Mosaic DCX deletion causes subcortical band heterotopia in males.

Subcortical band heterotopia (SBH) is a neuronal migration disorder usually described in females carrying heterozygous mutations in the X-linked doublecortin (DCX) gene. Hemizygous DCX mutations in males result in lissencephaly. Recently, exonic deletions of DCX resulting in a severer form of agyria have been reported. Nevertheless, rare male patients with SBH have been described with somatic mosaicism of point mutations. Here, we identified a somatic mosaicism for a deletion of exon 4 in the DCX gene in a male patient with SBH detected prenatally. This finding points to the possible implication of mosaic deletions in the DCX gene in unexplained forms of SBH and may allow for detection of SBH prenatally.

Motor and respiratory heterogeneity in Duchenne patients: implication for clinical trials.

AIMS: Our objective was to clarify the clinical heterogeneity in Duchenne muscular dystrophy (DMD). METHODS: The French dystrophinopathy database provided clinical, histochemical and molecular data of 278 DMD patients (mean longitudinal follow-up: 14.2 years). Diagnosis was based on mutation identification in the DMD gene. Three groups were defined according to the age at ambulation loss: before 8 years (group A); between 8 and 11 years (group B); between 11 and 16 years (group C). RESULTS: Motor and respiratory declines were statistically different between the three groups, as opposed to heart involvement. When acquired, running ability was lost at the mean age of 5.41 (group A), 7.11 (group B), 9.19 (group C) years; climbing stairs ability at 6.24 (group A), 7.99 (group B), 10,42 (group C) years, and ambulation at 7.10 (group A), 9.25 (group B), 12.01 (group C) years. Pulmonary growth stopped at 10.26 (group A), 12.45 (group B), 14.58 (group C) years. Then, forced vital capacity decreased at the rate of 8.83 (group A), 7.52 (group B), 6.03 (group C) percent per year. Phenotypic variability did not rely on specific mutational spectrum. CONCLUSION: Beside the most common form of DMD (group B), we provide detailed description on two extreme clinical subgroups: a severe one (group A) characterized by early severe motor and respiratory decline and a milder subgroup (group C). Compared to group B or C, four to six times fewer patients from group A are needed to detect the same decrease in disease progression in a clinical trial.

A visual processing but no phonological disorder in a child with mixed dyslexia.

The case study of Martial, a French 9-year-old boy, who exhibits severe mixed dyslexia and surface dysgraphia is reported. Despite very poor pseudo-word reading, Martial has preserved phonological processing skills as his good oral language, good phoneme awareness and good verbal short-term memory show. He exhibited a strong length effect when reading briefly presented words but no sign of mini-neglect. His letter-string processing abilities were assessed through tasks of whole and partial report. In whole report, Martial could only name a few letters from briefly displayed 5-consonant strings. He showed an initial-position advantage and a sharper than expected left-to-right gradient of performance. He performed better when asked to report a single cued letter within the string but then showed an atypical right-side advantage. The same rightward attentional bias was observed in whole report when top-down control was prevented. Otherwise, Martial showed preserved single letter identification skills and good processing of 5-letter strings when letters were sequentially displayed one at a time. His poor letter-string processing thus reflects a parallel visual processing disorder that is compatible with either a visual attention (VA) span or a visual short-term memory disorder. Martial was further engaged in a complex reaching movement task involving VA and simultaneous processing. He performed motor sequences not as a whole but as a succession of independent motor units, suggesting that his attention was not allocated in parallel to the two to-be-reached targets prior to movement execution. Against a more basic motor disorder however, he showed good performance in a task of cyclical pointing movements. The overall findings suggest that Martial suffers from a visual simultaneous processing disorder that disturbs letter identification in strings. Instead of being restricted to letter-string processing, this VA disorder might extend to non-verbal task.

Key clinical features to identify girls with CDKL5 mutations.

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.

Sequential or simultaneous visual processing deficit in developmental dyslexia?

The ability of dyslexic children with or without phonological problems to process simultaneous and sequential visual information was assessed using two tasks requiring the oral report of simultaneously or sequentially displayed letter-strings. The two groups were found to exhibit a simultaneous visual processing deficit but preserved serial processing skills. However, the impairment in simultaneous processing was larger in the dyslexic group with no phonological disorder. Although sequential and simultaneous processing skills both related to reading performance, simultaneous processing alone significantly contributed to reading speed and accuracy. These findings suggest that a simultaneous processing disorder might contribute to developmental dyslexia.