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Patient 1 at age 42 years. Note the bulbous nasal tip. Small ear with attached lobule, flat midface and prognathism are evident on the lateral view.
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22q11.2 Deletion syndrome has become an important model for understanding the pathophysiology of neurodevelopmental conditions, particularly schizophrenia which develops in about 20-25% of individuals with a chromosome 22q11.2 microdeletion. From the initial discovery of the syndrome, associated developmental delays made it clear that changes in br...
Interstitial telomeric sequences (ITSs) are common in human. We previously reported the presence of an ITS at 22q11.2 which is in the vicinity of the genomically unstable region involved in 22q11 rearrangements. Recently, we studied the molecular status of the ITS 22q11.2 in the normal population. The amplification of an ITS at 22q11.2 showed diffe...
Citations
... Individuals with this syndrome, who are at risk for psychosis, appear to share a common, genetically determined neurobiological vulnerability, involving both motor organisation and the emotion recognition process. Indeed, the 22q11.2DS is tightly associated with an increased risk of developing motor disorders [20,23,24,[90][91][92][93][94][95][96]; furthermore, people with this syndrome show higher impairments in SC abilities compared to the general population [58,59]. It has been suggested that parkinsonism in schizophrenia does not directly impact on social inference process but is rather mediated by the severity of psychopathology and poor neurocognition [62]. ...
Background. The 22q11.2 Deletion Syndrome (22q11.2DS) is a genetic condition at high risk of developing both psychosis and motor disorders. Social Cognition (SC) deficits have been associated not only with schizophrenia but also with Parkinson’s disease (PD). The present study assessed SC deficits in 22q11.2DS and investigated the interaction between motor symptoms and deficits in Facial Emotion Expressions (FEE) recognition and in Theory of Mind (ToM) tasks in people with 22q11.2DS. Methods. We recruited 38 individuals with 22q11.2DS without psychosis ( N = 38 , DEL) and 18 with 22q11.2DS and psychosis ( N = 18 , DEL_SCZ). The Positive And Negative Syndrome Scale (PANSS), Ekman’s 60 Faces Test (EK-60F), the Awareness of Social Inference Test (TASIT EmRec), and the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale part III (UPDRS III) were administered. Correlations were sought between UPDRS III and both TASIT EmRec and EK-60F scores. Analyses were conducted separately for each psychopathological subgroup. Results. Higher UPDRS III ( p = 0.04 ) and lower EK-60F ( p = 0.025 ) scores were observed in the DEL_SCZ group. We found inverse correlations between UPDRS III and both TASIT EmRec ( r = − 0.289 , p = 0.031 ) and EK-60F ( r = − 0.387 , p = 0.006 ) scores in the whole sample. Correlations were no longer significant in the DEL_SCZ group (UPDRS III-TASIT EmRec p = 0.629 ; UPDRS III-EK60F p = 0.933 ) whilst being stronger in the DEL group (TASIT EmRec, r = − 0.560 , p < 0.001 ; EK60F, r = − 0.542 , p < 0.001 ). Analyses were adjusted for CPZ Eq and IQ. Conclusions. A modulation between FEE recognition deficits and motor symptoms and signs was observed in the 22q11.2DS group, likely affecting patients’ quality of life.
... The role of 22q11.2 deletion syndrome as a risk factor for PD has been increasingly recognized [71][72][73][74][75][76][77]. In a Canadian study, in contrast with the general population estimate of 22q11.2 ...
Genetic early-onset Parkinsonism is unique due to frequent co-occurrence of hyperkinetic movement disorder(s) (MD), or additional neurological of systemic findings, including epilepsy in up to 10–15% of cases. Based on both the classification of Parkinsonism in children proposed by Leuzzi and coworkers and the 2017 ILAE epilepsies classification, we performed a literature review in PubMed. A few discrete presentations can be identified: Parkinsonism as a late manifestation of complex neurodevelopmental disorders, characterized by developmental and epileptic encephalopathies (DE-EE), with multiple, refractory seizure types and severely abnormal EEG characteristics, with or without preceding hyperkinetic MD; Parkinsonism in the context of syndromic conditions with unspecific reduced seizure threshold in infancy and childhood; neurodegenerative conditions with brain iron accumulation, in which childhood DE-EE is followed by neurodegeneration; and finally, monogenic juvenile Parkinsonism, in which a subset of patients with intellectual disability or developmental delay (ID/DD) develop hypokinetic MD between 10 and 30 years of age, following unspecific, usually well-controlled, childhood epilepsy. This emerging group of genetic conditions leading to epilepsy or DE-EE in childhood followed by juvenile Parkinsonism highlights the need for careful long-term follow-up, especially in the context of ID/DD, in order to readily identify individuals at increased risk of later Parkinsonism.
... Parkinson-like motor abnormalities, independent of antipsychotic treatment, have been observed in patients with schizophrenia spectrum disorders [21][22][23][24] and PD patients often exhibit pathological features that overlap with schizophrenia, including hallucinations, psychosis and cognitive dysfunction [25][26][27][28]. In addition, a recent GWAS investigation identified nine loci that were jointly associated with both PD and schizophrenia [29], with seven of these loci common in previous studies [30][31][32][33][34]. Deletions in 22q11 have been found to be a strong genetic risk factor for schizophrenia [35] and a number of studies suggest that individuals with 22q11 deletions also develop early-onset PD [36][37][38][39]. On a molecular level, alterations in dopaminergic neurotransmission play a central role in both disorders-PD is associated with loss of dopaminergic neurons of the substantia nigra pars compacta, whereas schizophrenia has been found to be associated with hypodopaminergic activity in the prefrontal cortex and hyperactive dopaminergic activity in the mesolimbic and striatal regions of the brain [40,41]. ...
... Childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ) [60]. Based on CTQ total score, the following cut-offs have been suggested: none to minimal trauma (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36), low to moderate trauma (41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51), moderate to severe trauma (56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68) and severe to extreme trauma [60]. We thus used a score ≥ 41 to identify individuals as having childhood trauma, as this represents the lowest level score indicative of abuse or neglect for each subscale. ...
Evidence suggests that shared pathophysiological mechanisms in neuropsychiatric disorders (NPDs) may contribute to risk and resilience. We used single-gene and network-level transcriptomic approaches to investigate shared and disorder-specific processes underlying posttraumatic stress disorder (PTSD), Parkinson’s disease (PD) and schizophrenia in a South African sample. RNA-seq was performed on blood obtained from cases and controls from each cohort. Gene expression and weighted gene correlation network analyses (WGCNA) were performed using DESeq2 and CEMiTool, respectively. Significant differences in gene expression were limited to the PTSD cohort. However, WGCNA implicated, amongst others, ribosomal expression, inflammation and ubiquitination as key players in the NPDs under investigation. Differential expression in ribosomal-related pathways was observed in the PTSD and PD cohorts, and focal adhesion and extracellular matrix pathways were implicated in PD and schizophrenia. We propose that, despite different phenotypic presentations, core transdiagnostic mechanisms may play important roles in the molecular aetiology of NPDs.
Supplementary Information
The online version contains supplementary material available at 10.1007/s44192-022-00009-y.
... Although the association between 22q11.2DS and parkinsonism was first observed in 1998 [17], only a few case reports and case series have been published that describe the early onset of symptoms in subjects with neither a family history of parkinsonism nor gene mutations commonly associated with early-onset Parkinson's disease (PD) [18][19][20][21][22][23][24]. A recent cross-sectional study revealed that among neurological manifestations of 22q11.2DS, ...
Background: The phenotypic expression of 22q11.2 deletion syndrome (22q11.2DS) is variable and may include cognitive, psychiatric, and neurological manifestations, e.g., parkinsonism. We investigated brain structural alterations in patients with 22q11.2DS with and without parkinsonism (Park+ and Park−) in comparison with healthy controls (HCs). Methods: Voxel-based morphometry was performed on 3D T1-weighted MR images to explore gray matter volume (GMV) differences between 29 patients (15 Park+, 14 Park−), selected from a consecutive series of 56 adults diagnosed with 22q11.2DS, and 24 HCs. One-way ANOVA and multiple linear regression analyses were performed to explore group differences in GMV and correlations between clinical scores (MDS-UPDR-III and MoCA scores) and structural alterations. Results: Significant between-group differences in GMV were found in the cerebellum, specifically in bilateral lobes VIII and left Crus II, as well as in the left superior occipital gyrus. Although both Park+ and Park− patients showed GMV decrements in these regions with respect to HCs, GMV loss in the right lobe VIII and left Crus II was greater in Park+ than in Park− patients. GMV loss did not correlate with clinical scores. Conclusions: Patients with 22q11.2DS and parkinsonism manifest specific cerebellar volume alterations, supporting the hypothesis of neurodegenerative processes in specific cerebellar regions as a putative pathophysiological mechanism responsible for parkinsonism in patients with 22q11.2DS.
... Approximately 5.9% of individuals with 22q11.2 deletion syndrome develop early-onset parkinsonism [131][132][133][134][135] . Neuropathological examination of a subset of these individuals identified loss of dopaminergic neurons within the substantia nigra as well as the presence of α-synuclein-positive Lewy bodies and neurites; these changes are consistent with PD 131 . ...
Intellectual disability and autism spectrum disorder (ASD) are common, and genetic testing is increasingly performed in individuals with these diagnoses to inform prognosis, refine management and provide information about recurrence risk in the family. For neurogenetic conditions associated with intellectual disability and ASD, data on natural history in adults are scarce; however, as older adults with these disorders are identified, it is becoming clear that some conditions are associated with both neurodevelopmental problems and neurodegeneration. Moreover, emerging evidence indicates that some neurogenetic conditions associated primarily with neurodegeneration also affect neurodevelopment. In this Perspective, we discuss examples of diseases that have developmental and degenerative overlap. We propose that neurogenetic disorders should be studied continually across the lifespan to understand the roles of the affected genes in brain development and maintenance, and to inform strategies for treatment.
... The genes codifying for CYP2D6 are located on chromosome 22 [189], where many genes correlated to PD disease are located as well (chromosome 22q11.2 deletion syndrome and early-onset PD) [190][191][192]. In addition, it seems that vitamin D inhibits the activity of Poly (ADP-Ribose) Polymerase-1 (PARP1) [193], a stress protein, which is over-expressed in the substantia nigra of PD patients [194]. ...
Vitamin D is a hormone with both genomic and non-genomic actions. It exerts its activity by binding vitamin D receptor (VDR), which belongs to the superfamily of nuclear receptors and ligand-activated transcription factors. Since VDR has been found in various tissues, it has been estimated that it regulates approximately 3% of the human genome. Several recent studies have shown pleiotropic effects of vitamin D in various processes such as cellular proliferation, differentiation, DNA repair and apoptosis and its involvement in different pathophysiological conditions as inflammation, diabetes mellitus, and anemia. It has been suggested that vitamin D could play an important role in neurodegenerative and cardiovascular disorders. Moderate to strong associations between lower serum vitamin D concentrations and stroke and cardiovascular events have been identified in different analytic approaches, even after controlling for traditional demographic and lifestyle covariates. The mechanisms behind the associations between vitamin D and cerebrovascular and cardiologic profiles have been widely examined both in animal and human studies. Optimization of vitamin D levels in human subjects may improve insulin sensitivity and beta-cell function and lower levels of inflammatory markers. Moreover, it has been demonstrated that altered gene expression of VDR and 1,25D3-membrane-associated rapid response steroid-binding (1,25D3-MARRS) receptor influences the role of vitamin D within neurons and allows them to be more prone to degeneration. This review summarizes the current understanding of the molecular mechanisms underlying vitamin D signaling and the consequences of vitamin D deficiency in neurodegenerative and cardiovascular disorders.
... patients. 46,[48][49][50][51][52][53][54] This association was first considered unexpected, as studies suggested 22q11.2DS is a hyperdopaminergic state. 47 Nonetheless, and despite the high prevalence of schizophrenia and concomitant antipsychotic medication, multiple cases have been demonstrated to have a typical reduced striatal binding on dopamine transporter DaTSCAN imaging, 55 and the presence of SN degeneration associated with α-synuclein-positive Lewy bodies in neuropathologic studies, the neuropathological hallmark of PD, has been demonstrated. ...
... 47 Nonetheless, and despite the high prevalence of schizophrenia and concomitant antipsychotic medication, multiple cases have been demonstrated to have a typical reduced striatal binding on dopamine transporter DaTSCAN imaging, 55 and the presence of SN degeneration associated with α-synuclein-positive Lewy bodies in neuropathologic studies, the neuropathological hallmark of PD, has been demonstrated. 48 A case-control study comparing 9387 PD patients and 13,863 healthy controls found a significantly higher frequency of 22q11.2 deletions in PD patients (0.09%, 8 of 9387 patients) and an even higher prevalence in early-onset PD (0.49%) than in healthy controls (0/13,863 cases). ...
The landscape of genetic forms of Parkinson's diseases (PD) has grown exponentially in recent years. Today, around 10% of PD cases are estimated to be of genetic etiology. However, the link between parkinsonism or tremor and chromosome disorders, both numerical and structural, has been neglected. We reviewed the occurrence and characteristics of parkinsonism and tremor syndromes in patients with chromosomic disorders. We searched PubMed for articles published until December 2018, using the non‐MESH terms “Chromosomopathy,” “karyotype,” “chromosome,” “aneuploidy,” “deletion,” “inversion,” “insertion,” “duplication,” and “Parkinson,” “Parkinsonism,” “Tremor,” and “Parkinsonian disorder.” We restricted the search to human studies and selected articles for further analysis after abstract review. Tremor syndromes in which patients had another possible clinical reason for syndromes were excluded, as well as tremor syndromes associated with point mutations, imprinting syndromes, and patients presenting with other hyperkinetic disorders. Fifty‐four articles were reviewed. Aneuploidies of sex chromosomes were the most common chromosomopathy. These patients more commonly exhibited postural and kinetic tremor, often meeting the description of essential tremor. In structural chromosomopathies, the most frequent association was PD and 22q11.2 deletion syndrome, but we found case reports and case series of several additional deletion and duplication syndromes. © 2021 International Parkinson and Movement Disorder Society
... However, more recent studies challenge this belief, since it is observed that the patients with DiGeorge syndrome show movement disorders even in their childhood. Additionally, PD develops in those adult patients with DiGeorge syndrome, who are not under the treatment with psychological drug regimens [13,20]. Therefore, PD can be considered to be an independent aspect of 22q11.2 ...
There are still unknown mechanisms involved in the development of Parkinson’s disease (PD), which elucidating them can assist in developing efficient therapies. Recently, studies showed that genes located on the human chromosomal location 22q11.2 might be involved in the development of PD. Therefore, the present study was designed to evaluate the role of two genes located on the chromosomal location (miR-185 and SEPT5), which were the most probable candidates based on our bibliography. In vivo and in vitro models of PD were developed using male Wistar rats and SHSY-5Y cell line, respectively. The expression levels of miR-185, SEPT5, LRRK2, and PARK2 genes were measured at a mRNA level in dopaminergic areas of rats’ brains and SHSY-5Y cells using the SYBR Green Real-Time PCR Method . Additionally, the effect of inhibition on the genes or their products on cell viability and gene expression pattern in SHSY-5Y cells was investigated. The level of miR-185 gene expression was significantly decreased in the substantia nigra (SN) and striatum (ST) of the rotenone-treated group (control group) compared to the healthy normal group ( P<0.05 ). In addition, there was a significant difference in the expression of SEPT5 gene ( P<0.05 ) in the substantia nigra between two studied groups. The results of an in vitro study showed no significant change in the expression of the genes; however, the inhibition on miR-185 gene expression led to the increase in LRRK2 gene expression in SHSY-5Y cells. The inhibition on LRRK2 protein also decreased the cellular toxicity effect of rotenone on SHSY-5Y cells. The results suggested the protective role of miR-185 gene in preventing the development of PD.
... Although the association between this genetic syndrome and Genotype-phenotype correlations parkinsonian features was first observed in 1998, 34 few case reports and case series have been published so far, describing the early onset of symptoms in subjects with neither a family history of parkinsonism nor gene mutations commonly associated with early-onset Parkinson's disease (PD). [35][36][37][38][39][40][41][42][43] Asymmetric clinical signs, disease course and response to treatment (L-dopa and dopamine agonists) in 22q11.2DS are all similar to those in PD. ...
Background
22q11.2 deletion syndrome (22q11.2DS) is considered as the genetic model of schizophrenia. However, its polymorphic nature has led researchers to further investigate its neuropsychiatric manifestations.
Methods
We enrolled 56 adults (38 men, 18 women) diagnosed with 22q11.2DS. All subjects were evaluated by a multidisciplinary team. The neuropsychiatric features were investigated by means of clinical and neurophysiological evaluation (video-EEG).
Results
Thirty per cent of our patients were left-handed. Fifty-eight per cent had a low IQ, and 22 of 56 subjects had psychotic disorders (13 of 22 with schizophrenia). Eighteen patients reported at least one seizure in their lifetime, and ten were diagnosed with epilepsy; among them, seven had genetic generalised epilepsy (GGE), and five of seven showed features suggestive of juvenile myoclonic epilepsy (JME). Video-EEG recordings revealed generalised epileptiform abnormalities in 24 of 56 cases. Besides, only one patient with epilepsy had a cardiac malformation. Lastly, 31 of 56 subjects presented with parkinsonism, 16 of whom were taking neuroleptics. None of the 15 patients with parkinsonism not related to neuroleptic therapy was diagnosed with epilepsy, compared with 6 of those taking antipsychotics.
Conclusions
22q11.2DS is characterised by left-handedness and neuropsychiatric features such as cognitive impairment, schizophrenia, epilepsy and parkinsonism. GGE, mostly the JME phenotype, is the predominant epilepsy type. The significant association between 22q11.2DS and parkinsonian features confirms these patients’ genetic susceptibility to parkinsonism. Despite the lack of any conclusive evidence, our study suggests a possible relationship between the analysed clinical variables: (1) an inverse correlation between low IQ/psychosis/epilepsy and major cardiac diseases; (2) a direct association between psychosis and both mental delay and epilepsy; and (3) an inverse correlation between parkinsonism and epilepsy.
... In one report of adults with 22qDS, the older they were at the time of assessment, the more noncongenital features were found, indicating an ongoing emergence of conditions that may affect communication skills (Bassett et al., 2005). Examples of this include early onset Parkinson's disease (Butcher et al., 2013;Zaleski et al., 2009), schizophrenia, and anxiety disorders (Philip & Bassett, 2011). Multiple studies have found cerebral alterations in adults with 22qDS (Gothelf, Schaer, & Eliez, 2008;Shprintzen, 2008). ...
Purpose
Speech and language disorders are hallmark features of 22q11.2 deletion syndrome (22qDS). Learning disabilities, cognitive deficits, palate abnormalities, velopharyngeal dysfunction, behavioral differences, and various medical and psychiatric conditions are also major features of this syndrome. The goal of this document is to summarize the state of the art of current clinical and scientific knowledge regarding 22qDS for speech-language pathologists (SLPs) and provide recommendations for clinical management.
Method
Best practices for management of individuals with 22qDS were developed by consensus of an expert international group of SLPs and researchers with expertise in 22qDS. These care recommendations are based on the authors' research, clinical experience, and literature review.
Results
This document describes the features of 22qDS as well as evaluation procedures, treatment protocols, and associated management recommendations for SLPs for the often complex communication disorders present in this population.
Conclusion
Early diagnosis and appropriate management of speech-language disorders in 22qDS is essential to optimize outcomes and to minimize the long-term effects of communication impairments. Knowledge of this diagnosis also allows anticipatory care and guidance regarding associated features for families, health care, and educational professionals.
