Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the ...neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 × 10(-10)) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Recurrent 15q13.3 microdeletions were recently identified with identical proximal (BP4) and distal (BP5) breakpoints and associated with mild to moderate mental retardation and epilepsy.
To assess ...further the clinical implications of this novel 15q13.3 microdeletion syndrome, 18 new probands with a deletion were molecularly and clinically characterised. In addition, we evaluated the characteristics of a family with a more proximal deletion between BP3 and BP4. Finally, four patients with a duplication in the BP3-BP4-BP5 region were included in this study to ascertain the clinical significance of duplications in this region.
The 15q13.3 microdeletion in our series was associated with a highly variable intra- and inter-familial phenotype. At least 11 of the 18 deletions identified were inherited. Moreover, 7 of 10 siblings from four different families also had this deletion: one had a mild developmental delay, four had only learning problems during childhood, but functioned well in daily life as adults, whereas the other two had no learning problems at all. In contrast to previous findings, seizures were not a common feature in our series (only 2 of 17 living probands). Three patients with deletions had cardiac defects and deletion of the KLF13 gene, located in the critical region, may contribute to these abnormalities. The limited data from the single family with the more proximal BP3-BP4 deletion suggest this deletion may have little clinical significance. Patients with duplications of the BP3-BP4-BP5 region did not share a recognisable phenotype, but psychiatric disease was noted in 2 of 4 patients.
Overall, our findings broaden the phenotypic spectrum associated with 15q13.3 deletions and suggest that, in some individuals, deletion of 15q13.3 is not sufficient to cause disease. The existence of microdeletion syndromes, associated with an unpredictable and variable phenotypic outcome, will pose the clinician with diagnostic difficulties and challenge the commonly used paradigm in the diagnostic setting that aberrations inherited from a phenotypically normal parent are usually without clinical consequences.
In the last few years Multifocal Vibration (MFV) has been evaluated as a tool to modify posture and to speed recovery after physical exercise. The aim of this study is to assess whether MFV can also ...modify resting state EEG. Eleven healthy subjects were included in this study. All subjects underwent a resting state EEG recording of six minutes (three with eyes closed and three minutes with eyes open) for evaluation of resting cortical rhythms, before and after one session of MFV with KEOPE-GPR. Data obtained were collapsed in four region of interest (ROIs): frontal, central, temporal and occipital. Frequency bands of interest were δ (0.5–3.5 Hz), θ (4–7.5 Hz), α 1 (8–10.5 Hz), α 2 (11–12.5 Hz), β 1 (13–19.5 Hz), and β 2 (20–30 Hz). The ratio between slow (delta + theta) and faster (alpha1 + alpha2) rhythms was evaluated using paired t -test. Subsequent statistical analysis was carried on using repeated measures ANOVA (RM-ANOVA) using time (2-levels), side (2-levels) and rhythm (6-levels) as within-subjects factors for each ROI. No statistically significant variations were observed on qEEG with eyes closed. The analysis of ratios between slow and faster frequencies after MFV identified significant variations following MFV ( p < .001 for all ROIs). RM-ANOVA identified a significant rhythm effect and time * rhythm interaction in frontal (p.046), central (p.003) and temporal (p.004) ROIs; only a trend was observed for occipital ROI (p.055). Post-hoc analysis showed increase in alpha1 band relative power and decrease in delta band in frontal, central and temporal ROIs. MFV can modulate oscillatory activity as observed by qEEG. The increase in alpha band observed in central regions could be related to an enhancement in mu rhythm.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Using array comparative genome hybridisation (CGH) 41 de novo reciprocal translocations and 18 de novo complex chromosome rearrangements (CCRs) were screened. All cases had been interpreted as ...“balanced” by conventional cytogenetics. In all, 27 cases of reciprocal translocations were detected in patients with an abnormal phenotype, and after array CGH analysis, 11 were found to be unbalanced. Thus 40% (11 of 27) of patients with a “chromosomal phenotype” and an apparently balanced translocation were in fact unbalanced, and 18% (5 of 27) of the reciprocal translocations were instead complex rearrangements with >3 breakpoints. Fourteen fetuses with de novo, apparently balanced translocations, all but two with normal ultrasound findings, were also analysed and all were found to be normal using array CGH. Thirteen CCRs were detected in patients with abnormal phenotypes, two in women who had experienced repeated spontaneous abortions and three in fetuses. Sixteen patients were found to have unbalanced mutations, with up to 4 deletions. These results suggest that genome-wide array CGH may be advisable in all carriers of “balanced” CCRs. The parental origin of the deletions was investigated in 5 reciprocal translocations and 11 CCRs; all were found to be paternal. Using customised platforms in seven cases of CCRs, the deletion breakpoints were narrowed down to regions of a few hundred base pairs in length. No susceptibility motifs were associated with the imbalances. These results show that the phenotypic abnormalities of apparently balanced de novo CCRs are mainly due to cryptic deletions and that spermatogenesis is more prone to generate multiple chaotic chromosome imbalances and reciprocal translocations than oogenesis.
Autosomal recessive primary microcephaly (MCPH) is a model disease to study human neurogenesis. In affected individuals the brain grows at a reduced rate during fetal life resulting in a small but ...structurally normal brain and mental retardation. The condition is genetically heterogeneous with mutations in ASPM being most commonly reported.
We have examined this further by studying three cohorts of microcephalic children to extend both the phenotype and the mutation spectrum. Firstly, in 99 consecutively ascertained consanguineous families with a strict diagnosis of MCPH, 41 (41%) were homozygous at the MCPH5 locus and all but two families had mutations. Thus, 39% of consanguineous MCPH families had homozygous ASPM mutations. Secondly, in 27 non-consanguineous, predominantly Caucasian families with a strict diagnosis of MCPH, 11 (40%) had ASPM mutations. Thirdly, in 45 families with a less restricted phenotype including microcephaly and mental retardation, but regardless of other neurological features, only 3 (7%) had an ASPM mutation. This report contains 27 novel mutations and almost doubles the number of MCPH associated ASPM mutations known to 57. All but one of the mutations lead to the use of a premature termination codon, 23 were nonsense mutations, 28 deletions or insertions, 5 splicing, and 1 was a translocation. Seventeen of the 57 mutations were recurrent. There were no definitive missense mutations found nor was there any mutation/phenotype correlation. ASPM mutations were found in all ethnic groups studied.
This study confirms that mutations in ASPM are the most common cause of MCPH, that ASPM mutations are restricted to individuals with an MCPH phenotype, and that ASPM testing in primary microcephaly is clinically useful.
To search for CDKL5 gene mutations in boys presenting with severe early-onset encephalopathy and intractable epilepsy, a clinical picture very similar to that already described in girls with CDKL5 ...mutations.
Eight boys (age range 3-16 years, mean age 8.5 years, SD 4.38) with severe or profound mental retardation and early-onset intractable seizures were selected for CDKL5 gene mutation screening by denaturing high-performance liquid chromatography analysis.
We found three unrelated boys carrying three different missense mutations of the CDKL5 gene: c.872G>A (p.C291Y), c.863C>T (p.T288I), and c.533G>C (p.R178P). They presented early-onset, polymorphous, and drug-resistant seizures, mostly myoclonic and tonic or spasms. EEG showed epileptiform abnormalities which were multifocal during wakefulness, and pseudoperiodic bisynchronous during sleep.
This study describes three boys carrying CDKL5 missense mutations and their detailed clinical and EEG data, and indicates that CDKL5 gene mutations may represent a cause of severe or profound mental retardation and early-onset intractable seizures, also in boys. Screening for CDKL5 mutations is strongly recommended in individuals with these clinical features.
Progressive supranuclear palsy-PSP is the second most common parkinsonian syndrome after Parkinson’s disease-PD, with some overlapping clinical features in the early phases. Non-invasive ...neurophysiological techniques, such as transcranial magnetic stimulation-TMS, could be useful for the differential diagnosis. Seventeen PD, 13 PSP and 11 healthy controls-HC subjects were included in this study. TMS evaluation included resting motor threshold-RMT, motor evoked potentials-MEP amplitude and latency, response to inhibitory-SICI and facilitating-ICF conditioned stimuli, cortical silent period-CSP, and ipsilateral silent period-iSP. Statistical analysis was performed using either parametric or non-parametric ANOVA according to data distribution. PSP and PD groups did not significantly differ in UPDRS. TMS assessment showed different distribution of RMT across the groups (p.008), with PSP patients showing the highest values and PD the lowest (PSP vs PD p.002). Group also affected iSP duration (p.016), being longest in PSP and lowest in HC (PSP vs HC p.005). On paired-pulse inhibition and facilitation, a significant effect for ISI ( p < .001) and GROUP (p.035), but not for their interaction, was found. Indeed, in PSP SICI was lower and ICF higher than both in PD (p.017) and HC (p.032), without significant difference between the latter two groups. This study suggests that TMS can help to differentiate PD and PSP.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Walking impairment has a strong impact on quality of life of multiple sclerosis (MS) patients. Excitatory Transcranial-Repetitive-Magnetic-Stimulation (rTMS) enhances corticospinal excitability and ...plasticity, potentially favouring the effects of neurorehabilitation. The aim of this study is to explore the impact of neurophysiological and clinical features on rTMS efficacy on walking in progressive MS patients undergoing neurorehabilitation. 42 progressive MS patients, randomized into real and sham-placebo rTMS, underwent 11 rTMS sessions during neurorehabilitation. Motor-threshold (RMT), duration of disease progression, walking speed (10mt-walking-test) and endurance (2 and 6 mwt) were assessed at baseline and at the end of treatment, as well as Modified-Ashworth-Scale (MAS), pain and spasticity VAS, Fatigue-Severity-Scale, EDSS, MS-walking-scale-12, PASAT and nine-hole-peg-test. Real rTMS patients showed greater improvement both in 10mt ( p = 0.007) and 6mwt ( p = 0.04). Greater disability was associated with greater 6mwt improvement in all patients ( p = 0.01) and in the real-rTMS subgroup ( p = 0.04), not in sham. In real-rTMS group, RMT negatively correlated with 6mwt improvement ( p = 0.003). The potential for improvement, greater in more disabled patients after rTMS, can be exploited using this treatment associated with neurorehabilitation. RMT, resulting from combination of corticospinal excitability and of corticomotor fibres available for conduction, could be considered a predictive marker of therapeutic response to rTMS neuromodulation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Objective Progressive Supranuclear Palsy-PSP is the second most common parkinsonian syndrome after Parkinson’s disease-PD. Non-invasive neurophysiological techniques, such as transcranial magnetic ...stimulation-TMS, could prove useful to gain insight into these pathologies and for differential diagnosis. Methods Seventeen PD, 13 PSP and 11 healthy controls-CT were included in this study. TMS evaluation included resting motor threshold-RMT, motor evoked potentials-MEP amplitude, response to inhibitory-SICI and facilitating-ICF conditioning stimuli, cortical-CSP and ipsilateral silent period-iSP. Statistical analysis was performed using either parametric or non-parametric ANOVA and post-hoc tests according to data distribution. Results PSP and PD groups did not significantly differ in UPDRS. RMT distributed differently across groups (p.008), with PSP patients showing highest values and PD lowest (PSPvs.PD p.002). Group also affected iSP duration (p.016), being longest in PSP and lowest in HC (PSPvs.CT p.005). On paired-pulse inhibition and facilitation, a significant effect for inter-stimulus interval-ISI ( p < .001) and group (p.035) but not interaction was found, with lower SICI and higher ICF in PSP vs. PD (p.017) and CT (p.032). Conclusions This study suggests that TMS can help differentiate PD and PSP. PSP patients displayed different response to the perturbation induced by conditioning stimuli and iSP elongation, probably due to impairment of GABA-mediated neurotransmission.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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