The prevalence of parent-reported autism spectrum disorder among US children

Kogan MD, Vladutiu CJ, Schieve LA, Ghandour RM, Blumberg SJ, Zablotsky B, Perrin JM, Shattuck P, Kuhlthau KA, Harwood RL, Lu MC. The Prevalence of Parent-Reported Autism Spectrum Disorder Among US Children. Pediatrics. 2018 Dec;142(6):e20174161. doi: 10.1542/peds.2017-4161. PMID: 30478241; PMCID: PMC6317762.

Abstract

Objectives: To estimate the national prevalence of parent-reported autism spectrum disorder (ASD) diagnosis among US children aged 3 to 17 years as well as their treatment and health care experiences using the 2016 National Survey of Children's Health (NSCH).

Methods: The 2016 NSCH is a nationally representative survey of 50 212 children focused on the health and well-being of children aged 0 to 17 years. The NSCH collected parent-reported information on whether children ever received an ASD diagnosis by a care provider, current ASD status, health care use, access and challenges, and methods of treatment. We calculated weighted prevalence estimates of ASD, compared health care experiences of children with ASD to other children, and examined factors associated with increased likelihood of medication and behavioral treatment.

Results: Parents of an estimated 1.5 million US children aged 3 to 17 years (2.50%) reported that their child had ever received an ASD diagnosis and currently had the condition. Children with parent-reported ASD diagnosis were more likely to have greater health care needs and difficulties accessing health care than children with other emotional or behavioral disorders (attention-deficit/hyperactivity disorder, anxiety, behavioral or conduct problems, depression, developmental delay, Down syndrome, intellectual disability, learning disability, Tourette syndrome) and children without these conditions. Of children with current ASD, 27% were taking medication for ASD-related symptoms, whereas 64% received behavioral treatments in the last 12 months, with variations by sociodemographic characteristics and co-occurring conditions.

Conclusions: The estimated prevalence of US children with a parent-reported ASD diagnosis is now 1 in 40, with rates of ASD-specific treatment usage varying by children's sociodemographic and co-occurring conditions.

SUDEP counseling: Where do we stand?

Whitney R, Jones KC, Sharma S, RamachandranNair R. SUDEP counseling: Where do we stand? Epilepsia. 2023 Jun;64(6):1424-1431. doi: 10.1111/epi.17617. Epub 2023 Apr 21. PMID: 37039574.

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death in children and adults living with epilepsy. Several recent clinical practice guidelines have recommended that all individuals living with epilepsy and their caregivers be informed about SUDEP as a part of routine epilepsy counseling. Furthermore, several studies over the last two decades have explored the state of SUDEP counseling. Patients with epilepsy and their families want to be informed about the risk of SUDEP at or near the time of diagnosis, and preferably in person. Despite guideline recommendations, many pediatric and adult neurologists do not routinely inform individuals with epilepsy and their families about SUDEP. Some neurologists discuss SUDEP with only a subset of patients with epilepsy, such as those with risk factors like frequent generalized or focal to bilateral tonic-clonic seizures, nocturnal seizures, noncompliance, or medically refractory epilepsy. Proponents of routine SUDEP counseling argue that patients with epilepsy and their families have a "right to know" and that counseling may positively impact epilepsy self-management (i.e., behavioral modification and risk reduction). Some neurologists still believe that SUDEP counseling may cause unnecessary stress and anxiety for patients and their families (although this is erroneous) and that they also have a "right not to know." This narrative review explores the current gaps in SUDEP counseling, patients' and caregivers' perspectives of SUDEP counseling, and SUDEP prevention.

Euthanasia for autism!

Netherlands programs have euthanized otherwise healthy individuals with autism and intellectual handicaps in recent years, researchers have found. 

Five individuals under the age of 30, who cited autism as a factor in their decision to seek legal euthanasia, are among the cases reviewed by specialists at the U.K.'s Kingston University. 

"Factors directly associated with intellectual disability and/or ASD were the sole cause of suffering described in 21% of cases and a major contributing factor in a further 42% of cases," Kingston University's report on the issue found. 

The study noted that in many cases, doctors determined there was "no prospect of improvement" for intellectually challenged individuals because there is no treatment for their handicap.

"Reasons for the EAS [euthanasia and physician-assisted suicide] request included social isolation and loneliness (77%), lack of resilience or coping strategies (56%), lack of flexibility (rigid thinking or difficulty adapting to change) (44%) and oversensitivity to stimuli (26%). In one-third of cases, physicians noted there was ‘no prospect of improvement’ as ASD and intellectual disability are not treatable," the study reads.

Palliative care specialist Irene Tuffrey-Wijne — one of the lead authors of the Kingston University report — found Dutch doctors were legally killing patients who sought their own euthanasia because their intellectual disability or mental condition prevented them from leading a normal life, according to The Associated Press.

One record includes the case of a Dutch woman in her 30s with autism and borderline personality disorder. Doctors determined her afflictions prevented her from maintaining relationships and made forming connections with others "too difficult."

"There’s no doubt in my mind these people were suffering," Tuffrey-Wijne said. "But is society really OK with sending this message, that there’s no other way to help them, and it’s just better to be dead?"

Dutch psychologist Dr. Bram Sizoo expressed horror at the trend of autistic youths seeking assisted suicide and euthanasia's expanding acceptance.

"Some of them are almost excited at the prospect of death," Sizoo said. "They think this will be the end of their problems and the end of their family’s problems."

The Royal Dutch Medical Association has left the decision of who qualifies for assisted suicide up to medical professionals with few hard guidelines or rules.

https://www.foxnews.com/world/netherlands-euthanizing-autistic-intellectually-handicapped-people-researcher-finds

Normal outcome with prenatal intervention for riboflavin transporter defect

Elks N, Wilmshurst JM, Raga SV. Normal Outcome With Prenatal Intervention for Riboflavin Transporter Defect. Pediatr Neurol. 2023 Jul;144:16-18. doi: 10.1016/j.pediatrneurol.2023.04.004. Epub 2023 Apr 7. PMID: 37116404.

Abstract

Background: Riboflavin transporter deficiency is a rare but severe neurometabolic disorder.

Methods: We report two siblings with pathogenic variants in SLC52A3 gene, resulting in riboflavin transporter 3 deficiency.

Results: The first sibling was diagnosed at age 11 months with severe respiratory compromise and regression of developmental milestones. His symptoms significantly improved with riboflavin supplementation therapy. The younger sibling was diagnosed by antenatal genetic analysis; riboflavin supplementation was initiated in utero and continued from birth. Now at age two years, he remains clinically asymptomatic despite genetic confirmation of riboflavin transporter deficiency.

Conclusions: Antenatal riboflavin supplementation is a safe and effective treatment for the prevention of symptomatic manifestations of riboflavin transporter deficiency.

Association of MTOR mutations with developmental brain disorders

Inspired by a patient. See: https://childnervoussystem.blogspot.com/2023/05/what-is-this.html

Mirzaa GM, Campbell CD, Solovieff N, et al. Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism. JAMA Neurol. 2016;73(7):836–845. doi:10.1001/jamaneurol.2016.036

Abstract

Importance Focal cortical dysplasia (FCD), hemimegalencephaly, and megalencephaly constitute a spectrum of malformations of cortical development with shared neuropathologic features. These disorders are associated with significant childhood morbidity and mortality.

Objective To identify the underlying molecular cause of FCD, hemimegalencephaly, and diffuse megalencephaly.

Design, Setting, and Participants Patients with FCD, hemimegalencephaly, or megalencephaly (mean age, 11.7 years; range, 2-32 years) were recruited from Pediatric Hospital A. Meyer, the University of Hong Kong, and Seattle Children’s Research Institute from June 2012 to June 2014. Whole-exome sequencing (WES) was performed on 8 children with FCD or hemimegalencephaly using standard-depth (50-60X) sequencing in peripheral samples (blood, saliva, or skin) from the affected child and their parents and deep (150-180X) sequencing in affected brain tissue. Targeted sequencing and WES were used to screen 93 children with molecularly unexplained diffuse or focal brain overgrowth. Histopathologic and functional assays of phosphatidylinositol 3-kinase–AKT (serine/threonine kinase)–mammalian target of rapamycin (mTOR) pathway activity in resected brain tissue and cultured neurons were performed to validate mutations.

Main Outcomes and Measures Whole-exome sequencing and targeted sequencing identified variants associated with this spectrum of developmental brain disorders.

Results Low-level mosaic mutations of MTOR were identified in brain tissue in 4 children with FCD type 2a with alternative allele fractions ranging from 0.012 to 0.086. Intermediate-level mosaic mutation of MTOR (p.Thr1977Ile) was also identified in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin. Finally, a constitutional de novo mutation of MTOR (p.Glu1799Lys) was identified in 3 unrelated children with diffuse megalencephaly and intellectual disability. Molecular and functional analysis in 2 children with FCD2a from whom multiple affected brain tissue samples were available revealed a mutation gradient with an epicenter in the most epileptogenic area. When expressed in cultured neurons, all MTOR mutations identified here drive constitutive activation of mTOR complex 1 and enlarged neuronal size.

Conclusions and Relevance In this study, mutations of MTOR were associated with a spectrum of brain overgrowth phenotypes extending from FCD type 2a to diffuse megalencephaly, distinguished by different mutations and levels of mosaicism. These mutations may be sufficient to cause cellular hypertrophy in cultured neurons and may provide a demonstration of the pattern of mosaicism in brain and substantiate the link between mosaic mutations of MTOR and pigmentary mosaicism in skin.

Mirzaa GM, Campbell CD, Solovieff N, Goold C, Jansen LA, Menon S, Timms AE, Conti V, Biag JD, Adams C, Boyle EA, Collins S, Ishak G, Poliachik S, Girisha KM, Yeung KS, Chung BHY, Rahikkala E, Gunter SA, McDaniel SS, Macmurdo CF, Bernstein JA, Martin B, Leary R, Mahan S, Liu S, Weaver M, Doerschner M, Jhangiani S, Muzny DM, Boerwinkle E, Gibbs RA, Lupski JR, Shendure J, Saneto RP, Novotny EJ, Wilson CJ, Sellers WR, Morrissey M, Hevner RF, Ojemann JG, Guerrini R, Murphy LO, Winckler W, Dobyns WB. Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism. JAMA Neurol. 2016 Jul 1;73(7):836-845. doi: 10.1001/jamaneurol.2016.0363. PMID: 27159400; PMCID: PMC4979321.

Abstract

Importance: Focal cortical dysplasia (FCD), hemimegalencephaly, and megalencephaly constitute a spectrum of malformations of cortical development with shared neuropathologic features. These disorders are associated with significant childhood morbidity and mortality.

Objective: To identify the underlying molecular cause of FCD, hemimegalencephaly, and diffuse megalencephaly.

Design, setting, and participants: Patients with FCD, hemimegalencephaly, or megalencephaly (mean age, 11.7 years; range, 2-32 years) were recruited from Pediatric Hospital A. Meyer, the University of Hong Kong, and Seattle Children's Research Institute from June 2012 to June 2014. Whole-exome sequencing (WES) was performed on 8 children with FCD or hemimegalencephaly using standard-depth (50-60X) sequencing in peripheral samples (blood, saliva, or skin) from the affected child and their parents and deep (150-180X) sequencing in affected brain tissue. Targeted sequencing and WES were used to screen 93 children with molecularly unexplained diffuse or focal brain overgrowth. Histopathologic and functional assays of phosphatidylinositol 3-kinase-AKT (serine/threonine kinase)-mammalian target of rapamycin (mTOR) pathway activity in resected brain tissue and cultured neurons were performed to validate mutations.

Main outcomes and measures: Whole-exome sequencing and targeted sequencing identified variants associated with this spectrum of developmental brain disorders.

Results: Low-level mosaic mutations of MTOR were identified in brain tissue in 4 children with FCD type 2a with alternative allele fractions ranging from 0.012 to 0.086. Intermediate-level mosaic mutation of MTOR (p.Thr1977Ile) was also identified in 3 unrelated children with diffuse megalencephaly and pigmentary mosaicism in skin. Finally, a constitutional de novo mutation of MTOR (p.Glu1799Lys) was identified in 3 unrelated children with diffuse megalencephaly and intellectual disability. Molecular and functional analysis in 2 children with FCD2a from whom multiple affected brain tissue samples were available revealed a mutation gradient with an epicenter in the most epileptogenic area. When expressed in cultured neurons, all MTOR mutations identified here drive constitutive activation of mTOR complex 1 and enlarged neuronal size.

Conclusions and relevance: In this study, mutations of MTOR were associated with a spectrum of brain overgrowth phenotypes extending from FCD type 2a to diffuse megalencephaly, distinguished by different mutations and levels of mosaicism. These mutations may be sufficient to cause cellular hypertrophy in cultured neurons and may provide a demonstration of the pattern of mosaicism in brain and substantiate the link between mosaic mutations of MTOR and pigmentary mosaicism in skin.

Yield of neurodiagnostic testing in children presenting to a pediatric emergency department with altered mental status

Camila Ospina Jimenez, Lalitha Sivaswamy, Giovanni Castellucci, Birce Taskin, Ahmad Farooqi, 
Nirupama Kannikeswaran. Yield of Neurodiagnostic Testing in Children Presenting to a Pediatric Emergency Department With Altered Mental Status. Pediatric Neurology. In press.

Abstract

Background: Emergency department (ED) visits for altered mental status (AMS) in children are common. Neuroimaging is often performed to ascertain etiology, but its utility has not been well studied. Our objective is to describe the yield of neuroimaging studies in children who present to an ED with AMS. Methods: We performed a retrospective chart review of children 0-18 years of age, presenting to our PED between 2018 and 2021 with AMS. We abstracted patient demographics, physical examination, neuroimaging and EEG results, and final diagnosis. Neuroimaging and EEG studies were classified as normal or abnormal. Abnormal studies were categorized as clinically important and contributory: abnormalities that were clinically important and contributed to the etiology, clinically important but noncontributory: abnormalities that were clinically significant but did not explain the etiology, and incidental: abnormalities that were not clinically significant. Results: We analyzed 371 patients. The most common etiology of AMS was toxicologic (188, 51%) with neurologic causes (n = 50, 13.5%) accounting for a minority. Neuroimaging was performed in one-half (169, 45.5%) and abnormalities were noted in 44 (26%) studies. Abnormalities were clinically important and contributed to the etiologic diagnosis of AMS in 15/169 (8.9%), clinically important and noncontributory in 18/169 (10.7%), and incidental in 11/169 (6.5%). EEG was performed in 65 patients (17.5%), of which 17 (26%) were abnormal with only one being clinically important and contributory. Conclusions: Though neuroimaging was performed in approximately one half of the cohort, it was contributory in a minority. Similarly, diagnostic utility of EEG in children with AMS was low.

TANGO2 mutations 2

Dines JN, Golden-Grant K, LaCroix A, Muir AM, Cintrón DL, McWalter K, Cho MT, Sun A, Merritt JL, Thies J, Niyazov D, Burton B, Kim K, Fleming L, Westman R, Karachunski P, Dalton J, Basinger A, Ficicioglu C, Helbig I, Pendziwiat M, Muhle H, Helbig KL, Caliebe A, Santer R, Becker K, Suchy S, Douglas G, Millan F, Begtrup A, Monaghan KG, Mefford HC. TANGO2: expanding the clinical phenotype and spectrum of pathogenic variants. Genet Med. 2019 Mar;21(3):601-607. doi: 10.1038/s41436-018-0137-y. Epub 2018 Sep 24. Erratum in: Genet Med. 2018 Oct 15;: PMID: 30245509; PMCID: PMC6752277.

Abstract

Purpose: TANGO2-related disorders were first described in 2016 and prior to this publication, only 15 individuals with TANGO2-related disorder were described in the literature. Primary features include metabolic crisis with rhabdomyolysis, encephalopathy, intellectual disability, seizures, and cardiac arrhythmias. We assess whether genotype and phenotype of TANGO2-related disorder has expanded since the initial discovery and determine the efficacy of exome sequencing (ES) as a diagnostic tool for detecting variants.

Methods: We present a series of 14 individuals from 11 unrelated families with complex medical and developmental histories, in whom ES or microarray identified compound heterozygous or homozygous variants in TANGO2.

Results: The initial presentation of patients with TANGO2-related disorders can be variable, including primarily neurological presentations. We expand the phenotype and genotype for TANGO2, highlighting the variability of the disorder.

Conclusion: TANGO2-related disorders can have a more diverse clinical presentation than previously anticipated. We illustrate the utility of routine ES data reanalysis whereby discovery of novel disease genes can lead to a diagnosis in previously unsolved cases and the need for additional copy-number variation analysis when ES is performed.