Thursday, August 4, 2016

CDKL5 mutations

When Dustin and Penny Howard brought their newborn daughter Harper home from the hospital in spring 2010, all seemed normal for the Carrollton, Texas, family. But less than three weeks later, Harper began suffering from violent seizures that would ultimately lead to countless doctors’ visits, medications and therapies until her untimely death at age 5.

“For two weeks we were the perfect family of four,” Penny Howard, told “Then [Harper] had seizures starting at 2 weeks old, and from there, we were thrown into this life of special needs that we had no idea how to navigate.”

Over the next 10 months, the Howards traveled the country searching for a diagnosis for their daughter’s condition as well as any medications that would reduce the number of seemingly constant seizures that wracked her small body.

It wasn’t until they visited the Children’s Hospital of Boston, and met with an epilepsy specialist there, that her condition was given a name. A chromosome analysis revealed that Harper was living with a disorder known as CDKL5.

CDKL5 is a rare, non-hereditary genetic condition resulting in early onset seizures that are incredibly difficult to control, according to the International Foundation for CDKL5 Research. It is often associated with severe neurodevelopmental impairment as well.

“[CDKL5] does not allow the nerve cells to develop properly,” Dr. Richard Rivera, a pediatrician at Texas Physician’s Health Group in Carrollton, Texas, who treated Harper told “This results in developmental delay, mental retardation, growth retardation, and intractable seizures.”

The CDKL5 gene is located on the X-chromosome, according to Rivera, and typically codes for an enzyme that has been known to play a role in regulating and maintaining normal brain development. It is understood, Rivera said, that children with CDKL5 are missing that specific enzyme. However, the cause for CDKL5 and the role that the CDKL5 enzyme plays in the body is not entirely known.

CDKL5 is extremely rare; Rivera cites less than 200 documented cases of the disorder since the 1940s, when it was first described.

After Harper’s diagnosis, the Howards were unwavering in their search for a treatment for their daughter, who had been suffering from a multitude of symptoms including gastrointestinal and metabolic problems, cardiovascular issues and severe developmental delay. Additionally Harper’s seizures were occurring up to 20 times per day.

“Seizures stole everything from her,” Penny said. “Basically, we spent three years chasing a better quality of life. We traveled the U.S., went to several different doctors trying to figure out a way to make her life just a little bit better here and a little bit better there.”

Penny also detailed the numerous surgeries that Harper underwent throughout her life, including one that fitted her with a gastronomy tube – a tube that is inserted through the abdomen and allows for the delivery of medication and food directly to the stomach – and a vesicostomy, which is a surgical opening made in the bladder that allows urine to drain to the outside of the body, thus preventing urinary tract infections…

In July 2013, however, Penny discovered Real Scientific Hemp Oil (RSHO), a legal substance derived from cannabis that contains a substance called cannabidiol (CBD) which, according to, has been shown to provide relief from seizures that fail to be controlled by other treatments. RSHO contains no trace of Tetrahydrocannabinol (THC), the compound found in marijuana that is responsible for the drug’s hallucinogenic effects.

Harper’s treatment with RSHO began two months after her mother learned about the oil from, and after just a few months of it being administered to her, Harper’s family and doctors said they saw a noticeable change in the daily number of seizures she was experiencing.

“[Harper] ran the gamut of all the medications, some not effective at all, some improved [the seizures] slightly,” Rivera said. “Then I remember Penny coming to me [with RSHO] and I said ‘I can’t find a reason not to, let’s try it’, and a couple weeks later she seemed more alert, more awake, and the seizures started decreasing, after a couple of months they were down to one to two a day.”

Harper’s change, her mother recalled, was incredible.

“After we were able to find a way to help stop her seizures, she really came to life and had a wonderful life and was an amazing little girl who liked to do typical 5-year-old things,” Penny said. “She went from existing as part of our family, to being an interactive part of our family… and that’s a big deal, because for three years, we had no interaction from her whatsoever.”

For the next three years, the Howard family enjoyed their new life with Harper, who was still living with CDKL5 and its symptoms, but her attitude, interaction, and communication, they noticed, had improved substantially.

However, in January of 2016 Harper was diagnosed with a cold that then developed into pneumonia. Pneumonia was not uncommon for Harper, as children with CDKL5 and similar disorders are often at an increased risk for a compromised or sensitive immune system, Rivera asserts. 

“In most of children with [CDKL5], the disorder itself is not what is fatal; usually [death] is caused by secondary complications,” Rivera said. “[Kids with CDKL5] don’t have a strong cough and can’t take deep breaths unless you go to extreme lengths like intubation or putting them on a ventilator and [Harper’s family] didn’t want to do that.”

Harper entered the hospital on January 6 because her pneumonia had caused a life-threating metabolic imbalance and her organs were slowly shutting down. This imbalance, Penny said, was not detected until Harper was brought to the hospital, and by then, it was already too late. She died two days later; just three months shy of her sixth birthday.

The Howards made the decision to donate Harper’s brain and skin tissue to CDKL5 research in hopes of advancing a better understanding of the disorder and bring about a treatment that would help other children with CDKL5…

Today, researchers at the University of California, San Diego School of Medicine are utilizing Harper’s donation to aid their research which focuses on the causes of CDKL5 and any potential treatments. Harper’s tissue is also being studied at the University of Pennsylvania.

“We want to understand the gene that leads to the disorder and how that gene expression affects the cell, and how it creates problems in the patient,” Dr. Alysson Muotri, researcher and an associate professor at UC San Diego, told   “The other part focuses on finding treatments and drugs that can interfere with the pathway of CDKL5.”

Since Harper’s donation, researchers said they have managed to create a “mini-brain” that maps neurodevelopment in children with CDKL5 during the first trimester of human growth. This allows them to view the initial stages of the disease.

Harper’s brain was the first with CDKL5 to be donated towards research and is crucial to the work they are doing, researchers said.

“Part of the reason [for the difficulties of CDKL5 research] is the lack of materials to study. Without brain tissue, we can’t learn how CDKL5 works in the brain,” Muotri said. “Most donations we receive are from patients that are still alive, not the brain tissue, because it’s hard for families to donate the brains of loved ones, but it’s very important for research.”


  1. Kilstrup-Nielsen C, Rusconi L, La Montanara P, Ciceri D, Bergo A, Bedogni F, Landsberger N. What we know and would like to know about CDKL5 and its involvement in epileptic encephalopathy. Neural Plast. 2012;2012:728267.

    In the last few years, the X-linked serine/threonine kinase cyclin-dependent kinase-like 5 (CDKL5) has been associated with early-onset epileptic encephalopathies characterized by the manifestation of intractable epilepsy within the first weeks of life, severe developmental delay, profound hypotonia, and often the presence of some Rett-syndrome-like features. The association of CDKL5 with neurodevelopmental disorders and its high expression levels in the maturing brain underscore the importance of this kinase for proper brain development. However, our present knowledge of CDKL5 functions is still rather limited. The picture that emerges from the molecular and cellular studies suggests that CDKL5 functions are important for regulating both neuronal morphology through cytoplasmic signaling pathways and activity-dependent gene expression in the nuclear compartment. This paper surveys the current state of CDKL5 research with emphasis on the clinical symptoms associated with mutations in CDKL5, the different mechanisms regulating its functions, and the connected molecular pathways. Finally, based on the available data we speculate that CDKL5 might play a role in neuronal plasticity and we adduce and discuss some possible arguments supporting this hypothesis.

  2. Nemos C, Lambert L, Giuliano F, Doray B, Roubertie A, Goldenberg A, Delobel B, Layet V, N'guyen MA, Saunier A, Verneau F, Jonveaux P, Philippe C. Mutational spectrum of CDKL5 in early-onset encephalopathies: a study of a large collection of French patients and review of the literature. Clin Genet. 2009 Oct;76(4):357-71.

    The CDKL5 gene has been implicated in the molecular etiology of early-onset intractable seizures with infantile spasms (IS), severe hypotonia and atypical Rett syndrome (RTT) features. So far, 48 deleterious alleles have been reported in the literature. We screened the CDKL5 gene in a cohort of 177 patients with early-onset seizures, including 30 men and 10 girls with Aicardi syndrome. The screening was negative for all men as well as for women with Aicardi syndrome, excluding the CDKL5 gene as a candidate for this neurodevelopmental disorder. We report 11 additional de novo mutations in CDKL5 in female patients. For the first time, the MLPA approach allowed the identification of a partial deletion encompassing the promoter and the first two exons of CDKL5. The 10-point mutations consist of five missenses (with recurrent amino acid changes at p.Ala40 and p.Arg178), four splicing variants and a 1-base pair duplication. We present a review of all mutated alleles published in the literature. In our study, the overall frequency of mutations in CDKL5 in women with early-onset seizures is around 8.6%, a result comparable with previous reports. Noteworthy, the CDKL5 mutation rate is high (28%) in women with early-onset seizures and IS.

  3. Zhao Y, Zhang X, Bao X, Zhang Q, Zhang J, Cao G, Zhang J, Li J, Wei L, Pan H, Wu X. Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients. BMC Med Genet. 2014 Feb 25;15:24. doi:10.1186/1471-2350-15-24.

    Mutations in the cyclin-dependent kinase-like 5 (CDKL5) (NM_003159.2) gene have been associated with early-onset epileptic encephalopathies or Hanefeld variants of RTT(Rett syndrome). In order to clarify the CDKL5 genotype-phenotype correlations in Chinese patients, CDKL5 mutational screening in cases with early-onset epileptic encephalopathies and RTT without MECP2 mutation were performed.
    The detailed clinical information including clinical manifestation, electroencephalogram (EEG), magnetic resonance imaging (MRI), blood, urine amino acid and organic acid screening of 102 Chinese patients with early-onset epileptic encephalopathies and RTT were collected. CDKL5 gene mutations were analyzed by PCR, direct sequencing and multiplex ligation-dependent probe amplification (MLPA). The patterns of X-chromosome inactivation (XCI) were studied in the female patients with CDKL5 gene mutation.
    De novo CDKL5 gene mutations were found in ten patients including one missense mutation (c.533G > A, p.R178Q) which had been reported, two splicing mutations (ISV6 + 1A > G, ISV13 + 1A > G), three micro-deletions (c.1111delC, c.2360delA, c.234delA), two insertions (c.1791 ins G, c.891_892 ins TT in a pair of twins) and one nonsense mutation (c.1375C > T, p.Q459X). Out of ten patients, 7 of 9 females with Hanefeld variants of RTT and the remaining 2 females with early onset epileptic encephalopathy, were detected while only one male with infantile spasms was detected. The common features of all female patients with CDKL5 gene mutations included refractory seizures starting before 4 months of age, severe psychomotor retardation, Rett-like features such as hand stereotypies, deceleration of head growth after birth and poor prognosis. In contrast, the only one male patient with CDKL5 mutation showed no obvious Rett-like features as females in our cohort. The X-chromosome inactivation patterns of all the female patients were random.
    Mutations in CDKL5 gene are responsible for 7 with Hanefeld variants of RTT and 2 with early-onset epileptic encephalopathy in 71 girls as well as for 1 infantile spasms in 31 males. There are some differences in the phenotypes among genders with CDKL5 gene mutations and CDKL5 gene mutation analysis should be considered in both genders.

  4. Grosso S, Brogna A, Bazzotti S, Renieri A, Morgese G, Balestri P. Seizures and electroencephalographic findings in CDKL5 mutations: case report and review. Brain Dev. 2007 May;29(4):239-42.

    Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) have been detected in patients presenting with seizures in the first few months of life and Rett syndrome features. Twenty-seven cases have been detected to date. Generalized intractable seizures, as infantile spasms, and generalized tonic-clonic seizures and myoclonic seizures characterize the clinical picture of CDKL5 mutations. Here we report on a patient who presented with sleep-related hyperkinetic seizures. Our observation and review of the literature suggest that a broader polymorphic electroclinical pattern with both generalized and focal seizures may occur in patients with CDKL5 mutations. A screen for CDKL5 mutations is useful in patients, mainly females, with a history of early onset intractable seizures and becomes mandatory when idiopathic infantile spasms and/or atypical Rett syndrome features are also present.