Clinical and electroencephalographic features in patients with CDKL5 mutations: Two new Italian cases and review of the literature

Pintaudi, Maria; Baglietto, M. G.; Gaggero, R.; Parodi, E; Pessagno, A.; Marchi, Margherita; Russo, Silvia; Veneselli, E.

doi:10.1016/j.yebeh.2007.10.010

Cited by 37 publications

(44 citation statements)

References 13 publications

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“…This mutation, that we already described [14], has been recently reported in another patient [6] who is defined as an atypical Rett. Our patient is similar in the most frequent features, but differs for seizure onset, autonomic features and sleep disturbance.…”

Section: Discussionsupporting

confidence: 58%

“…MRI was abnormal in four of six tested patients. Additional clinical data concerning patients 1 and 3 have been reported by Pintaudi [14]. A few clinical traits were individual.…”

Section: Resultsmentioning

confidence: 70%

“…Thirty-eight CDKL5 mutations have so far been described [2,6,7,13,14], and recently, various missense mutations have been found in three unrelated boys affected by profound mental retardation and intractable seizures, thus suggesting that amino acid changes in the CDKL5 protein can be tolerated despite the hemizygous condition [15]. Given the small number of patients, genotype-phenotype correlation studies have been limited, but it has been suggested that mutations affecting the aminoterminal catalytic domain are associated with a more severe phenotype consisting of an earlier onset and intractable infantile spasms followed by late-onset multifocal and myoclonic epilepsy [7].…”

Section: Introductionmentioning

confidence: 99%

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Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes

et al. 2009

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It has been found that CDKL5 gene mutations are responsible for early-onset epilepsy and drug resistance. We screened a population of 92 patients with classic/ atypical Rett syndrome, 17 Angelman/Angelman-like patients and six idiopathic autistic patients for CDKL5 mutations and exon deletions and identified seven novel mutations: six in the Rett subset and one in an Angelman patient. This last, an insertion in exon 11, c.903_904 dupGA, p.Leu302Aspfx49X, is associated with a relatively mild clinical presentation as the patient is the only one capable of sitting and walking alone. Of the six mutations, two are de novo missense changes affecting highly conserved aminoacid residues, c.215 T>C p.Ile72Thr and c.380A>G p.His127Arg (present in a mosaic condition) found in two girls with the most severe clinical presentation, while the remaining are the splicing c.145+2 T>C and c.2376 + 5G > A, the c.1648C > T p.Arg550X and the MPLA-identified c.162_99del261 mutation. RNA characterisation of four mutations revealed the aberrant transcript of the missense allele (case 2) and not the stop mutation (case 3), but also allowed the splicing mutation (case 1) and the c.-162_99del261 (case 4) to be categorised as truncating. The obtained data reinforce the view that a more severe phenotype is due more to an altered protein than haploinsufficiency. Furthermore, the mutational repertoire of the CDKL5 gene is shown to be expanded by testing patients with phenotypical overlap to Rett syndrome and applying multiplex ligation-dependent probe amplification.

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Section: Discussionsupporting

confidence: 58%

“…MRI was abnormal in four of six tested patients. Additional clinical data concerning patients 1 and 3 have been reported by Pintaudi [14]. A few clinical traits were individual.…”

Section: Resultsmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 99%

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Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes

et al. 2009

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“…Infantile spasms and refractory myoclonic epilepsy are frequent during the course of epilepsy but not always present in CDKL5 mutation patients ( tables 1 and 2 ) [Tao et al, 2004;Weaving et al, 2004;Evans et al, 2005;Mari et al, 2005;Scala et al, 2005;Archer et al, 2006;Buoni et al, 2006;Nectoux et al, 2006;Grosso et al, 2007;Bahi-Buisson et al, 2008b;Pintaudi et al, 2008;Nemos et al, 2009;Russo et al, 2009;Sprovieri et al, 2009;Bahi-Buisson et al, 2010;Mei et al, 2010;Psoni et al, 2010;Arts, 2011;Castren et al, 2011;Melani et al, 2011;Rademacher et al, 2011]. Patients who presented with a disrupted CDKL5 gene due to unbalanced translocations were excluded.…”

Section: Common and Rare Featuresmentioning

confidence: 99%

“…To date, only 5 recurrent CDKL5 mutations have been reported: c.119C 1 T (p.A40V) reported in 5 patients [Bahi-Buisson et al, 2008b;Rosas-Vargas et al, 2008;Nemos et al, 2009], c.533G 1 C (p.R178W) [Evans et al, 2005;Nemos et al, 2009] and c.2635_2636delCT both reported in 3 unrelated patients each [Elia et al, 2008;Nemos et al, 2009], and c.145+2 T 1 C [Bahi- Buisson et al, 2008a;Pintaudi et al, 2008] and c.175C 1 T (p.R59X) both reported in 2 unrelated patients each [Archer et al, 2006;Ricciardi et al, 2009].…”

Section: Mutations In the Cdkl5mentioning

confidence: 99%

<i>CDKL5</i>-Related Disorders: From Clinical Description to Molecular Genetics

Bahi-Buisson¹,

Bienvenu

2011

Mol Syndromol

101

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Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in girls with Rett-like features and early-onset epileptic encephalopathy including infantile spasms. To date, with more than 80 reported cases, the phenotype of CDKL5-related encephalopathy is better defined. The main features consist of early-onset seizures starting before 5 months of age, severe mental retardation with absent speech and Rett-like features such as hand stereotypies and deceleration of head growth. On the other hand, neuro-vegetative signs and developmental regression are rare in CDKL5 mutation patients. The CDKL5 gene encodes a serine threonine kinase protein which is characterized by a catalytic domain and a long C-terminal extension involved in the regulation of the catalytic activity of CDKL5 and in the sub-nuclear localization of the protein. To our knowledge, more than 70 different point mutations have been described including missense mutations within the catalytic domain, nonsense mutations causing the premature termination of the protein distributed in the entire open reading frame, splice variants, and frameshift mutations. Additionally, CDKL5 mutations have recently been described in 7 males with a more severe epileptic encephalopathy and a worse outcome compared to female patients. Finally, about 23 male and female patients have been identified with gross rearrangements encompassing all or part of the CDKL5 gene, with a phenotype reminiscent of CDKL5-related encephalopathy combined with dysmorphic features. Even if recent data clearly indicate that CDKL5 plays an important role in brain function, the protein remains largely uncharacterized. Phenotype-genotype correlation is additionally hampered by the relatively small number of patients described.

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A novel mutation in the X‐linked cyclin‐dependent kinase‐like 5 (CDKL5) gene associated with a severe Rett phenotype

Sprovieri

Conforti

Fiumara

et al. 2009

American J of Med Genetics Pt A

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Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have recently been reported in patients with severe neurodevelopmental disorder characterized by early-onset seizures, infantile spasms, severe psychomotor impairment and very recently, in patients with Rett syndrome (RTT)-like phenotype. Although the involvement of CDKL5 in specific biological pathways and its neurodevelopmental role have not been completely elucidated, the CDKL5 appears to be physiologically related to the MECP2 gene. Here we report on the clinical and CDKL5 molecular investigation in a very unusual RTT case, with severe, early-neurological involvement in which we have shown in a previous report, a novel P388S MECP2 mutation [Conforti et al. (2003); Am J Med Genet A 117A: 184-187]. The patient has had severe psychomotor delay since the first month of life and infantile spasms since age 5 months. Moreover, at age 5 years the patient suddenly presented with renal failure. The severe pattern of symptoms in our patient, similar to a CDKL5 phenotype, prompted us to perform an analysis of the CDKL5, which revealed a novel missense mutation never previously described. The X-inactivation assay was non-informative. In conclusion, this report reinforces the observation that the CDKL5 phenotype overlaps with RTT and that CDKL5 analysis is recommended in patients with a seizure disorder commencing during the first months of life.

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Clinical and electroencephalographic features in patients with CDKL5 mutations: Two new Italian cases and review of the literature

Cited by 37 publications

References 13 publications

Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes

Novel mutations in the CDKL5 gene, predicted effects and associated phenotypes

<i>CDKL5</i>-Related Disorders: From Clinical Description to Molecular Genetics

A novel mutation in the X‐linked cyclin‐dependent kinase‐like 5 (CDKL5) gene associated with a severe Rett phenotype

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