Clinical characteristics.

CDKL5 deficiency disorder (CDD) is a developmental and epileptic encephalopathy (DEE) characterized by severe early-onset intractable epilepsy and motor, cognitive, visual, and autonomic disturbances. Movement disorders include chorea, dystonia, and stereotypical hand and leg movements.

Although females are more commonly affected than males (female-to-male ratio is approximately 4:1), the severity of manifestations in heterozygous females and hemizygous males can be equivalent. However, the severity of the phenotype can vary depending on the type and position of the CDKL5 pathogenic variant, pattern of X-chromosome inactivation in females, and presence of postzygotic mosaicism in males or females, who can have mild manifestations.

Diagnosis/testing.

The diagnosis of CDD is established in a female proband with suggestive clinical findings and a heterozygous CDKL5 pathogenic variant identified by molecular genetic testing.

The diagnosis of CDD is established in a male proband with suggestive clinical findings and a hemizygous CDKL5 pathogenic variant identified by molecular genetic testing.

Management.

Treatment of manifestations: International consensus recommendations for the assessment and management of individuals with CDD have been published. The management of individuals with CDD is complex and requires multiple specialty evaluations; referral to a CDKL5 Center of Excellence may allow families to coordinate care more easily for affected individuals.

Targeted therapy: Ztalmy^® (ganaxolone) is a targeted therapy for the treatment of epilepsy associated with CDD in individuals aged two years and older. This is the first approved treatment for seizures associated with CDD and the first treatment specifically for CDD.

Supportive care: Multidisciplinary care by specialists in the fields of pediatric neurology including pediatric epilepsy, feeding and nutrition, sleep disorders, behavioral disorders, orthopedics, physical therapy, occupational therapy, speech-language disorders, and genetic counseling.

Surveillance: Annual assessments by a medical home / primary care physician and specialists.

Genetic counseling.

CDD is inherited in an X-linked manner. Approximately 99% of affected individuals represent simplex cases (i.e., a single occurrence in the family). The majority of individuals who represent simplex cases have the disorder as the result of a de novo germline or (rarely) postzygotic CDKL5 pathogenic variant. Rarely, an individual with CDD has the disorder as the result of a CDKL5 pathogenic variant inherited from a heterozygous or mosaic mother. If the mother of the proband has a CDKL5 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Females who inherit the pathogenic variant will be heterozygous and are at high risk of being affected, although skewed X-chromosome inactivation and the possibility of other attenuating factors may result in a variable phenotype. Males who inherit the pathogenic variant will be hemizygous and will most likely be severely affected. Once the CDKL5 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

CDD should be suspected in females and males with motor and cognitive developmental delays and epilepsy with onset in the first year of life (developmental delays and early-onset epilepsy constitute the minimal clinical diagnostic criteria proposed by Olson et al [2019]). Note: (1) Although females are more commonly affected than males with this X-linked disorder, the severity of manifestations in affected females and males can be equivalent. (2) The severity of the phenotype can vary depending on the type and position of the CDKL5 pathogenic variant, pattern of X-chromosome inactivation in females, and presence of postzygotic mosaicism.

Common clinical findings [Olson et al 2019] (full text)

• Early-onset epilepsy
  • Typically beginning within the first two months of life (up to age 12 months)
  • Usually severe, with multiple episodes per day
  • Seizure types vary over time. Epileptic spasms (without hypsarrhythmia in 50%) are the initial seizure type in nearly 25% of individuals; other seizure types include tonic, focal, myoclonic, and generalized tonic-clonic; and mixed types that include features of spasms, tonic seizures, and hypermotor seizures. EEG findings may be normal in early infancy.
  • Refractory to anti-seizure medications (ASMs)
• Severe developmental delays / intellectual disability involving motor, communication (speech and language), and cognitive development
• Cerebral visual impairment manifesting as:
  • Abnormal eye movements that include esotropia, exotropia, and horizontal and rotatory nystagmus
  • Abnormal fixation and responsiveness to bright lights
• Tone abnormalities, including generalized hypotonia
• Sleep disturbances
  • Inability to maintain nighttime sleep for extended periods
  • Excessive daytime sleepiness
• Movement abnormalities
  • Stereotypies of hands (e.g., putting hands in mouth), arms (e.g., flapping, waving), or legs (e.g., leg crossing)
  • Generalized chorea
  • Dystonia
• Autonomic dysfunction
  • Constipation
  • Gastroesophageal reflux disease
  • Abnormal breathing pattern

Brain MRI findings. Brain MRI findings, if present, are variable and nonspecific and include progressive cortical and cerebellar atrophy with reduction in both gray and white matter [Leonard et al 2022, Specchio et al 2023].

Family history. CDD is an X-linked disorder. Because CDD is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family).

Establishing the Diagnosis

Female proband. The diagnosis of CDD is established in a female proband with suggestive clinical findings and a heterozygous CDKL5 pathogenic (or likely pathogenic) variant identified by molecular genetic testing [Olson et al 2019, Amin et al 2022, Das 2023] (see Table 1).

Male proband. The diagnosis of CDD is established in a male proband with suggestive clinical findings and a hemizygous CDKL5 pathogenic (or likely pathogenic) variant identified by molecular genetic testing [Olson et al 2019, Amin et al 2022, Das 2023] (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a hemizygous or heterozygous CDKL5 variant of uncertain significance does not establish or rule out the diagnosis. (3) While most individuals with CDD have a germline (i.e., constitutional) CDKL5 pathogenic variant, some individuals have a postzygotic (i.e., mosaic) CDKL5 pathogenic variant, including single-nucleotide variants, deletions, and inversions (see Molecular Genetics).

Molecular genetic testing approaches in a proband can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (chromosomal microarray, exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Note: Single-gene testing (sequence analysis of CDKL5, followed by gene-targeted deletion/duplication analysis) is rarely used today and typically NOT recommended.

Clinical Description

CDKL5 deficiency disorder (CDD) is a developmental and epileptic encephalopathy (DEE) characterized by severe early-onset epilepsy and motor, cognitive, visual, and autonomic disturbances [Bahi-Buisson et al 2008, Nemos et al 2009, Castrén et al 2011, Melani et al 2011, Bahi-Buisson et al 2012, Fehr et al 2015, Fehr et al 2016, Mangatt et al 2016]. Movement disorders include chorea, dystonia, and stereotypical hand and leg movements [Olson et al 2019, Olson et al 2021, Leonard et al 2022]. Cardiac involvement is nonspecific [Stansauk et al 2023].

Because the full spectrum of phenotypic severity is still emerging, especially given the possibility of mosaicism (in males and females) and the potential for skewed X-chromosome inactivation (in females), an individual with a de novo CDKL5 pathogenic variant may have a mild phenotype (for example, minimal epilepsy and global developmental delays).

To date, approximately 500 individuals have been identified with CDD [Leonard et al 2022]. The following description of the phenotypic features associated with CDD is based on these reports.

Although females are more commonly affected than males (female-to-male ratio is approximately 4:1 [Demarest et al 2019]), the severity of manifestations in heterozygous females and hemizygous males can be equivalent. However, the severity of the phenotype can vary depending on the type and position of the CDKL5 pathogenic variant, pattern of X-chromosome inactivation in females, and presence of postzygotic mosaicism in males or females, who can have mild manifestations [Demarest et al 2019, MacKay et al 2021, Wong et al 2023].

Development. Gross motor, fine motor, and speech-language development are impaired in all affected individuals.

Gross motor abnormalities are accompanied by generalized hypotonia. Approximately 60% of individuals achieve sitting and approximately 20% achieve independent walking.

Approximately 40%-70% of individuals cannot grasp and hold objects.

Approximately 20% of individuals have spoken language. Most children can use some simple nonverbal communication methods.

Cerebral visual impairment, which affects 80% of individuals, may affect development in each of these areas.

Epilepsy. Most individuals have early-onset and severe intractable epilepsy. Seizures are variable in type over time. Epileptic spasms are the initial seizure type in nearly 25% of individuals (and in those individuals, 50% of seizures occur without hypsarrhythmia on EEG). Other seizure types include tonic, focal, myoclonic, and generalized tonic-clonic seizures, and mixed types that include features of spasms, tonic seizures, and hypermotor seizures.

In general, epilepsy is medically refractory throughout life but shows some improvements with age. In up to 40% of individuals there may be a relative temporary improvement in seizures ("honeymoon period") around ages one to two years [Fehr et al 2016, Demarest et al 2019].

EEG features may be normal in early infancy but subsequently evolve to abnormal background activity that can include a Lennox-Gastaut pattern.

Neuroimaging. Nonspecific but abnormal brain imaging may be more evident in males than in females; findings can include progressive cortical and cerebellar atrophy with reduction in white and gray matter thickness [Leonard et al 2022].

In one study, brain MRIs in 64% (n=14/22) of individuals were normal in the first year of life. Follow-up MRIs showed progressive cortical and cerebellar atrophy. These findings, which can be seen in other DEEs, were hypothesized to be due to either CDD pathogenesis or severe intractable epilepsy [Specchio et al 2023].

Sleep disturbances. Abnormal sleep patterns, typically with inability to maintain sleep, are common [Mangatt et al 2016]. Parents report lack of sleep overall for several nights followed by excessive somnolence in more severe cases. This feature is typically lifelong [Hagebeuk et al 2013].

Cerebral visual impairment. Abnormal visual function manifests as abnormal eye movements that include horizontal and rotatory nystagmus and dysconjugate eye movements with reduced tracking and fixation associated with difficulties in visually oriented tasks such as reaching. Response to bright light can be abnormal (e.g., lack of blink). There may be improvement of visual fixation and task performance with age [Demarest et al 2019, Olson et al 2019, Brock et al 2021].

Gastrointestinal problems. Constipation and gastroesophageal reflux disease requiring medical management are typically lifelong.

Feeding problems. While one third of individuals may require gastrostomy tube placement for feeding, the remainder usually have some degree of feeding challenges (likely influenced by hypotonia of the pharyngeal muscles) that may be associated with increased risk of aspiration.

Movement disorders. The incidence of movement disorders may be underappreciated due to variability in ascertainment. Chorea, dystonia, and stereotypical leg crossing are not uncommon. Abnormal movements such as stereotypical hand movements may be present.

Musculoskeletal involvement may include scoliosis and large joint abnormalities associated with severe hypotonia (subluxation/dislocation of hips and knees).

Respiratory problems. Aspiration pneumonia due to impaired ability to clear respiratory secretions may be more prevalent in those with severe hypotonia.

Behavioral problems. Occasionally, autistic behaviors including abnormal socialization and repetitive behaviors have been described.

Genotype-Phenotype Correlations

While genotype-phenotype correlations are emerging [MacKay et al 2021], there are two caveats regarding ascertainment: (1) the frequency of recurrent CDKL5 pathogenic variants is relatively low; and (2) measurements of severity with sufficient granularity to differentiate clinical severity have only recently become available.

CDKL5 pathogenic variants causing CDD are typically loss-of-function variants [Hector et al 2017b, Olson et al 2019, Leonard et al 2022]; however, duplications [Szafranski et al 2015] and missense gain-of-function variants [Frasca et al 2022] associated with different, and often milder, neurologic manifestations have been reported.

Phenotypes associated with nonsense alterations throughout the protein appear equally severe, suggesting that truncating variants located within the terminal region of the gene may be less severe [Wong et al 2023].

Nomenclature

CDKL5 deficiency disorder (CDD) was previously referred to as an early-onset seizure variant (Hanefeld variant) of Rett syndrome [Leonard et al 2022] and as CDKL5-related developmental and epileptic encephalopathy (CDKL5-DEE) in the International League Against Epilepsy (ILAE) Classification and Definition of Epilepsy Syndromes [Zuberi et al 2022].

Prevalence

The prevalence of CDD in the general population is unknown. An incidence of 2.36 in 100,000 live births (95% CI: 0.805-5.59) was estimated based on identification of CDD in four of 333 Scottish children with epilepsy tested over three years using an epilepsy multigene panel [Symonds et al 2019]. Note that this may or may not be an underestimate more broadly given the variability of the CDD phenotype and limited molecular investigations of individuals who are mildly affected (i.e., ascertainment bias).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CDD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for CDD to date [Olson et al 2021, Leonard et al 2022].

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended. In general, annual assessments by a medical home/primary care physician and specialists are needed.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Several therapies have been investigated or are ongoing for CDD [Leonard et al 2022] including the following:

• Soticlestat/TAK935 (NCT03694275) [Demarest et al 2023]
• Ataluren (NCT02758626) [Devinsky et al 2021a]
• Fenfluramine (NCT03861871, NCT05064878) [Devinsky et al 2021b]
• Canabidiol [Devinsky et al 2018]
• Ketogenic diet [Müller et al 2016, Lim et al 2017, Zhang et al 2022]
• Vagal nerve stimulation [Lim et al 2018]
• Protein and gene replacement therapies have been proposed.

Clinical trials and registries assessing natural history and outcome measures are ongoing (NCT05558371, NCT05373719, NCT04486768).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

CDKL5 deficiency disorder (CDD) is inherited in an X-linked manner.

Risk to Family Members

Parents of a proband

• Approximately 99% of affected individuals represent simplex cases (i.e., a single occurrence in the family). The majority of individuals who represent simplex cases have the disorder as the result of a de novo germline or (rarely) postzygotic CDKL5 pathogenic variant.
• Rarely, an individual with CDD has the disorder as the result of a CDKL5 pathogenic variant inherited from a heterozygous mother [Fraser et al 2019, Siri et al 2021]. A mother who is heterozygous for a CDKL5 pathogenic variant may have favorably skewed X-chromosome inactivation that results in her being unaffected or mildly affected. Of note, the absence of favorably skewed X-chromosome inactivation in blood does not rule out the possibility of favorably skewed X-chromosome inactivation in the brain.
• CDKL5 molecular genetic testing is recommended for the mother of the proband to evaluate her genetic status and to inform recurrence risk assessment.
• Evaluation/testing of the father of the proband is not required. If the proband is female, it is presumed that the father is not hemizygous for the CDKL5 pathogenic variant, as males with CDD are not known to reproduce. If the proband is male, the father will not have CDD and will not be hemizygous for the CDKL5 pathogenic variant.
• Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in germ (gonadal) cells only.
• If the CDKL5 pathogenic variant found in the proband cannot be detected in maternal leukocyte DNA, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Presumed maternal germline mosaicism has been reported in families with sib recurrence [Weaving et al 2004, Hagebeuk et al 2015].

Sibs of a proband. The risk to sibs depends on the genetic status of the parents:

• If the mother of the proband has a CDKL5 pathogenic variant, the chance of transmitting it in each pregnancy is 50%.
  • Females who inherit the pathogenic variant will be heterozygous and are at high risk of being affected, although skewed X-chromosome inactivation and the possibility of other attenuating factors may result in a variable phenotype.
  • Males who inherit the pathogenic variant will be hemizygous and will most likely be severely affected [Demarest et al 2019, Wong et al 2023]. Note: Although manifestations may be milder in males with mosaic, postzygotic CDKL5 pathogenic variants, the phenotype in hemizygous males with germline pathogenic variants is typically severe.
• If the proband represents a simplex case and if the CDKL5 pathogenic variant cannot be detected in maternal leukocyte DNA, the risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism. Presumed maternal germline mosaicism has been reported in families with sib recurrence [Weaving et al 2004, Hagebeuk et al 2015].

Offspring of a proband

• Each child of a female proband with CDD has a 50% chance of inheriting the CDKL5 pathogenic variant. Females with CDD generally do not reproduce; mildly affected females are not known to have reproduced.
• Males with CDD are not known to reproduce.

Other family members. The risk to other family members depends on the genetic status of the proband's mother: if the mother of the proband has a CDKL5 pathogenic variant, her family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a CDKL5 pathogenic variant.

Prenatal Testing and Preimplantation Genetic Testing

Once the CDKL5 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Males with a hemizygous CDKL5 pathogenic variant will most likely have severe intellectual disability. The phenotype in heterozygous females is difficult to predict and can range from mildly (in very rare cases) to severely affected.

Note: Because presumed maternal germline mosaicism for a CDKL5 pathogenic variant has occasionally been reported, it is appropriate to offer prenatal testing to the parents of a child with CDD whether or not the CDKL5 pathogenic variant has been identified in maternal leukocyte DNA [Weaving et al 2004, Hagebeuk et al 2015].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

CDKL5, an X-linked gene, encodes cyclin-dependent kinase-like 5 (CDKL5), a 115-kD serine-threonine kinase and member of the CMGC family, which includes cyclin-dependent kinases (CDK), MAP kinases, glycogen synthase kinases (GSK), and cyclin-dependent kinase-like (CDKL) [Manning et al 2002]. CDKL5 is expressed throughout the central nervous system, primarily in neurons, where it localizes to the dendritic spines of excitatory synapses as well as the nucleus [Jaffe et al 1989]. Its expression increases postnatally and is stabilized at peak levels in adult rodents and humans [Chen et al 2010, Hector et al 2016, Baltussen et al 2018].

CDKL5 interacts with PSD-95 [Zhu et al 2013], gephyrin [Uezu et al 2016, De Rosa et al 2022], NGL-1 [Ricciardi et al 2012], Shootin1 [Nawaz et al 2016], actin [Chen et al 2010], the microtubule-binding proteins (MAP1s and EB2), which are directly phosphorylated by CDKL5 [Baltussen et al 2018], as well as MeCP2, DNMT1, AMPH1, and HDAC4 [Zhu & Xiong 2019].

Loss of CDKL5 leads to a global reduction in excitatory synapse numbers [Ricciardi et al 2012, Della Sala et al 2016], reduced PSD-95 [Lupori et al 2019, Negraes et al 2021] and synapsin [Negraes et al 2021], with loss of AMPA-type glutamate receptors (GluA2 [Yennawar et al 2019]) and increased NMDA-type glutamate receptors (GluN2B [Okuda et al 2017]). Inhibitory synaptic currents are affected in some CDKL5 mouse models [Tang et al 2017].

Analysis of CDKL5 pathogenic variants has confirmed that CDKL5 kinase function is central to the pathogenesis of CDKL5 deficiency disorder (CDD) [Hector et al 2017b, Demarest et al 2019]. However, the precise role of loss of CDKL5 function in causing CDD-related manifestations could be due to several mechanisms including chronic CDKL5 dysfunction, compensatory effects due to CDKL5 dysfunction during a critical developmental period, or secondary effects due to severe and intractable epilepsy.

Mechanism of disease causation. Loss of function

Note: Duplications [Szafranski et al 2015] and missense gain-of-function variants [Frasca et al 2022] associated with milder neurologic manifestations have been reported. Missense variants (especially novel ones) outside of the kinase domain (where most CDKL5 pathogenic missense variants cluster) should be interpreted with caution, as the functional significance of these variants may be unknown [Diebold et al 2014].

CDKL5-specific laboratory technical considerations

• CDKL5 transcripts. CDKL5 has multiple transcripts and alternatively spliced exons [Hector et al 2016, Hector et al 2017a]. Historically, the longest transcripts, NM_003159 and NM_001037343, have been used in clinical diagnostic testing. However, the transcript NM_001323289 is the most highly expressed in the brain and contains 170 nucleotides at the 3' end of its last exon that are noncoding in other transcripts [Keehan et al 2022]. This has led to pathogenic CDKL5 variants within this region being missed by clinical testing laboratories [Bodian et al 2018, Schoch et al 2020, Keehan et al 2022]. Thus, it is critical that clinical testing laboratories assess for CDKL5 variants in this transcript.
• Mosaicism. Mosaic (or postzygotic) CDKL5 variants including single-nucleotide variants and deletions have been identified in individuals with CDD [Bartnik et al 2011, Stosser et al 2018, Cope et al 2021]. Therefore, attention to the sensitivity of the diagnostic method used (e.g., next-generation sequencing or array comparative genomic hybridization) is recommended.
• Noncoding variants. Deleterious CDKL5 missense variants and deletions in intronic regions have been reported [Nemos et al 2009, Bahi-Buisson et al 2010, Liang et al 2011, Mei et al 2014, Schoch et al 2020]. Thus, consideration of genome sequencing for individuals with features consistent with CDD who do not have a CDKL5 variant detected on multigene panel testing or exome sequencing is recommended.
• Variants of uncertain significance. Maternal testing is helpful for assessing the pathogenicity of CDKL5 variants of uncertain significance, especially missense variants (especially novel ones) outside of the kinase domain.

Author Notes

Tim Benke, MD, PhD
Ponzio Family Endowed Chair in Neurology Research
Medical Director, Rett Clinic
Research Director, Neuroscience Institute
Children's Hospital Colorado
Professor of Pediatrics, Neurology, Pharmacology & Otolaryngology
University of Colorado School of Medicine
International CDKL5 Clinical Research Network

Tim Benke (ude.ztuhcsnauc@ekneb.mit) and all authors are actively involved in clinical research regarding individuals with a developmental and epileptic encephalopathy (DEE) including Rett syndrome, MECP2-related disorders, CDKL5 deficiency disorder (CDD), and FOXG1 syndrome. They would be happy to communicate with persons who have any questions regarding diagnosis of these and similar disorders or other considerations.

Eric Marsh (ude.pohc@ehsram) is also interested in hearing from clinicians treating families of individuals with a DEE in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.

Contact Drs Tim Benke, Scott Demarest, Jenny Downs, Helen Leonard, Heather Olson, and Isa Haviland to inquire about individuals with CDKL5 variants of uncertain significance or pathogenic variants with a divergent phenotype.

Acknowledgments

The authors recognize the following support: NIH-NINDS: R21 NS112770 (Benke), U01NS114312 (PD/Benke); NIH-NICHD: U54 HD061222 (PD/Percy), Rocky Mountain Rett Association (Benke), International Foundation for CDKL5 Research (all), Children's Hospital Colorado Foundation: Ponzio Family Chair in Neurology Research (Benke), NIH-NINDS: 5K23NS107646 (Olson), Loulou Foundation (Olson, Haviland), NIH-NIMH: 2T32MH112510 (Haviland).

Revision History

• 11 April 2024 (bp) Review posted live
• 22 August 2023 (tb) Original submission

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