Bone health in children with Angelman syndrome at the ENCORE Expertise Center.

Angelman syndrome (AS) is a rare genetic disorder due to lack of UBE3A function on chromosome 15q11.2q13 caused by a deletion, uniparental paternal disomy (UPD), imprinting center disorder (ICD), or pathological variant of the UBE3A gene. AS is characterized by developmental delay, epilepsy, and lack of speech. Although fractures are observed frequently in our clinical practice, there are few studies on bone health in AS. The aim of this study is to investigate bone health in children with AS. In this prospective cohort study, we describe bone health in 91 children with AS visiting the ENCORE Expertise Center for AS between April 2010 and December 2021. Bone health was assessed with the bone health index (BHI) in standard deviation score (SDS) measured by digital radiogrammetry of the left hand using BoneXpert software. Risk factors analyzed were age, sex, genetic subtype, epilepsy, anti-seizure medication use, mobility, body mass index (BMI), and onset of puberty. Children with AS had a mean BHI of -1.77 SDS (SD 1.4). A significantly lower BHI was found in children with a deletion (-2.24 SDS) versus non-deletion (-1.02 SDS). Other factors associated with reduced BHI-SDS were inability to walk and late onset of puberty. Children with a history of one or more fractures (22%) had a significantly lower BHI than children without fractures (-2.60 vs -1.56 SDS). Longitudinal analysis showed a significant decrease in BHI-SDS with age in all genetic subtypes.  Conclusions: Children with AS have a reduced bone health. Risk factors are deletion genotype, no independent walking, and late onset of puberty. Bone health decreased significantly with age. What is Known: • Children with neurological disorders often have a low bone health and higher risk of fractures. • Little is known about bone health in children with Angelman syndrome (AS). What is New: • Children with AS showed a reduced bone health and this was significantly associated with having a deletion, not being able to walk independently, and late onset of puberty. • Longitudinal analysis showed a significant decrease in bone health as children got older.

A Dutch paediatric palliative care guideline: a systematic review and evidence-based recommendations for symptom treatment.

BACKGROUND: Children with life-threatening and life-limiting conditions can experience high levels of suffering due to multiple distressing symptoms that result in poor quality of life and increase risk of long-term distress in their family members. High quality symptom treatment is needed for all these children and their families, even more so at the end-of-life. In this paper, we provide evidence-based recommendations for symptom treatment in paediatric palliative patients to optimize care. METHODS: A multidisciplinary panel of 56 experts in paediatric palliative care and nine (bereaved) parents was established to develop recommendations on symptom treatment in paediatric palliative care including anxiety and depression, delirium, dyspnoea, haematological symptoms, coughing, skin complaints, nausea and vomiting, neurological symptoms, pain, death rattle, fatigue, paediatric palliative sedation and forgoing hydration and nutrition. Recommendations were based on evidence from a systematic literature search, additional literature sources (such as guidelines), clinical expertise, and patient and family values. We used the GRADE methodology for appraisal of evidence. Parents were included in the guideline panel to ensure the representation of patient and family values. RESULTS: We included a total of 18 studies that reported on the effects of specific (non) pharmacological interventions to treat symptoms in paediatric palliative care. A few of these interventions showed significant improvement in symptom relief. This evidence could only (partly) answer eight out of 27 clinical questions. We included 29 guidelines and two textbooks as additional literature to deal with lack of evidence. In total, we formulated 221 recommendations on symptom treatment in paediatric palliative care based on evidence, additional literature, clinical expertise, and patient and family values. CONCLUSION: Even though available evidence on symptom-related paediatric palliative care interventions has increased, there still is a paucity of evidence in paediatric palliative care. We urge for international multidisciplinary multi-institutional collaboration to perform high-quality research and contribute to the optimization of symptom relief in palliative care for all children worldwide.

De novo TRPV4 Leu619Pro variant causes a new channelopathy characterised by giant cell lesions of the jaws and skull, skeletal abnormalities and polyneuropathy.

BACKGROUND: Pathogenic germline variants in Transient Receptor Potential Vanilloid 4 Cation Channel (TRPV4) lead to channelopathies, which are phenotypically diverse and heterogeneous disorders grossly divided in neuromuscular disorders and skeletal dysplasia. We recently reported in sporadic giant cell lesions of the jaws (GCLJs) novel, somatic, heterozygous, gain-of-function mutations in TRPV4, at Met713. METHODS: Here we report two unrelated women with a de novo germline p.Leu619Pro TRPV4 variant and an overlapping systemic disorder affecting all organs individually described in TRPV4 channelopathies. RESULTS: From an early age, both patients had several lesions of the nervous system including progressive polyneuropathy, and multiple aggressive giant cell-rich lesions of the jaws and craniofacial/skull bones, and other skeletal lesions. One patient had a relatively milder disease phenotype possibly due to postzygotic somatic mosaicism. Indeed, the TRPV4 p.Leu619Pro variant was present at a lower frequency (variant allele frequency (VAF)=21.6%) than expected for a heterozygous variant as seen in the other proband, and showed variable regional frequency in the GCLJ (VAF ranging from 42% to 10%). In silico structural analysis suggests that the gain-of-function p.Leu619Pro alters the ion channel activity leading to constitutive ion leakage. CONCLUSION: Our findings define a novel polysystemic syndrome due to germline TRPV4 p.Leu619Pro and further extend the spectrum of TRPV4 channelopathies. They further highlight the convergence of TRPV4 mutations on different organ systems leading to complex phenotypes which are further mitigated by possible post-zygotic mosaicism. Treatment of this disorder is challenging, and surgical intervention of the GCLJ worsens the lesions, suggesting the future use of MEK inhibitors and TRPV4 antagonists as therapeutic modalities for unmet clinical needs.

An overview of health issues and development in a large clinical cohort of children with Angelman syndrome.

This study presents a broad overview of health issues and psychomotor development of 100 children with Angelman syndrome (AS), seen at the ENCORE Expertise Center for AS in Rotterdam, the Netherlands. We aimed to further delineate the phenotype of AS, to evaluate the association of the phenotype with genotype and other determinants such as epilepsy and to get insight in possible targets for intervention. We confirmed the presence of a more severe phenotype in the 15q11.2-q13 deletion subtype. Novel findings were an association of (early onset of) epilepsy with a negative effect on development, a high occurrence of nonconvulsive status epilepticus, a high rate of crouch gait in the older children with risk of deterioration of mobility, a relatively low occurrence of microcephaly, a higher mean weight for height in all genetic subtypes with a significant higher mean in the nondeletion children, and a high occurrence of hyperphagia across all genetic subtypes. Natural history data are needed to design future trials. With this large clinical cohort with structured prospective and multidisciplinary follow-up, we provide unbiased data on AS to support further intervention studies to optimize outcome and quality of life of children with AS and their family.

Tuberous sclerosis complex: Concerns and needs of patients and parents from the transitional period to adulthood.

INTRODUCTION: Transitioning into adulthood and from pediatric services to adult healthcare are both challenging processes for young adults with rare chronic disorders such as tuberous sclerosis complex (TSC) and their parents. Adult healthcare systems are often less family-oriented and lack multidisciplinary care and experience with TSC, which can result in increased health risks and morbidity. Patient-driven data on care needs are necessary to optimize support for this vulnerable patient group. AIM: The aim of this study was to explore the concerns and care needs of young adult patients with TSC in medical, psychological, and socioeconomical domains. METHOD: A qualitative study was performed using semistructured interviews with 16 patients (median age: 21years; range: 17 to 30) and 12 parents. Concerns and care needs were organized using the International Classification of Functioning, Disability, and Health (ICF). RESULTS: Main concerns involved mental and physical health, participation, self-management skills, family planning, and side effects of medications. Patients expressed the need for multidisciplinary care that is well-informed, easily accessible, and focused on the patient as a whole, including his/her family. Parents reported high stress levels. CONCLUSION: The current study provides patient-driven information, allowing recommendations to facilitate the (transition of) care for young adults with TSC. In addition to seizures, tumor growth, and TSC-associated neuropsychiatric disorders (TAND), more attention is needed for concerns and care needs specific to the transitional period, participation, and environmental factors. Adult healthcare providers should offer expert multidisciplinary care for adult patients with TSC, including attention for parental stress.

Germline activating AKT3 mutation associated with megalencephaly, polymicrogyria, epilepsy and hypoglycemia.

Activating germ-line and somatic mutations in AKT3 (OMIM 611223) are associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH; OMIM # 615937) and megalencephaly-capillary malformation (MCAP; OMIM # 602501). Here we report an individual with megalencephaly, polymicrogyria, refractory epilepsy, hypoglycemia and a germline AKT3 mutation. At birth, head circumference was 43 cm (5 standard deviations above the mean). No organomegaly was present, but there was generalized hypotonia, joint and skin laxity, developmental delay and failure to thrive. At 6 months of age the patient developed infantile spasms that were resistant to antiepileptic polytherapy. Recurrent hypoglycemia was noted during treatment with adrenocorticotropic hormone but stabilized upon introduction of continuous, enriched feeding. The infantile spasms responded to the introduction of a ketogenic diet, but the hypoglycemia recurred until the diet was adjusted for increased resting energy expenditure. A novel, de novo AKT3 missense variant (exon 5; c.548T>A, p.(V183D)) was identified and shown to activate AKT3 by in vitro functional testing. We hypothesize that the sustained hypoglycemia in this patient is caused by increased glucose utilization due to activation of AKT3 signaling. This might explain the efficacy of the ketogenic diet in this individual.

Epilepsy in children with tuberous sclerosis complex: Chance of remission and response to antiepileptic drugs.

OBJECTIVE: To describe treatment and outcome of epilepsy in children with tuberous sclerosis complex (TSC). METHODS: Seventy-one children with TSC and epilepsy treated at the ENCORE TSC Expertise Center between 1988 and 2014 were included. Patient characteristics and duration and effectiveness of antiepileptic treatments were extracted from our clinical database. Correlations were made between recurrence of seizures after response to treatment, and several patient characteristics. RESULTS: Median age at time of inclusion was 9.4 years (range 0.9-18.0). Seizure history showed that 55 children (77%) of 71 became seizure-free for longer than 1 month, and 21 (30%) of 71 for longer than 24 months. Remission of seizures was associated with higher IQ, and a trend was observed between seizure remission and age at onset of seizures. A total of 19 antiepileptic drugs (AEDs) were used. Valproic acid, vigabatrin, levetiracetam, and carbamazepine were used most frequently. Nonpharmacologic therapies (ketogenic diet, epilepsy surgery, and vagus nerve stimulation) were used 13 times. Epilepsy surgery was most effective, with four of five children becoming seizure-free. AEDs prescribed as first and second treatment were most effective. Valproic acid was prescribed most frequently as first and second treatment, followed by vigabatrin. Thirty-one children had infantile spasms, preceded by focal seizures in 18 children (58%). Vigabatrin was used by 29 children (94%), and was first treatment in 15 (48%). Vigabatrin was more effective than other AEDs when prescribed as first treatment. SIGNIFICANCE: We showed that, although 77% of children with epilepsy due to TSC reached seizure remission, usually after their first or second AED, this was sustained for at least 24 months in only 38%. Almost half of those with 24 months of remission later had relapse of seizures. Our results support vigabatrin as first choice drug, and show the need for better treatment options for these children.

Outcome measures in Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe intellectual disability, little to no expressive speech, visual and motor problems, emotional/behavioral challenges, and a tendency towards hyperphagia and weight gain. The characteristics of AS make it difficult to measure these children's functioning with standard clinical tests. Feasible outcome measures are needed to measure current functioning and change over time, in clinical practice and clinical trials. AIM: Our first aim is to assess the feasibility of several functional tests. We target domains of neurocognitive functioning and physical growth using the following measurement methods: eye-tracking, functional Near-Infrared Spectroscopy (fNIRS), indirect calorimetry, bio-impedance analysis (BIA), and BOD POD (air-displacement plethysmography). Our second aim is to explore the results of the above measures, in order to better understand the AS phenotype. METHODS: The study sample consisted of 28 children with AS aged 2-18 years. We defined an outcome measure as feasible when (1) at least 70% of participants successfully finished the measurement and (2) at least 60% of those participants had acceptable data quality. Adaptations to the test procedure and reasons for early termination were noted. Parents rated acceptability and importance and were invited to make recommendations to increase feasibility. The results of the measures were explored. RESULTS: Outcome measures obtained with eye-tracking and BOD POD met the definition of feasibility, while fNIRS, indirect calorimetry, and BIA did not. The most important reasons for early termination of measurements were showing signs of protest, inability to sit still and poor/no calibration (eye-tracking specific). Post-calibration was often applied to obtain valid eye-tracking results. Parents rated the BOD POD als most acceptable and fNIRS as least acceptable for their child. All outcome measures were rated to be important. Exploratory results indicated longer reaction times to high salient visual stimuli (eye-tracking) as well as high body fat percentage (BOD POD). CONCLUSIONS: Eye-tracking and BOD POD are feasible measurement methods for children with AS. Eye-tracking was successfully used to assess visual orienting functions in the current study and (with some practical adaptations) can potentially be used to assess other outcomes as well. BOD POD was successfully used to examine body composition. TRIAL REGISTRATION: Registered d.d. 23-04-2020 under number 'NL8550' in the Dutch Trial Register: https://onderzoekmetmensen.nl/en/trial/23075.

ACTA2 mutation with childhood cardiovascular, autonomic and brain anomalies and severe outcome.

Thoracic aortic aneurysm and dissection (TAAD) are associated with connective tissue disorders like Marfan syndrome and Loeys-Dietz syndrome, caused by mutations in the fibrillin-1, the TGFß-receptor 1- and -2 genes, the SMAD3 and TGFß2 genes, but have also been ascribed to ACTA2 gene mutations in adults, spread throughout the gene. We report on a novel de novo c.535C>T in exon 6 leading to p.R179C aminoacid substitution in ACTA2 in a toddler girl with primary pulmonary hypertension, persistent ductus arteriosus, extensive cerebral white matter lesions, fixed dilated pupils, intestinal malrotation, and hypotonic bladder. Recently, de novo ACTA2 R179H substitutions have been associated with a similar phenotype and additional cerebral developmental defects including underdeveloped corpus callosum and vermis hypoplasia in a single patient. The patient here shows previously undescribed abnormal lobulation of the frontal lobes and position of the gyrus cinguli and rostral dysplasis of the corpus callosum; she died at the age of 3 years during surgery due to vascular fragility and rupture of the ductus arteriosus. Altogether these observations support a role of ACTA2 in brain development, especially related to the arginine at position 179. Although all previously reported patients with R179H substitution successfully underwent the same surgery at younger ages, the severe outcome of our patient warns against the devastating effects of the R179C substitution on vasculature.

Sleep problems in children with Angelman Syndrome: The effect of a behavioral intervention program.

BACKGROUND & AIMS: The aim of this study was to investigate the effect of a behavioral intervention on sleep problems, which are significant and an unmet clinical need in children with Angelman Syndrome (AS). METHODS & PROCEDURES: Children (2-18 years) with AS and sleep problems were randomized to a behavioral intervention program or a control group. Intervention consisted of a standardized program including home visits, psycho-education, feedback based on direct observation of bedtime routine and video footage of the night and behavioral treatment techniques by a behavioral therapist. Change in sleep duration (primary) and parental sleep, nighttime visits, sleep hygiene, daytime behavior, parental stress and quality of life (secondary) were assessed post-intervention and at follow-up using questionnaires, diary, actigraphy and videosomnography. OUTCOMES & RESULTS: The groups, 9 children in each, did not differ at baseline. We found a significant effect of intervention on wake after sleep onset with classical statistical analysis (videosomnography). With single case analysis we found a positive effect on total sleep time (diary and actigraphy) and wake after sleep onset (diary) with a persistent effect on total sleep time (actigraphy) and wake after sleep onset (diary). On secondary outcome there was a significant and persistent effect on sleep hygiene and several quality of life domains. CONCLUSIONS & IMPLICATIONS: Behavioral intervention has a positive and persistent effect on sleep problems in children with AS. We advise psycho-education for all parents and use of videosomnography for both evaluation of and feedback on sleep behavior patterns, individual behavioral advice and specific behavioral techniques for children with sleep problems.

Hyperphagia, Growth, and Puberty in Children with Angelman Syndrome.

Angelman Syndrome (AS) is a rare genetic disorder caused by lack of maternal UBE3A protein due to a deletion of the chromosome 15q11.2-q13 region, uniparental paternal disomy, imprinting center defect, or pathogenic variant in the UBE3A gene. Characteristics are developmental delay, epilepsy, behavioral, and sleep problems. There is some evidence for hyperphagia, shorter stature, and higher BMI compared to neurotypical children, but longitudinal studies on growth are lacking. In this study, we analyzed prospectively collected data of 145 children with AS, who visited the ENCORE Expertise Center between 2010 and 2021, with a total of 853 visits. Children showed an elevated mean score of 25 on the Dykens Hyperphagia questionnaire (range 11-55) without genotype association. Higher scores were significantly associated with higher body mass index (BMI) standard deviation scores (SDS) (p = 0.004). Mean height was -1.2 SDS (SD 1.3), mean BMI-SDS was 0.6 (SD 1.7); 43% had a BMI-SDS > 1 and 20% had a BMI-SDS > 2. Higher BMI-SDS was significantly associated with non-deletion genotype (p = 0.037) and walking independently (p = 0.023). Height SDS decreased significantly with age (p < 0.001) and BMI-SDS increased significantly with age (p < 0.001. Onset of puberty was normal. In conclusion, children with AS showed moderate hyperphagia, lower height SDS, and higher BMI-SDS compared to norm data, with increasing deviation from the norm with age. It is uncertain how loss of maternal UBE3A function may influence growth. Attention to diet, exercise, and hyperphagia from an early age is recommended to prevent obesity and associated health problems.

Challenges in body composition assessment using air-displacement plethysmography by BOD POD in pediatric and young adult patients.

BACKGROUND & AIMS: Air-Displacement-Plethysmography (ADP) by BOD POD is widely used for body fat assessment in children. Although validated in healthy subjects, studies about use in pediatric patients are lacking. We evaluated user experience and usability of ADP measurements with the BOD POD system in healthy children and pediatric and young adult patients. METHODS: Using the experiences of seven cohort studies, which included healthy children and patients aged 2-22 years, we retrospectively evaluated the user experience with the User Experience Questionnaire (UEQ) (n = 13) and interviews (n = 7). Technical performance was studied using the quality control data collected by the ADP-system. RESULTS: From 2016 to 2022, 1606 measurements were scheduled. BOD POD was mostly rated 'user-friendly', with a generally neutral evaluation on all scales of the UEQ. However, questionable reliability and validity of the results were frequently (86%) reported. We found a high technical failure-rate of the device, predominantly in stability (17%) and accuracy of the measurement (12%), especially in the 'pediatric option' for children aged <6 years. Measurement failure-rate was 38%, mostly due to subject's fear or device failure, especially in young and lean children, and in children with physical and/or intellectual disabilities. CONCLUSION: We conclude that ADP by BOD POD in children and young adults is non-invasive and user-friendly. However, in specific pediatric populations, BOD POD has several limitations and high (technical) failure-rates, especially in young children with aberrant body composition. We recommend caution when interpreting body composition results of pediatric patients as assessed with BOD POD using the current default settings.

A multidisciplinary approach and consensus statement to establish standards of care for Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a rare neurogenetic disorder present in approximately 1/12,000 individuals and characterized by developmental delay, cognitive impairment, motor dysfunction, seizures, gastrointestinal concerns, and abnormal electroencephalographic background. AS is caused by absent expression of the paternally imprinted gene UBE3A in the central nervous system. Disparities in the management of AS are a major problem in preparing for precision therapies and occur even in patients with access to experts and recognized clinics. AS patients receive care based on collective provider experience due to limited evidence-based literature. We present a consensus statement and comprehensive literature review that proposes a standard of care practices for the management of AS at a critical time when therapeutics to alter the natural history of the disease are on the horizon. METHODS: We compiled the key recognized clinical features of AS based on consensus from a team of specialists managing patients with AS. Working groups were established to address each focus area with committees comprised of providers who manage >5 individuals. Committees developed management guidelines for their area of expertise. These were compiled into a final document to provide a framework for standardizing management. Evidence from the medical literature was also comprehensively reviewed. RESULTS: Areas covered by working groups in the consensus document include genetics, developmental medicine, psychology, general health concerns, neurology (including movement disorders), sleep, psychiatry, orthopedics, ophthalmology, communication, early intervention and therapies, and caregiver health. Working groups created frameworks, including flowcharts and tables, to help with quick access for providers. Data from the literature were incorporated to ensure providers had review of experiential versus evidence-based care guidelines. CONCLUSION: Standards of care in the management of AS are keys to ensure optimal care at a critical time when new disease-modifying therapies are emerging. This document is a framework for providers of all familiarity levels.

Epidemiology of low bone mineral density and fractures in children with severe cerebral palsy: a systematic review.

AIM: Children with severe cerebral palsy (CP) are at risk for developing low bone mineral density (BMD) and low-impact fractures. The aim of this study was to provide a systematic literature review of the epidemiology of fractures and low BMD in children with severe CP, with an emphasis on risk factors. Gross Motor Function Classification System (GMFCS) levels IV and V were criteria for severe cerebral palsy. METHOD: The literature (PubMed) was searched and eligible studies were given a level of evidence score using the Scottish Intercollegiate Guidelines Network criteria. RESULTS: Seven studies were found concerning epidemiology of fractures, 11 studies described epidemiology of low BMD, and 14 studies concerned risk factors. The methodological quality of most of these studies was poor. Five studies were considered well-conducted with low risk of confounding and bias. In these studies, the incidence of fractures in children with moderate to severe CP approached 4% per year, whereas the prevalence of low BMD in the femur was 77%. Limited ambulation, feeding difficulties, previous fractures, anticonvulsant use, and lower body fat mass were associated with low BMD z-scores. INTERPRETATION: There is only a limited amount of high-quality evidence on low BMD and fractures in children with severe CP.

A randomized controlled trial with everolimus for IQ and autism in tuberous sclerosis complex.

OBJECTIVE: To investigate whether mammalian target of rapamycin inhibitor everolimus can improve intellectual disability, autism, and other neuropsychological deficits in children with tuberous sclerosis complex (TSC). METHODS: In this 12-month, randomized, double-blind, placebo-controlled trial, we attempted to enroll 60 children with TSC and IQ <80, learning disability, special schooling, or autism, aged 4-17 years, without intractable seizures to be assigned to receive everolimus or placebo. Everolimus was titrated to blood trough levels of 5-10 ng/mL. Primary outcome was full-scale IQ; secondary outcomes included autism, neuropsychological functioning, and behavioral problems. RESULTS: Thirty-two children with TSC were randomized. Intention-to-treat analysis showed no benefit of everolimus on full-scale IQ (treatment effect -5.6 IQ points, 95% confidence interval -12.3 to 1.0). No effect was found on secondary outcomes, including autism and neuropsychological functioning, and questionnaires examining behavioral problems, social functioning, communication skills, executive functioning, sleep, quality of life, and sensory processing. All patients had adverse events. Two patients on everolimus and 2 patients on placebo discontinued treatment due to adverse events. CONCLUSIONS: Everolimus did not improve cognitive functioning, autism, or neuropsychological deficits in children with TSC. The use of everolimus in children with TSC with the aim of improving cognitive function and behavior should not be encouraged in this age group. CLINICALTRIALSGOV IDENTIFIER: NCT01730209. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for children with TSC, everolimus does not improve intellectual disability, autism, behavioral problems, or other neuropsychological deficits.

Sirolimus for epilepsy in children with tuberous sclerosis complex: A randomized controlled trial.

OBJECTIVE: To investigate whether mammalian target of rapamycin complex 1 (mTORC1) inhibitors could reduce seizure frequency in children with tuberous sclerosis complex (TSC). METHODS: Due to slow inclusion rate, target inclusion of 30 children was not reached. Twenty-three children with TSC and intractable epilepsy (age 1.8-10.9 years) were randomly assigned (1:1) to open-label, add-on sirolimus treatment immediately or after 6 months. Sirolimus was titrated to trough levels of 5-10 ng/mL. Primary endpoint was seizure frequency change during the sixth month of sirolimus treatment. RESULTS: Intention-to-treat analysis showed sirolimus treatment resulted in 41% seizure frequency decrease (95% confidence interval [CI] -69% to +14%; p = 0.11) compared to the standard-care period. Per protocol analysis of 14 children who reached sirolimus target trough levels in the sixth sirolimus month showed a seizure frequency decrease of 61% (95% CI -86% to +6%; p = 0.06). Cognitive development did not change. All children had adverse events. Five children discontinued sirolimus prematurely. CONCLUSIONS: We describe a randomized controlled trial for a non-antiepileptic drug that directly targets a presumed causal mechanism of epileptogenesis in a genetic disorder. Although seizure frequency decreased, especially in children reaching target trough levels, we could not show a significant benefit. Larger trials or meta-analyses are needed to investigate if patients with TSC with seizures benefit from mTORC1 inhibition. This trial was registered at trialregister.nl (NTR3178) and supported by the Dutch Epilepsy Foundation. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that sirolimus does not significantly reduce seizure frequency in children with TSC and intractable epilepsy. The study lacked the precision to exclude a benefit from sirolimus.

Transferring young people with profound intellectual and multiple disabilities from pediatric to adult medical care: parents' experiences and recommendations.

Many children with profound intellectual and multiple disabilities (PIMD) now reach adulthood. The aim of this study was to elicit parents' experiences with the transfer from pediatric to adult medical care. A convenience sample of 131 Dutch parents of young people with PIMD (16-26 years) completed a web-based questionnaire. Twenty-two percent of the young persons were still in pediatric care; 22% of the others had no care coordinator, although their health needs were the same. Parents valued the care provided by the pediatrician, and wished to see it continued. They were critical about how they had been prepared for transfer to adult care. Parents provided suggestions to improve transitional care, such as early start, information provision, and a joint consultation between pediatric and adult care.