Recurrent mutations in the CDKL5 gene: genotype-phenotype relationships.
Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in epileptic encephalopathies in females with infantile spasms with features that overlap with Rett syndrome. With more than 80 reported patients, the phenotype of CDKL5-related encephalopathy is well-defined. The main features consist of seizures starting before 6 months of age, severe intellectual disability with absent speech and hand stereotypies and deceleration of head growth, which resembles Rett syndrome. However, some clinical discrepancies suggested the influence of genetics and/or environmental factors. No genotype-phenotype correlation has been defined and thus there is a need to examine individual mutations. In this study, we analyzed eight recurrent CDKL5 mutations to test whether the clinical phenotype of patients with the same mutation is similar and whether patients with specific CDKL5 mutations have a milder phenotype than those with other CDKL5 mutations. Patients bearing missense mutations in the ATP binding site such as the p.Ala40Val mutation typically walked unaided, had normocephaly, better hand use ability, and less frequent refractory epilepsy when compared to girls with other CDKL5 mutations. In contrast, patients with mutations in the kinase domain (such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, or c.145 + 2T > C) and frameshift mutations in the C-terminal region (such as c.2635_2636delCT) had a more severe phenotype with infantile spasms, refractory epileptic encephalopathy, absolute microcephaly, and inability to walk. It is important for clinicians to have this information when such patients are diagnosed.
Inserm, U1016, Paris, France.
Nadia
N
Bahi-Buisson
Nathalie
N
Villeneuve
Emilie
E
Caietta
Aurélia
A
Jacquette
Helene
H
Maurey
Gert
G
Matthijs
Hilde
H
Van Esch
Andrée
A
Delahaye
Anne
A
Moncla
Mathieu
M
Milh
Flore
F
Zufferey
Bertrand
B
Diebold
Thierry
T
Bienvenu
D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics*; D015518:Rett Syndrome / Q000235:genetics; D013036:Spasms, Infantile / Q000235:genetics; D049951:X Chromosome Inactivation
D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human