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Multisystem involvement in 22q11.2 deletion syndrome
Source publication
Background
22q11.2 deletion syndrome (22q11.2DS) is a multisystem condition associated with an increased risk of early‐onset Parkinson's disease (PD).
Methods
We review the clinical, neuroimaging and neuropathological observations, as well as diagnostic challenges, of PD in 22q11.2DS. We conducted a search of PubMed up until June 1, 2018 and perso...
Contexts in source publication
Context 1
... is the most common human microdeletion syn- drome. 2 It is a multisystem condition (Table 1) known to have significant variability in the spectrum of its features and the sever- ity of their expression between individuals, even between affected family members. 2 Cardinal features often change with age. ...
Context 2
... model include: (1) the fact that, in contrast to other genetic forms of PD, patients with 22q11.2DS are clinically identifiable (see Table 1 for comorbid features that may increase the index of sus- picion for 22q11.DS) and that genetic testing is readily available; (2) young average age at PD onset (40 years), reducing the risk for age-related neurodegenerative processes other than PD that may affect study findings; (3) testable hypotheses concerning major mechanisms underlying idiopathic and 22q11.2DS- associated PD, including dopamine autotoxicity related to impaired dopamine clearance (genes of potential interest in the 22q11.2 ...
Citations
... deletion syndrome (22qDS, also known as DiGeorge syndrome and velocardiofacial syndrome). This condition is due to a 3-Mb hemizygous deletion of 42 protein-coding genes on chromosome 22 (24), and confers an increased risk for both neurodevelopmental conditions, including autism and attention deficit hyperactivity disorder, as well as neurodegenerative diseases, primarily Parkinson's disease (25,26). As this population is at a 25-fold increased risk for psychosis, the 22q11.2 ...
Maintenance of blood-brain barrier (BBB) integrity is critical to optimal brain function, and its impairment has been linked to multiple neurological disorders. A notable feature of the BBB is its elevated mitochondrial content compared to peripheral endothelial cells, although the functional implications of this phenomenon remain unknown. Here we studied BBB mitochondrial function in the context of the 22q11.2 deletion syndrome (22qDS), a condition associated with a highly increased risk for neuropsychiatric disease. As the 22q11.2 deletion includes 6 mitochondrial genes, and because we have previously identified BBB impairment in 22qDS, we addressed the hypothesis that mitochondrial deficits contribute to BBB dysfunction and impact behavior in this condition. We report mitochondrial impairment in human induced pluripotent stem cell (iPSC)-derived BBB endothelial cells from 22qDS patients, and in BBB endothelial cells from a mouse model of 22qDS. Remarkably, treatment to improve mitochondrial function attenuates mitochondrial deficits and enhances BBB function in both the iPSC and mouse 22qDS models. This treatment also corrected social memory in the mouse model, a deficit previously associated with BBB dysfunction. As BBB integrity correlated with social memory performance, together our findings suggest that mitochondrial dysfunction in the BBB influences barrier integrity and behavior in 22qDS.
... Patients with 22q11.2DS show a marked variability in clinical manifestations, that may include palatal abnormalities, congenital heart defects, intellectual disability, and an increased risk of developing psychiatric disorders (e.g., schizophrenia) and neurodegenerative disorders that may present at young age (e.g., early-onset Parkinson's disease) (Bassett et al., 2005;Boot et al., 2019;Campbell et al., 2018;Schneider et al., 2014). Previous studies in 22q11.2DS, ...
Previous studies have shown that the 22q11.2 microdeletion, associated with 22q11.2 deletion syndrome (22q11.2DS), conveys an increased risk of chronic otitis media, and hearing loss at young age. This study reports on hearing loss and history of otolaryngological conditions in adults with 22q11.2DS. We conducted a retrospective study of 60 adults with 22q11.2DS (41.7% male) at median age 25 (range 16–74) years who had visited an otolaryngologist and audiologist for routine assessment at a 22q11.2 expert center. Demographic, genetic, audiometric, and otolaryngological data were systematically extracted from the medical files. Regression analysis was used to evaluate the effect of age, sex, full‐scale intelligence quotient, and history of chronic otitis media on the severity of hearing loss. Hearing loss, mostly high‐frequency sensorineural, was found in 78.3% of adults. Higher age and history of chronic otitis media were associated with more severe hearing loss. Otolaryngological conditions with possible treatment implications included chronic otitis media (56.7%), globus pharyngeus (18.3%), balance problems (16.7%), and obstructive sleep apnea (8.3%). The results suggest that in 22q11.2DS, high‐frequency hearing loss appears to be common from a young adult age, and often unrecognized. Therefore, we recommend periodic audiometric screening in all adults, including high‐frequency ranges.
... Similarly, a higher incidence of Parkinson's Disease (PD) in 22q11.2DS compared to the general population has also been described [20,21]. It is estimated that 22q11.2 ...
... 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.
... 13 Although metabolic, cardiac and hematological manifestations, 17 or movement disorders such as parkinsonism or early dystonia, can occur independently of adverse effects from treatment, treatment itself may lower the threshold to develop such symptoms. 20,21 This warrants a close monitoring of antipsychotic prescription, while trying to limit polypharmacy in a population prone to comorbidities. 22 Sleep apnea should also be suspected with subjective cognitive symptoms, considering the risk factors of dysmorphic features and obesity. ...
... The clinical phenotype is highly heterogeneous and may include obesity [2], heart defects, facial anomalies, immune-related issues, and developmental delay [3]. Individuals with this syndrome further have a 20-fold increase in the risk of developing schizophrenia [4][5][6], and it is associated with a range of other neuropsychiatric disorders [7,8] including autism spectrum disorder (ASD) [9], intellectual disability [10], attention deficit hyperactivity disorder (ADHD) [11], Parkinson's disease [12], anxiety, and depression [13]. Patients with 22q11DS also exhibit a wide range of impairments in the linguistic, affective, and cognitive domains [14][15][16][17][18][19]. ...
22q11.2 deletion syndrome (22q11DS) is a clinically heterogeneous genetic syndrome, associated with a wide array of neuropsychiatric symptoms. The clinical presentation is likely to be influenced by environmental factors, yet little is known about this. Here, we review the available research literature on the role of the environment in 22q11DS. We find that within-patient design studies have mainly investigated the role of parental factors, stress, and substance use, reporting significant effects of these factors on the clinical profile. Case-control studies have been less successful, with almost no reports of significant moderating effects of the environment. We go on to hypothesize which specific environmental measures are most likely to interact with the 22q11 deletion, based on the genes in this region and their involvement in molecular pathways. We end by discussing potential reasons for the limited findings so far, including modest sample sizes and limited availability of environmental measures, and make recommendations how to move forward.
... For example, around 0.5% of individuals with early-onset PD have 22q11.2 deletion syndrome, also known as velocardiofacial syndrome 130 . This syndrome is characterized by multiple congenital anomalies including cardiac defects, skeletal anomalies, cleft palate, learning disabilities and/or intellectual disabilities and schizophrenia. ...
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.
... This topic has recently received much more attention than last years from researchers and clinicians, and a number of works aimed to assess the clinical characteristics, neuroimaging, neuropathological observations, as well as diagnostic challenges in PD 22q11.2 deletion carriers have been conducted [52][53][54]. From a genetic point of view, a whole genome sequencing study was recently carried out in nine adults with 22q11.2 deletion to investigate sequence variants and test candidate gene-sets relevant to PD. Findings suggested that the cumulative burden of genome-wide sequence variants may contribute to the expression of EOPD in the presence of threshold-lowering dosage effects and offered evidence of the potential effects of multiple within-individual rare variants outside the 22q11.2 ...
Alzheimer and Parkinson’s diseases are neurodegenerative aging-related pathological conditions, mainly caused by the interplay of genetic and non-genetic factors and whose incidence rate is going to drastically increase given the growing life expectancy. To address these complex multifactorial traits, a systems biology strategy is needed to highlight genotype–phenotype correlations as well as overlapping gene signatures. Copy number variants (CNVs) are structural chromosomal imbalances that can have pathogenic nature causing or contributing to the disease onset or progression. Moreover, neurons affected by CNVs have been found to decline in number depending on age in healthy controls and may be selectively vulnerable to aging-related cell-death. In this review, we aim to update the reader on the role of these variations in the pathogenesis of Alzheimer and Parkinson diseases. To widen the comprehension of pathogenic mechanisms underlying them, we discuss variations detected from blood or brain specimens, as well as overlapped signatures between the two pathologies.
... (22q11.2DS, OMIM # 188400) have only recently been implicated in PD [90,91]. The 22q11.2 deletion is considered to be one of the most common deletion syndromes (~1:1000-3000 births) and was first described in 1968 [92,93]. ...
... Recently, it has been recognized that adults with 22q11.2DS have a higher risk of developing PD [91] as illustrated by a PD prevalence of 5.9% in a cohort of 159 adults (ages 35-64 years) with 22q11.2DS [98]. ...
Neurodevelopmental and late-onset neurodegenerative disorders present as separate entities that are clinically and neuropathologically quite distinct. However, recent evidence has highlighted surprising commonalities and converging features at the clinical, genomic, and molecular level between these two disease spectra. This is particularly striking in the context of autism spectrum disorder (ASD) and Parkinson’s disease (PD). Genetic causes and risk factors play a central role in disease pathophysiology and enable the identification of overlapping mechanisms and pathways. Here, we focus on clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD. Several genes and genomic regions were selected for our review, including SNCA (alpha-synuclein), PARK2 (parkin RBR E3 ubiquitin protein ligase), chromosome 22q11 deletion/DiGeorge region, and FMR1 (fragile X mental retardation 1) repeat expansion, which influence the development of both ASD and PD, with converging features related to synaptic function and neurogenesis. Both PD and ASD display alterations and impairments at the synaptic level, representing early and key disease phenotypes, which support the hypothesis of converging mechanisms between the two types of diseases. Therefore, understanding the underlying molecular mechanisms might inform on common targets and therapeutic approaches. We propose to re-conceptualize how we understand these disorders and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration.
... (22q11.2DS, OMIM # 188400) have only recently been implicated in PD [97,98]. The 22q11.2 deletion is considered to be one of the most common deletion syndromes (~1:1,000-3,000 births) and was first described in 1968 [99,100]. ...
... Recently, it has been recognized that adults with 22q11.2DS have a higher risk of developing PD [98] as illustrated by a PD prevalence of 5.9% in a cohort of 159 adults (ages 35-64 years) with 22q11.2DS [105]. ...
Neurodevelopmental and late-onset neurodegenerative disorders present as separate entities that are clinically and neuropathologically quite distinct. However, recent evidence has highlighted surprising commonalities and converging features at the clinical, genomic, and molecular level between these two disease spectra. This is particularly striking in the context of autism spectrum disorder (ASD) and Parkinson's disease (PD). Genetic causes and risk factors play a central role in disease pathophysiology and enable the identification of overlapping mechanisms and pathways. Here, we focus on clinico-genetic studies of causal variants and overlapping clinical and cellular features of ASD and PD. Several genes and genomic regions were selected for our review, including SNCA (alpha-synuclein), PARK2 (parkin RBR E3 ubiquitin protein ligase), chromosome 22q11 deletion/DiGeorge region, and FMR1 (fragile X mental retardation 1) repeat expansion, which influence development of both ASD and PD with converging features related to synaptic function and neurogenesis. Both PD and ASD display alterations and impairments at the synaptic level, representing early and key disease phenotypes which support the hypothesis of converging mechanisms between the two types of diseases. Therefore, understanding the underlying molecular mechanisms might inform on common targets and therapeutic approaches. We propose to re-conceptualize how we understand these disorders and provide a new angle into disease targets and mechanisms linking neurodevelopmental disorders and neurodegeneration.
... Table 5 provides brief summaries of tremor disorders related to sex chromosome aneuploidies and structural chromosomal abnormalities. [153][154][155][156][157][158][159][160][161] ...
The 2018 consensus statement on the classification of tremors proposes a two-axis categorization scheme based on clinical features and etiology. It also defines “isolated” and “combined” tremor syndromes depending on whether tremor is the sole clinical manifestation or is associated with other neurological or systemic signs. This syndromic approach provides a guide to investigate the underlying etiology of tremors, either genetic or acquired.
Several genetic defects have been proven to cause tremor disorders, including autosomal dominant and recessive, X-linked, and mitochondrial diseases, as well as chromosomal abnormalities. Furthermore, some tremor syndromes are recognized in individuals with a positive family history, but their genetic confirmation is pending. Although most genetic tremor disorders show a combined clinical picture, there are some distinctive conditions in which tremor may precede the appearance of other neurological signs by years or remain the prominent manifestation throughout the disease course, previously leading to misdiagnosis as essential tremor (ET). Advances in the knowledge of genetically determined tremors may have been hampered by the inclusion of heterogeneous entities in previous studies on ET. The recent classification of tremors therefore aims to provide more consistent clinical data for deconstructing the genetic basis of tremor syndromes in the next-generation and long-read sequencing era.
This review outlines the wide spectrum of tremor disorders with defined or presumed genetic etiology, both isolated and combined, unraveling diagnostic clues of these conditions and focusing mainly on ET-like phenotypes. Furthermore, we suggest a phenotype-to-genotype algorithm to support clinicians in identifying tremor syndromes and guiding genetic investigations.
