Lamotrigine for cognitive deficits associated with neurofibromatosis type 1: A phase II randomized placebo-controlled trial.

AIM: To find proof-of-principle evidence for short-term treatment with lamotrigine to improve cognitive functioning of adolescents with neurofibromatosis type 1 (NF1). METHOD: This was a double-blind, parallel-group, randomized, placebo-controlled clinical trial (the NF1-EXCEL trial: Examining the Cognitive and Electrophysiological benefit of Lamotrigine in Neurofibromatosis type 1; Clinicaltrials.gov identifier NCT02256124), with the aim of enrolling 60 adolescents with NF1 aged 12 to 17 years 6 months. The short-term study intervention was 200 mg of lamotrigine taken orally for 26 weeks. The primary outcome was performance IQ tested with the Wechsler Intelligence Scale for Children, Third Edition, complemented with secondary outcomes for visuospatial learning efficacy, visual perception, visual sustained attention, fine motor coordination, attention-deficit/hyperactivity problems, and executive functioning. RESULTS: We screened 402 adolescents with NF1, of whom 31 (eight females) entered the study. Complete-case analysis showed no effect of lamotrigine on either performance IQ (-0.23, 95% CI -6.90 to 6.44) or most secondary outcomes. Visual sustained attention showed a trend towards better performance in the lamotrigine group (-0.81, 95% CI -1.67 to 0.04). INTERPRETATION: Lamotrigine did not improve cognitive functioning in adolescents with NF1. The small treatment effects make it unlikely that a larger sample size could have changed this conclusion.

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.

Clinical relevance of distinguishing autoimmune nodopathies from CIDP: longitudinal assessment in a large cohort.

BACKGROUND: The aim of this study was to determine treatment response and whether it is associated with antibody titre change in patients with autoimmune nodopathy (AN) previously diagnosed as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and to compare clinical features and treatment response between AN and CIDP. METHODS: Serum IgG antibodies to neurofascin-155 (NF155), contactin-1 (CNTN1) and contactin-associated protein 1 (CASPR1) were detected with cell-based assays in patients diagnosed with CIDP. Clinical improvement was determined using the modified Rankin scale, need for alternative and/or additional treatments and assessment of the treating neurologist. RESULTS: We studied 401 patients diagnosed with CIDP and identified 21 patients with AN (10 anti-NF155, 6 anti-CNTN1, 4 anti-CASPR1 and 1 anti-NF155/anti-CASPR1 double positive). In patients with AN ataxia (68% vs 28%, p=0.001), cranial nerve involvement (34% vs 11%, p=0.012) and autonomic symptoms (47% vs 22%, p=0.025) were more frequently reported; patients with AN improved less often after intravenous immunoglobulin treatment (39% vs 80%, p=0.002) and required additional/alternative treatments more frequently (84% vs 34%, p<0.001), compared with patients with CIDP. Antibody titres decreased or became negative in patients improving on treatment. Treatment withdrawal was associated with a titre increase and clinical deterioration in four patients. CONCLUSIONS: Distinguishing CIDP from AN is important, as patients with AN need a different treatment approach. Improvement and relapses were associated with changes in antibody titres, supporting the pathogenicity of these antibodies.

Meaningful outcomes for children and their caregivers attending a paediatric brain centre.

AIM: To identify meaningful outcomes of children and their caregivers attending a paediatric brain centre. METHOD: We compiled a long list of outcomes of health and functioning of children with brain-related disorders such as cerebral palsy, spina bifida, (genetic) neurodevelopmental disorders, and acquired brain injury. We incorporated three perspectives: patients, health care professionals, and published outcome sets. An aggregated list was categorized using the International Classification of Functioning, Disability, and Health: Children and Youth version in a patient validation survey for children and parent-caregivers to prioritize outcomes. Outcomes were considered meaningful when ranked 'very important' by 70% or more of the participants. RESULTS: We identified 104 outcomes from the three perspectives. After categorizing, 59 outcomes were included in the survey. Thirty-three surveys were completed by children (n = 4), caregivers (n = 24), and parent-caregivers together with their child (n = 5). Respondents prioritized 27 meaningful outcomes covering various aspects of health and functioning: emotional well-being, quality of life, mental and sensory functions, pain, physical health, and activities (communication, mobility, self-care, interpersonal relationships). Parent-caregiver concerns and environmental factors were newly identified outcomes. INTERPRETATION: Children and parent-caregivers identified meaningful outcomes covering various aspects of health and functioning, including caregiver concerns and environmental factors. We propose including those in future outcome sets for children with neurodisability. WHAT THIS PAPER ADDS: Outcomes that children with brain-related disorders and their parent-caregivers consider to be the most meaningful cover a wide range of aspects of functioning. Involving these children and their parent-caregivers resulted in the identification of important outcomes that were not covered by professionals and the literature. Parent-caregiver-related factors (coping, burden of care) and environmental factors (support, attitudes, and [health care] services) were identified as meaningful.

Loss of SMPD4 Causes a Developmental Disorder Characterized by Microcephaly and Congenital Arthrogryposis.

Sphingomyelinases generate ceramide from sphingomyelin as a second messenger in intracellular signaling pathways involved in cell proliferation, differentiation, or apoptosis. Children from 12 unrelated families presented with microcephaly, simplified gyral pattern of the cortex, hypomyelination, cerebellar hypoplasia, congenital arthrogryposis, and early fetal/postnatal demise. Genomic analysis revealed bi-allelic loss-of-function variants in SMPD4, coding for the neutral sphingomyelinase-3 (nSMase-3/SMPD4). Overexpression of human Myc-tagged SMPD4 showed localization both to the outer nuclear envelope and the ER and additionally revealed interactions with several nuclear pore complex proteins by proteomics analysis. Fibroblasts from affected individuals showed ER cisternae abnormalities, suspected for increased autophagy, and were more susceptible to apoptosis under stress conditions, while treatment with siSMPD4 caused delayed cell cycle progression. Our data show that SMPD4 links homeostasis of membrane sphingolipids to cell fate by regulating the cross-talk between the ER and the outer nuclear envelope, while its loss reveals a pathogenic mechanism in microcephaly.

A standard of care for individuals with PIK3CA-related disorders: An international expert consensus statement.

Growth promoting variants in PIK3CA cause a spectrum of developmental disorders, depending on the developmental timing of the mutation and tissues involved. These phenotypically heterogeneous entities have been grouped as PIK3CA-Related Overgrowth Spectrum disorders (PROS). Deep sequencing technologies have facilitated detection of low-level mosaic, often necessitating testing of tissues other than blood. Since clinical management practices vary considerably among healthcare professionals and services across different countries, a consensus on management guidelines is needed. Clinical heterogeneity within this spectrum leads to challenges in establishing management recommendations, which must be based on patient-specific considerations. Moreover, as most of these conditions are rare, affected families may lack access to the medical expertise that is needed to help address the multi-system and often complex medical issues seen with PROS. In March 2019, macrocephaly-capillary malformation (M-CM) patient organizations hosted an expert meeting in Manchester, United Kingdom, to help address these challenges with regards to M-CM syndrome. We have expanded the scope of this project to cover PROS and developed this consensus statement on the preferred approach for managing affected individuals based on our current knowledge.

Human RAD50 deficiency: Confirmation of a distinctive phenotype.

DNA double-strand breaks (DSBs) are highly toxic DNA lesions that can lead to chromosomal instability, loss of genes and cancer. The MRE11/RAD50/NBN (MRN) complex is keystone involved in signaling processes inducing the repair of DSB by, for example, in activating pathways leading to homologous recombination repair and nonhomologous end joining. Additionally, the MRN complex also plays an important role in the maintenance of telomeres and can act as a stabilizer at replication forks. Mutations in NBN and MRE11 are associated with Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT)-like disorder, respectively. So far, only one single patient with biallelic loss of function variants in RAD50 has been reported presenting with features classified as NBS-like disorder. Here, we report a long-term follow-up of an unrelated patient with facial dysmorphisms, microcephaly, skeletal features, and short stature who is homozygous for a novel variant in RAD50. We could show that this variant, c.2524G > A in exon 15 of the RAD50 gene, induces aberrant splicing of RAD50 mRNA mainly leading to premature protein truncation and thereby, most likely, to loss of RAD50 function. Using patient-derived primary fibroblasts, we could show abnormal radioresistant DNA synthesis confirming pathogenicity of the identified variant. Immunoblotting experiments showed strongly reduced protein levels of RAD50 in the patient-derived fibroblasts and provided evidence for a markedly reduced radiation-induced AT-mutated signaling. Comparison with the previously reported case and with patients presenting with NBS confirms that RAD50 mutations lead to a similar, but distinctive phenotype.

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.

Cortical dysplasia and autistic trait severity in children with Tuberous Sclerosis Complex: a clinical epidemiological study.

Tuberous Sclerosis Complex (TSC) is characterized by a high prevalence of autism spectrum disorders (ASD). Little is known about the relation between cortical dysplasia and ASD severity in TSC. We assessed ASD severity (using the Autism Diagnostic Observation Scale), tuber and radial migration line (RML) count and location, and cognitive functioning in 52 children with TSC and performed regression and mediation analyses. Tuber and RML count were strongly positively related to ASD severity. However, when correcting for cognitive functioning, the majority of associations became insignificant and only total tuber count remained associated to the severity of restricted/repetitive behaviors. Occipital RML count remained associated with overall ASD severity, and social communication/interaction deficit severity specifically. This study shows the important explanatory role of cognitive functioning in the association between cortical dysplasia and ASD severity, and the relevance of separately studying the two ASD subdomains.

Mycoplasma pneumoniae triggering the Guillain-Barré syndrome: A case-control study.

OBJECTIVE: Guillain-Barré syndrome (GBS) is an acute postinfectious immune-mediated polyneuropathy. Although preceding respiratory tract infections with Mycoplasma pneumoniae have been reported in some cases, the role of M. pneumoniae in the pathogenesis of GBS remains unclear. We here cultured, for the first time, M. pneumoniae from a GBS patient with antibodies against galactocerebroside (GalC), which cross-reacted with the isolate. This case prompted us to unravel the role of M. pneumoniae in GBS in a case-control study. METHODS: We included 189 adults and 24 children with GBS and compared them to control cohorts for analysis of serum antibodies against M. pneumoniae (n = 479) and GalC (n = 198). RESULTS: Anti-M. pneumoniae immunoglobulin (Ig) M antibodies were detected in GBS patients and healthy controls in 3% and 0% of adults (p = 0.16) and 21% and 7% of children (p = 0.03), respectively. Anti-GalC antibodies (IgM and/or IgG) were found in 4% of adults and 25% of children with GBS (p = 0.001). Anti-GalC-positive patients showed more-frequent preceding respiratory symptoms, cranial nerve involvement, and a better outcome. Anti-GalC antibodies correlated with anti-M. pneumoniae antibodies (p < 0.001) and cross-reacted with different M. pneumoniae strains. Anti-GalC IgM antibodies were not only found in GBS patients with M. pneumoniae infection, but also in patients without neurological disease (8% vs 9%; p = 0.87), whereas anti-GalC IgG was exclusively found in patients with GBS (9% vs 0%; p = 0.006). INTERPRETATION: M. pneumoniae infection is associated with GBS, more frequently in children than adults, and elicits anti-GalC antibodies, of which specifically anti-GalC IgG may contribute to the pathogenesis of GBS. Ann Neurol 2016;80:566-580.

Motor nerve excitability after childhood Guillain-Barré syndrome.

Residual motor nerve dysfunction after pediatric Guillain-Barré syndrome (GBS) was determined in an observational cross-sectional cohort study in patients who previously developed GBS during childhood (<18 years). Ulnar motor nerve dysfunction was defined by compound motor action potential (CMAP) scan in patients after a follow up of at least 1 year compared with age-matched healthy controls, in relation to clinical course and outcome. A total of 37 persons previously diagnosed with GBS in childhood were included with a mean age at current examination of 20.6 years (4-39 years). The median time between diagnosis and follow-up was 11 years (range: 1-22 years). CMAP scanning indicated ulnar motor nerve dysfunction in 25 (68%) participants. The most frequent abnormality was a reduction in nerve excitability observed both in those with residual limb weakness and in the majority of those with complete recovery. CMAP scan characteristics were not related to prognostic factors or outcome. In conclusion, GBS in childhood results in residual motor nerve excitability disturbances, even in those completely recovered, probably reflecting altered physiology of regenerated peripheral nerves.

RTTN mutations link primary cilia function to organization of the human cerebral cortex.

Polymicrogyria is a malformation of the developing cerebral cortex caused by abnormal organization and characterized by many small gyri and fusion of the outer molecular layer. We have identified autosomal-recessive mutations in RTTN, encoding Rotatin, in individuals with bilateral diffuse polymicrogyria from two separate families. Rotatin determines early embryonic axial rotation, as well as anteroposterior and dorsoventral patterning in the mouse. Human Rotatin has recently been identified as a centrosome-associated protein. The Drosophila melanogaster homolog of Rotatin, Ana3, is needed for structural integrity of centrioles and basal bodies and maintenance of sensory neurons. We show that Rotatin colocalizes with the basal bodies at the primary cilium. Cultured fibroblasts from affected individuals have structural abnormalities of the cilia and exhibit downregulation of BMP4, WNT5A, and WNT2B, which are key regulators of cortical patterning and are expressed at the cortical hem, the cortex-organizing center that gives rise to Cajal-Retzius (CR) neurons. Interestingly, we have shown that in mouse embryos, Rotatin colocalizes with CR neurons at the subpial marginal zone. Knockdown experiments in human fibroblasts and neural stem cells confirm a role for RTTN in cilia structure and function. RTTN mutations therefore link aberrant ciliary function to abnormal development and organization of the cortex in human individuals.

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.

Severe childhood Guillain-Barré syndrome associated with Mycoplasma pneumoniae infection: a case series.

We report seven children with recent Mycoplasma pneumoniae infection and severe Guillain-Barré syndrome (GBS) that presented to two European medical centres from 1992 to 2012. Severe GBS was defined as the occurrence of respiratory failure, central nervous system (CNS) involvement, or death. Five children had GBS, one Bickerstaff brain stem encephalitis (BBE), and one acute-onset chronic inflammatory demyelinating polyneuropathy (A-CIDP). The five patients with severe GBS were derived from an original cohort of 66 children with GBS. In this cohort, 17 children (26%) had a severe form of GBS and 47% of patients with M. pneumoniae infection presented with severe GBS. Of the seven patients in this case series, five were mechanically ventilated and four had CNS involvement (two were comatose). Most patients presented with non-specific clinical symptoms (nuchal rigidity and ataxia) and showed a rapidly progressive disease course (71%). Antibodies against M. pneumoniae were detected in all patients and were found to be intrathecally synthesised in two cases (GBS and BBE), which proves intrathecal infection. One patient died and only two patients recovered completely. These cases illustrate that M. pneumoniae infection in children can be followed by severe and complicated forms of GBS. Non-specific clinical features of GBS in such patients may predispose a potentially life-threatening delay in diagnosis.

Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors.

We describe a syndrome of primary microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes in two unrelated consanguineous families with at least three affected children. Linkage analysis revealed a region on chromosome 18 with a significant LOD score of 4.3. In this area, two homozygous nonconserved missense mutations in immediate early response 3 interacting protein 1 (IER3IP1) were found in patients from both families. IER3IP1 is highly expressed in the fetal brain cortex and fetal pancreas and is thought to be involved in endoplasmic reticulum stress response. We reported one of these families previously in a paper on Wolcott-Rallison syndrome (WRS). WRS is characterized by increased apoptotic cell death as part of an uncontrolled unfolded protein response. Increased apoptosis has been shown to be a cause of microcephaly in animal models. An autopsy specimen from one patient showed increased apoptosis in the cerebral cortex and pancreas beta cells, implicating premature cell death as the pathogenetic mechanism. Both patient fibroblasts and control fibroblasts treated with siRNA specific for IER3IP1 showed an increased susceptibility to apoptotic cell death under stress conditions in comparison to controls. This directly implicates IER3IP1 in the regulation of cell survival. Identification of IER3IP1 mutations sheds light on the mechanisms of brain development and on the pathogenesis of infantile epilepsy and early-onset permanent diabetes.

Long-term outcome of Guillain-Barré syndrome in children.

The objective of this study is to determine the long-term outcome and consequences of Guillain-Barré syndrome (GBS) in children. This is an observational cross-sectional cohort study of children diagnosed with GBS (0-18 years old) at the Sophia Children's Hospital in Rotterdam from 1987 to 2009. All patients were invited for a structured interview, questionnaires, and full neurologic exam to record their current clinical condition focused on complaints and symptoms, neurological deficits, disabilities, behavior, and quality of life. Thirty-seven patients participated, 23 were now adults, with a median age of 20 years (range 4-39 years) and a median follow-up time of 11 years (range 1-22 years). Residual complaints were reported by 24 (65%) patients, including paresthesias (38%), unsteadiness of gait in the dark (37%), painful hands or feet (24%), and severe fatigue (22%). Four patients had severe neurological deficits, including facial diplegia and limb weakness. Two patients had had a recurrence of GBS. In 10 patients (26%), GBS had a negative impact on their school career. Questionnaires identified a wide range of behavioral problems. Quality of life was below normal on the subscale vitality, and above normal on the subscales social functioning and positive emotions in the adult group. Most children show good recovery of neurological deficits after GBS, but many have persisting long-term residual complaints and symptoms that may lead to psychosocial problems interfering with participation in daily life.

Dementia in Rare Genetic Neurodevelopmental Disorders: A Systematic Literature Review.

BACKGROUND AND OBJECTIVES: Knowledge of young-onset Alzheimer disease in adults with Down syndrome has greatly improved clinical care. However, little is known about dementia in rare genetic neurodevelopmental disorders (RGNDs). In this review, a comprehensive overview is provided of reports on dementia and cognitive/adaptive trajectories in adults with RGNDs. METHODS: A systematic literature review was conducted in Embase, Medline ALL, and PsycINFO on December 6, 2022. The protocol was registered in PROSPERO (CRD42021223041). Search terms for dementia, cognitive and adaptive functioning, and RGNDs were combined using generic terms and the Orphanet database. Study characteristics and descriptive data on genetic diagnosis, clinical and neuropathologic features, comorbidities, and diagnostic methods were extracted using a modified version of the Cochrane Data Extraction Template. RESULTS: The literature search yielded 40 publications (17 cohorts, 23 case studies) describing dementia and/or cognitive or adaptive trajectories in adults with 14 different RGNDs. Dementia was reported in 49 individuals (5 cohorts, 20 cases) with a mean age at onset of 44.4 years. Diagnostics were not disclosed for half of the reported individuals (n = 25/49, 51.0%). A total of 44 different psychodiagnostic instruments were used. MRI was the most reported additional investigation (n = 12/49, 24.5%). Comorbid disorders most frequently associated with cognitive/adaptive decline were epilepsy, psychotic disorders, and movement disorders. DISCUSSION: Currently available literature shows limited information on aging in RGNDs, with relatively many reports of young-onset dementia. Longitudinal data may provide insights into converging neurodevelopmental degenerative pathways. We provide recommendations to optimize dementia screening, diagnosis, and research.

Autism Spectrum Disorder Symptom Profiles in Fragile X Syndrome, Angelman Syndrome, Tuberous Sclerosis Complex and Neurofibromatosis Type 1.

Studying Autism Spectrum Disorder (ASD) heterogeneity in biologically homogeneous samples may increase our knowledge of ASD etiology. Fragile X syndrome (FXS), Angelman syndrome (AS), Tuberous Sclerosis Complex (TSC), and Neurofibromatosis type 1 (NF1) are monogenic disorders with high a prevalence of ASD symptomatology. This study aimed to identify ASD symptom profiles in a large group of children and adolescents (0;9-28 years) with FXS, AS, TSC, and NF1. Data on ASD symptomatology (Autism Diagnostic Observation Scale (ADOS-2) & Social Responsiveness Scale (SRS-2)) were collected from children and adolescents with FXS (n = 54), AS (n = 93), TSC (n = 112), and NF1 (n = 278). To identify groups of individuals with similar ASD profiles, we performed two latent profile analyses. We identified a four-profile model based on the ADOS-2, with a (1) 'Non-spectrum symptom profile', (2) 'Social Affect symptom profile', (3)'Restricted/Repetitive Behaviors symptom profile', and (4)'ASD symptom profile'. We also identified a four-profile model based on the SRS, with a (1)'Non-clinical symptom profile', (2)'Mild symptom profile', (3)'Moderate symptom profile', and (4)'Severe symptom profile'. Although each syndrome group exhibited varying degrees of severity, they also displayed heterogeneity in the profiles in which they were classified. We found distinct ASD symptom profiles in a population consisting of children and adolescents with FXS, AS, TSC, and NF1. Our study highlights the importance of a personalized approach to the identification and management of ASD symptoms in rare genetic syndromes. Future studies should aim to include more domains of functioning and investigate the stability of latent profiles over time.

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.