Intragenic KANSL1 mutations and chromosome 17q21.31 deletions: broadening the clinical spectrum and genotype-phenotype correlations in a large cohort of patients.

BACKGROUND: The 17q21.31 deletion syndrome phenotype can be caused by either chromosome deletions or point mutations in the KANSL1 gene. To date, about 60 subjects with chromosome deletion and 4 subjects with point mutation in KANSL1 have been reported. Prevalence of chromosome deletions compared with point mutations, genotype-phenotype correlations and phenotypic variability have yet to be fully clarified. METHODS: We report genotype-phenotype correlations in 27 novel subjects with 17q21.31 deletion and in 5 subjects with KANSL1 point mutation, 3 of whom were not previously reported. RESULTS: The prevalence of chromosome deletion and KANSL1 mutation was 83% and 17%, respectively. All patients had similar clinical features, with the exception of macrocephaly, which was detected in 24% of patients with the deletion and 60% of those with the point mutation, and congenital heart disease, which was limited to 35% of patients with the deletion. A remarkable phenotypic variability was observed in both categories, mainly with respect to the severity of ID. Cognitive function was within normal parameters in one patient in each group. Craniosynostosis, subependymal heterotopia and optic nerve hypoplasia represent new component manifestations. CONCLUSIONS: In KANSL1 haploinsufficiency syndrome, chromosome deletions are greatly prevalent compared with KANSL1 mutations. The latter are sufficient in causing the full clinical phenotype. The degree of intellectual disability (ID) appears to be milder than expected in a considerable number of subjects with either chromosome deletion or KANSL1 mutation. Striking clinical criteria for enrolling patients into KANSL1 analysis include speech delay, distinctive facial dysmorphism, macrocephaly and friendly behaviour.

Response to rehabilitation of children and adolescents with epilepsy.

One hundred fifty-six children and adolescents with epilepsy from six Italian rehabilitation units were retrospectively enrolled to define the proportion of patients with epileptogenic developmental disorders who benefit from comprehensive rehabilitation programs and to identify factors predicting treatment response. The rehabilitation programs were classified as neuromotor, psychomotor, and speech and language. For each program, the response was coded as present or absent according to the caring physician's judgment. Selected demographic and clinical variables were correlated to treatment response. Neuromotor rehabilitation was performed in 86 cases (55%), psychomotor rehabilitation in 54 cases (34%), and speech and language rehabilitation in 40 cases (26%). Response rates were 58, 74, and 90%, respectively. Independent negative predictors of treatment response included severity of functional impairment (odds ratio=0.02, 95% confidence interval=0.01-0.14) and daily seizures (odds ratio=0.22, 95% confidence interval=0.08-0.58).

Early onset myoclonic epilepsy and 15q26 microdeletion: observation of the first case.

The authors report the study of a 30-month-old girl with refractory myoclonic epilepsy associated with mental retardation, growth delay, peculiar facial appearance, and minor physical anomalies. Extensive genetic studies were performed, including an array-based comparative genomic hybridization (array-CGH) that showed a cryptic interstitial deletion of 15q (5 Mb) affecting the 15q26.1-26.2 region. Partial deletions of the long arm of chromosome 15, including the 15q26 region, were observed in syndromic associations that typically include congenital diaphragmatic hernia, but neurologic features were poorly described and epileptic seizures were never reported. Our findings suggest that genes for seizures could be included in the 15q26.1q26.2 deletion interval.

Neuropsychological Deterioration Predicts Tumor Progression in a Young Boy With Bithalamic Glioma.

A description is given of the clinical, neuropsychological, and neuroimaging evolution of a 12-year-old boy (CG) who presented with bilateral thalamic astrocytoma (World Health Organization Grade 2). CG underwent an extensive neuropsychological assessment immediately after biopsy prior to any medical therapies and was followed up for 3 years until death. Neuropsychological functioning was thoroughly investigated by means of a detailed battery that included intelligence and cognitive functions. Evolution was characterized by cognitive deterioration that preceded neuroimaging signs of tumor progression. Starting from normal cognitive organization, the child exhibited visuospatial memory deficits and, afterward, diffuse cognitive impairment. The role of neuropsychological assessment in detecting early disease progression is discussed, mainly for rare pathologies whose evolution may be extremely variable.

Specific language disorders and season of birth: underlying environmental factors or chance findings?

The medical records of 358 children and adolescents with specific language disorders (SLD; 122 girls and 236 boys) seen in rehabilitation centers from Northern and Central Italy were examined to compare season of birth in these cases to those of the Italian population. Exposure was calculated using univariate and multivariate odds ratios (ORs) and 95% confidence intervals (CIs). Compared to the Italian population, patients with SLD had a 1.67 (95% CI [1.35-2.07]) chance of birth in October-December. Independent predictors were younger age at inclusion and being firstborn. Different neurobiological hypotheses can be drawn to explain these findings.

Visual hallucinations and pontine demyelination in a child: possible REM dissociation?

An 11 year-old-boy acutely developed complex visual and acoustic hallucinations. Hallucinations, consisting of visions of a threatening, evil character of the Harry Potter saga, persisted for 3 days. Neurological and psychiatric examinations were normal. Ictal EEG was negative. MRI documented 3 small areas of hyperintense signal in the brainstem, along the paramedian and lateral portions of pontine tegmentum, one of which showed post-contrast enhancement. These lesions were likely of inflammatory origin, and treatment with immunoglobulins was started. Polysomnography was normal, multiple sleep latency test showed a mean sleep latency of 8 minutes, with one sleep-onset REM period. The pontine tegmentum is responsible for REM sleep regulation, and contains definite "REM-on" and "REM-off" regions. The anatomical distribution of the lesions permits us to hypothesize that hallucinations in this boy were consequent to a transient impairment of REM sleep inhibitory mechanisms, with the appearance of dream-like hallucinations during wake.