ABSTRACT
PURPOSE: This study aimed to identify continuous epileptiform discharges (CEDs) on electroencephalograms (EEG) and to determine their clinical significance in children with congenital Zika syndrome (CZS). METHODS: This prospective cohort study included 75 children diagnosed with CZS born from March 2015 and followed up until September 2018 (age up to 36 months). EEG was performed to detect CEDs up to 24 months old. Data on obstetric, demographic, and clinical signs; cranial computed tomography (CT); ophthalmology examination; anti-seizure medication; growth; and motor development were collected. Fisher's exact test was used to verify the associations between categorical variables, and the T- test was used to compare the mean z-scores of anthropometric measurements between the groups with and without CED. RESULTS: CEDs were identified in 41 (54.67 %) children. The mean age of CEDs identification was 12.24 ± 6.86 months. Bilateral CEDs were shown in 62.89 % of EEGs. CEDs were associated with severe congenital microcephaly, defined by z-score >3 standard deviation of head circumference (HC) below the mean for sex and age (p = 0.025), and worse outcomes, including first seizure before 6 months (p = 0.004), drug-resistant epilepsy (p < 0.001), chorioretinal scarring or mottling (p = 0.002), and severe CT findings (p = 0.002). The CED group had lower mean z-scores of HC up to 24 months of age. CONCLUSION: This is the first description of the prevalence and significance of CEDs that also remains during wakefulness in patients with CZS. New investigations may suggest that it is more appropriate to classify the EEG not as a CED, but as a periodic pattern. Anyway, CEDs may be a marker of neurological severity in children with CSZ.
Subject(s)
Electroencephalography , Zika Virus Infection , Humans , Zika Virus Infection/complications , Zika Virus Infection/physiopathology , Zika Virus Infection/congenital , Female , Male , Infant , Prospective Studies , Child, Preschool , Microcephaly/physiopathology , Microcephaly/diagnostic imaging , Epilepsy/physiopathology , Neurodevelopmental Disorders/etiology , Neurodevelopmental Disorders/physiopathologyABSTRACT
OBJECTIVES: Children with microcephaly exhibit neurodevelopmental delays and compromised communicative functioning, yielding challenges for clinical assessment and informed intervention. This study characterized auditory neural function and communication abilities in children with microcephaly due to congenital Zika syndrome (CZS). DESIGN: Click-evoked auditory brainstem responses (ABR) at fast and slow stimulation rates and natural speech-evoked cortical auditory evoked potentials (CAEP) were recorded in 25 Brazilian children with microcephaly related to CZS ( M age: 5.93 ± 0.62 years) and a comparison group of 25 healthy children ( M age: 5.59 ± 0.80 years) matched on age, sex, ethnicity, and socioeconomic status. Communication abilities in daily life were evaluated using caregiver reports on Vineland Adaptive Behavior Scales-3. RESULTS: Caregivers of children with microcephaly reported significantly lower than typical adaptive functioning in the communication and socialization domains. ABR wave I latency did not differ significantly between the groups, suggesting comparable peripheral auditory function. ABR wave V absolute latency and waves I-V interwave latency were significantly shorter in the microcephaly group for both ears and rates. CAEP analyses identified reduced N2 amplitudes in children with microcephaly as well as limited evidence of speech sound differentiation, evidenced mainly by the N2 response latency. Conversely, in the comparison group, speech sound differences were observed for both the P1 and N2 latencies. Exploratory analyses in the microcephaly group indicated that more adaptive communication was associated with greater speech sound differences in the P1 and N2 amplitudes. The trimester of virus exposure did not have an effect on the ABRs or CAEPs. CONCLUSIONS: Microcephaly related to CZS is associated with alterations in subcortical and cortical auditory neural function. Reduced ABR latencies differ from previous reports, possibly due to the older age of this cohort and careful assessment of peripheral auditory function. Cortical speech sound detection and differentiation are present but reduced in children with microcephaly. Associations between communication performance in daily life and CAEPs highlight the value of auditory evoked potentials in assessing clinical populations with significant neurodevelopmental disabilities.
Subject(s)
Evoked Potentials, Auditory, Brain Stem , Microcephaly , Zika Virus Infection , Humans , Female , Zika Virus Infection/physiopathology , Zika Virus Infection/complications , Zika Virus Infection/congenital , Male , Microcephaly/physiopathology , Child, Preschool , Evoked Potentials, Auditory, Brain Stem/physiology , Child , Case-Control Studies , Evoked Potentials, Auditory/physiology , BrazilABSTRACT
OBJECTIVE: To assess the longitudinal evolution of EEG findings in children with Zika related-microcephaly (ZRM) and to evaluate the associations of these patterns with the children's clinical and neuroimaging characteristics. METHODS: As part of the follow-up of the Microcephaly Epidemic Research Group Pediatric Cohort (MERG-PC) in Recife, Brazil, we performed serial EEG recordings in a subgroup of children with ZRM to evaluate changes in background rhythms and epileptiform activity (EA). Latent class analysis was used to identify patterns in the evolution of EA over time; clinical and neuroimaging findings were compared across the identified groups. RESULTS: Out of the 72 children with ZRM who were evaluated during 190 EEGs/videoEEGs, all participants presented with abnormal background activity, 37.5% presented with an alpha-theta rhythmic activity, and 25% presented with sleep spindles, which were less commonly observed in children with epilepsy. EA changed over time in 79.2% of children, and three distinct trajectories were identified: (i) multifocal EA over time, (ii) no discharges/focal EA evolving to focal/multifocal EA, and (iii) focal/multifocal EA evolving to epileptic encephalopathy patterns (e.g., hypsarrhythmia or continuous EA in sleep). The multifocal EA over time trajectory was associated with periventricular and thalamus/basal ganglia calcifications, brainstem and corpus callosum atrophy and had less focal epilepsy, whereas the children in the trajectory which evolved to epileptic encephalopathy patterns had more frequently focal epilepsy. SIGNIFICANCE: These findings suggest that, in most children with ZRM, trajectories of changes in EA can be identified and associated with neuroimaging and clinical features.
Subject(s)
Electroencephalography , Epilepsy , Microcephaly , Zika Virus Infection , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Age of Onset , Alpha Rhythm , Biomedical Research , Cerebral Cortex/abnormalities , Cerebral Cortex/diagnostic imaging , Cerebral Cortex/pathology , Cerebral Cortex/physiopathology , Epilepsies, Partial/diagnostic imaging , Epilepsies, Partial/etiology , Epilepsies, Partial/pathology , Epilepsies, Partial/physiopathology , Epilepsy/diagnostic imaging , Epilepsy/etiology , Epilepsy/pathology , Epilepsy/physiopathology , Eye Movements , Follow-Up Studies , Latent Class Analysis , Longitudinal Studies , Microcephaly/diagnostic imaging , Microcephaly/etiology , Microcephaly/pathology , Microcephaly/physiopathology , Neuroimaging , Sleep Stages , Theta Rhythm , Wakefulness , Zika Virus Infection/complications , Zika Virus Infection/diagnostic imaging , Zika Virus Infection/pathology , Zika Virus Infection/physiopathologyABSTRACT
Congenital Zika Syndrome (CZS) is characterized by changes in cranial morphology associated with heterogeneous neurological manifestations and cognitive and behavioral impairments. In this syndrome, longitudinal neuroimaging could help clinicians to predict developmental trajectories of children and tailor treatment plans accordingly. However, regularly acquiring magnetic resonance imaging (MRI) has several shortcomings besides cost, particularly those associated with childrens' clinical presentation as sensitivity to environmental stimuli. The indirect monitoring of local neural activity by non-invasive functional near-infrared spectroscopy (fNIRS) technique can be a useful alternative for longitudinally accessing the brain function in children with CZS. In order to provide a common framework for advancing longitudinal neuroimaging assessment, we propose a principled guideline for fNIRS acquisition and analyses in children with neurodevelopmental disorders. Based on our experience on collecting fNIRS data in children with CZS we emphasize the methodological challenges, such as clinical characteristics of the sample, desensitization, movement artifacts and environment control, as well as suggestions for tackling such challenges. Finally, metrics based on fNIRS can be associated with established clinical metrics, thereby opening possibilities for exploring this tool as a long-term predictor when assessing the effectiveness of treatments aimed at children with severe neurodevelopmental disorders.
Subject(s)
Functional Neuroimaging/standards , Microcephaly/therapy , Neurodevelopmental Disorders/diagnosis , Spectroscopy, Near-Infrared/standards , Zika Virus Infection/complications , Brain/diagnostic imaging , Brain/physiopathology , Brazil , Child, Preschool , Functional Neuroimaging/methods , Humans , Longitudinal Studies , Male , Microcephaly/physiopathology , Microcephaly/virology , Neurodevelopmental Disorders/physiopathology , Neurodevelopmental Disorders/prevention & control , Practice Guidelines as Topic , Treatment Outcome , Zika Virus Infection/virologyABSTRACT
Normal neurodevelopment relies on intricate signaling pathways that balance neural stem cell (NSC) self-renewal, maturation, and survival. Disruptions lead to neurodevelopmental disorders, including microcephaly. Here, we implicate the inhibition of NSC senescence as a mechanism underlying neurogenesis and corticogenesis. We report that the receptor for activated C kinase (Rack1), a family member of WD40-repeat (WDR) proteins, is highly enriched in NSCs. Deletion of Rack1 in developing cortical progenitors leads to a microcephaly phenotype. Strikingly, the absence of Rack1 decreases neurogenesis and promotes a cellular senescence phenotype in NSCs. Mechanistically, the senescence-related p21 signaling pathway is dramatically activated in Rack1 null NSCs, and removal of p21 significantly rescues the Rack1-knockout phenotype in vivo. Finally, Rack1 directly interacts with Smad3 to suppress the activation of transforming growth factor (TGF)-ß/Smad signaling pathway, which plays a critical role in p21-mediated senescence. Our data implicate Rack1-driven inhibition of p21-induced NSC senescence as a critical mechanism behind normal cortical development.
Subject(s)
Cellular Senescence , Cerebral Cortex/metabolism , Cyclin-Dependent Kinase Inhibitor p21/metabolism , Microcephaly/metabolism , Neural Stem Cells/metabolism , Neurogenesis , Receptors for Activated C Kinase/metabolism , Animals , Cell Proliferation , Cellular Senescence/drug effects , Cerebral Cortex/drug effects , Cerebral Cortex/growth & development , Cyclin-Dependent Kinase Inhibitor p21/genetics , Gene Expression Regulation, Developmental , Genetic Predisposition to Disease , HEK293 Cells , Humans , Mice, Inbred C57BL , Mice, Knockout , Microcephaly/genetics , Microcephaly/pathology , Microcephaly/physiopathology , Neural Stem Cells/drug effects , Neural Stem Cells/pathology , Neurogenesis/drug effects , Phenotype , Receptors for Activated C Kinase/genetics , Signal Transduction , Smad3 Protein/genetics , Smad3 Protein/metabolism , Transforming Growth Factor beta1/pharmacologyABSTRACT
RBL2/p130, a member of the retinoblastoma family of proteins, is a key regulator of cell division and propagates irreversible senescence. RBL2/p130 is also involved in neuronal differentiation and survival, and eliminating Rbl2 in certain mouse strains leads to embryonic lethality accompanied by an abnormal central nervous system (CNS) phenotype. Conflicting reports exist regarding a role of RBL2/p130 in transcriptional regulation of DNA methyltransferases (DNMTs), as well as the control of telomere length. Here we describe the phenotype of three patients carrying bi-allelic RBL2-truncating variants. All presented with infantile hypotonia, severe developmental delay and microcephaly. Malignancies were not reported in carriers or patients. Previous studies carried out on mice and human cultured cells, associated RBL2 loss to DNA methylation and telomere length dysregulation. Here, we investigated whether patient cells lacking RBL2 display related abnormalities. The study of primary patient fibroblasts did not detect abnormalities in expression of DNMTs. Furthermore, methylation levels of whole genome DNA, and specifically of pericentromeric repeats and subtelomeric regions, were unperturbed. RBL2-null fibroblasts show no evidence for abnormal elongation by telomeric recombination. Finally, gradual telomere shortening, and normal onset of senescence were observed following continuous culturing of RBL2-mutated fibroblasts. Thus, this study resolves uncertainties regarding a potential non-redundant role for RBL2 in DNA methylation and telomere length regulation, and indicates that loss of function variants in RBL2 cause a severe autosomal recessive neurodevelopmental disorder in humans.
Subject(s)
Cognitive Dysfunction/genetics , DNA Methylation/genetics , Retinoblastoma-Like Protein p130/genetics , Telomere Shortening/genetics , Adolescent , Adult , Alleles , Animals , Child , Cognitive Dysfunction/complications , Cognitive Dysfunction/physiopathology , Developmental Disabilities/complications , Developmental Disabilities/genetics , Developmental Disabilities/physiopathology , Female , Fibroblasts/metabolism , Genetic Predisposition to Disease , Humans , Male , Methyltransferases/genetics , Mice , Microcephaly/complications , Microcephaly/genetics , Microcephaly/physiopathology , Motor Activity/physiology , Muscle Hypotonia/complications , Muscle Hypotonia/genetics , Muscle Hypotonia/physiopathology , Telomere/genetics , Exome SequencingABSTRACT
Filippi syndrome (MIM #272440), one of the craniodigital syndromes, is a rare genetic entity with autosomal recessive inheritance and characterized by pre- and postnatal growth retardation, microcephaly, distinctive facial appearance, developmental delay/intellectual disability, and variable syndactylies of the fingers and toes. In this report, a further female patient of Filippi syndrome who additionally had a unilateral congenital talipes equinovarus (CTEV), a feature not previously recorded, is described. Genetic testing revealed a novel homozygous frameshift pathogenic variant (c.552_555delCAAA, p.Asn184Lysfs*8) in CKAP2L and thus confirmed the diagnosis of Filippi syndrome. We hope that the newly recognized feature (CTEV) will contribute to expand the clinical spectrum of this extremely rare condition. In view of the paucity of reported cases, the full spectrum of clinical findings of Filippi syndrome necessitates obviously further affected individuals/pedigrees delineation in order to elucidate the etiological and phenotypic aspects of this orphan disease appropriately.
Subject(s)
Abnormalities, Multiple/genetics , Clubfoot/genetics , Cytoskeletal Proteins/genetics , Growth Disorders/genetics , Intellectual Disability/genetics , Microcephaly/genetics , Syndactyly/genetics , Abnormalities, Multiple/physiopathology , Child, Preschool , Clubfoot/physiopathology , Facies , Female , Frameshift Mutation/genetics , Growth Disorders/physiopathology , Humans , Infant , Infant, Newborn , Intellectual Disability/physiopathology , Male , Microcephaly/physiopathology , Syndactyly/physiopathology , Toes/physiopathologyABSTRACT
Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage-sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi-faceted complications due to haploinsufficiency of BPTF.
Subject(s)
Chromatin Assembly and Disassembly/genetics , Epilepsy/genetics , Microcephaly/genetics , Neurodevelopmental Disorders/genetics , Abnormalities, Multiple/genetics , Abnormalities, Multiple/physiopathology , Adolescent , Adult , Child , Child, Preschool , Chromosome Deletion , Developmental Disabilities/genetics , Developmental Disabilities/physiopathology , Epilepsy/physiopathology , Facies , Female , Haploinsufficiency/genetics , Humans , Infant , Intellectual Disability/genetics , Intellectual Disability/physiopathology , Language Development Disorders/genetics , Language Development Disorders/physiopathology , Male , Microcephaly/physiopathology , Middle Aged , Neurodevelopmental Disorders/physiopathology , Phenotype , Transcription Factors/genetics , Young AdultABSTRACT
Microcephaly and macrocephaly can be considered both cranial growth defects and clinical symptoms. There are two assessment criteria: one applied in dysmorphology and another conventionally used in clinical practice. The determination of which definition or under which paradigm the terminology should be applied can vary on a daily basis and from case to case as necessity dictates, as can defining the relationship between microcephaly or macrocephaly and syndromes or diseases associated with neurodysfunction. Thus, there is a need for standardization of the definition of microcephaly and macrocephaly. This study was designed to investigate associations between abnormal cranial development (head size) and diseases or syndromes linked to neurodysfunction based on essential data collected upon admission of patients to the Neurological Rehabilitation Ward for Children and Adolescents in Poland. The retrospective analysis involved 327 children and adolescents with medical conditions associated with neurodysfunction. Two assessment criteria were applied to identify subgroups of patients with microcephaly, normal head size, and macrocephaly: one system commonly used in clinical practice and another applied in dysmorphology. Based on the results, children and adolescents with syndromes or diseases associated with neurodysfunction present abnormal cranial development (head size), and microcephaly rarely co-occurs with neuromuscular disease. Macrocephaly frequently co-occurs with neural tube defects or neuromuscular diseases and rarely with cerebral palsy (p < 0.05); microcephaly frequently co-occurs with epilepsy and hypothyroidism (p < 0.001). Traditional classification facilitates the identification of a greater number of relationships and is therefore recommended for use in daily practice. There is a need to standardize the definition of microcephaly and macrocephaly and to include them in 'Human Phenotype Ontology' terms.
Subject(s)
Cephalometry/standards , Megalencephaly/diagnosis , Microcephaly/diagnosis , Nervous System Diseases/complications , Skull/growth & development , Adolescent , Adolescent Development/physiology , Child , Child Development/physiology , Child, Preschool , Female , Humans , Male , Megalencephaly/etiology , Megalencephaly/physiopathology , Microcephaly/etiology , Microcephaly/physiopathology , Nervous System Diseases/physiopathology , Poland , Retrospective Studies , SyndromeABSTRACT
Distal 1q21.1 microdeletions have shown highly variable clinical expressivity and incomplete penetrance, with affected individuals manifesting a broad spectrum of nonspecific features. The goals of this study were to better describe the phenotypic spectrum of patients with distal 1q21.1 microdeletions and to compare the clinical features among affected individuals. We performed a retrospective chart review of 47 individuals with distal 1q21.1 microdeletions tested at a large clinical genetic testing laboratory, with most patients being clinically evaluated in the same children's hospital. Health information such as growth charts, results of imaging studies, developmental history, and progress notes were collected. Statistical analysis was performed using Fisher's exact test to compare clinical features among study subjects. Common features in our cohort include microcephaly (51.2%), seizures (29.8%), developmental delay (74.5%), failure to thrive (FTT) (68.1%), dysmorphic features (63.8%), and a variety of congenital anomalies such as cardiac abnormalities (23.4%) and genitourinary abnormalities (19.1%). Compared to prior literature, we found that seizures, brain anomalies, and FTT were more prevalent among our study cohort. Females were more likely than males to have microcephaly (p = 0.0199) and cardiac abnormalities (p = 0.0018). Based on existing genome-wide clinical testing results, at least a quarter of the cohort had additional genetic findings that may impact the phenotype of the individual. Our study represents the largest cohort of distal 1q21.1 microdeletion carriers available in the literature thus far, and it further illustrates the wide spectrum of clinical manifestations among symptomatic individuals. These results may allow for improved genetic counseling and management of affected individuals. Future studies may help to elucidate the underlying molecular mechanisms impacting the phenotypic variability observed with this microdeletion.
Subject(s)
Abnormalities, Multiple/genetics , Heart Defects, Congenital/genetics , Intellectual Disability/genetics , Megalencephaly/genetics , Microcephaly/genetics , Abnormalities, Multiple/diagnosis , Abnormalities, Multiple/physiopathology , Adolescent , Adult , Child , Child, Preschool , Chromosome Deletion , Chromosomes, Human, Pair 1/genetics , DNA Copy Number Variations/genetics , Developmental Disabilities/complications , Developmental Disabilities/genetics , Developmental Disabilities/physiopathology , Failure to Thrive/complications , Failure to Thrive/genetics , Failure to Thrive/physiopathology , Female , Genetic Counseling , Genetic Testing/methods , Heart Defects, Congenital/complications , Heart Defects, Congenital/diagnosis , Heart Defects, Congenital/physiopathology , Humans , Infant , Intellectual Disability/complications , Intellectual Disability/diagnosis , Intellectual Disability/physiopathology , Male , Megalencephaly/complications , Megalencephaly/diagnosis , Megalencephaly/physiopathology , Microcephaly/complications , Microcephaly/diagnosis , Microcephaly/physiopathology , Pedigree , Seizures/complications , Seizures/genetics , Seizures/physiopathology , Young AdultABSTRACT
Two brothers with an IQSEC2 pathogenic variant presented with early onset intellectual disability, intractable epileptic seizures, autism spectrum disorders, postnatal microcephalus and slowly progressive rigid-spasticity. Their epileptic seizures were characterized by intractability, early onset epileptic spasms, and then clusters of tonic/tonic-clonic seizures, exacerbated by valproate. Electroencephalography showed periodic discharges, including periodic high voltage slow complexes and burst-suppression activity. Whole exome sequencing, using DNA from peripheral blood of both brothers, identified a pathogenic variant, c.2776 C > T, p.(Arg 926*) in exon 9 of IQSEC2 (NM 001111125.3). Their parents and another brother did not have this variant, which may suggest that maternal gonadal mosaicism is the most likely mechanism.
Subject(s)
Brain Diseases/diagnosis , Brain Diseases/physiopathology , Guanine Nucleotide Exchange Factors/genetics , Muscle Spasticity/genetics , Adult , Autism Spectrum Disorder/diagnosis , Autism Spectrum Disorder/genetics , Autism Spectrum Disorder/pathology , Autism Spectrum Disorder/physiopathology , Brain Diseases/genetics , Brain Diseases/pathology , Electroencephalography , Epilepsy/diagnosis , Epilepsy/genetics , Epilepsy/pathology , Epilepsy/physiopathology , Humans , Intellectual Disability/diagnosis , Intellectual Disability/genetics , Intellectual Disability/pathology , Intellectual Disability/physiopathology , Male , Microcephaly/diagnosis , Microcephaly/genetics , Microcephaly/pathology , Microcephaly/physiopathology , Muscle Spasticity/diagnosis , Muscle Spasticity/pathology , Muscle Spasticity/physiopathology , Pedigree , Seizures/diagnosis , Seizures/genetics , Seizures/pathology , Seizures/physiopathology , Siblings , Exome SequencingABSTRACT
The phosphatidylinositol glycan anchor biosynthesis class S protein (PIGS) gene has recently been implicated in a novel congenital disorder of glycosylation resulting in autosomal recessive inherited glycosylphosphatidylinositol-anchored protein (GPI-AP) deficiency. Previous studies described seven patients with biallelic variants in the PIGS gene, of whom two presented with fetal akinesia and five with global developmental delay and epileptic developmental encephalopathy. We present the molecular and clinical characteristics of six additional individuals from five families with unreported variants in PIGS. All individuals presented with hypotonia, severe global developmental delay, microcephaly, intractable early infantile epilepsy, and structural brain abnormalities. Additional findings include vision impairment, hearing loss, renal malformation, and hypotonic facial appearances with minor dysmorphic features but without a distinctive facial gestalt. Four individuals died due to neurologic complications. GPI anchoring studies performed on one individual revealed a significant decrease in GPI-APs. We confirm that biallelic variants in PIGS cause vitamin pyridoxine-responsive epilepsy due to inherited GPI deficiency and expand the genotype and phenotype of PIGS-related disorder. Further delineation of the molecular spectrum of PIGS-related disorders would improve management, help develop treatments, and encourage the expansion of diagnostic genetic testing to include this gene as a potential cause of neurodevelopmental disorders and epilepsy.
Subject(s)
Acyltransferases/genetics , Developmental Disabilities/genetics , GPI-Linked Proteins/deficiency , Nervous System Malformations/genetics , Spasms, Infantile/genetics , Brain/abnormalities , Brain/diagnostic imaging , Child, Preschool , Developmental Disabilities/physiopathology , Facies , Female , Hearing Loss/genetics , Hearing Loss/physiopathology , Humans , Infant , Kidney/abnormalities , Male , Microcephaly/genetics , Microcephaly/physiopathology , Muscle Hypotonia/genetics , Muscle Hypotonia/physiopathology , Nervous System Malformations/diagnostic imaging , Nervous System Malformations/physiopathology , Phenotype , Spasms, Infantile/physiopathology , Vision Disorders/genetics , Vision Disorders/physiopathologyABSTRACT
Congenital disorders of glycosylation (CDG) are an expanding group of metabolic disorders that result from abnormal protein glycosylation. A special subgroup of CDG type II comprises defects in the Conserved Oligomeric Golgi Complex (COG). In order to further delineate the genotypic and phenotypic spectrum of COG complex defect, we describe a novel variant of COG6 gene found in homozygosity in a Moroccan patient with severe presentation of COG6-CDG (OMIM #614576). We compared the phenotype of our patient with other previously reported COG6-CDG cases. Common features in COG6-CDG are facial dysmorphism, growth retardation, microcephaly, developmental disability, liver or gastrointestinal disease, recurrent infections, hypohidrosis/hyperthermia. In addition to these phenotypic features, our patient exhibited a disorder of sexual differentiation, which has rarely been reported in COG6-CDG. We hypothesize that the severe COG6 gene mutation interferes with glycosylation of a disintegrin and metalloprotease family members, inhibiting the correct gonadal distal tip cells migration, fundamental for the genitalia morphogenesis. This report broadens the genetic and phenotypic spectrum of COG6-CDG and provides further supportive evidence that COG6-CDG can present as a disorder of sexual differentiation.
Subject(s)
Abnormalities, Multiple/genetics , Adaptor Proteins, Vesicular Transport/genetics , Craniofacial Abnormalities/genetics , Disorders of Sex Development/genetics , Muscular Atrophy/genetics , Sexual Development/genetics , Abnormalities, Multiple/physiopathology , Codon, Nonsense/genetics , Congenital Disorders of Glycosylation/complications , Congenital Disorders of Glycosylation/genetics , Congenital Disorders of Glycosylation/physiopathology , Craniofacial Abnormalities/complications , Craniofacial Abnormalities/physiopathology , Disorders of Sex Development/complications , Disorders of Sex Development/physiopathology , Genetic Predisposition to Disease , Golgi Apparatus/genetics , Homozygote , Humans , Infant , Infant, Newborn , Karyotype , Male , Microcephaly/complications , Microcephaly/genetics , Microcephaly/physiopathology , Muscular Atrophy/complications , Muscular Atrophy/physiopathology , PhenotypeABSTRACT
BACKGROUND: Microcephalic osteodysplastic primordial dwarfism type I (MOPD I, also known as Taybi-Linder syndrome) is a rare genetic disorder associated with severe intrauterine growth retardation, short stature, microcephaly, brain anomalies, stunted limbs, and early mortality. RNU4ATAC, the gene responsible for this disorder, does not encode a protein but instead the U4atac small nuclear RNA (snRNA), a crucial component of the minor spliceosome. Roifman syndrome is an allelic disorder of MOPD I that is characterized by immunodeficiency complications. CASE REPORT: The patient described herein is an 18-year-old woman exhibiting congenital dwarfism and microcephaly with structural brain anomaly. She suffered human herpesvirus 6 (HHV-6)-associated acute necrotizing encephalopathy at the age of one, thereafter resulting in severe psychomotor disabilities. Genetic analysis using gene microarray and whole-exome sequencing could not identify the cause of her congenital anomalies. However, Sanger sequencing revealed a compound heterozygous mutation within RNU4ATAC (NR_023343.1:n.[50G > A];[55G > A]). Immunological findings showed decreases in total lymphocytes, CD4+ T cells, and T cell regenerative activity. Furthermore, antibodies against varicella-zoster, rubella, measles, mumps, and influenza were very low or negative despite having received vaccinations for these viruses. HHV-6 IgG antibodies were also undetected. DISCUSSION: The patient here exhibited a marked MOPD I phenotype complicated by various immunodeficiencies. Previous studies have not demonstrated immunodeficiency comorbidities within MOPD I subjects, but this report suggests an evident immunodeficiency in MOPD I. Patients with MOPD I should be treated with one of the immunodeficiency syndromes.
Subject(s)
Cardiomyopathies/genetics , Dwarfism/genetics , Fetal Growth Retardation/genetics , Mental Retardation, X-Linked/genetics , Microcephaly/genetics , Osteochondrodysplasias/genetics , Primary Immunodeficiency Diseases/genetics , RNA, Small Nuclear/genetics , Retinal Diseases/genetics , Adolescent , Alleles , Cardiomyopathies/physiopathology , Dwarfism/physiopathology , Female , Fetal Growth Retardation/physiopathology , Humans , Mental Retardation, X-Linked/physiopathology , Microcephaly/physiopathology , Mutation , Osteochondrodysplasias/physiopathology , Pedigree , Phenotype , Primary Immunodeficiency Diseases/physiopathology , Retinal Diseases/physiopathology , Exome SequencingABSTRACT
Genetic studies identified multiple mutations associated with malformations of cortical development (MCD) in humans. When analyzing the underlying mechanisms in non-human experimental models it became increasingly evident, that these mutations accumulate in genes, which functions evolutionary progressed from rodents to humans resulting in an incomplete reflection of the molecular and cellular alterations in these models. Human brain organoids derived from human pluripotent stem cells resemble early aspects of human brain development to a remarkable extent making them an attractive model to investigate MCD. Here we review how human brain organoids enable the generation of fundamental new insight about the underlying pathomechanisms of MCD. We show how phenotypic features of these diseases are reflected in human brain organoids and discuss challenges and future considerations but also limitations for the use of human brain organoids to model human brain development and associated disorders.
Subject(s)
Cerebral Cortex/metabolism , Lissencephaly/genetics , Megalencephaly/genetics , Microcephaly/genetics , Nerve Tissue Proteins/genetics , Organoids/metabolism , Periventricular Nodular Heterotopia/genetics , Cell Differentiation , Cerebral Cortex/abnormalities , Cerebral Cortex/growth & development , Cerebral Cortex/physiopathology , Ependymoglial Cells/cytology , Ependymoglial Cells/metabolism , Gene Expression Regulation , Humans , Lissencephaly/metabolism , Lissencephaly/pathology , Lissencephaly/physiopathology , Megalencephaly/metabolism , Megalencephaly/pathology , Megalencephaly/physiopathology , Microcephaly/metabolism , Microcephaly/pathology , Microcephaly/physiopathology , Models, Biological , Mutation , Nerve Tissue Proteins/metabolism , Neural Stem Cells/cytology , Neural Stem Cells/metabolism , Neurogenesis/genetics , Neurons/cytology , Neurons/metabolism , Organoids/pathology , Periventricular Nodular Heterotopia/metabolism , Periventricular Nodular Heterotopia/pathology , Periventricular Nodular Heterotopia/physiopathology , Pluripotent Stem Cells/cytology , Pluripotent Stem Cells/metabolism , Primary Cell CultureABSTRACT
Congenital Zika syndrome (CZS) constitutes a recently identified malformation caused by Zika virus infection during pregnancy. Limited data is available to date on the facial dysmorphic features of these patients. This study evaluated the facial dysmorphisms of children with CZS, compared with clinically healthy children, using clinical examination and standardized photographic images. Sixty-three children with CZS (9.70 ± 3.2 months-age), and 31 Controls (8.67 ± 6.2 months-age) joined the study. Seven out of 15 indices differed between groups: midfacial height (MFH)/horizontal facial reference (HFR) (p = .0003), interalar distance/HFR (p = .0027), nasal root depth/MFH (p = .0030), posterior nasal length/MFH (p = .0002), vertical position of the ear/MFH (p <.0001), ear length/MFH (p = .0005), chin height/total facial height (CH/TFH) (p <.0001). A CH/TFH of 0.229 showed 93.9% sensitivity and 80.6% specificity in diagnosing CZS. Children with CZS had broad, short faces, decreased intercanthal distance, short posterior nasal length, prominent nasal root, broad nasal wings, and high-set and long ears. Increased chin height index provided the most accurate diagnostic potential.
Subject(s)
Face/abnormalities , Microcephaly/genetics , Zika Virus Infection/diagnosis , Zika Virus Infection/genetics , Face/diagnostic imaging , Female , Humans , Infant , Male , Microcephaly/diagnosis , Microcephaly/physiopathology , Pregnancy , Zika Virus/genetics , Zika Virus/pathogenicity , Zika Virus Infection/pathology , Zika Virus Infection/virologyABSTRACT
BACKGROUND: Little information on gross motor function of congenital Zika syndrome (CZS) children is available. OBJECTIVES: To evaluate gross motor function in CZS children aged up to 3 years, and its associated factors and changes in a minimum interval of 6 months. METHODS: One hundred children with CZS and cerebral palsy (36 with confirmed and 64 with presumed CZS) were evaluated with the Gross Motor Function Classification System (GMFCS) and Gross Motor Function Measure (GMFM-88/GMFM-66). Forty-six were reevaluated. Wilcoxon tests, Wilcoxon tests for paired samples, percentile scores, and score changes were performed. RESULTS: Clinical and socioeconomic characteristics (except maternal age), GMFM scores and GMFCS classification of confirmed and probable cases, which were analyzed together, were similar. The mean age was 25.6 months (±5.5); the median GMFM-88 score was 8.0 (5.4-10.8); and the median GMFM-66 score was 20.5 (14.8-23.1); 89% were classified as GMFCS level V. Low economic class, microcephaly at birth, epilepsy, and brain parenchymal volume loss were associated with low GMFM-66 scores. The median GMFM-66 percentile score was 40 (20-55). On the second assessment, the GMFM-66 scores in two GMFCS level I children and one GMFCS level IV child improved significantly. In one GMFCS level III child, one GMFCS level IV child, and the group of GMFCS level V children, no significant changes were observed. CONCLUSIONS: Almost all CZS children had severe cerebral palsy; in the third year of life, most presented no improvement in gross motor function and were likely approaching their maximal gross motor function potential.
Subject(s)
Cerebral Palsy/physiopathology , Epilepsy/physiopathology , Motor Skills/physiology , Nervous System Malformations/physiopathology , Zika Virus Infection/congenital , Zika Virus Infection/physiopathology , Cerebral Palsy/etiology , Child, Preschool , Epilepsy/etiology , Female , Follow-Up Studies , Humans , Infant , Male , Microcephaly/etiology , Microcephaly/physiopathology , Nervous System Malformations/etiology , Severity of Illness Index , Social Class , Zika Virus Infection/complicationsABSTRACT
Purpose: The purpose of this study was to analyze the natural history and phenotypic overlap of patients with microcephaly and a chorioretinopathy or familial exudative vitreoretinopathy (FEVR) ocular phenotype caused by mutations in KIF11, TUBGCP4, or TUBGCP6. Methods: Patients diagnosed with congenital microcephaly and chorioretinopathy or FEVR were included. Molecular investigations consisted of targeted genetic sequencing. Data from medical records, ophthalmologic examination and imaging, electroretinography, and visual fields were analyzed for systemic and ophthalmic features and evidence of posterior segment disease progression. Results: Twelve patients from 9 families were included and had a median of 8 years of follow-up. Nine patients had KIF11 variants, two had heterozygous TUBGCP6 variants, and one had heterozygous variants in TUBGCP4. All patients had reduced visual function and multiple individuals and families showed features of both chorioretinopathy and FEVR. Progression of posterior segment disease was highly variable, with some degree of increased atrophy of the macula or peripheral retina or increased vitreoretinal traction observed in 9 of 12 patients. Conclusions: Microcephaly due to mutations in KIF11, TUBGCP4, or TUBGCP6 can be associated with retinal disease on a spectrum from chorioretinal atrophy to FEVR-like posterior segment changes. Visually significant disease progression can occur and patients should be monitored closely by a team experienced in ophthalmic genetics.
Subject(s)
Familial Exudative Vitreoretinopathies/genetics , Kinesins/genetics , Microcephaly/genetics , Microtubule-Associated Proteins/genetics , Mutation , Retinal Diseases/genetics , Adolescent , Child , Child, Preschool , DNA Mutational Analysis , Electroretinography , Familial Exudative Vitreoretinopathies/diagnosis , Familial Exudative Vitreoretinopathies/physiopathology , Female , Follow-Up Studies , Genetic Association Studies , Humans , Infant , Infant, Newborn , Male , Microcephaly/diagnosis , Microcephaly/physiopathology , Retinal Diseases/diagnosis , Retinal Diseases/physiopathology , Vision Disorders/diagnosis , Vision Disorders/physiopathology , Visual Acuity/physiology , Visual Field Tests , Visual Fields/physiologyABSTRACT
AIM OF THE STUDY: Mowat Wilson syndrome (MWS) is a complex genetic disorder due to mutation or deletion of the ZEB2 gene (ZFHX1B), including multiple clinical features. Hirschsprung disease is associated with this syndrome with a prevalence between 43 and 57%. The aim of this study was to demonstrate the severe outcomes and the high complication rates in children with MWS, focusing on their complicated follow-up. METHODS: A retrospective comparative study was conducted on patients referred to Robert-Debré Children's Hospital for MWS from 2003 to 2018. Multidisciplinary follow-up was carried out by surgeons, geneticists, gastroenterologists, and neurologists. Data regarding patient characteristics, surgical management, postoperative complications, and functional outcomes were collected. RESULTS: Over this period of 15 years, 23 patients were diagnosed with MWS. Hirschsprung disease was associated with 10 of them (43%). Of these cases, two patients had recto-sigmoïd aganglionosis (20%), three had aganglionic segment extension to the left colic angle (30%), two to the right colic angle (20%), and three to the whole colon (30%). The median follow-up was 8.5 years (2 months-15 years). All patients had seizures and intellectual disability. Six children (60%) presented with cardiac defects. At the last follow-up, three patients still had a stoma diversion and 7 (70%) were fed orally. One patient died during the first months. Eight (80%) of these children required a second surgery due to complications. At the last follow-up, three patients reported episodes of abdominal bloating (42%), one recurrent treated constipation (14.3%), and one soiling (14.3%). Genetic analysis identified three patients with heterozygous deletions, three with codon mutations, and three with frameshift mutations. CONCLUSIONS: MWS associated with Hirschsprung disease has a high rate of immediate surgical complications but some patients may achieve bowel function comparable with non-syndromic HD patients. A multidisciplinary follow-up is required for these patients. LEVEL OF EVIDENCE: Retrospective observational single cohort study, Level 3.
Subject(s)
Defecation/physiology , Digestive System Surgical Procedures/methods , Forecasting , Hirschsprung Disease/physiopathology , Intellectual Disability/physiopathology , Microcephaly/physiopathology , DNA Mutational Analysis , Facies , Female , Follow-Up Studies , Hirschsprung Disease/genetics , Hirschsprung Disease/surgery , Humans , Infant, Newborn , Intellectual Disability/genetics , Intellectual Disability/surgery , Male , Microcephaly/genetics , Microcephaly/surgery , Mutation , Retrospective Studies , Treatment Outcome , Zinc Finger E-box Binding Homeobox 2/genetics , Zinc Finger E-box Binding Homeobox 2/metabolism , Zinc FingersABSTRACT
OBJECTIVES: This study aimed to describe the demographic and clinical parameters of women infected by Zika virus who had infants with stigmata of Congenital Zika Syndrome (CZS) versus those who had normal-appearing infants at birth, thereby providing further details on the clinical caveats of neonatal ZIKV infection. METHODOLOGY: This cross-sectional study was performed in the state of Mato Grosso do Sul, Central-West region of Brazil, and included 117 mother-infant pairs who were interviewed and 120 gestational outcomes. All mothers had laboratory confirmation by qRT-PCR of ZIKV infection during pregnancy. RESULTS: The prevalence of congenital abnormalities related to ZIKV was 2.69 cases per 10,000 live births during this period. Exanthem was the main clinical finding, observed in 92.5% of the mothers in this study. Regarding the timing of ZIKV infection, the first trimester was the most frequent time of infection among mothers of infants with CZS (54.55%) (p=0.0007). The case fatality rate was 5% (n=6). Among the 23 children who were classified as having CZS, 13 (56.52%) of them presented with microcephaly. Only 13 (56.52%) children with CZS were tested by qRT-PCR for ZIKV infection at birth, five (38%) were positive. CONCLUSIONS: This study highlights the congenital alterations of ZIKV infection during pregnancy in an epidemic burst, demonstrating that the alterations found in other studies are similar to the present research.