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Indian Pediatr 2015;52: 537 |
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CDKL5 Encephalopathy: A Rare Cause of
Infantile Epileptic Encephalopathy
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*Mahesh Kamate and Mayank Detroja
Department of Pediatrics, JN Medical College, Belgaum,
Karnataka, India.
Email:
[email protected]
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‘Epileptic encephalopathy’ is defined as an epilepsy syndrome where the
seizures and/or interictal EEG discharge have permanent deleterious
effects on brain development [1]. Most of them present with seizures
that are refractory to treatment, and have a poor prognosis. The
etiology is very diverse and most of them are due to a genetic or
metabolic cause. While the metabolic causes for refractory epilepsy in
infancy (e.g. pyridoxine dependency, non-ketotic hyperglycinemia)
are commonly thought of and investigated for, many pediatricians may not
be well versed with the genetic causes of epileptic encephalopathy.
Recently many genes have been found to be associated
with early onset epileptic encephalopathy [2]. A correct diagnosis helps
in counseling of parents, avoiding unnecessary treatment with
antiepileptic drugs, hormones and vitamins, and enabling prenatal
diagnosis.
Mutations within the X-linked Cyclin-dependent kinase-like
5 (CDKL5) gene are one of the important causes of
early-onset epileptic encephalopathies [2]. Patients present with
refractory epilepsy, beginning before the age of three months, often in
neonatal period, with very frequent seizures and severe developmental
delay or regression. We herein report a girl with CDKL5
encephalopathy where the diagnosis was delayed by almost 18 months. She
had seizures (clonic seizures and spasms, 5-15 episodes per day)
starting at age of 1 month with significant developmental delay. There
was severe microcephaly (head circumference 40 cm). hypotonia and poor
eye contact. Biochemical tests including tests, for neurometabolic
disorders (tandem mass spectrometry, lactate, ammonia, urine gas
chromatography/mass spectrometry) were all within normal limits.
Cerebrospinal fluid (CSF) analysis was normal with normal sugar,
lactate, pipecolic acid and glycine levels. Magnetic resonance imaging
(MRI) of brain was normal (done twice at 12 months interval). While the
first EEG was normal, subsequent EEGs showed multifocal epilepsy with
burst suppression pattern both during sleep and while awake. She did not
respond to multiple antiepileptic drugs (newer and conventional in
combination), trial of pyridoxine, folinic acid, pyridoxal phosphate and
ketogenic diet.
Finally, genetic study for infantile epileptic
encephalopathy panel (next generation sequencing) was done and a novel
heterozygous missense mutation in CDKL5 gene (chrX: 18598083;
A>A/G) which causes an amino acid change in codon 133, exon 7
[c.398A>A/G (ENST00000379989); p.H133R] was detected. This mutation was
also found to be damaging by SIFT, PolyPhen, likelihood ratio test and
Mutation Taster.
CDKL5 encephalopathy is rare disorder causing
refractory epilepsy and Rett’s syndrome like phenotype. It is
characterized by refractory epilepsy in girls, severe hypotonia, with
severe psychomotor delay and features that overlap with Rett syndrome.
There are three clinical stages of epilepsy in patients with CDKL5
mutations: (i) early-onset, recurrent convulsive seizures, severe
hypotonia, and normal findings of interictal electroencephalograms; (ii)
epileptic encephalopathy with infantile spasms and hypsarrhythmia; and (iii)
refractory tonic or myoclonic epilepsy with EEG showing multifocal
epilepsy [3-5]. Treatment is only supportive and symptomatic.
Contributors: MK: diagnosed the condition in the
patient and was involved in the management of the case. He has drafted
the article and will act as the guarantor of the manuscript; MD: did the
literature search and helped in the drafting of the article.
Funding: None; Competing interests: None
stated.
References
1. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J,
Cross JH, van Emde Boas W, et al. Revised terminology and
concepts for organization of seizures and epilepsies: Report of the ILAE
Commission on Classification and Terminology, 2005-2009. Epilepsia.
2010;51:76-85.
2. Mastrangelo M, Leuzzi V. Genes of early-onset
epileptic Encephalopathies: From genotype to phenotype. Pediatr Neurol.
2012;46:24-31.
3. Bahi-Buisson N, Kaminska A, Boddaert N, Rio M,
Afenjar A, Gérard M, et al. The three stages of epilepsy in
patients with CDKL5 mutations. Epilepsia. 2008;49:1027-37.
4. Moseley BD, Dhamija R, Wirrell EC, Nickels KC.
Historic, clinical, and prognostic features of epileptic
encephalopathies caused by CDKL5 mutations. Pediatr Neurol.
2012;46:101-5.
5. Saitsu H, Osaka H, Nishiyama K, Tsurusaki Y, Doi
H, Miyake N, et al. A girl with early-onset epileptic
encephalopathy associated with microdeletion involving CDKL5. Brain Dev.
2012;34:364-7.
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