There is a strong genetic influence on the clinicopathological phenotypes associated with frontotemporal lobar degeneration (FTLD) and frontotemporal dementia (FTD). Intracellular deposition of TDP-43 is the phenotypical hallmark of a frequent subgroup of cases. Mutations in the sequestosome 1 (SQSTM1) gene have rarely been found in individuals with FTD. Here we provide a comprehensive clinicopathological description of two cases with a SQSTM1 mutation. The clinical phenotype of patient 1 (mutation p.Glu396*) was compatible with the behavioural variant (bv) of FTD. TDP-43 pathology was consistent with the features of type B of FTLD-TDP pathology. However, prominent neuronal granular cytoplasmic TDP-43 immunoreactivity and abundant oligodendroglial inclusions, proven by colocalization with the oligodendroglial-marker TPPP/p25, were also seen. The clinical phenotype of patient 2 was compatible with bvFTD associated with parkinsonism and bulbar symptoms in the later stage. Genetic testing of patient 2 identified a C9orf72 repeat expansion mutation together with a missense mutation (p.Arg212Cys) in SQSTM1. TDP-43 pathology was characterized by neuritic profiles compatible mostly with type A. In contrast to patient 1, p62 pathology was seen to a greater extent as TDP-43 immunoreactivity in neurons. Using an antibody that detects poly(GP) peptides produced via repeat associated non-ATG translation associated with expanded hexanucleotide repeat in the C9orf72 gene, we confirmed the presence of pathognomonic inclusions. The present study supports previous observations on amyotrophic lateral sclerosis (ALS) that SQSTM1 mutations consistently associate with TDP-43 pathology. The co-presence of C9orf72 mutation may influence the phenotype, thus finding one FTLD (or ALS) related mutation does not exclude the presence of further influential genetic alterations. Oligodendroglial TDP-43 pathology is considerable in some forms of FTLD-TDP, thus their evaluation might be considered to be included in classification systems.

• Klíčová slova
• FTD, SQSTM1, TDP-43, amyotrophic lateral sclerosis, p62,
• MeSH
• adaptorové proteiny signální transdukční genetika   MeSH
• chování MeSH
• dospělí MeSH
• expanze repetic DNA MeSH
• frontotemporální demence genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• missense mutace genetika   MeSH
• mutační analýza DNA MeSH
• neurity patologie   MeSH
• neurony patologie   MeSH
• oligodendroglie patologie   MeSH
• progrese nemoci MeSH
• protein C9orf72 MeSH
• proteinopatie TDP-43 genetika   patologie   MeSH
• proteiny genetika   MeSH
• protoonkogenní proteiny c-myc genetika   MeSH
• sekvestosom 1 MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• C9orf72 protein, human MeSH Prohlížeč
• protein C9orf72 MeSH
• proteiny MeSH
• protoonkogenní proteiny c-myc MeSH
• sekvestosom 1 MeSH
• SQSTM1 protein, human MeSH Prohlížeč

Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features. Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel KV1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of KV1.2-expressing neurons.

• MeSH
• dítě MeSH
• dospělí MeSH
• draslíkový kanál Kv1.2 genetika   MeSH
• epilepsie genetika   MeSH
• genetická predispozice k nemoci MeSH
• kohortové studie MeSH
• kojenec MeSH
• křeče u dětí genetika   MeSH
• lidé MeSH
• mladý dospělý MeSH
• mutace * MeSH
• předškolní dítě MeSH
• rodokmen MeSH
• sekvence aminokyselin MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• kojenec MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• draslíkový kanál Kv1.2 MeSH
• KCNA2 protein, human MeSH Prohlížeč