• MeSH
• dítě MeSH
• genetické markery MeSH
• geny MeSH
• hemofilie A diagnóza   genetika   MeSH
• lidé MeSH
• mutace MeSH
• mutační analýza DNA MeSH
• polymorfismus genetický MeSH
• prenatální diagnóza MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH

Kongenitální hypomyelinizační neuropatie (CHN) je nejtěžší formou Dejerineovy-Sottasovy neuropatie (DSN). Neuropatie či syndrom typu Déjerine-Sottas (DSN či DSS) je těžkou formou dědičné periferní neuropatie s velmi časným začátkem, poměrně stabilním průběhem, extrémně sníženou rychlostí vedení periferním nervem a extrémní redukcí myelinizováných axonů v kombinaci s hypertrofickými projevy v biopsii nervu suralis. U pacientů s fenotypem DSS a CHN byly dosud nalezeny mutace v genech MPZ, EGR2 a PMP22. Bodové mutace v PMP22 jsou relativně vzácnou příčinou hereditárních motoricko-senzitivních neuropatií (HMSN), byly však nalezeny častěji u pacientů s HMSNtypu III, kteří měli zdravé rodiče. Mutace v PMP22 vznikají často de-novo a mají dominantní efekt. Popisujeme případ llletého chlapce, potomka zdravých rodičů u něhož byla od novorozeneckého období pozorována svalová hypotonie a později výrazná retardace výlučně motorického vývoje. Chlapec nebyl dosud nikdy schopen normální samostatné chůze. Intelekt chlapce je výrazně nadprůměrný. V neurologickém vyšetření je výrazná svalová hypotonie, slabost a svalové hypotrofie. Slachosvalové reflexy byly výrazně snížené či vyhaslé. Motorická rychlost vedení periferním nervem byla téměř neměřitelná. V biopsii nervus suralis byla extrémní demyelinizace až amyelinizace s chybením myelinizovanych vláken V kombinaci s rozsáhlými hypertrofickými projevy typu cibulovitých formací. Chlapec neměl žádné známky postižení CNS. V 11 letech byla stanovena klinická diagnóza kongenitální hypomyelinizace následné molekulárně genetické vyšetření prokázalo u pacienta heterozygotní mutaci C na T v pozici 215 v genu pro PMP22, která vede k výměně aminokyseliny serinu za leucin. Tuto mutaci jsme nenalezli ani u jednoho z rodičů, což nás vedlo k závěru o de-novo původu této dominantní mutace. Tato mutace byla již dříve opakovaně popsána u sporadických případů s obdobným fenotypem CHN resp. DSS. Náš nález podporuje předchozí teorie o tzv. bot spotu pro mutace v genu PMP22. Pacienti s extrémně nízkou rychlostí vedení periferním nervem by měli být vyšetřeni na přítomnost mutací v genu PMP22.

Congenital hypomyelination neuropathy (CHN) is the most severe form of Dejerine-Sottas neuropathy (DSN). Neuropathies of the Dejerine-Sottas (DSN or DSS) type are a severe form of hereditary peripheral neuropathy with a very early onset, relatively stable course and extremely reduced rate of conduction throught the peripheral nerve and extreme reduction of myelinized axons in combination with hypertrophic manifestations in the biopsy of the sural nerve. In patients with phenotype DSS and CHN so far mutations were found in genes MPZ, EGR2 and PMP22. Point mutations in PMP22 are a relatively rare cause of hereditary motor-sensory neuropathies (HMSN), they were however found more frequently in patients with HMSN type III, who had healthy parents. Mutations in PMP22 develop often de novo and have a dominant effect. The authors describe the case of an ll-year-old boy, the offspring of healthy parents where from the neonatal period muscular hypotonia was observed and later marked retardation of the motor development only. The boy was so far unable to walk by himself. The intellect of the boy is markedly above the average. The neurological examination revealed marked muscular hypotonia and weakness and muscular hypotrophies. Tendinous muscular reflexes were markedly reduced or extinct. The motor rate of conduction through peripheral nerves was hardly detectable. In *he biopsy of the sural nerve there was extreme demyelination to amyelination with absence of myelinated fibres combined with extensive hypertrophic manifestations of the type of onion bulb formations. The boy had no signs of affection of the CNS. At the age of 11 the clinical diagnosis of congenital hypomyelination was made, subsequent molecular genetic examination revealed in the patient a heterozygote mutation C on T in position 215 in the gene for PMP22, which causes the substitution of the amino acid serine for leucine. This mutation was not found in neither of the parents which made us conclude that it was a de novo dominant mutation. This mutation was already previously repeatedly described in sporadic cases with a similar CHN resp. DSS phenotype. Our finding supports previous theories on the so-called hot spot for mutations in gene PMP22. Patients with an extremely low rate of conduction through the peripheral nerve should be examined for the presence of mutations in gene PMP22.

• MeSH
• biopsie MeSH
• Charcotova-Marieova-Toothova nemoc diagnóza   MeSH
• diagnostické techniky neurologické metody   MeSH
• dítě MeSH
• fenotyp MeSH
• finanční podpora výzkumu jako téma MeSH
• hereditární motorické a senzitivní neuropatie diagnóza   genetika   MeSH
• lidé MeSH
• nervus suralis patologie   MeSH
• svalová hypotonie MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH
• přehledy MeSH

• Publikační typ
• abstrakt z konference MeSH

• Publikační typ
• novinové články MeSH
• rozhovory MeSH

We report here a case of a newborn with hypotrophy and somatic stigmatization: microcephaly, facial dysmorphism, heart defect and immunodeficiency syndrome. The proband's karyotype was 46,XY,dup(4)(q28q35.2) de novo with chromosomal breaks in 4% of metaphases. We demonstrate the usefulness of a combination of physical examination, classical cytogenetics, FISH and PCR techniques in order to establish correct diagnosis because of overlap of some clinical and cytogenetic features of Nijmegen breakage syndrome (NBS) and duplication 4q in our patient. Although FISH technique detected translocation t(14q;21q) in 4 metaphases, deletion 657del5 in exon 6 of the NBS1 gene associated with NBS in Slavic population was not confirmed. We compare in this report similarity of the clinical picture of our patient, NBS cases and other patients carrying a duplication of the distal part of 4q as described in the literature.

• MeSH
• chromozomální aberace MeSH
• defekty septa síní genetika   MeSH
• hybridizace in situ fluorescenční MeSH
• lidé MeSH
• lidské chromozomy, pár 4 genetika   MeSH
• mnohočetné abnormality genetika   MeSH
• novorozenec MeSH
• obličej abnormality   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873-4881 duplication) in the SCN8A gene and an inherited heterozygous variant (c.952G > A) in the CACNA1H gene encoding for Nav1.6 voltage-gated sodium and Cav3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Nav1.6 and Cav3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of SCN8A and CACNA1H, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.

• MeSH
• aktivační mutace MeSH
• bodová mutace MeSH
• duplikace genu MeSH
• epilepsie tonicko-klonická genetika   MeSH
• gating iontového kanálu genetika   fyziologie   MeSH
• genetická predispozice k nemoci MeSH
• lidé MeSH
• missense mutace MeSH
• mnohočetné abnormality genetika   MeSH
• napěťově řízený sodíkový kanál, typ 6 genetika   fyziologie   MeSH
• novorozenec MeSH
• refrakterní epilepsie genetika   MeSH
• rodokmen MeSH
• skolióza genetika   MeSH
• vápníkové kanály - typ T genetika   fyziologie   MeSH
• vývojové poruchy u dětí genetika   MeSH
• Check Tag
• lidé MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Calcium/calmodulin-dependent protein kinases (CaMKs) are key mediators of calcium signaling and underpin neuronal health. Although widely studied, the contribution of CaMKs to Mendelian disease is rather enigmatic. Here, we describe an unusual neurodevelopmental phenotype, characterized by milestone delay, intellectual disability, autism, ataxia, and mixed hyperkinetic movement disorder including severe generalized dystonia, in a proband who remained etiologically undiagnosed despite exhaustive testing. We performed trio whole-exome sequencing to identify a de novo essential splice-site variant (c.981+1G>A) in CAMK4, encoding CaMKIV. Through in silico evaluation and cDNA analyses, we demonstrated that c.981+1G>A alters CAMK4 pre-mRNA processing and results in a stable mRNA transcript containing a 77-nt out-of-frame deletion and a premature termination codon within the last exon. The expected protein, p.Lys303Serfs*28, exhibits selective loss of the carboxy-terminal regulatory domain of CaMKIV and bears striking structural resemblance to previously reported synthetic mutants that confer constitutive CaMKIV activity. Biochemical studies in proband-derived cells confirmed an activating effect of c.981+1G>A and indicated that variant-induced excessive CaMKIV signaling is sensitive to pharmacological manipulation. Additionally, we found that variants predicted to cause selective depletion of CaMKIV's regulatory domain are unobserved in diverse catalogs of human variation, thus revealing that c.981+1G>A is a unique molecular event. We propose that our proband's phenotype is explainable by a dominant CAMK4 splice-disrupting mutation that acts through a gain-of-function mechanism. Our findings highlight the importance of CAMK4 in human neurodevelopment, provide a foundation for future clinical research of CAMK4, and suggest the CaMKIV signaling pathway as a potential drug target in neurological disease.

• MeSH
• aktivační mutace genetika   MeSH
• cerebelární ataxie genetika   MeSH
• exom MeSH
• exony genetika   MeSH
• fenotyp MeSH
• hyperkineze genetika   MeSH
• lidé MeSH
• mentální retardace genetika   MeSH
• mutace MeSH
• nesmyslný kodon genetika   MeSH
• posunová mutace genetika   MeSH
• proteinkinasa závislá na vápníku a kalmodulinu typ 4 genetika   metabolismus   MeSH
• rodokmen MeSH
• sekvenování exomu MeSH
• sestřih RNA genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

De novo sequence variants, including truncating and splicing variants, in the additional sex‑combs like 3 gene (ASXL3) have been described as the cause of Bainbridge‑Ropers syndrome (BRS). This pathology is characterized by delayed psychomotor development, severe intellectual disability, growth delay, hypotonia and facial dimorphism. The present study reports a case of a girl (born in 2013) with severe global developmental delay, central hypotonia, microcephaly and poor speech. The proband was examined using a multi‑step molecular diagnostics algorithm, including karyotype and array‑comparative genomic hybridization analysis, with negative results. Therefore, the proband and her unaffected parents were enrolled for a pilot study using targeted next‑generation sequencing technology (NGS) with gene panel ClearSeq Inherited DiseaseXT and subsequent validation by Sanger sequencing. A novel de novo heterozygous frameshift variant in the ASXL3 gene (c.3006delT, p.R1004Efs*21), predicted to result in a premature termination codon, was identified. In conclusion, the present study demonstrated that targeted NGS using a suitable, gene‑rich panel may provide a conclusive molecular genetics diagnosis in children with severe global developmental delays.

• MeSH
• dítě MeSH
• lidé MeSH
• mikrocefalie genetika   MeSH
• pilotní projekty MeSH
• poruchy řeči genetika   MeSH
• posunová mutace MeSH
• rodokmen MeSH
• svalová hypotonie genetika   MeSH
• transkripční faktory genetika   MeSH
• vývojové poruchy u dětí genetika   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant genetic disorder characterised by prenatal and postnatal growth and mental retardation, facial dysmorphism and upper limb abnormalities. Germline mutations of cohesin complex genes SMC1A, SMC3, RAD21 or their regulators NIPBL and HDAC8 have been identified in CdLS as well as somatic mutations in myeloid disorders. We describe the first case of a paediatric patient with CdLS with B-cell precursor Acute Lymphoblastic Leukaemia (ALL). The patient did not show any unusual cytogenetic abnormality, and he was enrolled into the high risk arm of AIEOP-BFM ALL2009 protocol because of slow early response, but 3 years after discontinuation, he experienced an ALL relapse. We identified a heterozygous mutation in exon 46 of NIPBL, causing frameshift and a premature stop codon (RNA-Targeted Next generation Sequencing Analysis). The analysis of the family indicated a de novo origin of this previously not reported deleterious variant. As for somatic cohesin mutations in acute myeloid leukaemia, also this ALL case was not affected by aneuploidy, thus suggesting a major impact of the non-canonical role of NIPBL in gene regulation. A potential biological role of NIPBL in leukaemia has still to be dissected.

• MeSH
• de Langeové syndrom diagnóza   genetika   MeSH
• dědičnost MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• lidé MeSH
• mutace * MeSH
• mutační analýza DNA MeSH
• pre-B-buněčná leukemie diagnóza   genetika   terapie   MeSH
• předškolní dítě MeSH
• proteiny genetika   MeSH
• recidiva MeSH
• rodokmen MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH