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The CDKL5 Disorder Is An Independent Clinical Entity Associated With Early-onset Encephalopathy

Individuals with mutations in the CDKL5 gene have been variably classified as having early infantile epileptic encephalopathy, X-linked dominant infantile spasm syndrome, the ESV RTT or diagnosed with other epileptic disorders such as West syndrome.1, 3 We described the clinical presentation and physical appearance of individuals with the CDKL5 disorder, providing information from a large international dataset. The CDKL5 disorder appears to be characterised by seizure onset in the majority before 3 months of age, severely impaired gross motor, language and hand function skills, and subtle but shared physical characteristics such as a prominent/broad forehead, deep-set but large-appearing eyes, full lips and tapered fingers. Our findings suggest that the CDKL5 disorder is an independent entity and should not be considered part of the RTT spectrum, as <25% of the cases in our study would meet the clinical criteria for ESV RTT. Therefore, we propose that females and males with a mutation in the CDKL5 gene be given a specific diagnosis of the CDKL5 disorder.

Our study found that early-onset epilepsy was one of the hallmark features of the CDKL5 disorder. In the literature many seizure types and EEG changes have been described. These include infantile spasms, multifocal and generalised seizures with myoclonic, tonic (tonic vibratory) and clonic features. Reported EEG patterns include a normal background, background slowing and a burst-suppression pattern.10, 12 Although no specific seizure semiology has been described, two reports have noted a seizure pattern that may be unique to this disorder.31, 34 The first (n=4) reported a seizure pattern of tonic–tonic/vibratory contraction, followed by a clonic phase with spasms and finishing with distal myoclonus.34 The second (n=4) reported an initial hypermotor phase, then tonic extension, followed by spasms. Severe developmental delay was typical of the CDKL5 disorder. Learning to sit and walk was usually considerably delayed or not achieved, more so in males.42 Communication was usually restricted to non-verbal strategies. It would be important to further investigate the influences of genotype, seizure severity or therapy utilisation on early development in those with the CDKL5 disorder. Consistent with other literature1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 our large case series confirms that early-onset of epilepsy and severe developmental delay are key features.

Males with the CDKL5 disorder in this study tended to be more severely affected. None learned to walk, with or without assistance, and few acquired spoken communication and hand function. Seizure onset was slightly earlier than in females, and all males were having either daily or monthly seizures. Hand stereotypies were reported in only a third of males compared with 80% of females. Some of these differences may be due to amelioration of the phenotype in females because of X-inactivation resulting in a mosaic expression of normal and mutant CDKL5 protein. In RTT, males tend to be either extremely affected, often dying at an early age due to severe infantile encephalopathy, or more mildly affected than females.43 Those who are more mildly affected tend to have hypomorphic MECP2 mutations that are not found in females with RTT. It would be of interest to further investigate the genetic variability between males and females with the CDKL5 disorder to determine whether a similar phenomenon exists.

We observed a shared physical resemblance between females with the CDKL5 disorder, with the most consistent features being a prominent/broad forehead, deep-set but 'large-appearing' eyes, full lips and tapered fingers. Most affected males were more obviously dysmorphic, with distinctly anteverted nares, and several males also had a short philtrum and everted upper lip. Previous studies of the CDKL5 disorder have also reported dysmorphic features including: large deep-set eyes, strabismus, high forehead, full lips, wide mouth, widely spaced teeth and a high palate.1, 4, 5, 7, 13, 18, 20, 22, 25, 26, 28, 29, 30, 35 Dysmorphic features have been described in other conditions presenting with early-onset encephalopathy, such as those with FOXG1 mutations and in Pitt-Hopkins syndrome (PHS). In those with FOXG1 mutations, subtle, non-specific dysmorphic features have been reported, along with severe microcephaly, which is typical of FOXG1 syndrome but not common in individuals with the CDKL5 disorder.44 The facial features in PHS include a high nasal bridge and prominent, beaked nose, different from the consistently straight nose and normal or low nasal bridge seen in the CDKL5 disorder. Although both can have prominent lips, the lips in PHS have a more marked cupid's-bow contour. Individuals with PHS may have clubbing of the fingertips whereas in the CDKL5 disorder the distal phalanges are relatively narrow and/or short.45 In classical RTT no typical facial gestalt has been described, although some clinicians have suggested a facial similarity to Angelman syndrome.46 A recent study using a combination of measurement and subjective impression found the only distinctive facial profile difference in RTT was a relatively broad upper face, especially in girls <3 years old.47 Although subtle, the features that we have described appear to be characteristic of the CDKL5 disorder population and could therefore be useful in determining whether the patient warranted CDKL5-specific mutation testing.

The majority of patients in this study with the CDKL5 disorder did not meet the new criteria for the ESV RTT, mainly because of the absence of regression in over two-thirds. Several of the specific supportive criteria, such as diminished response to pain, a spinal curvature and intense eye pointing, were also infrequently reported. Some of these supportive characteristics appear age-dependent and were observed more commonly in those aged over 5 years. Longitudinal monitoring of these features would contribute to a better understanding of the evolution of this disorder.

Considering only the females with the CDKL5 disorder, the differences in comparison to RTT persisted. Early development was more severely impaired in those with the CDKL5 disorder, with approximately half learning to sit and 10% learning to walk in comparison with ∼80% learning to sit and just under half learning to walk in a recent study of 293 females with RTT.48 Those with the CDKL5 disorder were less likely to use words whereas use of some words was acquired by nearly 90% of females with RTT before regression.48 Females with the CDKL5 disorder were also less likely to develop hand stereotypies, breathing disturbances, gastrointestinal problems and a spinal curvature, but were much more likely to develop seizures and have sleep disturbances. These findings again suggest that the CDKL5 disorder is clinically separate to RTT, indicating the need to develop independent clinical criteria for the identification of the CDKL5 disorder.

The two largest studies conducted to date (n=9 and n=20) found that the classical period of regression was rarely present in females with the CDKL5 disorder and that autonomic, gastrointestinal, breathing and spinal problems were rare and lack of eye contact, hypotonia and epilepsy common.11, 22 Our study also found that regression, autonomic disturbances, breathing disturbances and a spinal curvature occurred less frequently than in RTT, but that the prevalence increased with age. Gastrointestinal problems were quite common, although occurring less frequently than in females with RTT. In contrast to other CDKL5 studies,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 we found that sleep problems were reported frequently. Small case series may be less likely to accurately identify some of the patterns detectable by a larger study, which could account for this difference. Clearly large sample sizes, preferably population-based, are needed to provide accurate representation of the clinical features of such a rare condition. Our study is the first to have had the capacity to compare the characteristics of males and females with the CDKL5 disorder. Further investigation of the natural history is still required, and there are likely other features that have not been captured by existing studies.

This study is the first international case collection investigating the clinical presentation of the CDKL5 disorder and includes more than four times the number of individuals than the largest previously reported case series. It is also the first to examine whether these individuals meet the criteria set forth for the ESV RTT. However, our study is not population-based, and we suggest the development of a population-based register of this disorder, as has occurred in RTT.49 Because we used the infrastructure of InterRett, our data collection tools were initially designed for RTT and therefore we may not have been able to capture the presence of features that are unique to the CDKL5 disorder. Our study population was also weighted towards younger children, and some clinical features are likely to evolve with age. With regard to the identification of 'dysmorphic' features, our study was limited by the lack of a photographic control group, the variable quality of images used and the subjective nature of the assessments (although the latter has been a traditional approach to dysmorphology). Acknowledging these limitations, and that the features noted were variable, we felt the combined gestalt in a child with early-onset encephalopathy, without major malformations, could suggest a CDKL5 mutation as a likely underlying aetiology.

Many of the early-onset encephalopathies have overlapping phenotypes, including severe developmental compromise with or without prior regression, early-onset seizures, abnormal movements (stereotypies or dyskinesias) and respiratory irregularities. Some are distinctive either by dysmorphism (PHS), or typical neurodevelopmental profile (classical RTT). Others may be less easily recognised, which is why classifications evolve using terms such as 'Rett variant' or 'PHS-like'. Although use of such terms in some conditions (eg, Noonan or Noonan-like) has been borne out by discovering mutations in genes in shared pathways, this type of classification should be approached with some caution. Although mutations in the CDKL5 gene have been found in association with a clinical picture similar to RTT in some instances, the majority of cases are different. It may be more accurate and beneficial for families and clinicians if the CDKL5 disorder is considered independent of RTT, rather than another variant. Therefore, we suggest that when describing the clinical picture of females and males with the CDKL5 disorder, researchers should not only concentrate on features that should be present in RTT, but also on the features that are present in the CDKL5 disorder. Only then will it be possible to develop accurate clinical diagnostic and management guidelines.

Recognizing CDKL5 Deficiency Disorder

News-Medical speaks to Dr. Dan Lavery about the LouLou Foundation, a non-profit organization dedicated to CDLK5 Deficiency Disorder.

Could you please tell us about the LouLou foundation? Why did the foundation aim to tackle CDKL5 deficiency?

The Loulou Foundation is a private, non-profit foundation dedicated to developing meaningful therapeutics, and eventual cures, for CDKL5 Deficiency Disorder (CDD).

It was founded in 2015 by a family touched by CDD, and since its inception, the Foundation has focused on therapeutic development, which was lacking in the CDD community, and not on patient education and clinical standards of care, which have been very effectively served by patient organizations working at the national level.

What is CDD?

CDKL5 Deficiency Disorder (CDD) is a rare disorder which is caused by mutations in the CDKL5 gene. Nearly all CDKL5 mutations leading to the disorder arise de novo and lead to loss of function of the CDKL5 gene.

Patients living with CDD show a significant neurodevelopmental delay, including severe hypotonia, motor and visual impairment, and little to no communication skills. In addition, CDD patients suffer gastrointestinal, respiratory, and sleep issues, and a complex profile of epileptic seizures which are, in general, poorly controlled by medications. Most CDD patients will thus require near-constant care for their entire lives.

Recent estimates place the incidence of CDD at approximately one in 40,000 live births, making it one of the most common monogenic epileptic disorders. Several hundred CDD patients have been diagnosed worldwide, but many thousands more remain to be identified.

While several clinical trials are underway for novel therapeutics for CDD, there are no current therapies for the neurodevelopmental symptoms associated with CDD.

Image Credit: Evgeniy Kalinovskiy/Shutterstock.Com

90% of children affected by CDKL5 are girls. Why is this?

It is believed that this is because the CDKL5 gene is located on the X chromosome. As girls have two X chromosomes and boys have only one, the expression of the two X chromosomes in girls is balanced to the single copy in boys through a process called X inactivation, in which one of the two X chromosomes in each cell is randomly but stably silenced.

In girls with CDD, carrying in each cell a mutant CDKL5 gene on one X chromosome and an unmutated, "wild type" CDKL5 gene on the other, X inactivation means that half of all of their cells express the mutant CDKL5 gene and the other half of their cells express the unmutated CDKL5 gene.

In boys carrying a CDKL5 mutation on their single X chromosome, all cells express the mutant CDKL5 gene. One hypothesis is that since in boys, all cells are expressing the mutant CDKL5 gene, they are in general more severely affected than girls, and many may not survive to term. This could explain the skewing of the population of CDD patients toward girls (80-90%) over boys (10-20%).

Image Credit: Chiari VFX/Shutterstock.Com

Why is it important to get an early diagnosis of CDD?

Early diagnosis of CDD will allow the CDD patient and family to benefit from a more defined clinical treatment regimen, particularly as more therapies developed specifically for CDD become available; and may avoid testing treatments that are known to be contraindicated in CDD patients.

Early diagnosis can also lead to inclusion in robust therapy programs (physical, vision, occupational, etc.) that can be of greater benefit with earlier intervention.

Early diagnosis can also allow families to connect with the CDD community, to learn from and share with other families living with CDD, to become active in the community, and to learn about potential clinical studies involving CDD patients and families.

Why was it important to receive recognition for this disease from the WHO and get an ICD-10 code?

There are many advantages to having a specific ICD-10 code assigned by the WHO to CDD. The first is that it allows clinicians to identify CDD patients in medical records using an unambiguous code.

In the past, a series of different codes could have been used to classify CDD in a patient's medical records, including "generalized epilepsy," "atypical Rett syndrome," or even just "genetic mutation." This made tracking of patients, medications, and therapies for CDD virtually impossible.

Now, with a unique ICD-10 code, all CDD patients can be identified and tracked, for epidemiological and clinical therapeutic studies. Also, an ICD-10 code is the recognition that CDD is a distinct, clinically and genetically defined disorder, and should not be confused with or lumped together with some larger syndromic diagnoses like atypical Rett syndrome or West syndrome.

Image Credit: LouLouFoundation

As you now have an ICD-10 code for this disease, do you believe this will help in monitoring the number of people with this disease?

Yes, this will allow us to track new diagnoses, and with some effort, it may also help us identify and track patients with CDD who might have never received an accurate diagnosis.

What does this classification mean for people living with CDD? How will this improve their quality of life?

For patients and families living with CDD, the ICD-10 code allows them to have a clearly defined, distinct diagnosis that allows them to access truly relevant information from their clinicians and other families living with CDD. This alone can improve the quality of life of the patient and family.

However, the specific ICD-10 code for CDD vastly improves the quality and scope of epidemiological and clinical studies on the disorder, including offering the families the opportunity to learn about clinical trials for new treatments for CDD.

Already our community has one active Phase 3 and several active Phase 2 trials specific to patients with CDD.

What are the next steps in your research in CDD?

As mentioned, there are already Phase 2 and Phase 3 studies ongoing with CDD patients for the evaluation of next-generation anti-seizure medications, which might also impact other aspects of the disorder beyond seizures.

Likewise, there are two publicly announced pre-clinical programs at experienced rare disease companies that are using virus-based gene therapy approaches to offer potentially disease-modifying therapeutics for CDD.

In addition, more research is being conducted to learn more about the basic mechanisms of the disorder and to discover novel pathways to target for improved treatment of the disorder.

Where can readers find more information?

Vyant Bio Announces Participation At The 2022 CDKL5 Forum Hosted By The Loulou Foundation On November 7-8, 2022

Vyant Bio, Inc.

Platform and Poster Presentations on Vyant Bio's Human First Drug Discovery Platform and Progress on CDKL5 Deficiency Disorder (CDD)

CHERRY HILL, N.J., Oct. 27, 2022 (GLOBE NEWSWIRE) -- Vyant Bio, Inc. ("Vyant Bio" or "Company") (Nasdaq: VYNT) is an innovative biotechnology company reinventing drug discovery for complex neurodevelopmental and neurodegenerative disorders. The Company's proprietary central nervous system ("CNS") drug discovery platform combines human-derived organoid models of brain disease, scaled biology, and machine learning to identify novel therapeutic candidates for neurodevelopmental and neurodegenerative disorders. Today, Vyant Bio announced their participation at the 2022 CDKL5 Forum Hosted by the Loulou Foundation on November 7th and 8th, 2022, in Boston, MA through platform and poster presentations. In addition, Vyant Bio will participate in a CDKL5 deficiency disorder scientific workshop on Monday October 31st from 1-4 pm EDT and will present an industry perspective for the best practices for the use of human induced pluripotent stem cell (iPSC) derived brain organoids in drug discovery research.

Details for the platform talk and poster presentation include:

Title: High-throughput functional screening to develop novel therapies for CDKL5-deficiency disorder using human iPSC-derived cortical organoidsAuthors: Matthew V. Green, Tori Alstat, Huda Ahmed, Kendra Prum, Cassiano Carromeu, Andrew LaCroix, Robert T. Fremeau, Jr.Session: Molecular and Cellular FunctionSession Date / Time: November 7, 11:35 am EDT

ABOUT CDKL5

CDKL5 stands for cyclin-dependent kinase-like 5, a protein whose gene is located on the X chromosome. The CDKL5 gene provides instructions for making a protein that is essential in forming the connections for normal brain development, with mutations causing a deficiency in the protein level. Mutations in the gene are usually spontaneous 'de novo' occurrences, rather than inherited. About 90% of patients with CDKL5 deficiency disorder (CDD) are girls. CDD patients suffer from seizures that usually begin within the first few months of life, as well as from profound neurodevelopmental delay. Estimates suggest that one in 40,000-60,000 live births develop the disorder, making it difficult to study when compared to common diseases like cancer and heart disease.

ABOUT THE LOULOU FOUNDATION

The Loulou Foundation is a private non-profit organization founded in 2015 to support the development of effective therapeutics and eventual cures for CDD. Through robust grant and directed research programs, the Foundation provides tools and resources to basic and clinical scientists to enable the development of disease-modifying therapeutics for CDD. These programs include support for pre-clinical, translational, and clinical research into basic CDKL5 biology, CDD disease mechanisms, and the proof-of-concept studies for gene therapy and genome modifying therapeutics. Visit www.Louloufoundation.Org for more information.

Story Continues

ABOUT VYANT BIO, INC.

Vyant Bio, Inc. ("Vyant Bio" or the "Company") (Nasdaq: VYNT) is an innovative biotechnology company focused on identifying unique biological targets and novel and repurposed therapeutics for treating the debilitating neurodevelopmental and neurodegenerative disorders for which there are no current therapies.. Vyant Bio has built a platform of therapeutics seeking to treat neurodevelopmental and neurodegenerative diseases, with current programs targeting Rett Syndrome ("Rett"), CDKL5 Deficiency Disorders ("CDD"), and Parkinson's Disease. The Company's approach to drug discovery integrates human-derived biology with artificial intelligence and machine learning technologies to de-risk candidate selection, with the goal of improving the potential effectiveness of drugs discovered earlier in the development cycle. Vyant Bio's management believes that drug discovery needs to progressively shift to more efficient methods as the widely used models for predicting safe and effective drugs have under-performed, as evidenced by the significant time and cost of bringing novel drugs to patients. By combining sophisticated data science capabilities with highly functional human cell derived disease models, Vyant Bio seeks to leverage its current ability to screen and test therapeutic candidates, and create a unique approach to assimilating data that supports decision making iteratively throughout the discovery phase of drug development to identify both novel and repurposed CNS therapeutic candidates.

For more information, please visit or follow Vyant Bio at:Internet: www.Vyantbio.ComLinkedIn: https://www.Linkedin.Com/company/vyant-bioTwitter: @VyantBio

Forward Looking Statements:

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements pertaining to Vyant Bio, Inc.'s expectations regarding future financial and/or operating results, the efficacy of our drug screening and discovery process, and potential for our services, future revenue or growth in this press release constitute forward-looking statements. Any statements that are not historical fact (including, but not limited to, statements that contain words such as "will," "believes," "plans," "anticipates," "expects," and "estimates") should also be considered to be forward-looking statements. Forward-looking statements involve risks and uncertainties, including, without limitation, risks inherent in our attempts to discover drug candidates, partner with pharmaceutical and other biotechnology companies, achieve profitability, adapt to the global coronavirus pandemic, raise capital to meet our liquidity needs, and other risks discussed in the Vyant Bio, Inc. Form 10-K for the year ended December 31, 2021, and any subsequent filings with the Securities and Exchange Commission. These forward-looking statements speak only as of the date hereof. Vyant Bio disclaims any obligation to update these forward-looking statements.

Investor Contact:Skyline Corporate Communications Group, LLCScott Powell, PresidentOne Rockefeller Plaza, 10th FloorNew York, NY 10020 USAOffice: (646) 893-5835 x2Email: info@skylineccg.Com

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