Ikääntyminen ja kehitysvammaisuus – kognitiiviset muutokset Williamsin, fragile X- ja Downin oireyhtymässä

During the few past decades the lifespan of persons with intellectual disability has increased significantly, though only little is known how ageing affects cognition and health of intellectually disabled persons. In this longitudinal study the changes in cognition, development of dementia signs along with other health events were followed in persons with Williams and males with fragile X- yndrome. Persons with Down syndrome, who have participated our earlier studies, acted as a control group when assessing health and signs indicating dementia. In addition, preattentive auditory processing of persons with Down syndrome was assessed with magnetoencephalography (MEG) and compared to healthy peers. Study participants were recruited from Päijät- ja Kanta-Häme, Pirkanmaa, Northern Ostrobothnia, and Southwest Finland. The ageing affects differently cognition and health in Williams, fragile X and Down syndrome and the deterioration of cognition is also significantly more rapid compared to the general main population. In Williams syndrome the cognitive functions continued to improve until 40 years of age after which especially the verbal functions started to deteriorate. On the other hand, the non-verbal functions of men with fragile X syndrome started to weaken already from young adulthood without any clear health reason. In Down syndrome the preattentive auditory processing underlying stimulus detection is impaired in middle-age compared to healthy controls of same age indicating neuropathological changes in the brain. Symptoms of memory disorder are very frequent in Down syndrome persons aged over 35 in whom Alzheimer’s disease is the most common dementia type. Some persons with Williams syndrome had memory impairments whereas none of the males with fragile X-syndrome showed signs indicating dementia though the median age was the highest in this group. The occurrence of health problems increased along ageing in all three syndromes, most in Williams syndrome. The follow-up of the health and cognition of intellectually disabled persons from middle age onward is supported. The psychological assessment carried out in young adulthood is essential to verify the deterioration of cognitive functions later. In order to prevent premature ageing and development of dementia it is of uttermost important to offer and organize meaningful case-by-case tailored daily activities and active support to enable in this way the person to be a part in community.Kehitysvammaisten henkilöiden elinikä on viimeisten vuosikymmenien kuluessa pidentynyt huomattavasti, mutta ikääntymisen vaikutuksista kehitysvammaisten henkilöiden kognitioon ja terveyteen tiedetään varsin vähän. Tässä pitkittäistutkimuksessa arvioitiin Williams-henkilöiden ja fragile X-miesten) kognitiota sekä muistisairausoireiden ilmenemistä muun terveydentilan ohella. Vertailuryhmänä muistisairausoireiden ja terveydentilan arvioinnissa olivat Downhenkilöt, jotka ovat osallistuneet aiempiin tutkimuksiimme. Seuranta-aika oli keskimäärin kaksikymmentä vuotta. Lisäksi keski-ikäisillä Down-henkilöillä selvitettiin rinnakkaisten auditiivisten kuuloärsykkeiden automaattista prosessointia magnetoelektrogrammilla (MEG) verrattuna terveeseen vertailuryhmään. Tutkimushenkilöt koottiin Päijät- ja Kanta-Hämeen, Pirkanmaan, Pohjois-Pohjanmaan ja Varsinais-Suomen sairaanhoitopiirien ja erityishuoltopiirien alueilta. Ikääntyminen vaikuttaa eri tavoin Williams-, fragile X- ja Down-henkilöiden kognitiivisiin toimintoihin, ja kognitiivinen heikentyminen oli huomattavasti nopeampaa kaikissa kolmessa ryhmässä verrattuna valtaväestöön. Williams-henkilöiden kognitiiviset toiminnot vahvistuivat noin 40 ikävuoteen asti, jonka jälkeen erityisesti kielelliset toiminnot alkoivat heiketä. Fragile X -miesten ei-kielelliset kognitiiviset toiminnot heikkenivät jo varhaisesta aikuisuudesta alkaen ilman mitään selkeää terveydellistä syytä. Downin oireyhtymässä rinnakkainen auditiivinen prosessointi keski-iässä on vahingoittunut tai poikkeava verrattuna vertailuryhmään viitaten neuropatologisiin muutoksiin aivoissa. Muistisairausoireet olivat erittäin yleisiä yli 35-vuotiailla Down-henkilöillä yleisimmän muistisairauden ollessa Alzheimerin taudin. Yksittäisillä Williams-henkilöillä ilmeni muistisairausoireita, kun taas fragile Xmiehillä ei ilmennyt muistisairauksia, vaikka ryhmän iän mediaani oli korkein. Terveyspulmia ilmeni runsaasti ikääntymisen myötä kaikissa kolmessa ryhmässä, eniten niitä oli Williams-henkilöillä. Kehitysvammaisten henkilöiden kognitiivista toimintakyvyn ja terveydentilan seuranta keski-iästä lähtien on tärkeää. Kognitiivisen toimintakyvyn heikkenemisen toteaminen edellyttää nuorena aikuisena tehtyjä psykologisia tutkimuksia. Ennenaikaisen vanhenemisen ja muistisairauksien ehkäisemiseksi on ensiarvoisen tärkeää tarjota ja järjestää kehitysvammaisille henkilöille kullekin mielekästä päiväaikaista toimintaa ja aktiivista tukea ja näin edesauttaa osallisuutta yhteiskuntaan

Neurocognitive follow-up in adult siblings with Phelan-McDermid syndrome due to a novel SHANK3 splicing site mutation

Background: Phelan-McDermid syndrome (PMD) is usually not only caused by 22q13.3 deletion but also pathogenic variants (mutations) of SHANK3 gene. PMD is characterized by global intellectual disability, severely delayed or absent speech, and features of autism spectrum disorder and susceptibility to psychotic behavior. Here, we describe a neurocognitive follow-up and genetic etiology for two siblings with PMD. Method: Comparative genomic hybridization (CGH) array test was normal and no 22q13.3 deletion was observed. For this reason, whole exome sequencing (WES) analyzed the siblings' and the parents' DNA sample. Results: The results of the siblings strongly suggest that the SHANK3 gene variant c.2313+1G>A is pathogenic and PMD can be inherited from a mosaic father for this gene variant. Both siblings learned new skills until puberty but experienced a neuropsychiatric disaster after the age of 14 years experienced neurocognitive decline and it was sharp for one of the siblings. Conclusion: The long-term observations are sparse in PMD and SHANK3 mutations. This is the neurocognitive follow-up from childhood to middle ages, where a sharp neurocognitive decline was observed. We conclude that progressive neuropsychiatric symptoms in adolescence are a universal clinical clue for PMD diagnosis and an underlying SHANK3 splicing site mutation.Peer reviewe

Neurocognitive follow-up in adult siblings with Phelan-McDermid syndrome due to a novel SHANK3 splicing site mutation

Background: Phelan-McDermid syndrome (PMD) is usually not only caused by 22q13.3 deletion but also pathogenic variants (mutations) of SHANK3 gene. PMD is characterized by global intellectual disability, severely delayed or absent speech, and features of autism spectrum disorder and susceptibility to psychotic behavior. Here, we describe a neurocognitive follow-up and genetic etiology for two siblings with PMD. Method: Comparative genomic hybridization (CGH) array test was normal and no 22q13.3 deletion was observed. For this reason, whole exome sequencing (WES) analyzed the siblings' and the parents' DNA sample. Results: The results of the siblings strongly suggest that the SHANK3 gene variant c.2313+1G>A is pathogenic and PMD can be inherited from a mosaic father for this gene variant. Both siblings learned new skills until puberty but experienced a neuropsychiatric disaster after the age of 14 years experienced neurocognitive decline and it was sharp for one of the siblings. Conclusion: The long-term observations are sparse in PMD and SHANK3 mutations. This is the neurocognitive follow-up from childhood to middle ages, where a sharp neurocognitive decline was observed. We conclude that progressive neuropsychiatric symptoms in adolescence are a universal clinical clue for PMD diagnosis and an underlying SHANK3 splicing site mutation.Peer reviewe

Intellectual disability in patients with epilepsy with eyelid myoclonias

We describe here the clinical outcome of four women with epilepsy with eyelid myoclonia (aged 21-53years). All patients had an uneventful early history, normal physical growth and appearance and no comorbid sensory or motor disability and normal brain magnetic resonance imaging finding. Two women were moderately and one mildly intellectually disabled and one showed a low-average intelligence. The overall well-being of the patients was hampered by psychiatric or various somatic comorbidities and related psychosocial problems. The three women with an intellectual disability had been treated with narrow-spectrum antiepileptic drugs and one also with vigabatrin during childhood and adolescence. The patient with a low-average intelligence had been on broad-spectrum antiepileptic medication (i.e. valproate and ethosuximide) since the epilepsy diagnosis but she has had compliance problems. Based on these cases, the cognitive deficits in patients with epilepsy with eyelid myoclonia may occur more commonly than what has been thought hitherto. We discuss the role of narrow-spectrum antiepileptic drugs as a contributing factor to poor seizure control and an impaired intelligence.Peer reviewe

Cognition in adults with Williams syndrome-A 20-year follow-up study

BackgroundWilliams syndrome (WBS) is a genetic multisystem disorder. The main symptom is borderline (intelligence quotient, IQ 70-79) or abnormally low intelligence (IQ MethodsWe followed 25 adults (age at baseline 19-68, median 38) with genetically confirmed WBS for about 20years. The study subjects underwent medical and neuropsychological assessments at the baseline and at the end of follow-up. ResultsThe mean VIQ remained quite stable from early adulthood up to 40years of age after which it declined. The mean PIQ kept on improving from early adulthood until 50years of age after which it gradually declined. At the end of the study, all study subjects had at least two longstanding health problems out of which hypertension, psychiatric disorder, and scoliosis or kyphosis occurred most frequently. At end of the study, two patients suffered from vascular dementia. Seven patients died during the follow-up. ConclusionsIn adults with WBS, the course of cognition is uneven across the cognitive profile. Their verbal functions both develop and deteriorate earlier than performance/nonverbal functions. Frequent somatic co-morbidities may increase risk to shortened life span.Peer reviewe

Signs indicating dementia in Down, Williams and Fragile X syndromes

Background: Intellectual disability (ID) and dementia reflect disturbed cortical function during and after developmental age, respectively. Due to the wide heterogeneity of ID population the decline in cognitive and adaptive skills may be different in distinct genetic subgroups.Methods: Using the British Present Psychiatric State–learning Disabilities assessment (PPS‐LD) questionnaire the dementia signs were screened in 62, 22 and 44 individuals (> 35 year of age) with Down (DS, OMIM number 190685), Williams (WS, OMIM number, 194050), and Fragile X syndrome (FXS, OMIM number 309550), respectively. The median age of those with FXS (59 years) was higher than of those with DS (50 years) and WS (53 years).Results: Most study participants with DS (80%) and FXS (89%) were or had been moderately or severely intellectually disabled while most participants with WS (73%) were or had been mildly or moderately disabled at adolescent age. The adolescent (premorbid) level of ID did not correlate with the dementia score. The median scores were 11/27, 1/27, and 0/27 in DS, WS, and FXS subgroups, respectively. Dementia that was confirmed by brain imaging, manifested as Alzheimer disease and as moya‐moya disease associated vascular dementia in DS and as vascular dementia in WS.Conclusions: This survey suggests that the risk of dementia varies depending on the cause of ID and that the severity of ID in adolescence does not predict the development of dementia at a later age. Consequently, the ID and dementia should be understood as separate clinical entities that need to be taken into account in the health management of intellectually disabled people. This is important for the arrangement of appropriate and timely interventions, which can be expected to delay the need for institutionalization.</p

Intellectual disability in patients with epilepsy with eyelid myoclonias

We describe here the clinical outcome of four women with epilepsy with eyelid myoclonia (aged 21-53years). All patients had an uneventful early history, normal physical growth and appearance and no comorbid sensory or motor disability and normal brain magnetic resonance imaging finding. Two women were moderately and one mildly intellectually disabled and one showed a low-average intelligence. The overall well-being of the patients was hampered by psychiatric or various somatic comorbidities and related psychosocial problems. The three women with an intellectual disability had been treated with narrow-spectrum antiepileptic drugs and one also with vigabatrin during childhood and adolescence. The patient with a low-average intelligence had been on broad-spectrum antiepileptic medication (i.e. valproate and ethosuximide) since the epilepsy diagnosis but she has had compliance problems. Based on these cases, the cognitive deficits in patients with epilepsy with eyelid myoclonia may occur more commonly than what has been thought hitherto. We discuss the role of narrow-spectrum antiepileptic drugs as a contributing factor to poor seizure control and an impaired intelligence

Ageing and cognition in men with fragile X syndrome

Background Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. The aim of our longitudinal study was to describe ageing-related cognitive changes in men with FXS.Method A neuropsychologist determined the raw scores (RSs) of 19 men with FXS twice with the Leiter International Performance Scale at an average interval of 22 years. The ages of the participants at baseline ranged from 16 to 50 (mean 27) years.Results At follow-up, the RSs improved in two men, remained the same in two men and declined in 15 men. Overall, the RS of the study group deteriorated by an average 4 points in RSs (p Conclusion Cognitive ageing in men with FXS started earlier than that in men in the general population; in many cases, cognitive ageing in men with FXS began before middle age, usually without any medical or other underlying cause.</div

Ageing and cognition in men with fragile X syndrome

Background Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. The aim of our longitudinal study was to describe ageing-related cognitive changes in men with FXS. Method A neuropsychologist determined the raw scores (RSs) of 19 men with FXS twice with the Leiter International Performance Scale at an average interval of 22 years. The ages of the participants at baseline ranged from 16 to 50 (mean 27) years. Results At follow-up, the RSs improved in two men, remained the same in two men and declined in 15 men. Overall, the RS of the study group deteriorated by an average 4 points in RSs (p <.001). Conclusion Cognitive ageing in men with FXS started earlier than that in men in the general population; in many cases, cognitive ageing in men with FXS began before middle age, usually without any medical or other underlying cause.Peer reviewe