PIGA related disorder as a range of phenotypes rather than two distinct subtypes

Patients with germline phosphatidylinositol glycan biosynthesis class A (PIGA) related disorder have historically been categorized into one of two distinct subtypes: a severe form which is often fatal, and a less severe form. However, the increasing number of cases with features indicative of both subtypes raise the possibility of a phenotypic spectrum associated with PIGA disorder.In order to further characterize this phenotypic spectrum, we present two patients with features of both the severe and less severe subtypes with a review of phenotypes reported to date in the literature. In eight year old patient 1, a maternally inherited PIGA likely pathogenic variant was discovered using exome sequencing. He presented with myoclonic epilepsy, mild intellectual disability, spastic diplegia, developmental motor delay, and autism spectrum disorder. Patient 2 is a 13 year old with focal epilepsy, profound developmental delay, coarse facial features, severe intellectual disability and autism spectrum disorder. A de novo PIGA likely pathogenic variant was found through exome sequencing. Both patients had normal alkaline phosphatase levels and are without related organ abnormalities. We conclude that pathogenic PIGA variants cause a spectrum of phenotypes rather than the categories of “severe” and “less severe” as previously posited.     

A novel variant in NEUROD2 in a patient with Rett-like phenotype points to Glu130 codon as a mutational hotspot

BackgroundNEUROD2, encoding the neurogenic differentiation factor 2, is essential for neurodevelopment. To date, heterozygous missense variants in this gene have been identified in eight patients (from six unrelated families) with epileptic encephalopathy and developmental delay.Case reportWe describe a child with initial clinical suspicion of Rett/Rett-like syndrome, in whom exome sequencing detected a novel de novo variant (c.388G > A, p.Glu130Lys) in NEUROD2. Interestingly, a missense change affecting the same codon, c.388G > C (p.Glu130Gln), was previously identified in other two patients.ConclusionsOur results suggest that Glu130 might represent a potential mutational hotspot of NEUROD2. Furthermore, the clinical findings (especially the absence of clinically overt seizures) strengthen the NEUROD2-phenotypic spectrum, implying that developmental delay may also manifest isolatedly. We suggest inclusion of NEUROD2-associated developmental and epileptic encephalopathies (DEEs) in the differential diagnosis of atypical Rett syndrome as well as gene panels related to autism spectrum disorder.     

Expanding the clinical phenotype and genetic spectrum of PURA-related neurodevelopmental disorders

BackgroundPURA-related neurodevelopmental disorders (PURA-NDDs) include 5q31.3 deletion syndrome and PURA syndrome. PURA-NDDs are characterized by neonatal hypotonia, moderate to severe global developmental delay/intellectual disability (GDD/ID), facial dysmorphism, epileptic seizures, nonepileptic movement disorders, and ophthalmological problems. PURA-NDDs have recently been identified and underestimated in neurodevelopmental cohorts, but their diagnosis is still challenging.MethodsWe retrospectively reviewed the clinical characteristics, genetic spectrum, and diagnostic journey of patients with PURA-NDDs.ResultsWe report 2 patients with 5q31.3 microdeletion and 5 with PURA pathogenic variants. They demonstrated hypotonia (7/7, 100%), feeding difficulties (4/5, 80%), and respiratory problems (4/7, 57%) in the neonatal period. All of them had severe GDD/ID and could not achieve independent walking and verbal responses. Distinctive facial features of open-tented upper vermilion, long philtrum, and anteverted nares and poor visual fixation and tracking with or without nystagmus were most commonly found (5/7, 71.4%). There were no significant differences in clinical phenotypes between 5q31.3 microdeletion syndrome and PURA syndrome. PURA-NDDs need to be considered as a differential diagnosis in individuals who show severe hypotonia, including feeding difficulties since birth and severe developmental retardation with distinctive facial and ophthalmological features.ConclusionsOur data expands the phenotypic and genetic spectrum of PURA-NDD. Next-generation sequencing methods based on the detailed phenotypic evaluation would shorten the diagnostic delay and would help this rare disorder become a recognizable cause of neurodevelopmental delay.     

A new case of concurrent existence of PRRT2-associated paroxysmal movement disorders with c.649dup variant and 16p11.2 microdeletion syndrome

BackgroundThe PRRT2 gene located at 16p11.2 encodes proline-rich transmembrane protein 2. In recent reviews, clinical spectrum caused by pathogenic PRRT2 variants is designated as PRRT2-associated paroxysmal movement disorders, which include paroxysmal kinesigenic dyskinesia, benign familial infantile epilepsy, and infantile convulsions with choreoathetosis, and hemiplegic migraine. The recurrent 16p11.2 microdeletion encompassing PRRT2 has also been reported to cause neurodevelopmental syndrome, associated with autism spectrum disorder. Although PRRT2 variants and 16p11.2 microdeletion cause each disease with the autosomal dominant manner, rare cases with bi-allelic PRRT2 variants or concurrent existence of PRRT2 variants and 16p11.2 microdeletion have been reported to show more severe phenotypes.Case reportA 22-year-old man presents with episodic ataxia, paroxysmal kinesigenic dyskinesia, seizure, intellectual disability and autism spectrum disorder. He also has obesity, hypertension, hyperuricemia, and mild liver dysfunction. Exome sequencing revealed a c.649dup variant in PRRT2 in one allele and a de novo 16p11.2 microdeletion in another allele.ConclusionsOur case showed combined clinical features of PRRT2-associated paroxysmal movement disorders and 16p11.2 microdeletion syndrome. We reviewed previous literatures and discussed phenotypic features of patients who completely lack the PRRT2 protein.     

A novel splice site CUL3 variant in a patient with neurodevelopmental delay

BackgroundCUL3-related neurodevelopmental disorder is a recently described rare genetic condition characterized by global developmental delay and intellectual disability. Five affected individuals have been reported worldwide. The molecular and phenotypic spectrum of the disorder has yet to be fully elucidated. Splice variants in CUL3 are a well-described cause of pseudohypoaldosteronism type IIE; however, splice variants have not been associated with the neurodevelopmental disorder. We report the first individual with a neurodevelopmental disorder attributed to a CUL3 splice site variant.Case ReportThe patient presented with congenital developmental dysplasia of the hip and global developmental delay. A de novo splice site variant (c.379-2A > G) was identified in CUL3 and is predicted to abolish the acceptor splice site.ConclusionThis is the first report of an individual with a splice site variant causing CUL3-related neurodevelopmental disorder and expands our understanding of this rare condition.     

Neuropsychological and neurophysiological features of WAGR syndrome: Detailed comprehensive evaluation of a patient with severe intellectual disability and autism spectrum disorder

BackgroundWilms’ tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome is a contiguous gene deletion syndrome caused by a de novo deletion including the 11p13 region. Although autism spectrum disorder (ASD) is frequently observed in patients with WAGR syndrome, few reports have comprehensively described its characteristics. We herein present the detailed neuropsychological and neurophysiological findings of a patient with WAGR syndrome complicated with severe psychomotor developmental delay and ASD.Case presentationThe patient is presently a 6-year-old boy. Microarray analysis revealed a 7.1 Mb loss at 11p14.3-p13 and a 9.3 Mb loss at 11p13-p12, which encompassed the PAX6, WT1, and PRRG4 genes. His behavioral features were characteristic even among the ASD population: severe hypoesthesia to touch, pain, and temperature in addition to remarkable sensory seeking posing a high risk of serious accident. Sensory Profile analysis objectively identified a strong preference for sensory stimulation. Furthermore, his somatosensory evoked potential (SSEP) showed a mild delay in central conduction time, suggesting partial brain stem dysfunction-induced hypoalgesia.DiscussionThis first attempt to characterize sensory dysfunction using Sensory Profile and SSEP in WAGR syndrome may contribute to understanding its neuropsychological features and improve the quality of rehabilitation and socioeducational support in affected children.     

Autism Spectrum Disorder in a Term Birth Neonatal Intensive Care Unit Population

BackgroundNonspecific perinatal risk factors have been revealed to be associated with the development of autism spectrum disorder. However, term at-risk infants, as a distinct population, are underrepresented in the literature. This study examines the incidence and neonatal risk factors for autism spectrum disorder in term neonatal intensive care unit survivors.MethodsWe performed a retrospective analysis from a single university-practice database of neonates admitted to the neonatal intensive care unit and followed by a single pediatric neurologist. Term infants (≥37 weeks), born between 1991 and 2011, with at least 2 years (or 1 year if found to be neurologically normal) of follow-up were included. Principle outcomes were autism spectrum disorder, cerebral palsy, global developmental delay, and epilepsy.ResultsOne hundred eighty infants were included from a database of 564 neonates. Twelve (6.6%) developed autism spectrum disorder, 53 (29.4%) cerebral palsy, 77 (42.7%) global developmental delay, and 47 (26.1%) epilepsy. Seventy-one (39.4%) developed no adverse outcomes. Nine patients with autism spectrum disorder (75%) were diagnosed with at least one other adverse outcome. No neonatal or perinatal variables were evident to be significantly associated with later autism spectrum disorder.ConclusionsIn term neonatal intensive care unit survivors, autism spectrum disorder occurs at a greater frequency than in the general population and often develops alongside comorbid conditions. This highlights the importance of screening term neonatal intensive care unit survivors for autism spectrum disorder, particularly when comorbidities are present.     

Neurocristopathies presenting with neurologic abnormalities associated with Hirschsprung's disease

Neurocristopathies are a group of diverse disorders resulting from defective growth, differentiation, and migration of the neural crest cells. Hirschsprung’s disease, namely aganglionic megacolon, is the consequence of defective migration of neural crest cells on to the colonic submucosa and is therefore considered a neurocristopathy. We report on four children in whom was diagnosed a neurocristopathy, associating Hirschsprung’s disease with a wide spectrum of neurologic abnormalities. The patients included two children presenting the phenotypic features of the Goldberg-Shprintzen syndrome: distinct dysmorphic facial features, microcephaly, and mental retardation, along with agenesis of the corpus callosum and cortical malformations associated with intractable seizures in one child. The third newborn presented with the Haddad syndrome: short-segment Hirschsprung’s disease associated with the congenital central hypoventilation syndrome requiring permanent artificial ventilation. In the fourth child, absence of the corpus callosum was associated with mild dysmorphic features, borderline cognitive abilities, and attention-deficit disorder. Therefore, awareness of a possible neurocristopathy associated with neurologic abnormalities should be taken into account in any patient newly diagnosed with Hirschsprung’s disease to detect the abnormalities early and promptly manage them. A thorough neurologic examination and a developmental assessment, including magnetic resonance imaging of the brain and electroencephalography, should be performed for any child presenting with an aganglionic megacolon, especially those presenting with seizures, developmental delay, or even congenital hypoventilation.     

Clinical Exome Sequencing Identifies a Novel TUBB4A Mutation in a Child With Static Hypomyelinating Leukodystrophy

BackgroundLeukodystrophies are a large group of inherited diseases of central nervous system myelin. There are few treatments, and most patients do not receive a final genetic diagnosis.PatientWe report a novel presentation of a female child with hypotonia, global developmental delay, and rotatory nystagmus. Brain MRI demonstrated profound hypomyelination and minimal or no atrophy in the brain stem or cerebellum.ResultsExtensive testing failed to yield a diagnosis until clinical whole-exome sequencing revealed a novel pathogenic mutation in the β-tubulin gene TUBB4A. TUBB4A is a cause of hereditary dystonia type 4 and has recently been reported to cause hypomyelination with atrophy of the basal ganglia and cerebellum.ConclusionsThis report expands the phenotypic spectrum of TUBB4A-associated neurological diseases to include static hypomyelinating leukodystrophy and supports the clinical relevance of next-generation sequencing diagnosis approaches.     

A case of CHOPS syndrome accompanied with moyamoya disease and systemic vasculopathy

BackgroundCHOPS syndrome, caused by a mutation in the AFF4 gene, is a recently established and extremely rare genetic disorder, which has moderate phenotypic overlap with Cornelia de Lange syndrome. The main phenotypes include characteristic facial features, short stature, obesity, skeletal and pulmonary involvement, and neurodevelopmental impairment.Case reportWe report on a Korean girl with CHOPS syndrome presenting with an atypical manifestation. The patient was referred to the out-patient clinic to evaluate the underlying etiology of short stature, obesity, developmental delay, and Moyamoya disease. The patient showed characteristic facial features including a round face, thick eyebrows, and synophrys. Her developmental milestones had been delayed since infancy and a moderate degree of intellectual disability persisted. She was also diagnosed with Moyamoya disease at 6 years of age and had undergone synangiosis surgery thrice. Her renal arteries and infrarenal aorta were diffusely narrowed. A novel de novo missense variant, c.758C > T (p.Pro253Leu) in AFF4 was identified by whole exome sequencing. No additional candidate variants for her vascular manifestation were found except a susceptibility variant, c.14429G > A (p.Arg4810Lys) in RNF213, inherited from asymptomatic mother.ConclusionThis is the first case of CHOPS syndrome accompanied by systemic vasculopathy. More clinical observations and functional studies are required to clarify this association.     

Hemidystonia with polymicrogyria is part of ATP1A3-related disorders

IntroductionPathogenic variants in ATP1A3 cause various phenotypes of neurological disorders, including alternating hemiplegia of childhood 2, CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) and rapid-onset dystonia-parkinsonism (RDP). Early developmental and epileptic encephalopathy has also been reported. Polymicrogyria has recently been added to the phenotypic spectrum of ATP1A3-related disorders.Case report.We report here a male patient with early developmental delay who at 12 months presented dystonia of the right arm which evolved into hemidystonia at the age of 2. A cerebral MRI showed bilateral perisylvian polymicrogyria with intact basal ganglia. Whole-exome and whole-genome sequencing analyses identified a de novo new ATP1A3 missense variant (p.Arg914Lys) predicted pathogenic. Hemidystonia was thought not to be due to polymicrogyria, but rather a consequence of this variant.ConclusionThis case expands the phenotypic spectrum of ATP1A3-related disorders with a new variant associated with hemidystonia and polymicrogyria and thereby, suggests a clinical continuum between the different phenotypes of this condition.     

Okamoto syndrome in a girl of Caucasian origin

We report the clinical and genetic evaluation of a 2‐year‐old Greek female with striking phenotypic similarities to the three previously published cases of Okamoto syndrome. The main features were characteristic facies, cleft palate, generalized hypotonia, severe developmental delay, congenital hydronephrosis, and congenital heart defects. Routine chromosome testing and whole‐genome high‐resolution comparative genetic hybridization analysis were negative for any gross numerical or structural chromosome aberrations and for microdeletions/duplications of more than 3 million base pairs respectively. Fluorescence in situ hybridization analysis for 22q11.2 deletion and DNA analysis of the protein tyrosine phosphatase, non‐receptor type II gene were normal, thus excluding DiGeorge and Noonan syndromes. Our patient did not show most of the cardinal features of Schinzel–Giedion, otopalatodigital, and C‐trigonocephaly syndromes. Moreover, in our patient some new malformations were identified: unilateral kidney hypoplasia and severe anal stenosis. The latter was considered as pertinent and is described here to establish a wider clinical spectrum of Okamoto syndrome. At the age of 3 years 6 months the child continues to show severe growth failure and significant global developmental delay. For the practising paediatrician it is prudent to bear Okamoto syndrome in mind, especially in children with learning disability and a pattern of dysmorphic features.     

Polymicrogyria in a child with KCNMA1-related channelopathy

Back groundPolymicrogyria is a malformation of cortical development with overfolding of the cerebral cortex and abnormal cortical layering. Polymicrogyria constitutes a heterogenous collection of neuroimaging features, neuropathological findings, and clinical associations, and is due to multiple underlying etiologies. In the last few years, some glutamate and sodium channelopathies have been associated with cortical brain malformations such as polymicrogyria. The potassium calcium-activated channel subfamily M alpha 1 (KCNMA1) gene encodes each of the four alpha-subunits that make up the large conductance calcium and voltage-activated potassium channel “Big K+”. KCNMA1-related channelopathies are associated with various neurological abnormalities, including epilepsy, ataxia, paroxysmal dyskinesias, developmental delay and cognitive disorders.Case reportWe report the observation of a patient who presented since the age of two months with drug-resistant epilepsy with severe developmental delay initially related to bilateral asymmetric frontal polymicrogyria. Later, exome sequencing revealed a de novo heterozygous variation in the KCNMA1 gene (c.112delG) considered pathogenic.ConclusionThis first case of polymicrogyria associated with KCNMA1-related channelopathy may expand the phenotypic spectrum of KCNMA1-related channelopathies and enrich the recently identified group of developmental channelopathies with polymicrogyria.     

Personality disorders and autism spectrum disorders: what are the connections?

BackgroundThe relationship between autism spectrum disorders/pervasive developmental disorders and personality disorders is not completely clear, although both concepts imply lifelong impairment. The purpose of the present study was to investigate the presence of possible personality disorders in a group of young adults with Asperger syndrome.MethodFifty-four young adults with a clinical diagnosis of Asperger syndrome were assessed with Structured Clinical Interview for DSM-IV Axis II disorders to evaluate the presence of a concomitant personality disorder and completed the Autism Spectrum Quotient to measure level of autistic features. Autism spectrum diagnosis was confirmed by Diagnostic Interview for Social and Communication Disorders with a collateral informant.ResultsApproximately half of the study group fulfilled criteria for a personality disorder, all belonging to cluster A or C. There was a significant difference across sex: men with Asperger syndrome meeting personality disorder criteria much more often than women with Asperger syndrome (65% vs 32%). Participants fulfilling criteria for a personality disorder showed more marked autistic features according to the Autism Spectrum Quotient.ConclusionsThere is a considerable overlap in symptoms between Asperger syndrome and certain personality disorders. Similarities and differences of the two concepts are discussed in the framework of the Diagnostic and Statistical Manual of Mental Disorders classification system.     

Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants

ObjectivePatients with pathogenic cyclin-dependent kinase-like-5 gene (CDKL5) variants are designated CDKL5 deficiency disorder (CDD). This study aimed to delineate the clinical characteristics of Japanese patients with CDD and elucidate possible appropriate treatments.MethodsWe recruited patients with pathogenic or likely pathogenic CDKL5 variants from a cohort of approximately 1,100 Japanese patients with developmental and epileptic encephalopathies, who underwent genetic analysis. We retrospectively reviewed clinical, electroencephalogram, neuroimaging, and genetic information.ResultsWe identified 29 patients (21 females, eight males). All patients showed severe developmental delay, especially in males. Involuntary movements were observed in 15 patients. No antiepileptic drugs (AEDs) achieved seizure freedom by monotherapy. AEDs achieving ≥ 50% reduction in seizure frequency were sodium valproate in two patients, vigabatrin in one, and lamotrigine in one. Seizure aggravation was observed during the use of lamotrigine, potassium bromide, and levetiracetam. Adrenocorticotrophic hormone (ACTH) was the most effective treatment. The ketogenic diet (KD), corpus callosotomy and vagus nerve stimulation did not improve seizure frequency in most patients, but KD was remarkably effective in one. The degree of brain atrophy on magnetic resonance imaging (MRI) reflected disease severity. Compared with females, males had lower levels of attained motor development and more severe cerebral atrophy on MRI.ConclusionOur patients showed more severe global developmental delay than those in previous studies and had intractable epilepsy, likely because previous studies had lower numbers of males. Further studies are needed to investigate appropriate therapy for CDD, such as AED polytherapy or combination treatment involving ACTH, KD, and AEDs.     

Novel copy number variants in children with autism and additional developmental anomalies

Autism is a neurodevelopmental disorder characterized by three core symptom domains: ritualistic-repetitive behaviors, impaired social interaction, and impaired communication and language development. Recent studies have highlighted etiologically relevant recurrent copy number changes in autism, such as 16p11.2 deletions and duplications, as well as a significant role for unique, novel variants. We used Affymetrix 250K GeneChip Microarray technology (either NspI or StyI) to detect microdeletions and duplications in a subset of children from the Autism Genetic Resource Exchange (AGRE). In order to enrich our sample for potentially pathogenic CNVs we selected children with autism who had additional features suggestive of chromosomal loss associated with developmental disturbance (positive criteria filter) but who had normal cytogenetic testing (negative criteria filter). We identified families with the following features: at least one child with autism who also had facial dysmorphology, limb or digit abnormalities, or ocular abnormalities. To detect changes in copy number we used a publicly available program, Copy Number Analyser for GeneChip® (CNAG) Ver. 2.0. We identified novel deletions and duplications on chromosomes 1q24.2, 3p26.2, 4q34.2, and 6q24.3. Several of these deletions and duplications include new and interesting candidate genes for autism such as syntaxin binding protein 5 (STXBP5 also known as tomosyn) and leucine rich repeat neuronal 1 (LRRN1 also known as NLRR1). Lastly, our data suggest that rare and potentially pathogenic microdeletions and duplications may have a substantially higher prevalence in children with autism and additional developmental anomalies than in children with autism alone.