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

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.

scholarly journals Pediatric Multiple Sclerosis in Portugal: A Multicentre Study

2016 ◽  
Vol 29 (7-8) ◽  
pp. 425 ◽  
Author(s):  
Ana Sofia Correia ◽  
Luís Augusto ◽  
Joana Meireles ◽  
Joana Pinto ◽  
Ana Paula Sousa
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Brain Magnetic Resonance Imaging ◽  
Oligoclonal Bands ◽  
Childhood Onset ◽  
Multicentric Study ◽  
Pediatric Multiple Sclerosis ◽  
Adolescent Groups ◽  
Reported Data ◽  
Cerebrospinal Fluid Pleocytosis

Introduction: Multiple sclerosis is most often diagnosed among young adults but less frequently it may present during childhood or adolescence. In Portugal, there has been only one previous single-center, pediatric multiple sclerosis study. The main objective was the evaluation of the demographic, clinical, laboratorial and neuroradiological characteristics of patients with pediatric-onset multiple sclerosis in Portugal. The secondary objectives were to compare the characteristics of childhood-onset multiple sclerosis and adolescent-onset multiple sclerosis and to characterize the treatments prescribed.Material and Methods: We performed a retrospective observational, multicentric study. We reviewed data of all patients with multiple sclerosis younger than 18 years at the onset of their first multiple sclerosis symptoms.Results: There were 46 patients (72% female) included with a mean age at diagnosis of 16.1 years. Six cases had childhood-onset and 40 cases had adolescence-onset. The median value of Expanded Disability Status Scale was two. Relapsing-remitting multiple sclerosis was most prevalent (98% of cases). In the cerebrospinal fluid study, 74% of patients had positive oligoclonal bands. Brain magnetic resonance imaging studies showed a predominant supratentorial involvement (98% of cases), whereas the cervical segment was the most frequently affected in the spinal cord. All the patients enrolled in the study underwent immunomodulatory therapy, 75% ofpatients with beta-interferon. Concerning differences between the childhood and the adolescent groups, we found a greater proportion of male patients and of individuals with cerebrospinal fluid pleocytosis among the childhood-onset group.Discussion: This study provides new data on pediatric multiple sclerosis characteristics in Portugal and our results are similar to previously reported data in other parts of the worldConclusion: This is the first multicentric study characterizing pediatric multiple sclerosis in Portugal. The mechanisms underlying the particularities of pediatric multiple sclerosis remain largely unknown and further studies are required.

A de novo mutation affecting human TrkB associated with severe obesity and developmental delay

2004 ◽  
Vol 7 (11) ◽  
pp. 1187-1189 ◽  
Author(s):  
Giles S H Yeo ◽  
Chiao-Chien Connie Hung ◽  
Justin Rochford ◽  
Julia Keogh ◽  
Juliette Gray ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Severe Obesity ◽  
De Novo ◽  
De Novo Mutation

scholarly journals A novel de novo mutation inATP1A3and childhood-onset schizophrenia

2016 ◽  
Vol 2 (5) ◽  
pp. a001008 ◽  
Author(s):  
Niklas Smedemark-Margulies ◽  
Catherine A. Brownstein ◽  
Sigella Vargas ◽  
Sahil K. Tembulkar ◽  
Meghan C. Towne ◽  
...  
Keyword(s):  
De Novo ◽  
De Novo Mutation ◽  
Childhood Onset ◽  
Childhood Onset Schizophrenia

scholarly journals Case Report: A Novel de novo Mutation in DNM1L Presenting With Developmental Delay, Ataxia, and Peripheral Neuropathy

2021 ◽  
Vol 9 ◽  
Author(s):  
Yanping Wei ◽  
Min Qian
Keyword(s):  
Peripheral Neuropathy ◽  
Developmental Delay ◽  
De Novo ◽  
Refractory Epilepsy ◽  
De Novo Mutation ◽  
Global Developmental Delay ◽  
Missense Mutations ◽  
Related Protein ◽  
Resonance Imaging ◽  
Genetic Results

DNM1L encodes dynamin-related protein 1 (Drp1), which is a member of the dynamin superfamily of GTPases and mediates mitochondrial and peroxisomal fission. In humans, several de novo heterozygous missense mutations in DNM1L have been reported, which were characterized by devastating courses with refractory epilepsy, myoclonus, and brain atrophy on MRI. We describe a 4.5-year-old male child harboring a novel de novo mutation in DNM1L presenting a phenotype of developmental delay, ataxia, and peripheral neuropathy. The clinical features, magnetic resonance imaging findings, and genetic results were summarized. Meanwhile, all the cases of DNM1L mutations reported were reviewed. DNM1L variants may need to be considered in phenotypes that include global developmental delay, peripheral neuropathy, and ataxia.

scholarly journals Neurodevelopmental disease genes implicated by de novo mutation and CNV morbidity

2017 ◽  
Author(s):  
Bradley P. Coe ◽  
Holly A.F. Stessman ◽  
Arvis Sulovari ◽  
Madeleine Geisheker ◽  
Fereydoun Hormozdiari ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Gene Dosage ◽  
De Novo Mutation ◽  
Disease Genes ◽  
Missense Mutations ◽  
Genomic Disorder ◽  
Network Analyses ◽  
Neurodevelopmental Disease ◽  
Deletion Syndromes

ABSTRACTWe combined de novo mutation (DNM) data from 10,927 cases of developmental delay and autism to identify 301 candidate neurodevelopmental disease genes showing an excess of missense and/or likely gene-disruptive (LGD) mutations. 164 genes were predicted by two different DNM models, including 116 genes with an excess of LGD mutations. Among the 301 genes, 76% show DNM in both autism and intellectual disability/developmental delay cohorts where they occur in 10.3% and 28.4% of the cases, respectively. Intersecting these results with copy number variation (CNV) morbidity data identifies a significant enrichment for the intersection of our gene set and genomic disorder regions (36/301, LR+ 2.53, p=0.0005). This analysis confirms many recurrent LGD genes and CNV deletion syndromes (e.g., KANSL1, PAFAH1B1, RA1, etc.), consistent with a model of haploinsufficiency. We also identify genes with an excess of missense DNMs overlapping deletion syndromes (e.g., KIF1A and the 2q37 deletion) as well as duplication syndromes, such as recurrent MAPK3 missense mutations within the chromosome 16p11.2 duplication, recurrent CHD4 missense DNMs in the 12p13 duplication region, and recurrent WDFY4 missense DNMs in the 10q11.23 duplication region. Finally, we also identify pathogenic CNVs overlapping more than one recurrently mutated gene (e.g., Sotos and Kleefstra syndromes) raising the possibility that multiple gene-dosage imbalances may contribute to phenotypic complexity of these disorders. Network analyses of genes showing an excess of DNMs confirm previous well-known enrichments but also highlight new functional networks, including cell-specific enrichments in the D1+ and D2+ spiny neurons of the striatum for both recurrently mutated genes and genes where missense mutations cluster.

Clinical and Cytogenomic Characterization of De Novo 11p14.3-p15.5 Duplication Associated with 18q23 Deletion in an Egyptian Female Infant

2020 ◽  
Author(s):  
Hanan H. Afifi ◽  
Ghada Y. El-Kamah ◽  
Alaa K. Kamel ◽  
Sally G. Abd Allah ◽  
Sayda Hammad ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Ductus Arteriosus ◽  
Chromosomal Rearrangements ◽  
Clinical Manifestations ◽  
Brain Magnetic Resonance Imaging ◽  
Comparative Genomic ◽  
Septal Hypertrophy

AbstractPaternal microduplication of 11p14.3-p15.5 causes the clinical manifestations of Beckwith–Wiedemann syndrome (BWS), while microdeletion of 18q23-ter is clinically characterized by short stature, congenital malformations, and developmental delay. We describe a 15-month-old girl presenting with protruding tongue, dysmorphic facial features, moderate developmental delay, umbilical hernia, hypotonia, mild-to-moderate pulmonary hypertension, small patent ductus arteriosus, and mild ventricular septal hypertrophy. Brain magnetic resonance imaging showed mild atrophic changes. Chromosomal analysis revealed 46, XX, add(18)(q23). Fluorescence in situ hybridization using subtelomere 18q and whole chromosome painting 18 showed subtelomere deletion in 18q, and the add segment was not derived from chromosome 18. Microarray-based comparative genomic hybridization detected a 22 Mb duplication of chromosome 11p15.5p14.3 and a 3.7 Mb deletion of chromosome 18q23. The phenotype of the chromosomal rearrangements is probably resulted from a combination of dosage-sensitive genes. Our patient had clinical manifestations of both 18q deletion and BWS.

scholarly journals ATP1A1 de novo Mutation-Related Disorders: Clinical and Genetic Features

2021 ◽  
Vol 9 ◽  
Author(s):  
Zehong Lin ◽  
Jinliang Li ◽  
Taoyun Ji ◽  
Ye Wu ◽  
Kai Gao ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Wide Spectrum ◽  
De Novo Mutation ◽  
Loss Of Function ◽  
Severe Phenotype ◽  
Related Disorder ◽  
Genetic Features ◽  
Refractory Seizures ◽  
Transmembrane Regions

Background:ATP1A1 encodes an α1 isoform of Na+/K+-ATPase, which is expressed abundantly in kidneys and central nervous system. ATP1A1 variants may cause Na+/K+-ATPase loss of function and lead to a wide spectrum of phenotypes. This study aims to summarize the clinical and genetic features of ATP1A1 de novo mutation-related disorders and explore the potential correlations between phenotypes and genotypes.Methods: We analyzed two new cases harboring novel de novo ATP1A1 variants and reviewed all reported cases.Results: Both our probands had developmental delay, patient 1 accompanied with sleep disorders, irritability, and patient 2 with refractory seizures. They each had a novel de novo heterozygous missense variant, c.2797G>A[p.Asp933Asn] (NM_000701) and c.2590G>A[p.Gly864Arg] (NM_000701) respectively. Four patients with de novo ATP1A1 variants have been reported in two previous papers. Among them, three patients had refractory seizures and one patient had complex hereditary spastic paraplegia (HSP). Therefore, all six patients had developmental delay, and four of them had epilepsy. All variants located in the transmembrane regions M3, M4, M7, and M8 of ATP1A1 protein. Four patients with mutations in M3 and M7 had more severe phenotypes, including developmental delay and epileptic encephalopathy, three of them with hypomagnesemia, whereas two patients with mutations in M4 and M8 had milder phenotypes, only with mild developmental delay, without seizures or hypomagnesemia. Correcting hypomagnesemia had not controlled those seizures.Conclusions: Two novel de novo ATP1A1 variants identified in two patients here enriched the genotypic and phenotypic spectrum of ATP1A1 mutation-related disorder. Our findings suggest that hypomagnesemia in this disorder might relate to more severe phenotype and indicate more severe Na+/K+-ATPase dysfunction. Variations in M3 and M7 transmembrane regions were related to more severe phenotype than those in M4 and M8, which suggested that variations in M3 and M7 might cause more severe ATP1A1 functional defect.

scholarly journals Case Report of a de Novo Mutation of PCDH19 in Saudi Family Limited to Females

2021 ◽  
Vol 6 (12) ◽  
pp. 940-943
Author(s):  
Rawan Alsheikh, MD ◽  
Amal Al-Qassmi, MD
Keyword(s):  
De Novo ◽  
Somatic Mosaicism ◽  
Febrile Illness ◽  
Autistic Traits ◽  
De Novo Mutation ◽  
Epilepsy Syndrome ◽  
Childhood Onset ◽  
Behavioral Abnormalities ◽  
Nucleotide Mutation ◽  
Saudi Family

Up to date more than 60 different mutations in PCDH19 have been identified. Most of PCDH19 gene is located in Xq22 and produces nonclustered delta protocadherin. This disorder primarily manifests in heterozygote females due to random X chromosome inactivation leading to somatic mosaicism and abnormal cellular interference between cells with and without delta-protocadherin., but we a heterozygous nucleotide mutation causing amino acid 561 to change from Pro to Ser (p.Pro561Ser). This mutation was de novo, and this alteration was not found in her parents. PCDH19-related epilepsy is a distinct childhood-onset epilepsy syndrome characterized by brief clusters of febrile and afebrile seizures with onset primarily before the age of three years, cognitive impairment, autistic traits, and behavioral abnormalities. We describe the features of a de novo mutation in 3 sibling, presented with early onset of seizure, two of them were controlled and wean off medication was at age of six year and her sister at age of 10 year .The youngest sister still partially controlled on medication, she had seizure only during febrile illness.

scholarly journals Spastic Diplegia in a Haitian Girl with Angelman Syndrome

2019 ◽  
Vol 09 (02) ◽  
pp. 104-108
Author(s):  
Kumarie Latchman ◽  
Margarita Nieto-Moreno ◽  
Roberto Lopez Alberola
Keyword(s):  
Developmental Delay ◽  
Angelman Syndrome ◽  
African Descent ◽  
Neurodevelopmental Disorder ◽  
Brain Magnetic Resonance Imaging ◽  
Medical Intervention ◽  
Common Mechanism ◽  
Spastic Diplegia ◽  
Speech Impairment ◽  
Ataxic Gait

AbstractSpastic diplegia, a muscle hypertonia motor syndrome, can occur in conjunction with the characteristic abnormal movement features of Angelman syndrome (AS), a neurodevelopmental disorder with primary features of ataxic gait, happy demeanor, developmental delay, speech impairment, intellectual disability, microcephaly, and seizures. Spastic diplegia is classically associated with cerebral palsy (CP), an umbrella term encompassing developmental delay, abnormal brain magnetic resonance imaging findings, and various types of CP including spastic, ataxic, dyskinetic, and mixed types. We present a 12-year-old Haitian patient of African descent with AS due to a microdeletion involving the entire UBE3A (ubiquitin-protein ligase E3A) gene and spastic diplegia. She was initially given a clinical diagnosis of CP. Cases of AS in patients of African descent have been rarely reported and this case of severe spastic diplegia, unresponsive to medical intervention, reflects a rarely reported presentation of AS in patients of African descent and possibly the first reported case of a Haitian patient with this clinical presentation. Given that deletions are the most common mechanism resulting in AS, this case report provides supportive evidence that chromosome 15q11 deletion-type AS is most frequently associated with spastic diplegia, a more severe motor impairment phenotype in AS.

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