Respiratory and sleep disorders in female children with atypical Rett syndrome caused by mutations in the CDKL5 gene

Abstract

AIM In female children with drug-resistant seizures and developmental delay from birth, atypical Rett syndrome caused by mutations in the CDKL5 gene should be considered. Several clinical features resemble classic Rett syndrome. Respiratory and sleep abnormalities are frequently present in Rett syndrome, whereas little is known in patients with CDKL5 mutations.METHOD In four genetically confirmed female patients with CDKL5 mutations (age range 2-15y), the presence of breathing and sleep abnormalities was evaluated using the validated Sleep Disturbance Scale for Children and polysomnography (PSG). RESULTSThe Sleep Disturbance Scale for Children indicated disorders of initiating and maintaining sleep, daytime somnolence, and sleep breathing disorders. In one patient, PSG showed central apnoeas during sleep: her total apnoea-hypopnoea index (AHI) was 4.9, of which the central AHI was 3.4 ⁄ h. When awake, central apnoeas were present in two of the four female children (central AHI 28 ⁄ h and 41 ⁄ h respectively), all preceded by hyperventilation. PSG showed low rapid eye movement (REM) sleep (9.7-18.3%), frequent awakenings, and low sleep efficiency (range 59-78%).INTERPRETATION Episodic hyperventilation followed by central apnoeas was present while awake in two of four patients. This may indicate failure of brainstem respiratory centres. In addition, low REM sleep, frequent arousals (not caused by apnoeas ⁄ seizures), and low sleep efficiency were present. Similar to Rett syndrome, in patients with CDKL5 mutations PSG seems warranted to evaluate breathing and sleep disturbances.

Effect of desipramine on patients with breathing disorders in RETT syndrome

“…First, as described by several authors, breathing dysfunction in RTT is very complex and highly variable 5, 6, 7, 8, 22. We monitored the breathing disorders in awake patients at each visit and found similar results on AHI to those reported in two patients with atypical Rett 23. We also confirmed the high variability of breathing patterns shown by the measurements of AHI at baseline (see Fig.…”

Phosphoproteomic screening identifies physiological substrates of the CDKL 5 kinase

“…We next investigated the impact of pathogenic mutations on the activity of CDKL5 towards MAP1S. Most of the pathogenic mutations are located in the kinase catalytic domain (Fig A; Krishnaraj et al , ), and we investigated the impact of pathogenic kinase domain mutations Gly 20 Asp (Raymond et al , ), Leu 64 Pro (Fichou et al , ), Ile 72 Thr (Saletti et al , ), Arg 178 Trp (Nemos et al , ) and Gln 219 Pro (Hagebeuk et al , ). We also investigated a series of CDKL5 variants that are either benign: Gln 791 Pro (Tao et al , ) and Val 999 Met (Nectoux et al , ) or of uncertain significance: Leu 302 Phe (Liang et al , ), Asn 399 Thr (Sprovieri et al , ), Val 718 Met (Krishnaraj et al , ) and Val 793 Ala (Archer et al , ; Fig A).…”

CDKL5 deficiency disorder: Relationship between genotype, epilepsy, cortical visual impairment, and development

“…Patients with CDD are reported to have very early onset of epilepsy (median of 6 weeks) and severe developmental delay, with many patients unable to achieve independent walking or speech . However, CDD also affects several other neurologic domains, with evidence of disrupted sleep, gastrointestinal problems, dysautonomia, and cortical visual impairment (CVI) . CVI is also seen in rodent models of CDKL5 and has been demonstrated to be an important comorbidity and potentially a marker of clinical improvement in other epileptic encephalopathies .…”