Elsevier

Pediatric Neurology

Volume 97, August 2019, Pages 18-25
Pediatric Neurology

Topical Review
Cyclin-Dependent Kinase-Like 5 Deficiency Disorder: Clinical Review

https://doi.org/10.1016/j.pediatrneurol.2019.02.015Get rights and content

Abstract

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a developmental encephalopathy caused by pathogenic variants in the gene CDKL5. This unique disorder includes early infantile onset refractory epilepsy, hypotonia, developmental intellectual and motor disabilities, and cortical visual impairment. We review the clinical presentations and genetic variations in CDD based on a systematic literature review and experience in the CDKL5 Centers of Excellence. We propose minimum diagnostic criteria. Pathogenic variants include deletions, truncations, splice variants, and missense variants. Pathogenic missense variants occur exclusively within the kinase domain or affect splice sites. The CDKL5 protein is widely expressed in the brain, predominantly in neurons, with roles in cell proliferation, neuronal migration, axonal outgrowth, dendritic morphogenesis, and synapse development. The molecular biology of CDD is revealing opportunities in precision therapy, with phase 2 and 3 clinical trials underway or planned to assess disease specific and disease modifying treatments.

Introduction

Pathologic variants in cyclin-dependent kinase-like 5 (CDKL5)1, 2, 3, 4, 5 cause CDKL5 deficiency disorder (CDD; OMIM 300203, 300672), a developmental encephalopathy.6 Developmental encephalopathies share common constellations of features that extend beyond traditional criteria of autism spectrum disorder or intellectual disability such as treatment-resistant epilepsy, movement disorders, and autonomic dysfunction. Pathologic variants in CDKL5 cause early life epilepsy in one in 40,000 to 60,000 live births,7, 8, 9 half to a third as prevalent as Dravet (1:20,000 to 50,000)10, 11 or Rett (1:10,000 females)12 syndrome. Common features include infantile-onset refractory epilepsy, hypotonia, developmental delay, intellectual disability, and visual impairment.13, 14, 15 CDD is an X-linked disorder that affects females more than males (∼4:1) (Olson et al., unpublished data, 2018) as males with germline variants have no normal CDKL5 gene and may not survive fetal life. CDD was initially identified as the early seizure variant of Rett syndrome, but only 23.7% of females and no males with CDD met criteria for typical or atypical Rett syndrome and diagnosis of atypical Rett syndrome is even rarer in recent clinical experience (Olson et al., unpublished data, 2018).13, 16

The literature on CDD includes case series and data from the International CDKL5 Disorder Database, based on caregiver questionnaires.13, 17, 18, 19, 20, 21 Prospective data collection is occurring through the Natural History Study for Rett and Rett-related disorders (U54 HD061222; ClinicalTrials.gov: NCT00299312/NCT02738281) and through a clinic-based study by the International Foundation for CDKL5 Research Centers of Excellence (COEs). Initial sites were Boston Children's Hospital, Children's Hospital Colorado, and Cleveland Clinic. The COEs provide comprehensive care and collaborate on research for CDD. The COEs have collected data on more than 93 individuals with CDD between 0 and 34 years to inform the typical features and spectrum of CDD (Olson et al., unpublished data, 2018).

Section snippets

CDKL5 protein and molecular biology

CDKL5 is a serine threonine kinase. The N-terminal catalytic domain starts in exon 2 and the long C-terminus may have a regulatory role.22 CDKL5 is highly expressed in the brain, predominantly in neuronal nuclei and dendrites, with peak expression in early postnatal life, when symptoms typically begin.23, 24, 25, 26 The CDKL5 protein has roles in cell proliferation, neuronal migration, axonal outgrowth, dendritic morphogenesis and synapse development, and function in the adult brain.27

CDKL5 has

Epilepsy and treatment

Refractory epilepsy severely impacts quality of life and neurodevelopment.14, 34 Median age of epilepsy onset is six weeks with 90% onset by three months.13, 14 Eighty percent of children with CDD have daily seizures and 20% have weekly to monthly seizures.47 Fewer than half (43.6%) of caregivers reported more than 2 months of sustained seizure freedom.14, 34 Among individuals with more than two months of seizure freedom (N = 71 of 163 families reporting information on seizure freedom), in

Development

All individuals with CDD have severe global developmental delays and intellectual disability, although regression is rare except with worsening of seizures or epileptic encephalopathy.13, 15, 17, 18, 19, 67, 68, 69, 70 Individuals with CDD achieve gross motor milestones at a slowed pace compared with normal. Assessing in girls for whom there are more data, independent walking was attained by 22% to 23%, raking grasp by 49% by five years, and pincer grasp by only 13% at any time point.34, 68

Movement disorders

Hand stereotypies were reported in 80% of individuals, and 59% of females and 12.5% of males achieve functional hand use, which may be limited by stereotypies.13 The hand stereotypies that we have observed are more consistent with self-stimulatory behavior versus the type of hand stereotypies observed in Rett syndrome (Olson et al., unpublished data, 2018). Repetitive leg crossing is also commonly observed (Olson et al., unpublished data, 2018). We lack data on other movement disorders although

Physical examination findings

Hypotonia is a nearly universal feature.14, 15 Cortical visual impairment is common, occurring in at least 75% of individuals (Olson et al., unpublished data, 2018), with reports of poor eye contact and lack of visual tracking with an otherwise normal ophthalmologic examination.15, 16, 17, 19, 34, 69, 70 Rotatory and horizontal nystagmus, dysconjugate gaze, abnormal fixation, and reduced or absent optokinetic nystagmus response are features observed in individuals with visual impairment.

Neuroimaging

Neuroimaging has not yet been systematically reported in individuals with CDD, although case reports document normal brain anatomy or less often, show cortical atrophy or T2 fluid-attenuated inversion recovery hyperintensities in the white matter.15, 17, 18, 19, 48, 52, 54, 55, 67, 69, 70, 72, 73

Neuropathology findings

There is very little literature describing the neuropathologic findings in individuals with CDD. One case report described the brain as the sole organ with abnormalities in a postmortem examination.74 In addition to brain and cerebellar atrophy and ventricular enlargement, microscopic examination of the brain revealed gliosis in the cerebral cortex with preservation of the hexalaminar layers, neuronal heterotopias in the white matter of the cerebellar vermis, and gliosis of the cerebellar

Other comorbidities

Gastrointestinal symptoms were reported by parents in up to 86.5% in the International CDKL5 Disorder Database (122/141), most often constipation (70.9%), reflux (64.1%), or air swallowing (27.1%).13, 47 Orthopedic complications of hypotonia include scoliosis (68.5% by 10 years).13, 47 Dysphagia is common and may require gastrostomy. Although 79.3% of individuals with CDD in the International CDKL5 Disorder Database fed orally and 20.7% were exclusively fed by gastrostomy or nasogastric tube,

Clinical criteria

We propose minimum CDD diagnostic criteria to include a pathogenic or likely pathogenic variant in the CDKL5 gene along with motor and cognitive developmental delays and epilepsy with onset in the first year of life. We recognize that some patients with CDKL5 deficiency may be atypical and not meet these formal criteria. Table includes a list of common clinical features and what we determine to be the minimum diagnostic criteria.

Genotype-phenotype correlations

Genotype-phenotype correlations are limited. Compared with individuals with truncating variants, those with pathogenic missense variants in the adenosine triphosphate binding site had a milder disorder, some with ability to walk unaided, better hand use, and less refractory epilepsy.4 One individual in the COE cohort with a missense variant, p.Tyr24Cys, in the adenosine triphosphate binding site has refractory epilepsy but is making more developmental progress than most individuals with CDD and

Clinical trials and treatments suggested from animal studies

The ultimate goal of understanding the genetics and molecular biology of CDD is to establish precision therapies, targeting the underlying biologic pathways, although the complex biology of CDD makes this challenging. This may include small molecules or perhaps genetic or genomic treatment approaches. The hope is that these therapies may be more effective than currently available treatments.

An open-label phase 2 clinical trial of cannabidiol in CDD and three other early life genetic epileptic

Conclusions

The typical individual with CDD, defined by having a pathogenic gene variant that impairs CDKL5 function, is characterized by onset of treatment-resistant epilepsy and severe cognitive and motor developmental delays. Epilepsy usually begins in the first three months of life and includes tonic seizures, epileptic spasms without hypsarrhythmia, a seizure-free honeymoon period around one to two years old that may last up to 12 months, followed by multiple (2+) seizure types including sequences of

Acknowledgements

This work was supported by the National Institute of Neurological Disorders and Stroke (U54 HD061222, 1K23 NS107646-01, and 1K12NS089417-01), Rocky Mountain Rett Association, International Foundation for CDKL5 Research, the Ponzio Family Chair in Neurology Research, and NHMRC Senior Research Fellowship (#1117105). Drs. Walter E. Kaufmann and Sumit Parikh also participated in data collection by the International Foundation for CDKL5 Research Centers of Excellence.

Declaration of interest: Scott

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