<%server.execute "isdev.asp"%> Neurobehavioral phenotype in cyclin-dependent kinase-like 5 syndrome: Case report and review of literature Posar A, Faggioli R, Visconti P - J Pediatr Neurosci
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Year : 2015  |  Volume : 10  |  Issue : 3  |  Page : 258-260

Neurobehavioral phenotype in cyclin-dependent kinase-like 5 syndrome: Case report and review of literature

1 Child Neurology and Psychiatry Unit, IRCCS Institute of Neurological Sciences of Bologna; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
2 Department of Pediatrics, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
3 Child Neurology and Psychiatry Unit, IRCCS Institute of Neurological Sciences of Bologna, Bologna, Italy

Date of Web Publication18-Sep-2015

Correspondence Address:
Annio Posar
Child Neurology and Psychiatry Unit, Department of Biomedical and Neuromotor Sciences, University of Bologna, IRCCS Institute of Neurological Sciences of Bologna, Via Altura 3, 40139 Bologna
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1817-1745.165685

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The phenotype of cyclin-dependent kinase-like 5 (CDKL5) syndrome includes Rett syndrome variant with early onset seizures, early onset epileptic encephalopathy; and severe developmental delay. Autistic features have often been reported in literature, but detailed reports of the behavior of these individuals are lacking. We describe the clinical picture of a girl aged 15 years 9 months affected by CDKL5 syndrome, with special attention to the neurobehavioral phenotype. The evaluation showed, apart from a profound intellectual disability, the presence of atypical features of behavior, mainly in relating to people, in imitation, and in verbal and nonverbal communication, thus justifying the diagnosis of comorbid autism spectrum disorder. A formal assessment of the behavior, through appropriate tools, is necessary to choose the most appropriate rehabilitative intervention and to characterize in more detail the CDKL5 syndrome phenotype. We propose a testing protocol for the neurobehavioral assessment of these patients.

Keywords: Autism, cyclin-dependent kinase-like 5, intellectual disability, neurobehavioral phenotype

How to cite this article:
Posar A, Faggioli R, Visconti P. Neurobehavioral phenotype in cyclin-dependent kinase-like 5 syndrome: Case report and review of literature. J Pediatr Neurosci 2015;10:258-60

How to cite this URL:
Posar A, Faggioli R, Visconti P. Neurobehavioral phenotype in cyclin-dependent kinase-like 5 syndrome: Case report and review of literature. J Pediatr Neurosci [serial online] 2015 [cited 2023 Jan 30];10:258-60. Available from: https://www.pediatricneurosciences.com/text.asp?2015/10/3/258/165685

   Introduction Top

Mutations of cyclin-dependent kinase-like 5 (CDKL5) gene, located on the short arm of X chromosome, have been found in individuals with: Rett syndrome variant with early onset seizures, described by Hanefeld in 1985; early onset epileptic encephalopathy; severe developmental delay. [1],[2],[3] Within the phenotypic spectrum of CDKL5 gene alterations, male cases tend to be more impaired. [3],[4] Autistic features (stereotypies, eye contact deficit, and reduced social interaction) have been reported by many authors, [1],[2],[3],[4],[5],[6],[7],[8],[9],[10] but detailed reports specifically addressing the neurobehavioral phenotype are lacking.

We describe a girl affected by CDKL5 syndrome, with special attention to the neurobehavioral phenotype.

   Case Report Top

The patient's family history was negative for neuropsychiatric disorders. The mother had one spontaneous abortion. Pre-, peri-, and neonatal periods were normal. Weight growth was mildly impaired (3 rd to 10 th percentile) while height growth was normal. A mild, global delay of psychomotor development was present from the beginning, but, after the onset of epilepsy at the age of 7 months, a regression has been detected and over time poor participation and interest in the environment became evident. The girl started to walk without support at 2 years of age and never developed speech. She had drug-resistant seizures occurring more than once a day: generalized tonic-clonic, myoclonic, and spasms in flexion. The following genetic and neurometabolic investigations were negative: CGH-array, molecular analysis of SCN1A and MECP2 genes, sialotransferrin isoelectric focusing, dosage of ammonia, lactic acid, plasmatic amino acids, urinary organic acids, and acilcarnitine. Molecular analysis of CDKL5 gene revealed a nucleotide deletion mutation in the exon 12 (c. 1853-1854delC), absent in the parents. Brain magnetic resonance imaging was normal. At our observation (15 years 9 months), she was on phenobarbital and levetiracetam: seizures persisted and were frequent. Neurological examination showed: absent speech, bilateral alternating strabismus, hypotonia, bruxism, wide-based "robot-like" gait, joint laxity, and muscle hypotrophy. Electroencephalogram showed diffuse alterations of electrogenesis and frequent, diffuse paroxysmal abnormalities in both hemispheres prevailing in the fronto-temporal regions.

Neurobehavioral assessment

The administration of a standardized test to measure the intelligence quotient was impossible, mainly due to lack of cooperation and understanding of the verbal message. Vineland scales, designed to assess adaptive behavior, showed a profound impairment, with scores corresponding to an age <18 months in all four domains explored: communication; daily living skills; socialization; and motor skills. According to Diagnostic and Statistical Manual of Mental Disorders-5 th edition (DSM-5) criteria, [11] the degree of intellectual disability has been judged as profound. International Scoring System (ISS) [12] is a tool aimed at evaluating the features usually associated with the Rett syndrome phenotypes (classic or variant). ISS includes 20 items that assess the following areas: growth and development; musculo-skeletal system; movement; cortical functioning; brainstem and autonomic functioning. Item scores range from 0 (no abnormality) to 2 (severe abnormality), with an intermediate possibility = 1 (mild severity). The ISS score of our patient was 15, compatible with a level of mild-moderate severity. Unstructured observation of behavior showed: inconstant eye contact; absence of joint attention; absence of both declarative and imperative pointing; very poor social initiative, despite the acceptance of the interaction initiated by others; inadequate response to verbal call; absent speech, uttering of not finalized vocalizations; lack of purposeful use of the hands; stereotypies such as hand-mouthing; breathing irregularities such as apneas alternating with hyperventilation; very restricted and repetitive interests and activities, such as opening and closing the doors iteratively. Childhood Autism Rating Scale, Second Edition - Standard Version (CARS2-ST) is a 15-item rating scale aimed at identifying children with autism spectrum disorder and evaluating symptom severity by attributing to each item a score from a minimum = 1 (normotypic) to a maximum = 4 (the most atypical). CARS2-ST showed a total score = 36/60, higher than the cut-off (= 35) for the presence of severe signs of autism spectrum disorder. The most impaired CARS2-ST items (such as those with a score of at least 3) were: relating to people; imitation; verbal communication; and nonverbal communication [Table 1].
Table 1: Profile of the scores (from 1 = normotypic to 4 = the most atypical) of the 15 categories of signs included in the Childhood Autism Rating Scale, Second Edition – Standard Version, when our patient was 15 years and 9 months old

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In conclusion, the data from the neurobehavioral assessment showed a profound intellectual disability and a comorbid autism spectrum disorder according to DSM-5 criteria. [11]

   Discussion Top

Literature data suggest some heterogeneity of the neurobehavioral phenotype in individuals with CDKL5 gene alterations, but detailed reports regarding this topic are lacking. In fact, there are other aspects of the phenotype of this syndrome, particularly the early onset severe epilepsy with impairment of developmental skills, which have so far been more frequently described. [13] In our view, there is a risk of overshadowing the clinical features of the CDKL5 syndrome related to the behavior, thus losing an opportunity to find a correlation between a well-defined genetic disorder and the associated phenotype, as well as suggestions for tailored treatment strategies. In the description of our case with CDKL5 syndrome, we specifically intended to focus on the characteristics of behavior.

The neurodevelopment of our patient was not only very poor but also atypical. In fact, there were significant pathological features of behavior, mainly in relating to people, in imitation, and in verbal and nonverbal communication, thus justifying the diagnosis of autism spectrum disorder comorbid with the intellectual disability. These features should be considered for a detailed clinical characterization as well as for a better development of rehabilitation programs for patients. With this aim, we emphasize the usefulness of a systematic study of cases with CDKL5 gene alterations, through a formal evaluation, in order to assess behavior phenotype at onset and during the follow-up, and monitoring intervention effects. We consider it necessary to set up a neurobehavioral protocol, involving the use of at least the following tools: CARS2-ST, Vineland scales, ISS and, whenever possible, a scale of intelligence (Wechsler or Leiter, as appropriate), even if this is often unfeasible due to the severity of intellectual disability. Indeed, the Autism Diagnostic Observation Schedule, Second Edition would be the most suitable tool for a formal autism diagnosis, but most of the times it cannot be used because it requires the presence of motor, in particular manual, skills which are very often lacking in these patients.

   Conclusion Top

CDKL5 syndrome constitutes a well-studied genetic nosographic entity. In our opinion, it requires an in-depth analysis of the phenotype through a systematic study of the behavior, which should be carried out using reliable assessment tools in order to acquire data and suggestions to set up rehabilitation programs and to monitor outcomes.


The authors would like to thank Cecilia Baroncini for linguistic support.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Tao J, Van Esch H, Hagedorn-Greiwe M, Hoffmann K, Moser B, Raynaud M, et al. Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation. Am J Hum Genet 2004;75:1149-54.  Back to cited text no. 1
Evans JC, Archer HL, Colley JP, Ravn K, Nielsen JB, Kerr A, et al. Early onset seizures and Rett-like features associated with mutations in CDKL5. Eur J Hum Genet 2005;13:1113-20.  Back to cited text no. 2
Guerrini R, Parrini E. Epilepsy in Rett syndrome, and CDKL5- and FOXG1-gene-related encephalopathies. Epilepsia 2012;53:2067-78.  Back to cited text no. 3
Fehr S, Wilson M, Downs J, Williams S, Murgia A, Sartori S, et al. The CDKL5 disorder is an independent clinical entity associated with early-onset encephalopathy. Eur J Hum Genet 2013;21:266-73.  Back to cited text no. 4
Weaving LS, Christodoulou J, Williamson SL, Friend KL, McKenzie OL, Archer H, et al. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet 2004;75:1079-93.  Back to cited text no. 5
Archer HL, Evans J, Edwards S, Colley J, Newbury-Ecob R, O′Callaghan F, et al. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients. J Med Genet 2006;43:729-34.  Back to cited text no. 6
Bahi-Buisson N, Nectoux J, Rosas-Vargas H, Milh M, Boddaert N, Girard B, et al. Key clinical features to identify girls with CDKL5 mutations. Brain 2008;131(Pt 10):2647-61.  Back to cited text no. 7
Artuso R, Mencarelli MA, Polli R, Sartori S, Ariani F, Pollazzon M, et al. Early-onset seizure variant of Rett syndrome: Definition of the clinical diagnostic criteria. Brain Dev 2010;32:17-24.  Back to cited text no. 8
Pini G, Bigoni S, Engerström IW, Calabrese O, Felloni B, Scusa MF, et al. Variant of Rett syndrome and CDKL5 gene: Clinical and autonomic description of 10 cases. Neuropediatrics 2012;43:37-43.  Back to cited text no. 9
Zhao Y, Zhang X, Bao X, Zhang Q, Zhang J, Cao G, et al. Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients. BMC Med Genet 2014;15:24.  Back to cited text no. 10
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5 th Edition (DSM-5). Washington, DC: American Psychiatric Association; 2013.  Back to cited text no. 11
Kerr AM, Nomura Y, Armstrong D, Anvret M, Belichenko PV, Budden S, et al. Guidelines for reporting clinical features in cases with MECP2 mutations. Brain Dev 2001;23:208-11.  Back to cited text no. 12
Melani F, Mei D, Pisano T, Savasta S, Franzoni E, Ferrari AR, et al. CDKL5 gene-related epileptic encephalopathy: Electroclinical findings in the first year of life. Dev Med Child Neurol 2011;53:354-60.  Back to cited text no. 13


  [Table 1]

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