Deep intronic KRIT1 mutation in a family with clinically silent multiple cerebral cavernous malformations.

Loss-of-function mutations in CCM1/KRIT1, CCM2/MGC4607 and CCM3/PDCD10 genes are identified in the vast majority of familial cases with multiple cerebral cavernous malformations (CCMs). However, genomic DNA sequencing combined to large rearrangement screening fails to detect a mutation in 5% of those cases. We report a family in which CCM lesions were discovered fortuitously because of the investigation of a developmental delay in a boy. Three members of the family on three generations had typical multiple CCM lesions and no clinical signs related to CCM. No mutation was detected using genomic DNA sequencing and quantitative multiplex PCR of short fluorescent fragments (QMPSF). cDNA sequencing showed a 99-nucleotide insertion between exons 5 and 6 of CCM1, resulting from a mutation located deep into intron 5 (c.262+132_262+133del) that activates a cryptic splice site. This pseudoexon leads to a premature stop codon. These data highly suggest that deep intronic mutations explain part of the incomplete mutation detection rate in CCM patients and underline the importance of analyzing the cDNA to provide comprehensive CCM diagnostic tests. This kind of mutation may be responsible for apparent sporadic presentations due to a reduced penetrance.

[Understand the neurodevelopment of language: a necessity to prevent learning disabilities in children]. / Comprendre le neurodéveloppement du langage, une nécessité pour prévenir les troubles des apprentissages de l'enfant ?

Clinical and radiological knowledge of language development in the former premature infant compared to the newborn allows us to argue for exploration of the sensorimotor co-factors required for proper language development. There are early representations of the maternal language in the infant's visual, auditory, and sensorimotor areas, activated or stabilized by orofacial and articulatory movements. The functional architecture of language is different for vulnerable children such as premature infants. We have already mentioned the impact of early dysfunction of the facial praxis fine motor skills in this population presenting comprehension disorders. A recent meta-analysis confirms the increasing difficulty of understanding between 3 and 12 years, questioning the quality of the initial linguistic processes. A precise analysis of language, referenced from 3 years of age, should be completed by sensorimotor tests to assess possible constraints in automating neurolinguistic foundations. The usual assessment at this age can exclude sensory disturbances and communication and offers guidance and socialization. However, a recent study shows the ineffectiveness of "language-reinforced immersion" at 2 and 3 years in a population of vulnerable children. The LAMOPRESCO study of language and motor skills in the premature infant (National PHRC 2010) has assessed language and sensorimotor skills of preterm-born (<33 weeks) 3.5-year-old children without cerebral palsy. Fragile children were randomized into 2 groups, 1 stimulated by a specific individual protocol, the other given guidance. The primary endpoint was phonology, assuming that it is composed of very early good-quality sensorimotor integration stabilized by the child's oral facial motor skills before 5 years of age. This developmental integrative dynamic validates the "motor theory of speech perception." Early and accurate assessment of language and the patient's constraints should differentiate and specify management strategies for all children, whatever their background and pathologies.

Prognostic value of EEG in very premature newborns.

OBJECTIVE: To evaluate the prognostic value of EEG regarding the psychomotor outcomes of very premature newborns. METHODS: 76 premature infants <30 weeks gestation were enrolled between January 2001 and August 2004. They were examined at 4 and 9 months corrected ages, and at 18 months, 3-4 years and 5-6 years. EEGs performed in the neonatal period were analysed by two neurologists blind to the child's outcome. RESULTS: The mean follow-up was 5.6 years. 25 infants had normal neurological development and all EEGs were normal for 22 of these. 36 others had developmental disabilities (7 motor sequelae and 29 delayed psychomotor development). Of 187 EEGs, 43 were dysmature, 13 disorganised, 2 displayed electrical seizures without clinical manifestations and 15 showed other abnormal features. Dysmaturity was the predominant EEG pattern in newborns with severe or moderate sequelae and was persistent on several EEGs in 12 of these. In contrast, only three infants with normal development had a dysmature pattern on one EEG. All infants with a disorganised pattern had cognitive sequelae, and two had cerebral palsy. The sensitivity of EEG regarding psychomotor outcome was 83.3%, the specificity was 88% and the positive predictive value was 90.9%. CONCLUSIONS: Very preterm neonates remain at high risk of neurological sequelae and EEG is a sensitive method for assessing neuromotor and cognitive prognosis. A dysmature pattern was the predominant EEG characteristic in infants who developed severe or moderate impairment. Early postnatal tracing is useful but additional recordings are generally necessary to detect high-risk newborns.

Molecular basis of a selective C1s deficiency associated with early onset multiple autoimmune diseases.

We have investigated the molecular basis of selective and complete C1s deficiency in 2-year-old girl with complex autoimmune diseases including lupus-like syndrome, Hashimoto's thyroiditis, and autoimmune hepatitis. This patient's complement profile was characterized by the absence of CH50 activity, C1 functional activity <10%, and undetectable levels of C1s Ag associated with normal levels of C1r and C1q Ags. Exon-specific amplification of genomic DNA by PCR followed by direct sequence analysis revealed a homozygous nonsense mutation in the C1s gene exon XII at codon 534, caused by a nucleotide substitution from C (CGA for arginine) to T (TGA for stop codon). Both parents were heterozygous for this mutation. We used the new restriction site for endonuclease Fok-1 created by the mutation to detect this mutation in the genomic DNA of seven healthy family members. Four additional heterozygotes for the mutation were identified in two generations. Our data characterize for the first time the genetic defect of a selective and complete C1s deficiency in a Caucasian patient.