Phenotypic variability in two infants sharing the same MECP2 mutation: evidence of chromosomal rearrangements and high sister-chromatid exchange levels in Rett syndrome.

Rett syndrome (RTT) whose major cause is the mutations in the X-linked MECP2 gene is a genetic disease that affects females. We screened two RTT patients using cytogenetic studies and in silico analysis as well as molecular analysis by the direct sequencing of MECP2. The cytogenetic results showed that although patient A was karyotypically normal, patient B showed chromosomal abnormalities, including chromosomal breakage in both chromosomes 2 and 5. In addition, chromosome 9 was detected on heteromorphic pattern (9ph+). A significant increase in sister-chromatid exchange (SCE) frequency was also observed in this patient. Although both patients were karyotypically different, they share the same MeCP2 mutation (p.P152R) which was predicted to be deleterious. To our knowledge, we describe the first association between MECP2 mutation, chromosomal abnormalities and high SCE frequency, which further validates the importance of the thorough chromosomal and molecular analyses that should be performed on the suspected RTT cases.

MRI features in 17 patients with l2 hydroxyglutaric aciduria.

l-2-Hydroxyglutaric (l-2-HG) aciduria is a rare inherited metabolic disease usually observed in children. Patients present a very slowly progressive deterioration with cerebellar ataxia, mild or severe mental retardation, and various other clinical signs including extrapyramidal and pyramidal symptoms, and seizures Goffette et al. [1]. This leukencephalopathy was first described in 1980 Duran et al. [2]. Brain magnetic resonance imaging (MRI) demonstrates nonspecific subcortical white matter (WM) loss, cerebellar atrophy and changes in dentate nuclei and putamen Steenweg et al. [3]. The diagnosis is highlighted by increased levels of l-2-HG in body fluids such as urine and cerebrospinal fluid. The purpose of this study is to retrospectively describe the brain MRI features in l-2-HG aciduria.

The effect of a motor skills training program in the improvement of practiced and non-practiced tasks performance in children with developmental coordination disorder (DCD).

The purpose of the present study was to examine the effect of a group-based task oriented skills training program on motor and physical ability for children with DCD. It was also investigated if there was an effect on fine motor and handwriting tasks that were not specifically practiced during the training program. Forty-one children aged 6-10years took part in this study. Children were assigned to three groups: an experimental training group consisting of 14 children with DCD, a control non-training group consisted of 13 children with DCD and a control non-training group consisting of 14 typically developed children. The measurements included were, the Movement Assessment Battery for Children (MABC), the Modified Agility Test (MAT), the Triple Hop Distance (THD), the 5 Jump-test (5JT) and the Handwriting Performance Test. All measures were administered pre and post an 8-week training program. The results showed that 10 children of the DCD training-group improved their performance in MABC test, attaining a score above the 15th percentile after their participation in the training program. DCD training-group showed a significant improvement on all cluster scores (manual dexterity (t (13)=5.3, p<.001), ball skills (t (13)=2.73, p<.05) and balance (t (13)=5.13, p<.001). Significant performance improvements were also found in MAT, THD, 5JT (t (13)=-4.55; p<.01), handwriting quality (t (12)=-2.73; p<.05) and speed (t (12)=-4.2; p<.01) after the training program. In conclusion, improvement in both practiced and non-practiced skills, in the training program, may reflect improvement in motor skill but also transfer to other skills.

The effects of 8 weeks of motor skill training on cardiorespiratory fitness and endurance performance in children with developmental coordination disorder.

Interventions based on everyday motor skills have been developed to be effective in children with developmental coordination disorder (DCD). The purpose of the present study was to examine the effects of motor skill training on exercise tolerance and cardiorespiratory fitness in children with DCD. Children were assigned to 3 groups: an experimental training group comprising 14 children with DCD, a control nontraining group comprising 13 children with DCD, and a control nontraining group comprising 14 typically developed children. All participants were tested twice with an interval of 8-weeks on a cardiopulmonary exercise test, pulmonary function testing, and a 6-min walk test. After the training program the maximal power output was significantly increased for DCD group at anaerobic threshold (p < 0.05) and at peak level (maximal oxygen uptake, p < 0.001). Improvement in power output was more pronounced at the anaerobic threshold (t (13) = -5.21, p < 0.001) than at the maximal intensity (maximal oxygen uptake, t (13) = -3.08, p < 0.01) in the DCD training group. Children with DCD that participated in the training program improved their walking distance (t (13) = -9.08, p < 0.001), had a higher maximum heart rate (t (13) = -3.41, p < 0.01), and reduced perceived exertion (t (13) = 2.75, p < 0.05). The DCD nontraining group and the typically developed group did not change on any of the measures. In conclusion, training delayed reaching the anaerobic threshold and improved aerobic endurance and exercise tolerance in children with DCD.

Assessment of physical fitness and exercise tolerance in children with developmental coordination disorder.

Children with developmental coordination disorder (DCD) have been shown to be less physically fit when compared to their typically developing peers. The purpose of the present study was to examine the relationships among body composition, physical fitness and exercise tolerance in children with and without DCD. Thirty-seven children between the ages of 7 and 9 years participated in this study. Participants were classified according to results obtained on the Movement Assessment Battery for Children (MABC) and were divided in 2 groups: 19 children with DCD and 18 children without DCD. All children performed the following physical fitness tests: The five-jump test (5JT), the triple-hop distance (THD) and the modified agility test (MAT). Walking distance was assessed using the 6-min walking test (6MWT). Children with DCD showed higher scores than children without DCD in all MABC subscale scores, as well as in the total score (p<0.001). Participants with DCD were found to perform significantly worse on the MAT (p<0.001), the THD (p<0.001) and 5JT (p<0.05). Moreover, children with DCD had poorer performance on the 6MWT than children without DCD (p<0.01). Our results found significant correlations among body mass index (BMI), THD (r=0.553, p<0.05), 5JT (r=0.480, p<0.05) and 6MWT (r=0.544, p<0.05) only in DCD group. A significant correlation between MAT and 5JT (r=-0.493, p<0.05) was found. Similarly, THD and 5JT (r=0.611, p<0.01) was found to be correlated in children with DCD. We also found relationships among 6MWT and MAT (r=-0.522, p<0.05) and the 6MWT and 5JT (r=0.472, p<0.05) in DCD group. In addition, we found gender specific patterns in the relationship between exercise tolerance, explosive strength, power, DCD, and BMI. In conclusion, the present study revealed that BMI was indicative of poorer explosive strength, power and exercise tolerance in children with DCD compared to children without DCD probably due to a limited coordination on motor control.

A Novel Mutation p.A59P in N-Terminal Domain of Methyl-CpG-Binding Protein 2 Confers Phenotypic Variability in 3 Cases of Tunisian Rett Patients: Clinical Evaluations and In Silico Investigations.

Rett syndrome is a monogenic X-linked dominant neurodevelopmental disorder related to mutation in MECP2, which encodes the methyl-CpG-binding protein MeCP2. The aim of this study was to search for mutations of MECP2 gene in Tunisian Rett patients and to evaluate the impact of the found variants on structural and functional features of MeCP2. The result of mutation analysis revealed that 3 Rett patients shared the same novel heterozygous point mutation c.175G>C (p.A59P). The p.A59P mutation was located in a conserved amino acid in the N-terminal segment of MeCP2. This novel mutation confers a phenotypic variability with different clinical severity scores (3, 8, and 9) and predicted by Sift and PolyPhen to be damaging. Modeling results showed that p.A59P adds 2 hydrogen bonds and changes the structural conformation of MeCP2 with a significant root mean square deviation value (9.66 Å), suggesting that this mutation could probably affect the conformation, function and stability of MeCP2.

Assessment of cardiorespiratory and neuromotor fitness in children with developmental coordination disorder.

The decreased participation in physical activity by children with probable developmental coordination disorder (pDCD) has raised concerns about their aerobic fitness and lung function levels. The purpose of the present study was to examine assessment of cardiorespiratory and neuromotor fitness, using laboratory-based tests during an incremental treadmill protocol in healthy children with and without pDCD. Twenty sex children ages 6-9 years took part in this study. Motor coordination was assessed using the Movement Assessment Battery for Children (MABC). All participants performed a cardiopulmonary exercise test (CPET) on a cycle ergometer. Pulmonary function was assessed by spirometric measurements (forced vital capacity: FVC, forced expiratory volume in 1s: FEV1) and walking distance (6MWD) was assessed using the 6-min walking test. The children with pDCD had lower VO2max than children without pDCD (p < 0.01). Moreover, FVC and FEV1 were significantly higher in children without pDCD than in children with the disorder (p < 0.05, p < 0.01 respectively). Likewise, children with pDCD had poorer performance on the 6MWD than children without pDCD (p < 0.01). A significant correlation between the absolute value for FEV1 and 6MWD (r = 0.637, p < 0.05) in pDCD group was observed. We found a significant correlation between VO2max and MABC score (r = -0.612, p < .001) and between VO2max and 6MWD (r = 0.502, p < .001) for all children. Moreover, a significant correlation between VO2max and FEV1 (r = 0.668, p < .05) was found in children with pDCD. Overall, the reduced aerobic capacity of DCD was associated with decreased of lung function, as well as an alteration of peripheral muscle responses.

Frontal motor seizure following non-convulsive status epilepticus in ring chromosome 20 syndrome.

The ring chromosome 20 syndrome is a rare syndrome characterized by intractable epilepsy with particular electro clinical features including episodes of prolonged confusional state and nocturnal frontal lobe seizures. We report a 17-year-old girl who had intractable epilepsy with frontal seizure and prolonged confusional state secondary to non-convulsive status epilepticus. The diagnosis of ring chromosome 20 was suspected and confirmed by karyotype. The cytogenetic study of CHRNA4 and KCNQ2 genes did not detect deletion in the ring chromosome 20. During video-EEG recording, this girl presented a non-convulsive status epilepticus that lasted more than 20 minutes followed by typical frontal lobe seizure. This association was not previously described, and was probably caused by chromosomal instability.

CAPN3 mRNA processing alteration caused by splicing mutation associated with novel genomic rearrangement of Alu elements.

Recessive mutations of CAPN3 gene are reported to be responsible for limb girdle muscular dystrophy type 2A (LGMD2A). In all, 15-25% of intronic nucleotide changes identified in this gene were investigated by in silico analysis, but occasionally supported by experimental data or reported in some cases as a polymorphism. We report here genetic and transcriptional analyses in three Tunisian patients belonging to the same consanguineous family sharing the same mutation c.1194-9 A>G and Alu repeats insertion in intron 7 of CAPN3 gene. Reverse transcriptase-PCR experiments performed on total RNA from the patient's muscle biopsy showed retention of the eight last nucleotides of intron 9 in the CAPN3 transcript lacking the first seven exons. Our results provide evidence regarding the potential involvement of Alu elements in aberrant processing of pre-mRNA owing to the disruption of pre-existing intronic splicing regulatory elements. We also demonstrated variable mRNA alternative splicing among tissues and between LGMD2A patients. A deep intronic variation and rearrangement have been reported in the literature as causing genetic diseases in humans. However, this is the first report on a potential pathogenic CAPN3 gene mutation resulting from an Alu insertion.

A putative disease-associated haplotype within the SCN1A gene in Dravet syndrome.

Dravet syndrome (DS), previously known as severe myoclonic epilepsy of infancy, is one of the most severe forms of childhood epilepsy. DS is caused by a mutation in the neuronal voltage-gated sodium-channel alpha-subunit gene (SCN1A). However, 25-30% of patients with DS are negative for the SCN1A mutation screening, suggesting that other molecular mechanisms may account for these disorders. Recently, the first case of DS caused by a mutation in the neuronal voltage-gated sodium-channel beta-subunit gene (SCN1B) was also reported. In this report we aim to make the molecular analysis of the SCN1A and SCN1B genes in two Tunisian patients affected with DS. The SCN1A and SCN1B genes were tested for mutations by direct sequencing. No mutation was revealed in the SCN1A and SCN1B genes by sequencing analyses. On the other hand, 11 known single nucleotide polymorphisms were identified in the SCN1A gene and composed a putative disease-associated haplotype in patients with DS phenotype. One of the two patients with putative disease-associated haplotype in SCN1A had also one known single nucleotide polymorphism in the SCN1B gene. The sequencing analyses of the SCN1A gene revealed the presence of a putative disease-associated haplotype in two patients affected with Dravet syndrome.

A case of a Tunisian Rett patient with a novel double-mutation of the MECP2 gene.

Rett syndrome is an X-linked dominant disorder caused frequently by mutations in the methyl-CpG-binding protein 2 gene (MECP2). Rett patients present an apparently normal psychomotor development during the first 6-18 months of life. Thereafter, they show a short period of developmental stagnation followed by a rapid regression in language and motor development. The aim of this study was to perform a mutational analysis of the MECP2 gene in a classical Rett patient by sequencing the corresponding gene and modeling the found variants. The results showed the presence of a double-mutation: a new and de novo mutation c.535C>T (p.P179S) and the common c.763C>T (p.R255X) transition of the MECP2 gene. The p.P179S mutation was located in a conserved amino acid in CRIR domain (corepressor interacting region). Modeling results showed that the P179S transition could change local electrostatic properties by adding a negative charge due to serine hydroxyl group of this region of MeCP2 which may affect the function and stability of the protein. The p.R255X mutation is located in TRD-NLS domain (transcription repression domain-nuclear localization signal) of MeCP2 protein.

A de novo mutation in the adenosine triphosphatase (ATPase) 8 gene in a patient with mitochondrial disorder.

Mitochondrial DNA defects were known to be associated with a wide spectrum of human diseases and patients might present a wide range of clinical features in various combinations. In the current study, we described a patient with psychomotor and neurodevelopmental delay, mild hyperintensity of posterior periventicular white matter, generalized clonic seizures, leukodystrophy, and congenital deafness. He also had tetraplegia, with central blindness and swallowing difficulty. Brain magnetic resonance imaging (MRI) showed involvement of the interpeduncular nucleus and central tegmental tract, white matter abnormalities, and cerebellar atrophy. A whole mitochondrial genome screening revealed the presence of 19 reported polymorphisms and an undescribed A to G mutation at nucleotide 8411 (p.M16V) affecting a conserved region of the mitochondrial adenosine triphosphatase (ATPase) 8 protein. This de novo mutation was detected in heteroplasmic form (97%) and was absent in 120 controls. Thus, the m.8411A>G mutation could strongly be associated with the disease in the tested patient.