Publications by authors named "Margje Sinnema"

25 Publications

  • Page 1 of 1

Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON.

Eur J Hum Genet 2021 Sep 15. Epub 2021 Sep 15.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON. Its encoded protein promotes pre-mRNA splicing of many genes essential for development. Whereas individual phenotypic traits have previously been linked to erroneous splicing of SON target genes, the phenotypic spectrum and the pathogenicity of missense variants have not been further evaluated. We present the phenotypic abnormalities in 52 individuals, including 17 individuals who have not been reported before. In total, loss-of-function variants were detected in 49 individuals (de novo in 47, inheritance unknown in 2), and in 3, a missense variant was observed (2 de novo, 1 inheritance unknown). Phenotypic abnormalities, systematically collected and analyzed in Human Phenotype Ontology, were found in all organ systems. Significant inter-individual phenotypic variability was observed, even in individuals with the same recurrent variant (n = 13). SON haploinsufficiency was previously shown to lead to downregulation of downstream genes, contributing to specific phenotypic features. Similar functional analysis for one missense variant, however, suggests a different mechanism than for heterozygous loss-of-function. Although small in numbers and while pathogenicity of these variants is not certain, these data allow for speculation whether de novo missense variants cause ZTTK syndrome via another mechanism, or a separate overlapping syndrome. In conclusion, heterozygous loss-of-function variants in SON define a recognizable syndrome, ZTTK, associated with a broad, severe phenotypic spectrum, characterized by a large inter-individual variability. These observations provide essential information for affected individuals, parents, and healthcare professionals to ensure appropriate clinical management.
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http://dx.doi.org/10.1038/s41431-021-00960-4DOI Listing
September 2021

Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.

Am J Hum Genet 2021 02 28;108(2):346-356. Epub 2021 Jan 28.

Department of Rehabilitation and Development, Randall Children's Hospital at Legacy Emanuel Medical Center, Portland, OR 97227, USA.

Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895900PMC
February 2021

Germline AGO2 mutations impair RNA interference and human neurological development.

Nat Commun 2020 11 16;11(1):5797. Epub 2020 Nov 16.

Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.

ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development.
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http://dx.doi.org/10.1038/s41467-020-19572-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670403PMC
November 2020

Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome.

Mol Psychiatry 2021 Jun 28;26(6):2013-2024. Epub 2020 Apr 28.

Center for Pediatric Genomic Medicine, Children's Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA.

Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.
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http://dx.doi.org/10.1038/s41380-020-0725-5DOI Listing
June 2021

Acute encephalopathy after head trauma in a patient with a RHOBTB2 mutation.

Neurol Genet 2020 Jun 1;6(3):e418. Epub 2020 Apr 1.

Department of Neurology (A.C.S.K., J.N.), Maastricht University Medical Center, Maastricht; Department of Pediatrics (L.A.B.), Màxima Medical Center, Veldhoven; and Department of Clinical Genetics (A.B., A.P.A.S., M.S., M.V.), Maastricht University Medical Center, Maastricht, the Netherlands.

Objective: De novo missense mutations in the gene have been described as causative for developmental and epileptic encephalopathy.

Methods: The clinical phenotype of this disorder includes early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorder. Three patients have been described with acute encephalopathy and febrile epileptic status. All showed severe EEG abnormalities during this episode and abnormal MRI with hemisphere swelling or reduced diffusion in various brain regions.

Results: We describe the episode of acute encephalopathy after head trauma in a 5-year-old RHOBTB2 patient. At admission, Glasgow coma scale score was E4M4V1. EEG was severely abnormal showing a noncontinuous pattern with slow activity without epileptic activity indicating severe encephalopathy. A second EEG on day 8 was still severely slowed and showed focal delta activity frontotemporal in both hemispheres. Gradually, he recovered, and on day 11, he had regained his normal reactivity, behavior, and mood. Two months after discharge, EEG showed further decrease in slow activity and increase in normal electroencephalographic activity. After discharge, parents noted that he showed more hyperkinetic movements compared to before this period of encephalopathy. Follow-up MRI showed an increment of hippocampal atrophy. In addition, we summarize the clinical characteristics of a second RHOBTB2 patient with increase of focal periventricular atrophy and development of hemiparesis after epileptic status.

Conclusions: Acute encephalopathy in RHOBTB2 patients can also be triggered by head trauma.
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http://dx.doi.org/10.1212/NXG.0000000000000418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164965PMC
June 2020

Pathogenic variants in cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD.

J Med Genet 2020 10 9;57(10):717-724. Epub 2020 Mar 9.

GeneDx, Gaithersburg, Maryland, USA.

Background: Rare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes. encodes a protein important for RNA silencing. Heterozygous truncating variants have been reported in three patients from large cohorts with autism, but no full phenotypic characterisation was described.

Methods: Clinical and molecular characterisation was performed on 17 patients with variants. Clinical data were obtained by retrospective chart review, parent interviews, direct patient interaction with providers and formal neuropsychological evaluation.

Results: Clinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygous variants were identified in 12 male and five female unrelated subjects by exome sequencing (14), a targeted panel (2) and a chromosomal microarray (1). The variants were nonsense (7), frameshift (5), splice site (2), intragenic deletions (2) and missense (1).

Conclusions: Variants in cause a novel genetic disorder characterised by recurrent neurocognitive and behavioural phenotypes featuring DD/ID, autism, ADHD and other behavioural abnormalities. Our data highly suggest that haploinsufficiency is the most likely pathogenic mechanism. should be added to the growing list of genes of the RNA-induced silencing complex associated with ID/DD, autism and ADHD.
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http://dx.doi.org/10.1136/jmedgenet-2019-106470DOI Listing
October 2020

Deleterious de novo variants of X-linked ZC4H2 in females cause a variable phenotype with neurogenic arthrogryposis multiplex congenita.

Hum Mutat 2019 12 21;40(12):2270-2285. Epub 2019 Aug 21.

Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.

Pathogenic variants in the X-linked gene ZC4H2, which encodes a zinc-finger protein, cause an infrequently described syndromic form of arthrogryposis multiplex congenita (AMC) with central and peripheral nervous system involvement. We present genetic and detailed phenotypic information on 23 newly identified families and simplex cases that include 19 affected females from 18 families and 14 affected males from nine families. Of note, the 15 females with deleterious de novo ZC4H2 variants presented with phenotypes ranging from mild to severe, and their clinical features overlapped with those seen in affected males. By contrast, of the nine carrier females with inherited ZC4H2 missense variants that were deleterious in affected male relatives, four were symptomatic. We also compared clinical phenotypes with previously published cases of both sexes and provide an overview on 48 males and 57 females from 42 families. The spectrum of ZC4H2 defects comprises novel and recurrent mostly inherited missense variants in affected males, and de novo splicing, frameshift, nonsense, and partial ZC4H2 deletions in affected females. Pathogenicity of two newly identified missense variants was further supported by studies in zebrafish. We propose ZC4H2 as a good candidate for early genetic testing of males and females with a clinical suspicion of fetal hypo-/akinesia and/or (neurogenic) AMC.
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http://dx.doi.org/10.1002/humu.23841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874899PMC
December 2019

SON haploinsufficiency causes impaired pre-mRNA splicing of CAKUT genes and heterogeneous renal phenotypes.

Kidney Int 2019 06 15;95(6):1494-1504. Epub 2019 Mar 15.

Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama, USA. Electronic address:

Although genetic testing is increasingly used in clinical nephrology, a large number of patients with congenital abnormalities of the kidney and urinary tract (CAKUT) remain undiagnosed with current gene panels. Therefore, careful curation of novel genetic findings is key to improving diagnostic yields. We recently described a novel intellectual disability syndrome caused by de novo heterozygous loss-of-function mutations in the gene encoding the splicing factor SON. Here, we show that many of these patients, including two previously unreported, exhibit a wide array of kidney abnormalities. Detailed phenotyping of 14 patients with SON haploinsufficiency identified kidney anomalies in 8 patients, including horseshoe kidney, unilateral renal hypoplasia, and renal cysts. Recurrent urinary tract infections, electrolyte disturbances, and hypertension were also observed in some patients. SON knockdown in kidney cell lines leads to abnormal pre-mRNA splicing, resulting in decreased expression of several established CAKUT genes. Furthermore, these molecular events were observed in patient-derived cells with SON haploinsufficiency. Taken together, our data suggest that the wide spectrum of phenotypes in patients with a pathogenic SON mutation is a consequence of impaired pre-mRNA splicing of several CAKUT genes. We propose that genetic testing panels designed to diagnose children with a kidney phenotype should include the SON gene.
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http://dx.doi.org/10.1016/j.kint.2019.01.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534475PMC
June 2019

Loss-of-function zinc finger mutation in the gene associated with erythrocytosis.

Blood 2018 09 15;132(13):1455-1458. Epub 2018 Aug 15.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.1182/blood-2018-06-854711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161772PMC
September 2018

De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.

Am J Hum Genet 2018 06 31;102(6):1195-1203. Epub 2018 May 31.

Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA 92656, USA.

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.
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http://dx.doi.org/10.1016/j.ajhg.2018.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5992133PMC
June 2018

A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis.

Am J Hum Genet 2018 05 12;102(5):995-1007. Epub 2018 Apr 12.

University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, the Netherlands.

Developmental and epileptic encephalopathies (DEEs) represent a large clinical and genetic heterogeneous group of neurodevelopmental diseases. The identification of pathogenic genetic variants in DEEs remains crucial for deciphering this complex group and for accurately caring for affected individuals (clinical diagnosis, genetic counseling, impacting medical, precision therapy, clinical trials, etc.). Whole-exome sequencing and intensive data sharing identified a recurrent de novo PACS2 heterozygous missense variant in 14 unrelated individuals. Their phenotype was characterized by epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism. Mixed focal and generalized epilepsy occurred in the neonatal period, controlled with difficulty in the first year, but many improved in early childhood. PACS2 is an important PACS1 paralog and encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Both proteins harbor cargo(furin)-binding regions (FBRs) that bind cargo proteins, sorting adaptors, and cellular kinase. Compared to the defined PACS1 recurrent variant series, individuals with PACS2 variant have more consistently neonatal/early-infantile-onset epilepsy that can be challenging to control. Cerebellar abnormalities may be similar but PACS2 individuals exhibit a pattern of clear dysgenesis ranging from mild to severe. Functional studies demonstrated that the PACS2 recurrent variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between the PACS2 FBR and client proteins, which may disturb cellular function. These findings support the causality of this recurrent de novo PACS2 heterozygous missense in DEEs with facial dysmorphim and cerebellar dysgenesis.
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http://dx.doi.org/10.1016/j.ajhg.2018.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986694PMC
May 2018

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

Nat Genet 2017 Feb 19;49(2):223-237. Epub 2016 Dec 19.

Child and Adolescent Health, University of Sydney, Sydney, New South Wales, Australia.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.
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http://dx.doi.org/10.1038/ng.3740DOI Listing
February 2017

De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome.

Am J Hum Genet 2016 09 18;99(3):711-719. Epub 2016 Aug 18.

Division of Genetics, Department of Pediatrics, San Antonio Military Medical Center, Fort Sam Houston, TX 78234, USA; Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.
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http://dx.doi.org/10.1016/j.ajhg.2016.06.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011044PMC
September 2016

The use of medical care and the prevalence of serious illness in an adult Prader-Willi syndrome cohort.

Eur J Med Genet 2013 Aug 20;56(8):397-403. Epub 2013 Jun 20.

Department of Clinical Genetics, Maastricht UMC, The Netherlands.

Introduction: Adults with Prader-Willi syndrome (PWS) have an increased occurrence of several medical conditions. We report on the consequences of high morbidity rates such as prevalence rate of hospital admissions, medication use and surgery in a Dutch cohort of adults with PWS. Special attention is paid to causes and symptoms of serious illness.

Method: Participants were contacted via the Dutch Prader-Willi Parent Association and through physicians specializing in persons with ID. The persons with PWS and their main caregivers were visited at home. Information was collected through semi-structured interviews on 102 adults with PWS.

Results: The need for medical care in the neonatal period is associated with hypotonia and feeding problems. Hospital admissions for respiratory tract infections are frequent. During childhood most hospital admissions were due to PWS syndrome specific surgery. During adolescence hospital admissions occurred for scoliosis surgery and endocrine evaluations. At adult age, hospitalization was associated with inguinal hernia surgery, diabetes mellitus, psychosis, erysipelas, water and drug intoxications. In the older group, respiratory infections were again the main reason for hospital admissions. Frequently used medications at adult age included psychotropics, laxatives, anti-diabetics and dermatologic preparations. Abnormal drinking patterns, problems with anesthesia, decreased ability to vomit, abnormal pain awareness and unpredictable fever responses were frequent and often lead to delayed diagnoses of serious conditions.

Discussion: People with PWS are frequent users of medical-care. Reasons for hospitalization and medication use are age specific. Knowledge on the different presentation of symptoms in people with PWS is needed. In case of unexplained illness, disturbances of consciousness and behavioral changes in people with PWS, an infection should be ruled out in the first place. Information from this study may help in preventing conditions and recognizing conditions in an early stage. Adequate preventive management and treatment of PWS related morbidity, could reduce medical care use in the long term and could improve quality adjusted life years.
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http://dx.doi.org/10.1016/j.ejmg.2013.05.011DOI Listing
August 2013

Aging in Prader-Willi syndrome: twelve persons over the age of 50 years.

Am J Med Genet A 2012 Jun 14;158A(6):1326-36. Epub 2012 May 14.

Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.

The life expectancy of persons with Prader-Willi syndrome (PWS) has increased in recent years. Because of the paucity of reports on older persons with PWS, the natural history, the onset, and type of age-related problems are poorly understood. Twelve persons with a genetically confirmed diagnosis of PWS aged over 50 years are described (4 deletion; 8 mUPD). Data on physical, behavioral, psychiatric, and aging characteristics were collected through semi-structured interviews with the individuals with PWS and their main carers. Cardiovascular diseases, diabetes, dermatological, and orthopedic problems were common physical complaints in older people with PWS. Functioning in activities of daily living, psychological functioning, physical functions, and care dependence were substantially worse in the older age group (50+) compared to the control group (18-49 years). Seven out of eight persons with mUPD had a history of psychiatric illness. Behavioral problems were observed in the older age group. Given the combination of age-related physical morbidity, physical appearance, behavioral and psychiatric problems, and functional decline in our cohort, we hypothesize that premature aging occurs in PWS. The care for older people with PWS requires a lifespan approach that recognizes the presence, progression, and consequences of specific morbidity. Special medical surveillance of people with PWS from 40 years onwards would ensure that intervention and support is offered with respect to specific areas of decline at the earliest possible time.
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http://dx.doi.org/10.1002/ajmg.a.35333DOI Listing
June 2012

Physical health problems in adults with Prader-Willi syndrome.

Am J Med Genet A 2011 Sep 10;155A(9):2112-24. Epub 2011 Aug 10.

Department of Clinical Genetics, Maastricht UMC, Maastricht University, Maastricht, The Netherlands.

Prader-Willi syndrome (PWS) is a genetic disorder which is characterized by severe hypotonia and feeding problems in early infancy. In later childhood and adolescence, this is followed by hyperphagia and extreme obesity if the diet is not strictly controlled. Data on physical health problems in adults with PWS are scarce. We report on the prevalence of physical health problems in a Dutch cohort of adults with PWS in relation to age, BMI, and genetic subtype. Participants (n = 102) were retrieved via the Dutch Prader-Willi Parent Association and through physicians specializing in persons with intellectual disabilities (ID). Details regarding physical health problem spanning the participants' lifespan were collected from caretakers through semi-structured interviews. Cardiovascular problems included diabetes mellitus, hypertension, and cerebrovascular accidents. Respiratory infections were frequent in adulthood. In males, cryptorchidism was almost universal, for which 28/48 males had a history of surgery, mostly orchidopexy. None of the women had a regular menstrual cycle. Sixteen individuals had a diagnosis of osteoporosis. Spinal deformation, hip dysplasia, and foot abnormalities were common. Skinpicking, leg edema, and erysipelas were frequent dermatological problems. The findings in our group support the notion that the prevalence of physical health problems is underestimated. This underscores the importance of developing monitoring programs which would help to recognize physical health problems at an early stage.
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http://dx.doi.org/10.1002/ajmg.a.34171DOI Listing
September 2011

Psychiatric illness in a cohort of adults with Prader-Willi syndrome.

Res Dev Disabil 2011 Sep-Oct;32(5):1729-35. Epub 2011 Mar 31.

Department of Clinical Genetics, Maastricht University Medical Centre, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.

Previous studies have suggested an association between PWS and comorbid psychiatric illness. Data on prevalence rates of psychopathology is still scarce. This paper describes a large-scale, systematic study investigating the prevalence of psychiatric illness in a Dutch adult PWS cohort. One hundred and two individuals were screened for psychiatric illness. Case vignettes were written by the first author on 63 individuals with a positive screening on psychopathology according to the interviews, medical history, medication use and behavioural questionnaires. These case vignettes were rated by two psychiatrists specializing in intellectual disability (ID). Psychopathology was divided into four diagnostic categories: bipolar disorder with psychotic symptoms, psychotic illness, depressive illness with psychotic symptoms and depressive illness without psychotic symptoms. Nine out of 53 persons (17%) with a 15q11-13 deletion and 28 out of 44 (64%) persons with maternal uniparental disomy (mUPD) were diagnosed with a current or previous psychiatric illness. Depressive illness with psychotic symptoms was the cause of psychiatric problems in the majority of persons with PWS due to deletion (56%). In the case of mUPD, almost all individuals with histories of psychopathology suffered from psychotic symptoms (85%) with or without affective component. Psychiatric examination should be part of general management of adults with PWS, especially when caused by mUPD. More attention should be paid to the presence of precursor symptoms, indicating a developing psychiatric episode. Longitudinal studies are needed to gain more insight into the natural history of psychiatric illness in adults with PWS.
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http://dx.doi.org/10.1016/j.ridd.2011.02.027DOI Listing
October 2011

Behavioral phenotype in adults with Prader-Willi syndrome.

Res Dev Disabil 2011 Mar-Apr;32(2):604-12. Epub 2011 Jan 11.

Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.

Prader-Willi syndrome (PWS) is characterized by temper tantrums, impulsivity, mood fluctuations, difficulty with change in routine, skinpicking, stubbornness and aggression. Many studies on behavior in PWS are limited by sample size, age range, a lack of genetically confirmed diagnosis of PWS and inconsistent assessment of behavior. The aim of this study was to explore systematically the relation between behavioral problems and age groups, genetic subtypes and BMI categories in an adult PWS population. Participants were contacted via the Dutch Prader-Willi Parent Association and through physicians specialized in persons with ID. Behaviors were studied using the Developmental Behavior Checklist for Adults (DBC-A). The forms were completed by the main caregivers of 98 adults with a genetically confirmed diagnosis of PWS. Differences between age groups were statistically significant (ANOVA, p=0.03). DBC-A total scores were higher in the consecutive age groups, with the most behavioral problems in the oldest age groups. Differences between genetic subtypes were also statistically significant (ANOVA, p<0.01). Persons with mUPD had higher total scores on the DBC-A than persons with a deletion. Those with a Type I deletion showed higher total DBC-A scores than persons with a Type II deletion. There were no statistically significant differences in DBC-A total scores between the different BMI categories. Individuals with a BMI<25 had higher scores on the self-absorbed subscale compared to persons with a BMI between 25 and 30. Unlike previous descriptions of the behavioral phenotype in adults with PWS, we did not find a reduction in behavioral problems in older adults. Therefore, special attention should be paid to behavioral problems as part of general management of adults with PWS. Longitudinal studies are warranted to gain more insight into the natural history and course of behavioral problems in adults and older people with PWS over the long term and possible risk and preventive factors.
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http://dx.doi.org/10.1016/j.ridd.2010.12.014DOI Listing
June 2011

Urinary incontinence in persons with Prader-Willi Syndrome.

BJU Int 2010 Dec;106(11):1758-62

Department of Child and Adolescent Psychiatry, Saarland University Hospital, Homburg, Germany.

Objective: To assess and identify the frequency and type of urinary incontinence (UI), as well as associated symptoms in persons with Prader-Willi syndrome (PWS). PWS is characterized by mental retardation, short stature, obesity and hypogonadism. The behavioural phenotype includes eating problems, temper outbursts, affective disorders, stereotypies and speech abnormalities. UI is common in children with mental retardation in general, but has not been reported systematically in children with PWS so far.

Materials And Methods: The Dutch version of the 'Parental Questionnaire: Enuresis/Urinary Incontinence' was completed by 118 parents of children with PWS. This questionnaire includes items referring to day- and night-time wetting, toilet habits, observable voiding behaviours and reactions, urinary tract infections, stool habits and behavioural symptoms.

Results: The rate of nocturnal enuresis in persons with PWS was 13.6% (16) at a mean age of 15.1 years. 3.8% (5) had additional daytime urinary incontinence, and 3.3% (4) had faecal incontinence. Lower urinary tract symptoms were commonly indicative of overactive bladder, dysfunctional voiding and postponement. Also, the rate of internalizing and externalizing behavioural problems was high.

Conclusion: Urinary incontinence is more common in persons with PWS than in typically developing children, adolescents and adults. As lower urinary tract symptoms are common, detailed assessment and specific treatment of UI should be part of the care of all persons with PWS.
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http://dx.doi.org/10.1111/j.1464-410X.2010.09457.xDOI Listing
December 2010

Different distribution of the genetic subtypes of the Prader-Willi syndrome in the elderly.

Eur J Hum Genet 2010 Sep 12;18(9):993-8. Epub 2010 May 12.

Department of Clinical Genetics, Maastricht UMC, Maastricht, The Netherlands.

The Prader-Willi syndrome (PWS) is a genetic disorder caused by the absent expression of the paternal copy of maternally imprinted genes in chromosome region 15q11-13. The frequencies of different subtypes in PWS are usually given in literature as 70% deletion, 25-30% maternal uniparental disomy (mUPD) and 3-5% others (imprinting centre (IC) defects and translocations). Little is known about factors that influence the frequency of genetic subtypes in PWS. The study sample comprised 102 adults with clinically and genetically confirmed PWS, contacted through the Dutch Prader-Willi Parent Association and through physicians specialized in treating persons with intellectual disabilities. Genetic testing showed 55 persons (54%) with a paternal deletion, 44 persons (43%) with an mUPD and 3 persons (3%) with a defect of the IC. The observed distribution in our study differed from that in literature (70% deletion, 30% mUPD), which was statistically significant (z-score: P<0.05). This was mainly caused by a higher proportion of mUPD in the advanced age groups. Differences in maternal age and BMI of persons with PWS could not explain the differences in distribution across the age groups. Our study population had a much broader age range, compared with other studies, because of a predominance of elderly people (40+ years) with PWS. In other studies, these elderly persons might have been undiagnosed and/or underreported because of a lack of genetic diagnosis. The results underline both the need for correct genetic diagnosis in all persons with PWS and adjustment of the guidelines for preventive management in adulthood.
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http://dx.doi.org/10.1038/ejhg.2010.67DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987424PMC
September 2010

Dementia in a woman with Prader-Willi syndrome.

Eur J Med Genet 2010 May-Jun;53(3):145-8. Epub 2010 Feb 26.

Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.

We report on a 58-year-old woman with Prader-Willi syndrome (PWS) and dementia. This case report illustrates a new research area in older adults with PWS. Dementia might be associated with PWS. In the case of dementia, more clinical studies are warranted to observe whether premature Alzheimer changes or indications of other dementia forms indeed occur more prevalent in people with PWS.
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http://dx.doi.org/10.1016/j.ejmg.2010.02.006DOI Listing
October 2010

Lymphedema in Prader-Willi syndrome.

Int J Dermatol 2008 Nov;47 Suppl 1:42-4

Department of Dermatology, Maastricht University Center for Molecular Dermatology, GROW-School for Oncology and Developmental Biology, and Governor Kremers Center, University Medical Center Maastricht, The Netherlands.

A 20-year-old woman with Prader-Willi syndrome presented with heaviness and swelling in the lower legs and feet, which had developed after a fall. Lymphoscintigraphy showed a disturbed lymphatic drainage pattern in both lower extremities. Based on the clinical findings and the results of lymphoscintigraphic examination we made the diagnosis of lymphedema. The patient was successfully treated with manual lymphatic drainage in combination with multilayer compressive bandaging. After edema reduction, elastic compressive stockings were fit. To the best of our knowledge, this is the first report on primary lymphedema in a patient with Prader-Willi syndrome, an association that is probably often missed.
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http://dx.doi.org/10.1111/j.1365-4632.2008.03959.xDOI Listing
November 2008

Healthcare transition in persons with intellectual disabilities: general issues, the Maastricht model, and Prader-Willi syndrome.

Am J Med Genet C Semin Med Genet 2007 Aug;145C(3):241-7

Department of Clinical Genetics, Academic Hospital Maastricht and Research Institute Growth & Development (GROW), Maastricht Univesity, The Netherlands.

In current healthcare, transitional healthcare is a very important and timely issue. Thanks to the major advances made in medical care and technology, many children with childhood onset diseases and/or genetic syndromes survive to adulthood. These children are at risk of not being provided with adequate healthcare as they reach adulthood. Healthcare transition is an essential part of healthcare provision, referred to as the shift from one type of healthcare to another. In Maastricht, we developed a transition/out clinic led by a medical doctor specialized in persons with intellectual disability (ID), together with a clinical geneticist. We aim to coordinate healthcare issues based on guidelines if available. Also questions concerning living, daily activities, relations, sexuality, and sterilization can be discussed. The aging process of persons with ID has been a topic of interest in recent years. Little is known about the aging process of people with specific syndromes, except for persons with Down syndrome. We present some data of a recent questionnaire study in persons with Prader-Willi syndrome. In only 50% in persons with a clinical diagnosis genetic test results could be reported. The majority of persons were obese. Diabetes mellitus, hypertension, skin problems, sleep apnea, and hormonal problems like osteoporosis and hypothyroidism were common. Psychiatric problems were frequent, especially in the persons with uniparental disomy. Osteoporosis and sleep apnoea seem to be underestimated. Further longitudinal research is necessary for a better understanding of the aging process in PWS.
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http://dx.doi.org/10.1002/ajmg.c.30136DOI Listing
August 2007
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