br Neuroimaging Neuroimaging has not
Neuroimaging Neuroimaging has not yet been systematically reported in individuals with CDD, although case reports document normal ion channel 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. 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 cortex with loss of Purkinje cells and axonal torpedoes. Perivascular lymphocytes and axonal swelling in the anterior horn were the main findings in the spinal cord. This child had a pathogenic splice variant c.2277-2A>G, predicted to destroy the splice acceptor site of exon 16.
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, some required supplemental tube feedings and only 5.3% were able to eat and drink independently. Notably, ∼33% of individuals treated with the ketogenic diet had a gastrostomy; a similar percentage, 11 of 36 (31%) individuals, had gastrostomy in a caregiver survey of individuals with CDD. Sleep difficulties are very common, reported by parents in over 85% of individuals, sometimes dubbed “all night parties.”13, 47 Night waking was reported in 72 of 123 (58.5%) individuals. The odds of sleep problems were highest in the five to 10 year age group compared with those aged <5 years. Using the Child Health Sleep Questionnaire, the team at Children\'s Hospital Colorado found significantly abnormal sleep maintenance and duration. Abnormal sleep duration was reported in 63% of individuals with CDD compared with age-based norms, and the mean scores for waking once per night and more than once per night were increased (2.45 and 2.25, respectively, P < 0.001 for both). Breathing abnormalities include hyperventilation reported in 13.6% of individuals, breath holding in 26.4%, and aspiration in 22.6%. Parents have expressed concerns about cardiac arrhythmias, and one study by caregiver survey reported arrhythmia in 11 of 29 individuals with CDD who underwent electrocardiogram. Arrhythmias have not, however, been confirmed in the COEs, and binary fission is an area of current investigation (Olson et al., unpublished data, 2018). Sudden unexpected death in epilepsy may occur but in large cohorts the frequency of CDD is much lower than Dravet syndrome or SCN8A-related epilepsy given the frequencies of these disorders.76, 77, 78 However, the high seizure frequency and severity suggest that individuals with CDD are at high risk of sudden unexpected death in epilepsy, with daily and often nocturnal tonic or tonic-clonic seizures. Metabolic abnormalities are rare; a boy with CDD had transient methylmalonic acidemia but the concurrence may be coincidental.
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.