc. Interestingly, the stronger the speech delay and sleep disorders, the more severe the behavioral issues. Sleep disturbances associate excessive daytime sleepiness with nighttime agitation. They are underpinned by an inversion of the melatonin secretion cycle. However, the combined intake of beta-blockers in the morning and melatonin in the evening may radically alleviate the circadian rhythm problems.
Once sleep disorders are treated, the next challenge is finding an effective treatment for the remaining behavioral problems. Unfortunately, there is a lack of objective guidelines. A comprehensive evaluation of such disorders should include sleep disorders, potential causes of pain, neurocognitive level and environment (i.e. family and school). In any case, efforts should focus on improving communication skills, identifying and treating attention deficit/hyperactivity, aggressiveness and anxiety. Treatment of Smith-Magenis syndrome is complex and requires a multidisciplinary team including, among others, geneticists, psychiatrists, neuropediatricians/neurologists, somnologists, developmental and behavioral pediatricians, and speech and language therapists.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Math learning difficulty (i.e., MLD) is common in children and can have far-reaching consequences in personal and professional life. Converging evidence suggests that MLD is associated with ...impairments in the intraparietal sulcus (IPS). However, the role that these impairments play in MLD remains unclear. Although it is often assumed that IPS deficits affect core numerical abilities, the IPS is also involved in several non-numerical processes that may contribute to math skills. For instance, the IPS supports transitive reasoning (i.e., the ability to integrate relations such as A > B and B > C to infer that A > C), a skill that is central to many aspects of math learning in children. Here we measured fMRI activity of 8- to 12-year-olds with MLD and typically developing (TD) peers while they listened to stories that included transitive relations. Children also answered questions evaluating whether transitive inferences were made during story comprehension. Compared to non-transitive relations (e.g., A > B and C > D), listening to transitive relations (e.g., A > B and B > C) was associated with enhanced activity in the IPS in TD children. In children with MLD, the difference in activity between transitive and non-transitive relations in the IPS was (i) non-reliable and (ii) smaller than in TD children. Finally, children with MLD were less accurate than TD peers when making transitive inferences based on transitive relations. Thus, a deficit in the online processing of transitive relations in the IPS might contribute to math difficulties in children with MLD.
•Transitive reasoning is central to mathematical thinking.•Transitive reasoning relies on the intra-parietal sulcus (IPS) in healthy children.•Math learning difficulty (MLD) is associated with IPS impairments.•Transitive reasoning is impaired in children with MLD.•Transitive reasoning does not engage the IPS in children with MLD.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The role of deleterious copy number variations in schizophrenia is well established while data regarding pathogenic variations remain scarce. We report for the first time a case of schizophrenia in a ...child with a pathogenic mutation of the chromodomain helicase DNA binding protein 2 (CHD2) gene.
The proband was the second child of unrelated parents. Anxiety and sleep disorders appeared at the age of 10 months. He presented febrile seizures and, at the age of 8, two generalized tonic-clonic seizures. At the age of 10, emotional withdrawal emerged, along with a flat affect, disorganization and paranoid ideation, without seizures. He began to talk and giggle with self. Eventually, the patient presented daily auditory and visual hallucinations. The diagnosis of childhood onset schizophrenia (DSM V) was then evoked. Brain imaging was unremarkable. Wakefulness electroencephalography showed a normal background and some bilateral spike-wave discharges that did not explain the psychosis features. A comparative genomic hybridization array (180 K, Agilent, Santa Clara, CA, USA) revealed an 867-kb 16p13.3 duplication, interpreted as a variant of unknown significance confirmed by a quantitative PCR that also showed its maternal inheritance. Risperidone (1,5 mg per day), led to clinical improvement. At the age of 11, an explosive relapse of epilepsy occurred with daily seizures of various types. The sequencing of a panel for monogenic epileptic disorders and Sanger sequencing revealed a de novo pathogenic heterozygous transition in CHD2 (NM_001271.3: c.4003G > T).
This case underlines that schizophrenia may be, sometimes, underpinned by a Mendelian disease. It addresses the question of systematic genetic investigations in the presence of warning signs such as a childhood onset of the schizophrenia or a resistant epilepsy. It points that, in the absence of pathogenic copy number variation, the investigations should also include a search for pathogenic variations, which means that some of the patients with schizophrenia should benefit from Next Generation Sequencing tools. Last but not least, CHD2 encodes a member of the chromodomain helicase DNA-binding (CHD) family involved in chromatin remodeling. This observation adds schizophrenia to the phenotypic spectrum of chromodomain remodeling disorders, which may lead to innovative therapeutic approaches.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alterations in cognitive functions in Parkinson's disease (PD) have been reported even in mild stages of the disease. These functions may play a role in complex daily activities, such as driving. ...This article provides an overview on the relationships between cognitive functions and driving behavior in PD in driving simulator and on-road studies. The role of attention, executive functions, visual memory, visuospatial construction and information processing speed is discussed. In driving simulator studies, driving performances were correlated with several neuropsychological measures, especially those of Trail Making Test (TMT), Brixton and Symbol Digit Modalities Test. In on-road studies, TMT, Useful Field Of View and Block Design tests appear as good predictors of driving performances. Most of these tests are also relevant to driving in Alzheimer's disease and traumatic brain injury.
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