Cyclin-Dependent Kinase-Like 5 (CDKL5) Mutation Screening in Rett Syndrome and Related Disorders

AbstractRett syndrome (RTT) is a severe neurodevelopmental disorder affecting females almost exclusively and is characterized by a wide spectrum of clinical manifestations. Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene have been found in up to 95% of classical RTT cases and a lesser proportion of atypical cases. Recently, mutations in another X-linked gene, CDKL5 (cyclin-dependent kinase-like 5) have been found to cause atypical RTT, in particular the early onset seizure (Hanefeld variant) and one female with autism. In this study we screened several cohorts of children for CDKL5 mutations, totaling 316 patients, including individuals with a clinical diagnosis of RTT but who were negative for MECP2 mutations (n = 102), males with X-linked mental retardation (n = 9), patients with West syndrome (n = 52), patients with autism (n = 59), patients with epileptic encephalopathy (n = 33), patients with Aicardi syndrome (n = 7) and other patients with intellectual disability with or without seizures (n = 54). In all, seven polymorphic variations and four de novo mutations (c.586C>T [p.S196L]; c.58G>C [p.G20R]; c.2504delC [p.P835fs]; deletion of exons 1 - 3) were identified, and in all instances of the latter the clinical phenotype was that of an epileptic encephalopathy. These results suggest that pathogenic CDKL5 mutations are unlikely to be identified in the absence of severe early-onset seizures and highlight the importance of screening for large intragenic and whole gene deletions.

Download Full-text

KCND3-Related Neurological Disorders: From Old to Emerging Clinical Phenotypes

International Journal of Molecular Sciences ◽

10.3390/ijms21165802 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5802

Author(s):

Luca Pollini ◽

Serena Galosi ◽

Manuela Tolve ◽

Caterina Caputi ◽

Carla Carducci ◽

...

Keyword(s):

Movement Disorders ◽

Early Onset ◽

Neurological Disorder ◽

De Novo ◽

Age Of Onset ◽

Late Onset ◽

Wide Spectrum ◽

Neurodevelopmental Disorder ◽

Clinical Phenotypes ◽

K Current

KCND3 encodes the voltage-gated potassium ion channel subfamily D member 3, a six trans-membrane protein (Kv4.3), involved in the transient outward K+ current. KCND3 defect causes both cardiological and neurological syndromes. From a neurological perspective, Kv4.3 defect has been associated to SCA type 19/22, a complex neurological disorder encompassing a wide spectrum of clinical features beside ataxia. To better define the phenotypic spectrum and course of KCND3-related neurological disorder, we review the clinical presentation and evolution in 68 reported cases. We delineated two main clinical phenotypes according to the age of onset. Neurodevelopmental disorder with epilepsy and/or movement disorders with ataxia later in the disease course characterized the early onset forms, while a prominent ataxic syndrome with possible cognitive decline, movement disorders, and peripheral neuropathy were observed in the late onset forms. Furthermore, we described a 37-year-old patient with a de novo KCND3 variant [c.901T>C (p.Ser301Pro)], previously reported in dbSNP as rs79821338, and a clinical phenotype paradigmatic of the early onset forms with neurodevelopmental disorder, epilepsy, parkinsonism-dystonia, and ataxia in adulthood, further expanding the clinical spectrum of this condition.

Download Full-text

Mouse Models Characterize GNAO1 Encephalopathy as a Neurodevelopmental Disorder Leading to Motor Anomalies: from a Severe G203R to a Milder C215Y Mutation

10.21203/rs.3.rs-1089935/v1 ◽

2021 ◽

Author(s):

Denis Silachev ◽

Alexey Koval ◽

Mikhail Savitsky ◽

Guru Padmasola ◽

Charles Quairiaux ◽

...

Keyword(s):

Mouse Models ◽

De Novo ◽

Late Onset ◽

Wide Spectrum ◽

Neurodevelopmental Disorder ◽

Point Mutations ◽

Clinical Manifestations ◽

Epileptic Seizures ◽

Motor Dysfunction ◽

Neuronal Precursor Cells

Abstract GNAO1 encephalopathy characterized by a wide spectrum of neurological deficiencies in pediatric patients originates from de novo heterozygous mutations in the gene encoding Gαo, the major neuronal G protein. Efficient treatments and even the proper understanding of the underlying etiology are currently lacking for this dominant disease. Adequate animal models of GNAO1 encephalopathy are urgently needed. Here we describe establishment and characterization of mouse models of the disease based on two point mutations in GNAO1 with different clinical manifestations. One of them is G203R leading to the early-onset epileptic seizures, motor dysfunction, developmental delay and intellectual disability. The other is C215Y producing much milder clinical outcomes, mostly – late-onset motor hyperactivity. The resultant mouse models show distinct phenotypes: severe neonatal lethality in GNAO1[G203R]/+ mice vs. normal vitality in GNAO1[C215Y]/+. The latter model further revealed strong hyperactivity and hyperlocomotion in a panel of behavioral assays, without signs of epilepsy, recapitulating the patients’ manifestations. Importantly, despite these differences the two models similarly revealed prenatal brain developmental anomalies, such as enlarged lateral ventricles and decreased numbers of neuronal precursor cells in the cortex. Thus, our work unveils GNAO1 encephalopathy as to a large extent neurodevelopmental malady. We expect that this understanding and the tools we established will be instrumental for future therapeutic developments.

Download Full-text

Pediatric leukemia susceptibility disorders: manifestations and management

Hematology ◽

10.1182/asheducation-2017.1.242 ◽

2017 ◽

Vol 2017 (1) ◽

pp. 242-250 ◽

Cited By ~ 6

Author(s):

Lisa J. McReynolds ◽

Sharon A. Savage

Keyword(s):

Early Onset ◽

Ribosome Biogenesis ◽

De Novo ◽

Disease Risk ◽

Bone Marrow Failure ◽

Clinical Manifestations ◽

Cancer Surveillance ◽

Therapeutic Interventions ◽

Pediatric Leukemia ◽

Inherited Susceptibility

Abstract The clinical manifestations of inherited susceptibility to leukemia encompass a wide phenotypic range, including patients with certain congenital anomalies or early-onset myelodysplastic syndrome (MDS) and some with no obvious medical problems until they develop leukemia. Leukemia susceptibility syndromes occur as a result of autosomal dominant, autosomal recessive, or X-linked recessive inheritance, or de novo occurrence, of germline pathogenic variants in DNA repair, ribosome biogenesis, telomere biology, hematopoietic transcription factors, tumor suppressors, and other critical cellular processes. Children and adults with cytopenias, MDS, dysmorphic features, notable infectious histories, immunodeficiency, certain dermatologic findings, lymphedema, unusual sensitivity to radiation or chemotherapy, or acute leukemia with a family history of early-onset cancer, pulmonary fibrosis, or alveolar proteinosis should be thoroughly evaluated for a leukemia susceptibility syndrome. Genetic testing and other diagnostic modalities have improved our ability to identify these patients and to counsel them and their family members for subsequent disease risk, cancer surveillance, and therapeutic interventions. Herein, the leukemia susceptibility syndromes are divided into 3 groups: (1) those associated with an underlying inherited bone marrow failure syndrome, (2) disorders in which MDS precedes leukemia development, and (3) those with a risk primarily of leukemia. Although children are the focus of this review, it is important for clinicians to recognize that inherited susceptibility to cancer can present at any age, even in older adults; genetic counseling is essential and prompt referral to experts in each syndrome is strongly recommended.

Download Full-text

Correction to: Perampanel treatment in early-onset epileptic encephalopathy with infantile movement disorders associated with a de novo GRIN1 gene mutation: a 3-year follow-up

Neurological Sciences ◽

10.1007/s10072-021-05084-7 ◽

2021 ◽

Author(s):

Daniela Dicanio ◽

Antonio Gennaro Nicotera ◽

F. Cucinotta ◽

G. Di Rosa

Keyword(s):

Gene Mutation ◽

Movement Disorders ◽

Early Onset ◽

De Novo ◽

Epileptic Encephalopathy

Download Full-text

Perampanel treatment in Early-onset Epileptic Encephalopathy with infantile movement disorders associated with a de novo GRIN1 gene mutation: a 3-year follow-up

Neurological Sciences ◽

10.1007/s10072-020-04935-z ◽

2021 ◽

Author(s):

Daniela Dicanio ◽

Antonio Gennaro Nicotera ◽

F. Cucinotta ◽

G. Di Rosa

Keyword(s):

Gene Mutation ◽

Movement Disorders ◽

Early Onset ◽

De Novo ◽

Epileptic Encephalopathy

Download Full-text

A Novel Heterozygous Missense Variant in YWHAG Gene Cause Early-Onset Epilepsy in a Chinese Family

10.21203/rs.3.rs-136482/v1 ◽

2020 ◽

Author(s):

Zhi Yi ◽

Zhenfeng Song ◽

Jiao Xue ◽

Chengqing Yang ◽

Fei Li ◽

...

Keyword(s):

Early Onset ◽

Seizure Control ◽

De Novo ◽

Missense Variant ◽

Epileptic Encephalopathy ◽

Chinese Family ◽

Gene Variants ◽

Case Presentation ◽

Epileptic Encephalopathies ◽

Refractory Seizures

Abstract Background: Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of severe disorders which are characterized by early-onset, refractory seizures and developmental slowing or regression. Genetic variations are significant causes for them. De novo variants in an increasing number of candidate genes have been found to be causal. YWHAG gene variants have been reported to cause developmental and epileptic encephalopathy 56 (DEE56). Case presentation: Here, we report a novel heterozygous missense variant c.170G>A (p.R57H) in YWHAG gene cause early-onset epilepsy in a Chinese family. Both the proband and his mother exhibit early onset seizures, intellectual disability, developmental delay. While the proband achieve seizure control with sodium valproate, his mother's seizures were not well controlled. Conclusions: Our report further confirming the haploinsufficiency of YWHAG results in developmental and epileptic encephalopathies.

Download Full-text

Epileptic Encephalopathy, Myoclonus–Dystonia, and Premature Pubarche in Siblings with a Novel C-Terminal Truncating Mutation in ATRX Gene

Neuropediatrics ◽

10.1055/s-0039-1692141 ◽

2019 ◽

Vol 50 (05) ◽

pp. 327-331 ◽

Cited By ~ 1

Author(s):

Thea Giacomini ◽

Maria Stella Vari ◽

Sara Janis ◽

Giulia Prato ◽

Livia Pisciotta ◽

...

Keyword(s):

Wide Spectrum ◽

Genetic Disorder ◽

Clinical Manifestations ◽

Epileptic Seizures ◽

Epileptic Encephalopathy ◽

Recessive Mutations ◽

Truncating Mutation ◽

Alpha Thalassemia ◽

Male Patients ◽

Myoclonus Dystonia

AbstractThe X-linked alpha thalassemia mental retardation (ATR-X) syndrome is a genetic disorder caused by X-linked recessive mutations in ATRX gene, related to a wide spectrum of clinical manifestations, such as alpha thalassemia, developmental delay, genital abnormalities, and gastrointestinal disorders. Patients with ATR-X syndrome can suffer from different types of epileptic seizures, but a severe epileptic encephalopathy pattern has not been described to date. We describe, for the first time, two brothers with genetically confirmed ATR-X syndrome who presented with drug-resistant epileptic encephalopathy, with tonic and polimorphic seizures reported in the elder brother and epileptic spasms in the younger brother. Moreover, both brothers showed a peculiar movement disorder with myoclonus–dystonia, worsened during periods of distress or pain. These cases expand the clinical spectrum of ATR-X syndrome and open new opportunities for the molecular diagnosis of ATRX mutations in male patients with severe epileptic encephalopathies and movement disorders.

Download Full-text

A case of early onset epileptic encephalopathy with de novo mutation in SLC35A2: Clinical features and treatment for epilepsy

Brain and Development ◽

10.1016/j.braindev.2016.09.009 ◽

2017 ◽

Vol 39 (3) ◽

pp. 256-260 ◽

Cited By ~ 20

Author(s):

Tomokazu Kimizu ◽

Yukitoshi Takahashi ◽

Taikan Oboshi ◽

Asako Horino ◽

Takayoshi Koike ◽

...

Keyword(s):

Clinical Features ◽

Early Onset ◽

De Novo ◽

Epileptic Encephalopathy ◽

De Novo Mutation

Download Full-text

Functional Network Mapping Reveals State-Dependent Response to IGF1 Treatment in Rett Syndrome

Brain Sciences ◽

10.3390/brainsci10080515 ◽

2020 ◽

Vol 10 (8) ◽

pp. 515 ◽

Cited By ~ 1

Author(s):

Conor Keogh ◽

Giorgio Pini ◽

Ilaria Gemo ◽

Walter E. Kaufmann ◽

Daniela Tropea

Keyword(s):

Clinical Response ◽

Rett Syndrome ◽

Network Formation ◽

Neurodevelopmental Disorder ◽

Clinical Manifestations ◽

Statistical Modelling ◽

Preliminary Evidence ◽

Response To Treatment ◽

Clinical Assessments ◽

Network Measures

Rett Syndrome (RTT) is a neurodevelopmental disorder associated with mutations in the gene MeCP2, which is involved in the development and function of cortical networks. The clinical presentation of RTT is generally severe and includes developmental regression and marked neurologic impairment. Insulin-Like growth factor 1 (IGF1) ameliorates RTT-relevant phenotypes in animal models and improves some clinical manifestations in early human trials. However, it remains unclear whether IGF1 treatment has an impact on cortical electrophysiology in line with MeCP2’s role in network formation, and whether these electrophysiological changes are related to clinical response. We performed clinical assessments and resting-state electroencephalogram (EEG) recordings in eighteen patients with classic RTT, nine of whom were treated with IGF1. Among the treated patients, we distinguished those who showed improvements after treatment (responders) from those who did not show any changes (nonresponders). Clinical assessments were carried out for all individuals with RTT at baseline and 12 months after treatment. Network measures were derived using statistical modelling techniques based on interelectrode coherence measures. We found significant interaction between treatment groups and timepoints, indicating an effect of IGF1 on network measures. We also found a significant effect of responder status and timepoint, indicating that these changes in network measures are associated with clinical response to treatment. Further, we found baseline variability in network characteristics, and a machine learning model using these measures applied to pretreatment data predicted treatment response with 100% accuracy (100% sensitivity and 100% specificity) in this small patient group. These results highlight the importance of network pathology in RTT, as well as providing preliminary evidence for the potential of network measures as tools for the characterisation of disease subtypes and as biomarkers for clinical trials.

Download Full-text