Effectiveness of Chloral Hydrate on Brain MRI in Children with Developmental Delay/Intellectual Disability Comparing with Normal Intelligence: Single Tertiary Center Experience

Neurodiagnostic investigation requirements are expanding for diagnostic and therapeutic purposes in children, especially in those with developmental delay/intellectual disability (DD/ID). Thus, determination of optimal sedatives to achieve successful sedation and immobility without further neurological compromise is important in children with DD/ID. The purpose of this study is to assess the effectiveness and adverse reactions of chloral hydrate (CH) for brain magnetic resonance imaging (B-MRI) in children with DD/ID compared to those with normal intelligence (NI). We performed a retrospective chart review of children aged from 1 day to 12 years who required elective sedation using CH for B-MRI. About 730 cases (415 with DD/ID and 315 with NI) of CH sedation were conducted for B-MRI. Children with DD/ID showed a higher failure rate (22%) than did those with NI (6%); additional CH and prolonged sedation time were required. There was no difference in incidence of adverse reactions between DD/ID and NI groups (p = 0.338). Older or heavier children with DD/ID (p = 0.036 and p = 0.013, respectively), as well as those diagnosed with epilepsy or neuropsychiatric disorders showed higher risk of sedation failure (p < 0.001 for each). In conclusion, CH was a suboptimal sedative drug for children with DD/ID compared with those with NI. Other alternative or supplementary sedatives should be taken into consideration especially for those vulnerable groups.

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Identifying Clinical Clues in Children With Global Developmental Delay / Intellectual Disability With Abnormal Brain Magnetic Resonance Imaging (MRI)

Journal of Child Neurology ◽

10.1177/0883073820977330 ◽

2020 ◽

pp. 088307382097733

Author(s):

Abdullah Alamri ◽

Yaser I. Aljadhai ◽

Abdullah Alrashed ◽

Bandar Alfheed ◽

Roba Abdelmoaty ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Intellectual Disability ◽

Magnetic Resonance ◽

Developmental Delay ◽

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

Global Developmental Delay ◽

Resonance Imaging ◽

Mri Findings ◽

Magnetic Resonance Imaging Mri

Global developmental delay / intellectual disability are common pediatric conditions. Brain magnetic resonance imaging (MRI), although an important diagnostic tool in the evaluation of these patients, often requires general anesthesia. Recent literature suggests that unnecessary general anesthesia exposure should be avoided in early years because of possible long-term negative neurodevelopmental sequelae. This study sought to identify clinical clues associated with brain MRI abnormalities in children with global developmental delay / intellectual disability in an attempt to provide guidance to physicians on selecting patients who would benefit from an MRI. Retrospective chart review analysis was conducted for patients presenting to a pediatric neurology tertiary care center between 2014 and 2017 for a first clinic evaluation for global developmental delay / intellectual disability. Detailed clinical history and physical examination findings were analyzed and correlated with brain MRI findings. The majority (218/327, 67%) of children referred for evaluation of global developmental delay / intellectual disability underwent complete clinical and radiologic evaluations. Mean age was 37.9 months (±32.5 standard deviation) and 116 were males (53%). Motor deficits were predominant in most subjects (122/218, 56%). Abnormal MRI findings were observed in 153 children (70%), with the most prevalent abnormalities noted within the white matter (104/153, 68%), corpus callosum (77/153, 50%), and the hippocampus (50/153, 33%). Abnormal MRI findings were prevalent in children with predominant motor delay (84, 69%) and cognitive disability (3, 100%) as well as those with visual and hearing impairment ( P < .05). The presence of facial dysmorphisms (57/71, P = .02); cranial nerve abnormalities (79/100; P = .007) and abnormal reflexes (16, P = .01) on examination also correlated significantly with increased MRI abnormalities.

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OTUD5 Variants Associated With X-Linked Intellectual Disability and Congenital Malformation

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.631428 ◽

2021 ◽

Vol 9 ◽

Author(s):

Ken Saida ◽

Tokiko Fukuda ◽

Daryl A. Scott ◽

Toru Sengoku ◽

Kazuhiro Ogata ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Ovarian Tumor ◽

Brain Magnetic Resonance Imaging ◽

Missense Variant ◽

The Novel ◽

Nasal Bridge ◽

Congenital Cardiac Anomalies ◽

Novel Variant ◽

Long Term Prognosis

BackgroundX-linked intellectual disability (XLID), which occurs predominantly in males, is a relatively common and genetically heterogeneous disorder in which over 100 mutated genes have been reported. The OTUD5 gene at Xp11.23 encodes ovarian tumor deubiquitinase 5 protein, which is a deubiquitinating enzyme member of the ovarian tumor family. LINKage-specific-deubiquitylation-deficiency-induced embryonic defects (LINKED) syndrome, arising from pathogenic OTUD5 variants, was recently reported as a new XLID with additional congenital anomalies.MethodsWe investigated three affected males (49- and 47-year-old brothers [Individuals 1 and 2] and a 2-year-old boy [Individual 3]) from two families who showed developmental delay. Their common clinical features included developmental delay, hypotonia, short stature, and distinctive facial features, such as telecanthus and a depressed nasal bridge. Individuals 1 and 2 showed epilepsy and brain magnetic resonance imaging showed a thin corpus callosum and mild ventriculomegaly. Individual 3 showed congenital malformations, including tetralogy of Fallot, hypospadias, and bilateral cryptorchidism. To identify the genetic cause of these features, we performed whole-exome sequencing.ResultsA hemizygous OTUD5 missense variant, c.878A>T, p.Asn293Ile [NM_017602.4], was identified in one family with Individuals 1 and 2, and another missense variant, c.1210 C>T, p.Arg404Trp, in the other family with Individual 3, respectively. The former variant has not been registered in public databases and was predicted to be pathogenic by multiple in silico prediction tools. The latter variant p.Arg404Trp was previously reported as a pathogenic OTUD5 variant, and Individual 3 showed a typical LINKED syndrome phenotype. However, Individuals 1 and 2, with the novel variant (p.Asn293Ile), showed no cardiac or genitourinary malformations.ConclusionsUnlike previous reports of LINKED syndrome, which described early lethality with congenital cardiac anomalies, our three cases are still alive. Notably, the adult brothers with the novel missense OTUD5 variant have lived into their forties. This may be indicative of a milder phenotype as a possible genotype-phenotype correlation. These findings imply a possible long-term prognosis for individuals with this new XLID syndrome, and a wider phenotypic variation than initially thought.

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Diagnostic approach with genetic tests for global developmental delay and/or intellectual disability: Single tertiary center experience

Annals of Human Genetics ◽

10.1111/ahg.12294 ◽

2018 ◽

Vol 83 (3) ◽

pp. 115-123 ◽

Cited By ~ 3

Author(s):

Ji Yoon Han ◽

Woori Jang ◽

Joonhong Park ◽

Myungshin Kim ◽

Yonggoo Kim ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Diagnostic Approach ◽

Global Developmental Delay ◽

Genetic Tests ◽

Tertiary Center

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Coexistence of neuronal intranuclear inclusion disease and amyotrophic lateral sclerosis: an autopsy case

BMC Neurology ◽

10.1186/s12883-021-02306-5 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Atsuhiko Sugiyama ◽

Takahiro Takeda ◽

Mizuho Koide ◽

Hajime Yokota ◽

Hiroki Mukai ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

Repeat Expansion ◽

Cerebellar Hemisphere ◽

Intranuclear Inclusions ◽

Intranuclear Inclusion ◽

Neuronal Intranuclear Inclusion ◽

Lateral Sclerosis

Abstract Background Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease. Pathologically, it is characterized by eosinophilic hyaline intranuclear inclusions in the cells of the visceral organs as well as central, peripheral, and autonomic nervous system cells. Recently, a GGC repeat expansion in the NOTCH2NLC gene has been identified as the etiopathological agent of NIID. Interestingly, this GGC repeat expansion was also reported in some patients with a clinical diagnosis of amyotrophic lateral sclerosis (ALS). However, there are no autopsy-confirmed cases of concurrent NIID and ALS. Case presentation A 60-year-old Taiwanese woman reported a four-month history of progressive weakness beginning in the right foot that spread to all four extremities. She was diagnosed with ALS because she met the revised El Escorial diagnostic criteria for definite ALS with upper and lower motor neuron involvement in the cervical, thoracic, and lumbosacral regions. She died of respiratory failure at 22 months from ALS onset, at the age of 62 years. Brain magnetic resonance imaging (MRI) revealed lesions in the medial part of the cerebellar hemisphere, right beside the vermis (paravermal lesions). The subclinical neuropathy, indicated by a nerve conduction study (NCS), prompted a potential diagnosis of NIID. Antemortem skin biopsy and autopsy confirmed the coexistence of pathology consistent with both ALS and NIID. We observed neither eccentric distribution of p62-positive intranuclear inclusions in the areas with abundant large motor neurons nor cytopathological coexistence of ALS and NIID pathology in motor neurons. This finding suggested that ALS and NIID developed independently in this patient. Conclusions We describe a case of concurrent NIID and ALS discovered during an autopsy. Abnormal brain MRI findings, including paravermal lesions, could indicate the coexistence of NIID even in patients with ALS showing characteristic clinical phenotypes.

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Sleep Exacerbations and Facial Twitching: Diagnostic Clues for ADCY5-Related Dyskinesias

Neuropediatrics ◽

10.1055/s-0040-1721685 ◽

2020 ◽

Author(s):

Margherita Nosadini ◽

Gianluca D'Onofrio ◽

Maria Federica Pelizza ◽

Concetta Luisi ◽

Davide Padrin ◽

...

Keyword(s):

Movement Disorder ◽

Developmental Delay ◽

De Novo ◽

Brain Magnetic Resonance Imaging ◽

Neurological Impairment ◽

De Novo Mutation ◽

Oligoclonal Bands ◽

Emotional Stimuli ◽

Childhood Onset ◽

Ataxic Gait

Abstract Background Mutations in the adenylate cyclase 5 (ADCY5) gene are associated with childhood-onset paroxysmal dyskinesia. Methods We report a new video-documented case of pediatric ADCY5-related dyskinesia with de novo ADCY5 mutation. Results A boy born to nonconsanguineous parents after an uneventful pregnancy had developmental delay and hypotonia. At the age of 7 months, he presented with paroxysmal jerky–choreic–dystonic involuntary movements in wakefulness involving limbs, trunk, and face, exacerbated by emotional stimuli. These episodes gradually worsened in duration and frequency: at the age of 2.5 years, they occurred up to six times per day, and appeared also during sleep in prolonged bouts; the boy also had basal choreoathetoid–dystonic movements, hyperactivity, paraparetic–ataxic gait, generalized hypotonia with brisk tendon reflexes, drooling, and language delay with intellectual disability. Brain magnetic resonance imaging, electroencephalogram, electromyogram, eye review, metabolic investigations, oligoclonal bands, and autoantibodies were normal. Extensive genetic testing had not let to a diagnosis, until a heterozygous de novo mutation c.1252C > T (p.Arg418Trp) was identified in the ADCY5 gene. Clonazepam had partial effectiveness. The boy walked at the age of 3.5 years. At the age of 5 years, the paroxysmal movement disorder has slightly improved. Conclusion ADCY5 mutations should be considered among the differential diagnoses of early-onset paroxysmal choreic–athetosic–myoclonic–dystonic movement disorder involving limbs, trunk, and face, in patients with global neurological impairment with hypotonia and developmental delay. Facial dyskinesias and exacerbation by drowsiness/sleep and emotional stimuli are important clues that may allow a timely recognition of the disorder and avoidance of unnecessary diagnostic investigations.

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Cerebrovascular diseases in two patients with entire NSD1 deletion

Human Genome Variation ◽

10.1038/s41439-021-00151-z ◽

2021 ◽

Vol 8 (1) ◽

Author(s):

Toshiyuki Itai ◽

Satoko Miyatake ◽

Taku Hatano ◽

Nobutaka Hattori ◽

Atsuko Ohno ◽

...

Keyword(s):

Intellectual Disability ◽

Brain Imaging ◽

Developmental Delay ◽

Movement Disorders ◽

Subdural Hematoma ◽

Early Onset ◽

Cerebrovascular Diseases ◽

Brain Contusion ◽

Abnormal Gait

AbstractWe describe two patients with NSD1 deletion, who presented with early-onset, or recurrent cerebrovascular diseases (CVDs). A 39-year-old female showed developmental delay and abnormal gait in infancy, and developed slowly-progressive intellectual disability and movement disorders. Brain imaging suggested recurrent parenchymal hemorrhages. A 6-year-old male had tremor as a neonate and brain imaging revealed subdural hematoma and brain contusion. This report suggests possible involvement of CVDs associated with NSD1 deletion.

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Clinical performance of the CytoScan Dx Assay in diagnosing developmental delay/intellectual disability

Genetics in Medicine ◽

10.1038/gim.2015.51 ◽

2015 ◽

Vol 18 (2) ◽

pp. 168-173 ◽

Cited By ~ 5

Author(s):

Rolph Pfundt ◽

Kat Kwiatkowski ◽

Alan Roter ◽

Anju Shukla ◽

Eric Thorland ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Clinical Performance

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Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay

Genetics in Medicine ◽

10.1038/s41436-020-01047-z ◽

2021 ◽

Author(s):

Uirá Souto Melo ◽

Devon Bonner ◽

Kevin C. Kent Lloyd ◽

Ala Moshiri ◽

Brandon Willis ◽

...

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Global Developmental Delay ◽

Loss Of Function

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Abstract 14258: Modulation of Kynurenine Pathway to Prevent Brain Injury After Cardiac Arrest and Cardiopulmonary Resuscitation in Mice

Circulation ◽

10.1161/circ.144.suppl_2.14258 ◽

2021 ◽

Vol 144 (Suppl_2) ◽

Author(s):

Aurora Magliocca ◽

Carlo Perego ◽

Francesca Motta ◽

Giulia Merigo ◽

Francesca M Fumagalli ◽

...

Keyword(s):

Cardiac Arrest ◽

Neurological Outcome ◽

Diffusion Tensor ◽

Neuroprotective Effect ◽

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

Kynurenine Pathway ◽

Baseline Heart Rate ◽

Brain White Matter ◽

Fluoro Jade B

Introduction: Kynurenine pathway (KP) is emerging as one of the potential components affecting cardiac arrest (CA) outcomes. The aim of this study is to evaluate the effects of KP inhibition through genetic deletion of the rate-limiting enzyme of the KP, indoleamine-2,3-dyoxygenase (IDO) on survival and neurological outcome after CA. Methods and Results: Sixteen adult male wild-type (WT) and IDO-deleted (IDO -/- ) mice were subjected to 8 min untreated CA followed by resuscitation. At baseline heart rate and mean arterial pressure (MAP) did not differ among groups. At the time of return of spontaneous circulation, 30 and 60 min later, MAP was higher in the IDO -/- group compared to the WT one (p=0.0005). IDO -/- mice showed higher survival compared to WT at 7 days after CA (68.5% in IDO -/- vs 37.5% in WT; log rank p=0.036). Neurological function was higher in IDO -/- than in WT mice during the 7 days following CA (p=0.0124). IDO -/- mice also showed an improved locomotor function compared to WT mice (p=0.037). Brain magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) sequences showed a reduction in fractional anisotropy in the external capsule of the corpus callosum in WT mice compared to IDO -/- mice at 7 days after resuscitation (p=0.015). We then treated additional IDO -/- mice with L-kyn 15 min before CA, to revert the IDO -/- phenotype. Brain MRI with diffusion-weighted imaging (DWI) sequences and histological analysis were performed 24h after CA in WT, IDO -/- , and IDO -/- +L-Kyn mice. Brain MRI revealed restriction of water diffusivity 24h after CA in WT mice. IDO-deletion reduced water diffusion abnormalities while the beneficial effect was reverted in the L-kyn group (p=0.01). Degenerating neurons in the frontal cortex, represented as Fluoro-Jade B positive cells, were more numerous in WT compared to IDO -/- mice; L-kyn halted this IDO deletion-induced reduction in degenerating cells (p=0.05). Conclusion: KP inhibition improves survival and neurological outcome after CA. The neuroprotective effect of IDO-deletion was associated with preservation of brain white matter microintegrity and with reduction of cerebral cytotoxic edema. Reversal of these beneficial effects by L-kyn administration in IDO -/- mice further confirm the KP role in CA outcome.

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IL1RAPL1 Gene Deletion in a Female Patient with Developmental Delay and Continuous Spike-Wave during Sleep

Journal of Pediatric Epilepsy ◽

10.1055/s-0041-1731816 ◽

2021 ◽

Author(s):

Evan Jiang ◽

Mark P. Fitzgerald ◽

Katherine L. Helbig ◽

Ethan M. Goldberg

Keyword(s):

Intellectual Disability ◽

Developmental Delay ◽

Synapse Formation ◽

De Novo ◽

Interleukin 1 ◽

Autism Spectrum ◽

Neurological Dysfunction ◽

Behavioral Disorder ◽

Clinical Genetic ◽

Severe Intellectual Disability

AbstractInterleukin-1 receptor accessory protein-like 1 (IL1RAPL1) encodes a protein that is highly expressed in neurons and has been shown to regulate neurite outgrowth as well as synapse formation and synaptic transmission. Clinically, mutations in or deletions of IL1RAPL1 have been associated with a spectrum of neurological dysfunction including autism spectrum disorder and nonsyndromic X-linked developmental delay/intellectual disability of varying severity. Nearly all reported cases are in males; in the few reported cases involving females, the clinical presentation was mild or the deletion was identified in phenotypically normal carriers in accordance with X-linked inheritance. Using genome-wide microarray analysis, we identified a novel de novo 373 kb interstitial deletion of the X chromosome (Xp21.1-p21.2) that includes exons 4 to 6 of the IL1RAPL1 gene in an 8-year-old girl with severe intellectual disability and behavioral disorder with a history of developmental regression. Overnight continuous video electroencephalography revealed electrical status epilepticus in sleep (ESES). This case expands the clinical genetic spectrum of IL1RAPL1-related neurodevelopmental disorders and highlights a new genetic association of ESES.

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