Description of a child with early infantile epileptic encephalopathy with genetically proven CDKL5 mutation

1. A Rare Case of CDKL5 Early
Infantile Epileptic Encephalopathy- 2
Dr Pramod Krishnan,
Department of Neurology,
Manipal Hospital, Bengaluru.

2. Introduction
• Early infantile epileptic encephalopathy-2 (EIEE-2) also known as X-
linked dominant infantile spasm syndrome-2 is caused by mutations in
the cyclin-dependent kinase-like 5 (CDKL5) gene.
• We present the electro-clinical phenotype of the first patient with
CDKL5 related EIEE-2 reported from India.
• Initially, it was thought to be a seizure onset variant of Retts syndrome.
• There is phenotypic variation, and therefore ‘CDKL5 disorder’ is now
used to describe this group of disorders.
Fehr H, Leonard H, Ho G, et al. Journal of Neurodevelopmental disorders 2015; 7:2.

3. Clinical features
• A 2-year-old female child with normal birth history, and non-
consanguineous parentage presented with recurrent generalised febrile
seizures since the age of 6 weeks.
• She developed daily clusters of epileptic spasms since 3 months of age.
• She was treated with ACTH, valproate and lamotrigine and these
spasms reduced by 6 months of age.
• Significant development lag, regression of milestones and motor
hypotonia was noted by this time.

4. Clinical features
• From the age of 6 months she had frequent generalised tonic, tonic
clonic seizures along with spasms, refractory to multiple AEDs,
cannabinoids and ketogenic diet.
• EEG showed disorganised background activity, generalised fast activity,
generalised and multifocal epileptiform discharges.
• MRI brain and blood investigations were unremarkable.

5. EEG bipolar montage showing generalised spike wave discharges and poorly formed background activity.

6. Polyspikes
EEG bipolar montage showing generalised polyspike discharges and poorly formed background activity.

7. Genetic test
• A heterozygous 3’ splice site variation in intron 5 of the CDKL5 gene
(chrX:18593473; G>G/A; Depth: 122x) that affects the invariant AG
acceptor splice site of exon 6 (c.146-1G>G/A; ENST00000379989) was
detected.
• This variant was not detected in both parents.
• This CDKL5 variant has not been reported in both the 1000 genomes
and ExAC databases.
• The in silico prediction of the variant is damaging by Mutation Taster 2
Liang JS, Shimojima K, Takayama R, et al. Epilepsia. 2011;52:1835–42.

8. Discussion
• EIEE-2 is an X-linked dominant severe neurologic disorder
characterized by seizure onset in the first months of life and severe
global developmental delay resulting in mental retardation and poor
motor control.
• Other features include poor language development, subtle dysmorphic
facial features, sleep disturbances, gastrointestinal problems and
stereotypic hand movements.
• There is some phenotypic overlap with Rett syndrome, but early
infantile epileptic encephalopathy-2 is considered to be a distinct entity.
Jähn J, Caliebe A, von Spiczak S, et al. J Child Neurol. 2013;28:937–41.

9. Conclusion
• CDKL5 mutations are a rare cause of early infantile epileptic
encephalopathy and has not been reported from India.
• It is characterized by intractable epilepsy and severe mental retardation,
followed later by the development of Rett syndrome like features.
• Long term prognosis for normal development is poor.
• No clear genotype-phenotype correlation has been identified.
• Genetic testing in children with typical phenotype is recommended.