Key clinical features to identify girls with CDKL5 mutations

Abstract

Mutations in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been shown to cause infantile spasms as well as Rett syndrome (RTT)-like phenotype. To date, less than 25 different mutations have been reported. So far, there are still little data on the key clinical diagnosis criteria and on the natural history of CDKL5-associated encephalopathy. We screened the entire coding region of CDKL5 for mutations in 183 females with encephalopathy with early seizures by denaturing high liquid performance chromatography and direct sequencing, and we identified in 20 unrelated girls, 18 different mutations including 7 novel mutations. These mutations were identified in eight patients with encephalopathy with RTT-like features, five with infantile spasms and seven with encephalopathy with refractory epilepsy. Early epilepsy with normal interictal EEG and severe hypotonia are the key clinical features in identifying patients likely to have CDKL5 mutations. Our study also indicates that these patients clearly exhibit some RTT features such as deceleration of head growth, stereotypies and hand apraxia and that these RTT features become more evident in older and ambulatory patients. However, some RTT signs are clearly absent such as the so called RTT disease profile (period of nearly normal development followed by regression with loss of acquired fine finger skill in early childhood and characteristic intensive eye communication) and the characteristic evolution of the RTT electroencephalogram. Interestingly, in addition to the overall stereotypical symptomatology (age of onset and evolution of the disease) resulting from CDKL5 mutations, atypical forms of CDKL5-related conditions have also been observed. Our data suggest that phenotypic heterogeneity does not correlate with the nature or the position of the mutations or with the pattern of X-chromosome inactivation, but most probably with the functional transcriptional and/or translational consequences of CDKL5 mutations. In conclusion, our report show that search for mutations in CDKL5 is indicated in girls with early onset of a severe intractable seizure disorder or infantile spasms with severe hypotonia, and in girls with RTT-like phenotype and early onset seizures, though, in our cohort, mutations in CDKL5 account for about 10% of the girls affected by these disorders.

Neurodevelopmental and neurobehavioral characteristics in males and females with CDKL5 duplications

“…18,[39][40][41] The vast majority of genetic alterations in CDKL5 45 reported a CDKL5 alteration in a 47,XXY boy with the early-onset seizure variant of Rett syndrome and concluded that a random pattern of XCI did not influence the severity of the disease. Skewed XCI has been proposed to explain the observed phenotypic variability in some females heterozygous for a mutated or deleted CDKL5 allele.…”

Mutations in the C-terminus of CDKL5: proceed with caution

“…The recurrent c.2635_2636delCT mutation was found in an 8-year-old girl with severe intellectual disability, poor eye fixation, hand mouthing, no walk, no speech, and seizures, and in a 2-year-old girl with regression, severe intellectual disability, poor eye fixation, stereotypies, hand apraxia, and seizures. 8,14 The p.Gln834X mutation was found in a 4-year-old girl with severe intellectual disability, stereotypies, hand apraxia, and seizures. 9 As the theoretical 107-kDa isoform appeared to be the major stable isoform in human brain, 5 and considering that the mouse cdkl5 protein contains only 938 amino acids, we can assume that genetic variations beyond the codon 938 in human CDKL5 115 protein may have minor or no significance.…”

“…8 Individual written consent was obtained from all sampled individuals or their legal guardians. The complete coding region of the CDKL5 gene (exons 2-21; GenBank accession number NM_003159) was screened for mutations using direct sequencing and multiplex ligation-dependent probe amplification.…”

West syndrome caused by homozygous variant in the evolutionary conserved gene encoding the mitochondrial elongation factor GUF1

“…The most frequent genetic causes of IS are mutations in TSC1 (about 9% of all IS/WS patients, OMIM#191100), CDKL5, ARX and STXBP1 genes, as well as multiple genomic imbalances, the commonest being Pallister-Killian syndrome (tetrasomy 12p; OMIM#601803) and 1p36 deletion (OMIM#607872). [7][8][9][10][11][12][13] These and other genetic causes such as genes encoding proteins involved in inborn errors of metabolism were recently reviewed in Paciorkowski et al 14 IS/WS also occur with a lower prevalence as a feature of other genetic diseases, such as Down syndrome. 14 This heterogeneity often impedes the identification of the etiology of IS/WS within the clinical practice.…”