Phenotype to Genotype and Back Again

Abstract

CDKL5 Deficiency Disorder: Relationship Between Genotype, Epilepsy, Cortical Visual Impairment, and Development

Demarest ST, Olson HE, Moss A, et al. Epilepsia. 2019;60(8):1733-1742. doi:10.1111/epi.16285. Epub 2019 Jul 16. PMID: 31313283

Objective:

The cyclin-dependent kinase-like 5 (CDKL5) gene is a known cause of early-onset developmental and epileptic encephalopathy, also known as CDKL5 deficiency disorder (CDD). We sought to (1) provide a description of seizure types in patients with CDD, (2) provide an assessment of the frequency of seizure-free periods and cortical visual impairment, (3) correlate these features with genotype and gender, and (4) correlate these features with developmental milestones.

Methods:

This is a cohort study of patients with CDD. Phenotypic features were explored and correlated with gene variant grouping and gender. A developmental score was created based on achieving 7 primary milestones. Phenotypic variables were correlated with the developmental score to explore markers of better developmental outcomes. Multivariate linear regression was used to account for age at last visit.

Results:

Ninety-two patients with CDD were seen during the enrollment period. Eighteen (19%) were male; median age at the last visit was 5 years (interquartile range: 2.0-11.0). Eighty-one percent of patients developed epileptic spasms, but only 47% of those also had hypsarrhythmia. Previously described hypermotor-tonic-spasms sequence was seen in only 24% of patients, but 56% of patients had seizures with multiple phases (often tonic and spasms). Forty-three percent of patients experienced a seizure-free period ranging from 1 to >12 months, but only 6% were still seizure-free at the last visit. Cortical visual impairment was present in 75% of all CDD patients. None of these features was associated with genotype group or gender. Cortical visual impairment was correlated with reduced milestone achievement after adjusting for age at the last visit and a history of hypsarrhythmia.

Significance:

The most common seizure types in CDD are epileptic spasms (often without hypsarrhythmia) and tonic seizures that may cluster together. Cortical visual impairment is a common feature in CDD and is correlated with achieving fewer milestones.

Commentary

Clinicians have been delineating syndromes for decades, long before the tools to identify genes—let alone pathogenic variants in those genes—were available. The first syndromes described were those with obvious, consistent, and recognizable physical features and associated congenital anomalies, though it often took years to identify even a handful of individuals with the same collection of clinical features comprising a specific syndrome. The gradual introduction of genetic testing provided molecular confirmation that 2 individuals had the same disorder, but often only those individuals with features highly suggestive of a clinical syndrome underwent testing—syndromes were defined on a “phenotype-first” basis. Advances in genomic technologies, most notably large gene panels and exome sequencing using massively parallel sequencing, have led to a shift from “phenotype-first” to “genotype-first” diagnosis such that many “syndromes” are now identified first by shared genetic etiology.¹

CDKL5 deficiency disorder (CDD) was first described in 2004^2,3 in several females with Rett-like phenotypes. Authors of one study noted that “it remains to be determined whether CDKL5 mutations are more prevalent in specific clinical subgroups…or in other clinical presentations” and emphasized the “need for a large-scale multicenter collaborative study using, when feasible, cases sourced on a population basis.”

Fast-forward to 2019: clinical genetic testing is increasingly available, and within minutes of receiving a genetic diagnosis, families can connect with each other, identify family support groups and foundations, and search for the expert physicians and scientists studying their child’s disorder. These shifts in both the identification of patients with specific genetic conditions and the ability of patients and families to rapidly connect are beneficial for patients and families, researchers, and physicians who care for children with rare disorders. Casting a wide, genetic testing net means sometimes identifying affected individuals with unexpected or nonclassical features, (re)defining the true phenotypic spectrum of a given disorder. For some disorders, including CDD, Centers of Excellence have emerged where multidisciplinary teams perform comprehensive evaluations and, when possible, long-term follow-up.

Demarest and colleagues⁴ revisited CDD phenotypes and genotypes by collecting standardized data from 3 CDKL5 Centers of Excellence over a 3-year period. They focused on seizures types and frequency, cortical visual impairment (CVI), and developmental milestones. Using systematic data collection in a relatively large (n = 92) cohort—enabled by online connections, foundation support, and the emergence of Centers of Excellence—some new findings emerged. Seizure types are variable and tend to cluster in phases, and spasms occur with or (more likely) without hypsarrhythmia. Cortical visual impairment was common, occurring in 75% of individuals studied, and the presence of CVI was associated with poorer developmental outcomes. The authors developed a simple developmental severity scale using 7 developmental milestones; although all individuals with CDD have significant developmental delays, developmental scores tended to increase with age, suggesting that affected children continue to make progress throughout childhood. Finally, they were unable to define any genotype–phenotype correlations.

Detailed phenotyping studies are often performed when a new genetic syndrome is identified, which is clearly an important step for understanding newly discovered disorders. But why continue to study phenotypes in well-established disorders such as CDD? As noted above, with the introduction of more widespread genetic testing, the number of individuals who can be identified is increasing; without the need to guess at the specific condition based on clinical features prior to testing, individuals with atypical or unexpected features are picked up through genetic testing. Understanding the full phenotypic spectrum is important for counseling newly diagnosed families and for recommending specific therapies and medical surveillance that are likely to be beneficial.

Furthermore, as we enter a new era characterized by emerging novel genetic and small molecule therapies for rare disorders, it will be especially important to have clinical and biological biomarkers to measure the effectiveness of new therapies in clinical trials. The developmental severity score proposed in the study by Demarest and colleagues is one example of a tool that could be implemented to evaluate patients enrolled in trials, for example. Understanding the typical seizure frequency and periods of seizure freedom is another important “marker” that might be used to establish whether a new therapy can change outcomes.

The CDD study is one example of “large-scale multicenter collaborative study” needed for rare disorders to be clinical trial ready. Most families are eager to contribute to the understanding of their child’s disorder and to be prepared to test novel treatments that may benefit their children and future affected families. Detailed phenotyping and natural history studies are an important step in the process.

By Heather C. Mefford