International Consensus Recommendations for the Assessment and Management of Individuals With CDKL5 Deficiency Disorder

Abstract

CDKL5 Deficiency Disorder (CDD) is a rare, X-linked dominant condition that causes a developmental and epileptic encephalopathy (DEE). The incidence is between ~ 1:40,000 and 1:60,000 live births. Pathogenic variants in CDKL5 lead to seizures from infancy and severe neurodevelopmental delay. During infancy and childhood, individuals with CDD suffer impairments affecting cognitive, motor, visual, sleep, gastrointestinal and other functions. Here we present the recommendations of international healthcare professionals, experienced in CDD management, to address the multisystem and holistic needs of these individuals. Using a Delphi method, an anonymous survey was administered electronically to an international and multidisciplinary panel of expert clinicians and researchers. To provide summary recommendations, consensus was set, a priori, as >70% agreement for responses. In the absence of large, population-based studies to provide definitive evidence for treatment, we propose recommendations for clinical management, influenced by this proposed threshold for consensus. We believe these recommendations will help standardize, guide and improve the medical care received by individuals with CDD.

Ganaxolone: A New Treatment for CDKL5 Deficiency Disorder

“…The phenotype of CDD encompasses intellectual disability, seizures, and impairments in speech, motor functions, vision, sleep, and gastrointestinal function. [1][2][3] Seizures usually begin during the first 3 months of life and can appear in neonates. The most common types are generalized tonic-clonic convulsions, tonic seizures, and epileptic spasms.…”

“…1,3 The electroencephalographic and magnetic resonance imaging findings have been reviewed in a recent international consensus document. 2 There are a few reports on the effectiveness of ASMs in patients with CDD. 2 Studies of corticosteroids, vigabatrin, valproic acid, phenytoin, felbamate, carbamazepine, clonazepam, oxcarbazepine, and lacosamide reported not only initial seizure frequency reduction followed by loss of efficacy but also exacerbation of seizures in some cases.…”

“…2 There are a few reports on the effectiveness of ASMs in patients with CDD. 2 Studies of corticosteroids, vigabatrin, valproic acid, phenytoin, felbamate, carbamazepine, clonazepam, oxcarbazepine, and lacosamide reported not only initial seizure frequency reduction followed by loss of efficacy but also exacerbation of seizures in some cases. 2 The consensus document recommended no specific ASM in CDD, but indicated that alternatives could include ketogenic diet, vagus nerve stimulation, corpus callosotomy, pharmaceutical-grade cannabidiol, and ganaxolone.…”

“…2 The consensus document recommended no specific ASM in CDD, but indicated that alternatives could include ketogenic diet, vagus nerve stimulation, corpus callosotomy, pharmaceutical-grade cannabidiol, and ganaxolone. 2 The importance of successful treatment of CDD is suggested by a recent study that reported a slight improvement in subsequent development among patients who had better early seizure control. 5 Ganaxolone (3 hydroxy-3b-methyl-5d-pregnane-20-one) belongs to a novel group of neuroactive steroids called epalons that act as positive allosteric modulators of synaptic and extrasynaptic GABA A receptors to enhance GABAergic inhibitory tone.…”

“… 1 Pathogenic loss-of-function gene variants (occurring most commonly de novo , but also due to other mechanisms) result in CDKL5 deficiency disorder (CDD). 2 CDKL5 deficiency disorder is an X-linked dominant disease that occurs in 1/40,000 to 1/60,000 live births with a strong (4:1 to 12:1) female preponderance. 2 CDKL5 deficiency disorder was once thought to be a variant of Rett syndrome (and was also known as early infantile epileptic encephalopathy type 2) but is now recognized as its own entity.…”