OBJECTIVES: To characterise the pattern and spectrum of involvement on muscle MRI in a large cohort of patients with sarcoglycanopathies, which are limb-girdle muscular dystrophies (LGMD2C-2F) caused by mutations in one of the four genes coding for muscle sarcoglycans. METHODS: Lower limb MRI scans of patients with LGMD2C-2F, ranging from severe childhood variants to milder adult-onset forms, were collected in 17 neuromuscular referral centres in Europe and USA. Muscle involvement was evaluated semiquantitatively on T1-weighted images according to a visual score, and the global pattern was assessed as well. RESULTS: Scans from 69 patients were examined (38 LGMD2D, 18 LGMD2C, 12 LGMD2E and 1 LGMD2F). A common pattern of involvement was found in all the analysed scans irrespective of the mutated gene. The most and earliest affected muscles were the thigh adductors, glutei and posterior thigh groups, while lower leg muscles were relatively spared even in advanced disease. A proximodistal gradient of involvement of vasti muscles was a consistent finding in these patients, including the most severe ones. CONCLUSIONS: Muscle involvement on MRI is consistent in patients with LGMD2C-F and can be helpful in distinguishing sarcoglycanopathies from other LGMDs or dystrophinopathies, which represent the most common differential diagnoses. Our data provide evidence about selective susceptibility or resistance to degeneration of specific muscles when one of the sarcoglycans is deficient, as well as preliminary information about progressive involvement of the different muscles over time.

• MeSH
• dítě MeSH
• dospělí MeSH
• fenotyp MeSH
• kosterní svaly patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• mladiství MeSH
• mutace MeSH
• předškolní dítě MeSH
• sarkoglykanopatie genetika   MeSH
• sarkoglykany nedostatek   genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa MeSH
• Spojené státy americké MeSH

BACKGROUND: Epilepsy is a heterogeneous disease with a broad phenotypic spectrum and diverse genotypes. A significant proportion of epilepsies has a genetic aetiology. In our study, a custom designed gene panel with 112 genes known to be associated with epilepsies was used. In total, one hundred and fifty-one patients were tested (86 males / 65 females). RESULTS: In our cohort, the highest probability for the identification of the cause of the disease was for patients with a seizure onset within the first four weeks of life (61.9% clarification rate) - about two times more than other groups. The level of statistical significance was determined using a chi-square analysis. From 112 genes included in the panel, suspicious and rare variants were found in 53 genes (47.3%). Among the 151 probands included in the study we identified pathogenic variants in 39 patients (25.8%), likely pathogenic variants in three patients (2%), variants of uncertain significance in 40 patients (26.5%) and likely benign variants in 69 patients (45.7%). CONCLUSION: Our report shows the utility of diagnostic genetic testing of severe childhood epilepsies in a large cohort of patients with a diagnostic rate of 25.8%. A gene panel can be considered as a method of choice for the detection of pathogenic variants within patients with unknown origin of early onset severe epilepsy.

• MeSH
• dítě MeSH
• epilepsie genetika   MeSH
• genetická predispozice k nemoci genetika   MeSH
• kojenec MeSH
• křeče u dětí genetika   MeSH
• lidé MeSH
• mutace MeSH
• předškolní dítě MeSH
• rozdělení chí kvadrát MeSH
• záchvaty genetika   MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

BACKGROUND: Variants in the human X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been reported as being etiologically associated with early infantile epileptic encephalopathy type 2 (EIEE2). We report on two patients, a boy and a girl, with EIEE2 that present with early onset epilepsy, hypotonia, severe intellectual disability, and poor eye contact. METHODS: Massively parallel sequencing (MPS) of a custom-designed gene panel for epilepsy and epileptic encephalopathy containing 112 epilepsy-related genes was performed. Sanger sequencing was used to confirm the novel variants. For confirmation of the functional consequence of an intronic CDKL5 variant in patient 2, an RNA study was done. RESULTS: DNA sequencing revealed de novo variants in CDKL5, a c.2578C>T (p. Gln860*) present in a hemizygous state in a 3-year-old boy, and a potential splice site variant c.463+5G>A in heterozygous state in a 5-year-old girl. Multiple in silico splicing algorithms predicted a highly reduced splice site score for c.463+5G>A. A subsequent mRNA study confirmed an aberrant shorter transcript lacking exon 7. CONCLUSIONS: Our data confirmed that variants in the CDKL5 are associated with EIEE2. There is credible evidence that the novel identified variants are pathogenic and, therefore, are likely the cause of the disease in the presented patients. In one of the patients a stop codon variant is predicted to produce a truncated protein, and in the other patient an intronic variant results in aberrant splicing.

• MeSH
• epilepsie genetika   MeSH
• exony MeSH
• genetická variace genetika   MeSH
• křeče u dětí genetika   MeSH
• lidé MeSH
• mutace MeSH
• předškolní dítě MeSH
• protein-serin-threoninkinasy genetika   metabolismus   MeSH
• Rettův syndrom genetika   MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

BACKGROUND: Inherited peripheral neuropathies (IPN) are the most common inherited neurological condition. It represents a highly heterogeneous group, both clinically and genetically. Targeted disease specific gene panel massively parallel sequencing (MPS) seems to be a useful tool in diagnosis of disorders with high genetic heterogeneity. METHODS: In our study, we have designed, validated and updated our own custom gene panel of all known genes associated with IPN. One hundred and ninety-eight patients have been tested so far. Only patients in whom mutations in more common causes or relevant genes have already been excluded were enrolled. Five consecutive panel designs were prepared according to recent literature search, the last one covering ninety-three genes. Each patient was tested only once. All data were evaluated with at least two different pipelines. RESULTS: In summary, causative mutation has been found in fifty-one patients (26 %). The results were inconclusive in thirty-one (16 %) patients. No variants of likely significance to IPN were found in one hundred and sixteen (58 %) patients. CONCLUSION: MPS gene panel enables testing of all known IPN causes at once with high coverage and at an affordable cost making it truly a method of choice also in IPN. Gene panel testing results in several interesting results and findings.

• MeSH
• Charcotova-Marieova-Toothova nemoc diagnóza   genetika   MeSH
• cytoplazmatické dyneiny genetika   MeSH
• genetické testování metody   MeSH
• genotyp MeSH
• hereditární motorické a senzitivní neuropatie genetika   MeSH
• intracelulární signální peptidy a proteiny genetika   MeSH
• konexiny genetika   MeSH
• lidé MeSH
• mutace MeSH
• nemoci periferního nervového systému diagnóza   genetika   MeSH
• proteiny buněčného cyklu genetika   MeSH
• RNA-helikasy genetika   MeSH
• věk při počátku nemoci MeSH
• vysoce účinné nukleotidové sekvenování metody   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Most hypotheses concerning the mechanisms underlying seizure activity in focal cortical dysplasia (FCD) are based on alterations in synaptic transmission and glial dysfunction. However, neurons may also communicate by extrasynaptic transmission, which was recently found to affect epileptiform activity under experimental conditions and which is mediated by the diffusion of neuroactive substances in the extracellular space (ECS). The ECS diffusion parameters were therefore determined using the real-time iontophoretic method in human neocortical tissue samples obtained from surgically treated epileptic patients. The obtained values of the extracellular space volume fraction and tortuosity were then correlated with the histologicaly assessed type of cortical malformation (FCD type I or II). While the extracellular volume remained unchanged (FCD I) or larger (FCD II) than in normal/control tissue, tortuosity was significantly increased in both types of dysplasia, indicating the presence of additional diffusion barriers and compromised diffusion, which might be another factor contributing to the epileptogenicity of FCD.

• MeSH
• dítě MeSH
• dospělí MeSH
• epilepsie patologie   MeSH
• extracelulární prostor fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• malformace mozkové kůry patologie   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mozková kůra abnormality   patologie   MeSH
• neurony patologie   fyziologie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH