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1.  Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients 
BMC Medical Genetics  2014;15:24.
Mutations in the cyclin-dependent kinase-like 5 (CDKL5) (NM_003159.2) gene have been associated with early-onset epileptic encephalopathies or Hanefeld variants of RTT(Rett syndrome). In order to clarify the CDKL5 genotype-phenotype correlations in Chinese patients, CDKL5 mutational screening in cases with early-onset epileptic encephalopathies and RTT without MECP2 mutation were performed.
The detailed clinical information including clinical manifestation, electroencephalogram (EEG), magnetic resonance imaging (MRI), blood, urine amino acid and organic acid screening of 102 Chinese patients with early-onset epileptic encephalopathies and RTT were collected. CDKL5 gene mutations were analyzed by PCR, direct sequencing and multiplex ligation-dependent probe amplification (MLPA). The patterns of X-chromosome inactivation (XCI) were studied in the female patients with CDKL5 gene mutation.
De novo CDKL5 gene mutations were found in ten patients including one missense mutation (c.533G > A, p.R178Q) which had been reported, two splicing mutations (ISV6 + 1A > G, ISV13 + 1A > G), three micro-deletions (c.1111delC, c.2360delA, c.234delA), two insertions (c.1791 ins G, c.891_892 ins TT in a pair of twins) and one nonsense mutation (c.1375C > T, p.Q459X). Out of ten patients, 7 of 9 females with Hanefeld variants of RTT and the remaining 2 females with early onset epileptic encephalopathy, were detected while only one male with infantile spasms was detected. The common features of all female patients with CDKL5 gene mutations included refractory seizures starting before 4 months of age, severe psychomotor retardation, Rett-like features such as hand stereotypies, deceleration of head growth after birth and poor prognosis. In contrast, the only one male patient with CDKL5 mutation showed no obvious Rett-like features as females in our cohort. The X-chromosome inactivation patterns of all the female patients were random.
Mutations in CDKL5 gene are responsible for 7 with Hanefeld variants of RTT and 2 with early-onset epileptic encephalopathy in 71 girls as well as for 1 infantile spasms in 31 males. There are some differences in the phenotypes among genders with CDKL5 gene mutations and CDKL5 gene mutation analysis should be considered in both genders.
PMCID: PMC3938974  PMID: 24564546
CDKL5 mutations; Early-onset epileptic encephalopathy; X chromosome inactivation
2.  CDKL5-Related Disorders: From Clinical Description to Molecular Genetics 
Molecular Syndromology  2011;2(3-5):137-152.
Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in girls with Rett-like features and early-onset epileptic encephalopathy including infantile spasms. To date, with more than 80 reported cases, the phenotype of CDKL5-related encephalopathy is better defined. The main features consist of early-onset seizures starting before 5 months of age, severe mental retardation with absent speech and Rett-like features such as hand stereotypies and deceleration of head growth. On the other hand, neuro-vegetative signs and developmental regression are rare in CDKL5 mutation patients. The CDKL5 gene encodes a serine threonine kinase protein which is characterized by a catalytic domain and a long C-terminal extension involved in the regulation of the catalytic activity of CDKL5 and in the sub-nuclear localization of the protein. To our knowledge, more than 70 different point mutations have been described including missense mutations within the catalytic domain, nonsense mutations causing the premature termination of the protein distributed in the entire open reading frame, splice variants, and frameshift mutations. Additionally, CDKL5 mutations have recently been described in 7 males with a more severe epileptic encephalopathy and a worse outcome compared to female patients. Finally, about 23 male and female patients have been identified with gross rearrangements encompassing all or part of the CDKL5 gene, with a phenotype reminiscent of CDKL5-related encephalopathy combined with dysmorphic features. Even if recent data clearly indicate that CDKL5 plays an important role in brain function, the protein remains largely uncharacterized. Phenotype-genotype correlation is additionally hampered by the relatively small number of patients described.
PMCID: PMC3366705  PMID: 22670135
CDKL5; Epileptic encephalopathy; Rett syndrome
3.  CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms 
Journal of Medical Genetics  2005;42(2):103-107.
Background: Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterised by a wide spectrum of clinical manifestations. Both the classic form and preserved speech variant of Rett syndrome are due to mutations in the MECP2 gene. Several other variants of Rett syndrome have been described. In 1985, Hanefeld described a variant with the early appearance of convulsions. In this variant, the normal perinatal period is soon followed by the appearance of seizures, usually infantile spasms. We have observed two patients with signs of Rett syndrome showing acquired microcephaly and stereotypic midline hand movements. The disease started with generalised convulsions and myoclonic fits at 1.5 months in the first patient and with spasms at 10 days in the other, suggesting a diagnosis of the Hanefeld variant. In these patients, MECP2 point mutations and gross rearrangements were excluded by denaturing high performance liquid chromatography and real time quantitative PCR. The ARX and CDKL5 genes have been associated with West syndrome (infantile spasms, hypsarrhythmia, and mental retardation).
Methods: Based on the clinical overlap between the Hanefeld variant and West syndrome, we analysed ARX and CDKL5 in the two girls.
Results: We found frameshift deletions in CDKL5 in both patients; one in exon 5 (c.163_166delGAAA) and the other in exon 18 (c.2635_2636delCT). CDKL5 was then analysed in 19 classic Rett and 15 preserved speech variant patients, all MECP2 negative, but no mutations were found.
Conclusion: Our results show that CDKL5 is responsible for a rare variant of Rett syndrome characterised by early development of convulsions, usually of the spasm type.
PMCID: PMC1735977  PMID: 15689447
4.  The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy 
The clinical understanding of the CDKL5 disorder remains limited, with most information being derived from small patient groups seen at individual centres. This study uses a large international data collection to describe the clinical profile of the CDKL5 disorder and compare with Rett syndrome (RTT). Information on individuals with cyclin-dependent kinase-like 5 (CDKL5) mutations (n=86) and females with MECP2 mutations (n=920) was sourced from the InterRett database. Available photographs of CDKL5 patients were examined for dysmorphic features. The proportion of CDKL5 patients meeting the recent Neul criteria for atypical RTT was determined. Logistic regression and time-to-event analyses were used to compare the occurrence of Rett-like features in those with MECP2 and CDKL5 mutations. Most individuals with CDKL5 mutations had severe developmental delay from birth, seizure onset before the age of 3 months and similar non-dysmorphic features. Less than one-quarter met the criteria for early-onset seizure variant RTT. Seizures and sleep disturbances were more common than in those with MECP2 mutations whereas features of regression and spinal curvature were less common. The CDKL5 disorder presents with a distinct clinical profile and a subtle facial, limb and hand phenotype that may assist in differentiation from other early-onset encephalopathies. Although mutations in the CDKL5 gene have been described in association with the early-onset variant of RTT, in our study the majority did not meet these criteria. Therefore, the CDKL5 disorder should be considered separate to RTT, rather than another variant.
PMCID: PMC3573195  PMID: 22872100
CDKL5; Rett syndrome; dysmorphology; natural history; phenotype
5.  CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients 
Journal of Medical Genetics  2006;43(9):729-734.
To determine the frequency of mutations in CDKL5 in both male and female patients with infantile spasms or early onset epilepsy of unknown cause, and to consider whether the breadth of the reported phenotype would be extended by studying a different patient group.
Two groups of patients were investigated for CDKL5 mutations. Group 1 comprised 73 patients (57 female, 16 male) referred to Cardiff for CDKL5 analysis, of whom 49 (42 female, 7 male) had epileptic seizure onset in the first six months of life. Group 2 comprised 26 patients (11 female, 15 male) with infantile spasms previously recruited to a clinical trial, the UK Infantile Spasms Study. Where a likely pathogenic mutation was identified, further clinical data were reviewed.
Seven likely pathogenic mutations were found among female patients from group 1 with epileptic seizure onset in the first six months of life, accounting for seven of the 42 in this group (17%). No mutations other than the already published mutation were found in female patients from group 2, or in any male patient from either study group. All patients with mutations had early signs of developmental delay and most had made little developmental progress. Further clinical information was available for six patients: autistic features and tactile hypersensitivity were common but only one had suggestive Rett‐like features. All had a severe epileptic seizure disorder, all but one of whom had myoclonic jerks. The EEG showed focal or generalised changes and in those with infantile spasms, hypsarrhythmia. Slow frequencies were seen frequently with a frontal or fronto‐temporal predominance and high amplitudes.
The spectrum of the epileptic seizure disorder, and associated EEG changes, in those with CDKL5 mutations is broader than previously reported. CDKL5 mutations are a significant cause of infantile spasms and early epileptic seizures in female patients, and of a later intractable seizure disorder, irrespective of whether they have suspected Rett syndrome. Analysis should be considered in these patients in the clinical setting.
PMCID: PMC2564572  PMID: 16611748
CDKL5 ; infantile spasms; epilepsy; Rett syndrome
6.  CDKL5, a novel MYCN-repressed gene, blocks cell cycle and promotes differentiation of neuronal cells 
Biochimica et Biophysica Acta  2012;1819(11-12):1173-1185.
Mutations in the CDKL5 (cyclin-dependent kinase-like 5) gene are associated with a severe epileptic encephalopathy (early infantile epileptic encephalopathy type 2, EIEE2) characterized by early-onset intractable seizures, infantile spasms, severe developmental delay, intellectual disability, and Rett syndrome (RTT)-like features. Despite the clear involvement of CDKL5 mutations in intellectual disability, the function of this protein during brain development and the molecular mechanisms involved in its regulation are still unknown. Using human neuroblastoma cells as a model system we found that an increase in CDKL5 expression caused an arrest of the cell cycle in the G0/G1 phases and induced cellular differentiation. Interestingly, CDKL5 expression was inhibited by MYCN, a transcription factor that promotes cell proliferation during brain development and plays a relevant role in neuroblastoma biology. Through a combination of different and complementary molecular and cellular approaches we could show that MYCN acts as a direct repressor of the CDKL5 promoter. Overall our findings unveil a functional axis between MYCN and CDKL5 governing both neuron proliferation rate and differentiation. The fact that CDKL5 is involved in the control of both neuron proliferation and differentiation may help understand the early appearance of neurological symptoms in patients with mutations in CDKL5.
► CDKL5 enhances neuronal differentiation. ► CDKL5 arrests cell cycle of neuronal precursor cells. ► MYCN directly represses transcription of CDKL5. ► These results may help explain the neurological symptoms of RTT patients.
PMCID: PMC3787793  PMID: 22921766
Rett's syndrome; CDKL5; MYCN; Neurogenesis; Differentiation
7.  Extrasynaptic N-Methyl-d-aspartate (NMDA) Receptor Stimulation Induces Cytoplasmic Translocation of the CDKL5 Kinase and Its Proteasomal Degradation* 
The Journal of Biological Chemistry  2011;286(42):36550-36558.
Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) have been found in patients with epileptic encephalopathy characterized by early onset intractable epilepsy, including infantile spasms and other types of seizures, severe developmental delay, and often the development of Rett syndrome-like features. Despite its clear involvement in proper brain development, CDKL5 functions are still far from being understood. In this study, we analyzed the subcellular localization of the endogenous kinase in primary murine hippocampal neurons. CDKL5 was localized both in nucleus and cytoplasm and, conversely to proliferating cells, did not undergo constitutive shuttling between these compartments. Nevertheless, glutamate stimulation was able to induce the exit of the kinase from the nucleus and its subsequent accumulation in the perinuclear cytoplasm. Moreover, we found that sustained glutamate stimulation promoted CDKL5 proteasomal degradation. Both events were mediated by the specific activation of extrasynaptic pool of N-methyl-d-aspartate receptors. Proteasomal degradation was also induced by withdrawal of neurotrophic factors and hydrogen peroxide treatment, two different paradigms of cell death. Altogether, our results indicate that both subcellular localization and expression of CDKL5 are modulated by the activation of extrasynaptic N-methyl-d-aspartate receptors and suggest regulation of CDKL5 by cell death pathways.
PMCID: PMC3196071  PMID: 21832092
Glutamate; Glutamate Receptors Ionotropic (AMPA and NMDA); Neurological Diseases; Neurons; Protein Degradation; Protein Translocation; Serine Threonine Protein Kinase; CDKL5; Excitotoxicity
8.  Loss of CDKL5 impairs survival and dendritic growth of newborn neurons by altering AKT/GSK-3β signaling 
Neurobiology of Disease  2014;70(100):53-68.
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in a neurodevelopmental disorder characterized by early-onset intractable seizures, severe developmental delay, intellectual disability, and Rett's syndrome-like features. Since the physiological functions of CDKL5 still need to be elucidated, in the current study we took advantage of a new Cdkl5 knockout (KO) mouse model in order to shed light on the role of this gene in brain development. We mainly focused on the hippocampal dentate gyrus, a region that largely develops postnatally and plays a key role in learning and memory. Looking at the process of neurogenesis, we found a higher proliferation rate of neural precursors in Cdkl5 KO mice in comparison with wild type mice. However, there was an increase in apoptotic cell death of postmitotic granule neuron precursors, with a reduction in total number of granule cells. Looking at dendritic development, we found that in Cdkl5 KO mice the newly-generated granule cells exhibited a severe dendritic hypotrophy. In parallel, these neurodevelopmental defects were associated with impairment of hippocampus-dependent memory. Looking at the mechanisms whereby CDKL5 exerts its functions, we identified a central role of the AKT/GSK-3β signaling pathway. Overall our findings highlight a critical role of CDKL5 in the fundamental processes of brain development, namely neuronal precursor proliferation, survival and maturation. This evidence lays the basis for a better understanding of the neurological phenotype in patients carrying mutations in the CDKL5 gene.
•Loss of Cdkl5 decreases survival of postmitotic granule cells.•Loss of Cdkl5 results in dendritic hypotrophy of newborn granule cells.•Loss of Cdkl5 impairs hippocampus-dependent behavior.•Loss of Cdkl5 alters the AKT/GSK-3β pathway.
PMCID: PMC4146476  PMID: 24952363
CDKL5 disorder; Rett's syndrome; Neurodevelopmental disorders; Neurogenesis impairment; Dendritic development; AKT/GSK-3β signaling
9.  iPS cells to model CDKL5-related disorders 
Rett syndrome is a progressive neurologic disorder representing one of the most common causes of mental retardation in females. To date mutations in 3 genes have been associated with this condition. Classic Rett syndrome is caused by mutations in the MECP2 gene, while variants can be due to mutations in either MECP2 or FOXG1 or CDKL5. Mutations in CDKL5 have been identified both in females with the early onset seizure variant of Rett syndrome and in males with X-linked epileptic encephalopathy. CDKL5 is a kinase protein highly expressed in neurons, but its exact function inside the cell is unknown. To address this issue we established a human cellular model for CDKL5-related disease using the recently developed technology of induced pluripotent stem cells (iPSCs). iPSCs can be expanded indefinitely and differentiated in vitro into many different cell types, including neurons. These features make them the ideal tool to study disease mechanisms directly on the primarily affected neuronal cells. We derived iPSCs from fibroblasts of one female with p.Q347X and one male with p.T288I mutation, affected by early onset seizure variant and X-linked epileptic encephalopathy, respectively. We demonstrated that female CDKL5-mutated iPSCs maintain X-chromosome inactivation and clones express either the mutant CDKL5 allele or the wild type allele, that serve as an ideal experimental control. Array CGH indicates normal isogenic molecular karyotypes without detection of de novo CNVs in the CDKL5-mutated iPSCs. Furthermore, the iPS cells can be differentiated into neurons and are thus suitable to model disease pathogenesis in vitro.
PMCID: PMC3218106  PMID: 21750574
CDKL5; Rett syndrome; induced Pluripotent Stem cells (iPSC); disease modelling
10.  iPS cells to model CDKL5-related disorders 
European Journal of Human Genetics  2011;19(12):1246-1255.
Rett syndrome (RTT) is a progressive neurologic disorder representing one of the most common causes of mental retardation in females. To date mutations in three genes have been associated with this condition. Classic RTT is caused by mutations in the MECP2 gene, whereas variants can be due to mutations in either MECP2 or FOXG1 or CDKL5. Mutations in CDKL5 have been identified both in females with the early onset seizure variant of RTT and in males with X-linked epileptic encephalopathy. CDKL5 is a kinase protein highly expressed in neurons, but its exact function inside the cell is unknown. To address this issue we established a human cellular model for CDKL5-related disease using the recently developed technology of induced pluripotent stem cells (iPSCs). iPSCs can be expanded indefinitely and differentiated in vitro into many different cell types, including neurons. These features make them the ideal tool to study disease mechanisms directly on the primarily affected neuronal cells. We derived iPSCs from fibroblasts of one female with p.Q347X and one male with p.T288I mutation, affected by early onset seizure variant and X-linked epileptic encephalopathy, respectively. We demonstrated that female CDKL5-mutated iPSCs maintain X-chromosome inactivation and clones express either the mutant CDKL5 allele or the wild-type allele that serve as an ideal experimental control. Array CGH indicates normal isogenic molecular karyotypes without detection of de novo CNVs in the CDKL5-mutated iPSCs. Furthermore, the iPS cells can be differentiated into neurons and are thus suitable to model disease pathogenesis in vitro.
PMCID: PMC3218106  PMID: 21750574
CDKL5; Rett syndrome; induced pluripotent stem cells (iPSC); disease modelling
11.  Analysis of FOXG1 Is Highly Recommended in Male and Female Patients with Rett Syndrome 
Molecular Syndromology  2011;1(6):290-293.
We screened a cohort of 5 male and 20 female patients with a Rett spectrum disorder for mutations in the coding region of FOXG1, previously shown to cause the congenital variant of Rett syndrome. Two de novo mutations were identified. The first was a novel missense mutation, p.Ala193Thr (c.577G>A), in a male patient with congenital Rett syndrome, and the second was the p.Glu154GlyfsX301 (c.460dupG) truncating mutation in a female with classical Rett syndrome, a mutation that was previously reported in an independent patient. The overall rate of FOXG1 mutations in our cohort is 8%. Our findings stress the importance of FOXG1 analysis in male patients with Rett syndrome and in female patients when mutations in the MECP2 and CDKL5 genes have been excluded.
PMCID: PMC3214958  PMID: 22190898
Congenital variant; FOXG1 gene; Male patient; Rett syndrome
12.  What We Know and Would Like to Know about CDKL5 and Its Involvement in Epileptic Encephalopathy 
Neural Plasticity  2012;2012:728267.
In the last few years, the X-linked serine/threonine kinase cyclin-dependent kinase-like 5 (CDKL5) has been associated with early-onset epileptic encephalopathies characterized by the manifestation of intractable epilepsy within the first weeks of life, severe developmental delay, profound hypotonia, and often the presence of some Rett-syndrome-like features. The association of CDKL5 with neurodevelopmental disorders and its high expression levels in the maturing brain underscore the importance of this kinase for proper brain development. However, our present knowledge of CDKL5 functions is still rather limited. The picture that emerges from the molecular and cellular studies suggests that CDKL5 functions are important for regulating both neuronal morphology through cytoplasmic signaling pathways and activity-dependent gene expression in the nuclear compartment. This paper surveys the current state of CDKL5 research with emphasis on the clinical symptoms associated with mutations in CDKL5, the different mechanisms regulating its functions, and the connected molecular pathways. Finally, based on the available data we speculate that CDKL5 might play a role in neuronal plasticity and we adduce and discuss some possible arguments supporting this hypothesis.
PMCID: PMC3385648  PMID: 22779007
13.  GluD1 is a common altered player in neuronal differentiation from both MECP2-mutated and CDKL5-mutated iPS 
Rett syndrome is a monogenic disease due to de novo mutations in either MECP2 or CDKL5 genes. In spite of their involvement in the same disease, a functional interaction between the two genes has not been proven. MeCP2 is a transcriptional regulator; CDKL5 encodes for a kinase protein that might be involved in the regulation of gene expression. Therefore, we hypothesized that mutations affecting the two genes may lead to similar phenotypes by dys-regulating the expression of common genes. To test this hypothesis we used induced pluripotent stem (iPS) cells derived from fibroblasts of one Rett patient with a MECP2 mutation (p.Arg306C) and 2 patients with mutations in CDKL5 (p.Gln347Ter and p.Thr288Ile). Expression profiling was performed in CDKL5-mutated cells and genes of interest were confirmed by real-time RT-PCR in both CDKL5 and MECP2 mutated cells. The only major change in gene expression common to MECP2-and CDKL5-mutated cells was for GRID1, encoding for glutamate D1 receptor (GluD1), a member of the delta family of ionotropic glutamate receptors. GluD1 does not form AMPA or NMDA - glutamate receptors. It acts like an adhesion molecule by linking the postsynaptic and presynaptic compartments, preferentially inducing the inhibitory presynaptic differentiation of cortical neurons. Our results demonstrate that GRID1 expression is down-regulated in both MECP2 and CDKL5-mutated iPS cells and up-regulated in neuronal precursors and mature neurons. These data provide novel insights into disease pathophysiology and identify possible new targets for therapeutic treatment of Rett syndrome.
PMCID: PMC4172451  PMID: 24916645
Rett syndrome; IPSCs; GRID1
14.  14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype 
Rett syndrome is a clinically defined neurodevelopmental disorder almost exclusively affecting females. Usually sporadic, Rett syndrome is caused by mutations in the X-linked MECP2 gene in ∼90–95% of classic cases and 40–60% of individuals with atypical Rett syndrome. Mutations in the CDKL5 gene have been associated with the early-onset seizure variant of Rett syndrome and mutations in FOXG1 have been associated with the congenital Rett syndrome variant. We report the clinical features and array CGH findings of three atypical Rett syndrome patients who had severe intellectual impairment, early-onset developmental delay, postnatal microcephaly and hypotonia. In addition, the females had a seizure disorder, agenesis of the corpus callosum and subtle dysmorphism. All three were found to have an interstitial deletion of 14q12. The deleted region in common included the PRKD1 gene but not the FOXG1 gene. Gene expression analysis suggested a decrease in FOXG1 levels in two of the patients. Screening of 32 atypical Rett syndrome patients did not identify any pathogenic mutations in the PRKD1 gene, although a previously reported frameshift mutation affecting FOXG1 (c.256dupC, p.Gln86ProfsX35) was identified in a patient with the congenital Rett syndrome variant. There is phenotypic overlap between congenital Rett syndrome variants with FOXG1 mutations and the clinical presentation of our three patients with this 14q12 microdeletion, not encompassing the FOXG1 gene. We propose that the primary defect in these patients is misregulation of the FOXG1 gene rather than a primary abnormality of PRKD1.
PMCID: PMC3641384  PMID: 22968132
rett syndrome; FOXG1; chromosome 14; 14q deletion; array-based comparative genomic hybridisation; PRKD1
15.  NTNG1 Mutations are a Rare Cause of Rett Syndrome 
A translocation that disrupted the Netrin G1 gene (NTNG1) was recently reported in a patient with the early seizure variant of Rett syndrome (RTT). The netrin G1 protein (NTNG1) has an important role in the developing central nervous system, particularly in axonal guidance, signalling and NMDA receptor function and was a good candidate gene for RTT. We recruited 115 patients with RTT (females: 25 classic and 84 atypical; 6 males) but no mutation in the MECP2 gene. For those 52 patients with epileptic seizure onset in the first six months of life, CDKL5 mutations were also excluded. We aimed to determine whether mutations in NTNG1 accounted for a significant subset of patients with RTT, particularly those with the early onset seizure variant and other atypical presentations. We sequenced the nine coding exons of NTNG1 and identified four sequence variants, none of which were likely to be pathogenic. Mutations in the NTNG1 gene appear to be a rare cause of RTT but NTNG1 function demands further investigation in relation to the central nervous system pathophysiology of the disorder.
PMCID: PMC2577736  PMID: 16502428
Rett syndrome; Netrin G1; Autism; NMDA receptor
16.  De novo SCN1A mutations in migrating partial seizures of infancy 
Neurology  2011;77(4):380-383.
To determine the genetic etiology of the severe early infantile onset syndrome of malignant migrating partial seizures of infancy (MPSI).
Fifteen unrelated children with MPSI were screened for mutations in genes associated with infantile epileptic encephalopathies: SCN1A, CDKL5, STXBP1, PCDH19, and POLG. Microarray studies were performed to identify copy number variations.
One patient had a de novo SCN1A missense mutation p.R862G that affects the voltage sensor segment of SCN1A. A second patient had a de novo 11.06 Mb deletion of chromosome 2q24.2q31.1 encompassing more than 40 genes that included SCN1A. Screening of CDKL5 (13/15 patients), STXBP1 (13/15), PCDH19 (9/11 females), and the 3 common European mutations of POLG (11/15) was negative. Pathogenic copy number variations were not detected in 11/12 cases.
Epilepsies associated with SCN1A mutations range in severity from febrile seizures to severe epileptic encephalopathies including Dravet syndrome and severe infantile multifocal epilepsy. MPSI is now the most severe SCN1A phenotype described to date. While not a common cause of MPSI, SCN1A screening should now be considered in patients with this devastating epileptic encephalopathy.
PMCID: PMC3140798  PMID: 21753172
17.  Rett syndrome: clinical review and genetic update 
Journal of Medical Genetics  2005;42(1):1-7.
Rett syndrome (RS) is a severe neurodevelopmental disorder that contributes significantly to severe intellectual disability in females worldwide. It is caused by mutations in MECP2 in the majority of cases, but a proportion of atypical cases may result from mutations in CDKL5, particularly the early onset seizure variant. The relationship between MECP2 and CDKL5, and whether they cause RS through the same or different mechanisms is unknown, but is worthy of investigation. Mutations in MECP2 appear to give a growth disadvantage to both neuronal and lymphoblast cells, often resulting in skewing of X inactivation that may contribute to the large degree of phenotypic variation. MeCP2 was originally thought to be a global transcriptional repressor, but recent evidence suggests that it may have a role in regulating neuronal activity dependent expression of specific genes such as Hairy2a in Xenopus and Bdnf in mouse and rat.
PMCID: PMC1735910  PMID: 15635068
18.  Mapping Pathological Phenotypes in a Mouse Model of CDKL5 Disorder 
PLoS ONE  2014;9(5):e91613.
Mutations in cyclin-dependent kinase-like 5 (CDKL5) cause early-onset epileptic encephalopathy, a neurodevelopmental disorder with similarities to Rett Syndrome. Here we describe the physiological, molecular, and behavioral phenotyping of a Cdkl5 conditional knockout mouse model of CDKL5 disorder. Behavioral analysis of constitutive Cdkl5 knockout mice revealed key features of the human disorder, including limb clasping, hypoactivity, and abnormal eye tracking. Anatomical, physiological, and molecular analysis of the knockout uncovered potential pathological substrates of the disorder, including reduced dendritic arborization of cortical neurons, abnormal electroencephalograph (EEG) responses to convulsant treatment, decreased visual evoked responses (VEPs), and alterations in the Akt/rpS6 signaling pathway. Selective knockout of Cdkl5 in excitatory and inhibitory forebrain neurons allowed us to map the behavioral features of the disorder to separable cell-types. These findings identify physiological and molecular deficits in specific forebrain neuron populations as possible pathological substrates in CDKL5 disorder.
PMCID: PMC4023934  PMID: 24838000
19.  Two female siblings with West syndrome: Familial idiopathic West syndrome with genetic susceptibility and variable phenotypic expression 
The West syndrome (WS) is a characteristic form of epilepsy which usually begins in the first year of life. We describe two female siblings, aged 4 and 2 years, respectively, born from third degree consanguineous parents, with infantile spasms and developmental delay. Epileptic spasms had not a good outcome under antiepileptic drug treatment. Clinical and imaging features were of different severity in both siblings. Routine biochemical tests, metabolic investigations, and chromosomal analysis were normal. We analyzed CDKL5 gene by direct sequences and denaturing high-performance liquid chromatography using Transgenomic WAVE system. Analysis of the CDKL5 gene, which is responsible for female patient with WS, did not show any disease-causing mutation. WS has heterogeneous backgrounds, and may be more than one gene is responsible for its familial forms. In this family, consanguinity is observed in parents, which usually suggests that autosomal recessive inheritance is likely.
PMCID: PMC3087996  PMID: 21559165
Genetics; West syndrome; CDKL5 gene; new genes
20.  CDKL5 and ARX mutations in males with early-onset epilepsy 
Pediatric neurology  2013;48(5):367-377.
Mutations in CDKL5 and ARX are known causes of early-onset epilepsy and severe developmental delay in males and females. While numerous males with ARX mutations associated with various phenotypes have been reported in the literature, the majority of CDKL5 mutations have been identified in females with a phenotype characterized by early-onset epilepsy, severe global developmental delay, absent speech, and stereotypic hand movements. To date, only ten males with CDKL5 mutations have been reported. Our retrospective study reports on the clinical, neuroimaging and molecular findings of 18 males with early-onset epilepsy caused by either CDKL5 or ARX mutations. The 18 patients include eight new males with CDKL5 mutations and ten with ARX mutations identified through sequence analysis of 266 and 346 males, respectively, at our molecular diagnostic laboratory. Our large data set therefore expands on the number of reported males with CDKL5 mutations and highlights that aberrations of CDKL5 and ARX combined are an important consideration in the genetic forms of early-onset epilepsy.
PMCID: PMC3742321  PMID: 23583054
21.  Analysis of Mutations in 7 Genes Associated with Neuronal Excitability and Synaptic Transmission in a Cohort of Children with Non-Syndromic Infantile Epileptic Encephalopathy 
PLoS ONE  2015;10(5):e0126446.
Epileptic Encephalopathy (EE) is a heterogeneous condition in which cognitive, sensory and/or motor functions deteriorate as a consequence of epileptic activity, which consists of frequent seizures and/or major interictal paroxysmal activity. There are various causes of EE and they may occur at any age in early childhood. Genetic mutations have been identified to contribute to an increasing number of children with early onset EE which had been previously considered as cryptogenic. We identified 26 patients with Infantile Epileptic Encephalopathy (IEE) of unknown etiology despite extensive workup and without any specific epilepsy syndromic phenotypes. We performed genetic analysis on a panel of 7 genes (ARX, CDKL5, KCNQ2, PCDH19, SCN1A, SCN2A, STXBP1) and identified 10 point mutations [ARX (1), CDKL5 (3), KCNQ2 (2), PCDH19 (1), SCN1A (1), STXBP1 (2)] as well as one microdeletion involving both SCN1A and SCN2A. The high rate (42%) of mutations suggested that genetic testing of this IEE panel of genes is recommended for cryptogenic IEE with no etiology identified. These 7 genes are associated with channelopathies or synaptic transmission and we recommend early genetic testing if possible to guide the treatment strategy.
PMCID: PMC4423861  PMID: 25951140
22.  Adult Phenotypes in Angelman- and Rett-Like Syndromes 
Molecular Syndromology  2012;2(3-5):217-234.
Angelman- and Rett-like syndromes share a range of clinical characteristics, including intellectual disability (ID) with or without regression, epilepsy, infantile encephalopathy, postnatal microcephaly, features of autism spectrum disorder, and variable other neurological symptoms. The phenotypic spectrum generally has been well studied in children; however, evolution of the phenotypic spectrum into adulthood has been documented less extensively. To obtain more insight into natural course and prognosis of these syndromes with respect to developmental, medical, and socio-behavioral outcomes, we studied the phenotypes of 9 adult patients who were recently diagnosed with 6 different Angelman- and Rett-like syndromes.
All these patients were ascertained during an ongoing cohort study involving a systematic clinical genetic diagnostic evaluation of over 250, mainly adult patients with ID of unknown etiology.
We describe the evolution of the phenotype in adults with EHMT1, TCF4, MECP2, CDKL5, and SCN1A mutations and 22qter deletions and also provide an overview of previously published adult cases with similar diagnoses.
These data are highly valuable in adequate management and follow-up of patients with Angelman- and Rett-like syndromes and accurate counseling of their family members. Furthermore, they will contribute to recognition of these syndromes in previously undiagnosed adult patients.
PMCID: PMC3366698  PMID: 22670143
Adult phenotypes; Angelman- and Rett-like syndromes; CDKL5; Dravet syndrome; Kleefstra syndrome; Male MECP2; Phelan-McDermid syndrome; Pitt Hopkins syndrome
23.  Variation in Novel Exons (RACEfrags) of the MECP2 Gene in Rett Syndrome Patients and Controls 
Human mutation  2009;30(9):E866-E879.
The study of transcription using genomic tiling arrays has lead to the identification of numerous additional exons. One example is the MECP2 gene on the X chromosome; using 5’RACE and RT-PCR in human tissues and cell lines, we have found more than 70 novel exons (RACEfrags) connecting to at least one annotated exon.. We sequenced all MECP2-connected exons and flanking sequences in 3 groups: 46 patients with the Rett syndrome and without mutations in the currently annotated exons of the MECP2 and CDKL5 genes; 32 patients with the Rett syndrome and identified mutations in the MECP2 gene; 100 control individuals from the same geoethnic group. Approximately 13kb were sequenced per sample, (2.4Mb of DNA resequencing). A total of 75 individuals had novel rare variants (mostly private variants) but no statistically significant difference was found among the 3 groups. These results suggest that variants in the newly discovered exons may not contribute to Rett syndrome. Interestingly however, there are about twice more variants in the novel exons than in the flanking sequences (44 vs. 21 for approximately 1.3 Mb sequenced for each class of sequences, p = 0.0025). Thus the evolutionary forces that shape these novel exons may be different than those of neighboring sequences.
PMCID: PMC3708316  PMID: 19562714
MECP2; Rett syndrome; RACEfrags; SNP; rare variants; positive selection
24.  The MEF2C-Related and 5q14.3q15 Microdeletion Syndrome 
Molecular Syndromology  2012;2(3-5):164-170.
Disorders related to the autosomal transcription factor MEF2C located in 5q14.3 were first described in 2009 and have since evolved to one of the more common microdeletion syndromes. Mutational screening in a larger cohort revealed heterozygous de novo mutations of MEF2C in about 1% of patients with moderate to severe intellectual disability, and the phenotype is similar in patients with intragenic deletions and multigenic microdeletions. Clinically, MEF2C-related disorders are characterized by severe intellectual disability with absent speech and limited walking abilities, hypotonia, seizures, and a variety of minor brain anomalies. The majority of patients show a similar facial gestalt with broad forehead, flat nasal bridge, hypotonic mouth, and small chin, as well as strabismus, but this phenotype is clinically not well recognized. The course of the disease is generally quite uniform, but patients with point mutations and smaller deletions seem to have a higher chance of walking skills and a lower risk of refractory seizures. Patients in whom the microdeletion also includes the RASA1 gene show features of the respective capillary and arterio-venous malformations and fistula syndrome. The phenotypic overlap with Rett syndrome is explained by a shared pathway and, accordingly, diminished MECP2 and CDKL5 expression is measureable in patients with MEF2C defects. Further research of this pathway may therefore eventually lead to a common therapeutic target.
PMCID: PMC3366707  PMID: 22670137
MEF2C; Microdeletion 5q14; Rett syndrome-like; Seizures; Severe intellectual disability; Severe mental retardation
25.  Immune Dysfunction in Rett Syndrome Patients Revealed by High Levels of Serum Anti-N(Glc) IgM Antibody Fraction 
Journal of Immunology Research  2014;2014:260973.
Rett syndrome (RTT), a neurodevelopmental disorder affecting exclusively (99%) female infants, is associated with loss-of-function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2) and, more rarely, cyclin-dependent kinase-like 5 (CDKL5) and forkhead box protein G1 (FOXG1). In this study, we aimed to evaluate the function of the immune system by measuring serum immunoglobulins (IgG and IgM) in RTT patients (n = 53) and, by comparison, in age-matched children affected by non-RTT pervasive developmental disorders (non-RTT PDD) (n = 82) and healthy age-matched controls (n = 29). To determine immunoglobulins we used both a conventional agglutination assay and a novel ELISA based on antibody recognition by a surrogate antigen probe, CSF114(Glc), a synthetic N-glucosylated peptide. Both assays provided evidence for an increase in IgM titer, but not in IgG, in RTT patients relative to both healthy controls and non-RTT PDD patients. The significant difference in IgM titers between RTT patients and healthy subjects in the CSF114(Glc) assay (P = 0.001) suggests that this procedure specifically detects a fraction of IgM antibodies likely to be relevant for the RTT disease. These findings offer a new insight into the mechanism underlying the Rett disease as they unveil the possible involvement of the immune system in this pathology.
PMCID: PMC4214166  PMID: 25389532

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