Epileptic Encephalopathy in Adams–Oliver Syndrome Associated to a New DOCK6 Mutation: A Peculiar Behavioral Phenotype

Pisciotta, Livia; Capra, Valeria; Accogli, Andrea; Giacomini, Thea; Prato, Giulia; Tavares, Purificação; Pinto‐Basto, Jorge; Morana, Giovanni; Mancardi, Maria Margherita

doi:10.1055/s-0038-1639372

Cited by 7 publications

(4 citation statements)

References 18 publications

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“…We found less frequent limb reduction to be less prevalent, with only 59 versus 92% in the literature. Finally, we have fewer patients with neurological abnormalities (1/3, 34%) compared with 57% in the 45 cases published with this data (Cohen et al, 2014;Lehman et al, 2014;Meester et al, 2015;Pisciotta et al, 2018;Shaheen et al, 2011;Shaheen et al, 2013;Southgate et al, 2015;Stittrich et al, 2014). These differences may be explained by the fact that published cases are those with a molecular finding, and, in our cohort, we started with a defined clinical inclusion criteria (ACC).…”

Section: Discussionmentioning

confidence: 91%

Expanding the phenotype in Adams–Oliver syndrome correlating with the genotype

Dudoignon

Huber

Michot

et al. 2019

American J of Med Genetics Pt A

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Rationale: Adams-Oliver syndrome (AOS) is a genetic disorder characterized by the association of aplasia cutis congenita (ACC), terminal transverse limb defect (TTLD), congenital cardiac malformation (CCM), and minor features, such as cutaneous, neurological, and hepatic abnormalities (HAs). The aim of the study is to emphasize phenotype-genotype correlations in AOS. Methods:We studied 29 AOS patients. We recorded retrospectively detailed phenotype data, including clinical examination, biological analyses, and imaging. The molecular analysis was performed through whole exome sequencing (WES).Results: Twenty-nine patients (100%) presented with ACC, the principal inclusion criteria in the study. Seventeen of twenty-one (81%) had cutis marmorata telangiectasia congenita, 16/26 (62%) had TTLD, 14/23 (61%) had CCM, 7/20 (35%) had HAs, and 9/27 (33%) had neurological findings. WES was performed in 25 patients.Fourteen of twenty-five (56%) had alterations in the genes already described in AOS.CCM and HAs are particularly associated with the NOTCH1 genotype. TTLD is present in patients with DOCK6 and EOGT alterations. Neurological findings of variable degree were associated sometimes with DOCK6 and NOTCH1 rarely with EOGT.Conclusion: AOS is characterized by a clinical and molecular variability. It appears that degrees of genotype-phenotype correlations exist for patients with identified pathogenic mutations, underlining the need to undertake a systematic but adjusted multidisciplinary assessment.

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Section: Discussionmentioning

confidence: 91%

Expanding the phenotype in Adams–Oliver syndrome correlating with the genotype

Dudoignon

Huber

Michot

et al. 2019

American J of Med Genetics Pt A

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“…Worth mentioning are proteins, which levels, are also dysregulated in other neurodevelopmental disorders, which patients show an overlap in neurological dysfunctions of RTT patients. We found changed levels in DOCK6 (at D3) [55,56], NPC1 (at D9) [57,58], CDK5 (at D9) [59,60], HINT1 (at D9) [61,62], CSTB (at D9) [63], ACSL4 (at D22) [64,65], KIF5C (at D22) [66,67], and TUBB2A (at D22) [68], which are respectively dysregulated in epilepsy, Niemann-Pick disease, mental retardation, cortical dysplasia, lissencephaly, neurotonia, and axonal neuropathy. Even though these candidate proteins were not associated with RTT before, these could be key in affected neuronal development in RTT and other neurological disorders, and therefore could be of special interest in identifying new disease mechanisms.…”

Section: Protein Expression Changes In Neuronal Progenitor Cells From...mentioning

confidence: 82%

Quantitative proteomic analysis of Rett iPSC-derived neuronal progenitors

et al. 2020

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Background Rett syndrome (RTT) is a progressive neurodevelopmental disease that is characterized by abnormalities in cognitive, social, and motor skills. RTT is often caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). The mechanism by which impaired MeCP2 induces the pathological abnormalities in the brain is not understood. Both patients and mouse models have shown abnormalities at molecular and cellular level before typical RTT-associated symptoms appear. This implies that underlying mechanisms are already affected during neurodevelopmental stages. Methods To understand the molecular mechanisms involved in disease onset, we used an RTT patient induced pluripotent stem cell (iPSC)-based model with isogenic controls and performed time-series of proteomic analysis using in-depth high-resolution quantitative mass spectrometry during early stages of neuronal development. Results We provide mass spectrometry-based quantitative proteomic data, depth of about 7000 proteins, at neuronal progenitor developmental stages of RTT patient cells and isogenic controls. Our data gives evidence of proteomic alteration at early neurodevelopmental stages, suggesting alterations long before the phase that symptoms of RTT syndrome become apparent. Significant changes are associated with the GO enrichment analysis in biological processes cell-cell adhesion, actin cytoskeleton organization, neuronal stem cell population maintenance, and pituitary gland development, next to protein changes previously associated with RTT, i.e., dendrite morphology and synaptic deficits. Differential expression increased from early to late neural stem cell phases, although proteins involved in immunity, metabolic processes, and calcium signaling were affected throughout all stages analyzed. Limitations The limitation of our study is the number of RTT patients analyzed. As the aim of our study was to investigate a large number of proteins, only one patient was considered, of which 3 different RTT iPSC clones and 3 isogenic control iPSC clones were included. Even though this approach allowed the study of mutation-induced alterations due to the usage of isogenic controls, results should be validated on different RTT patients to suggest common disease mechanisms. Conclusions During early neuronal differentiation, there are consistent and time-point specific proteomic alterations in RTT patient cells carrying exons 3–4 deletion in MECP2. We found changes in proteins involved in pathway associated with RTT phenotypes, including dendrite morphology and synaptogenesis. Our results provide a valuable resource of proteins and pathways for follow-up studies, investigating common mechanisms involved during early disease stages of RTT syndrome.

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“…Seizure activity: Epilepsy and epileptic encephalopathy have been reported as rare symptoms of AOS that are associated with the DOCK6 mutation. Patients with this mutation not only present with variable seizure severity, but also brain malformations, ocular anomalies, and intellectual disabilities [ 11 ]. It is unclear what mutation our patient has, but she has a history of controlled seizures.…”

Section: Discussionmentioning

confidence: 99%

Case report and review of literature of a rare congenital disorder: Adams-Oliver syndrome

et al. 2021

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Background Adams-Oliver syndrome is characterized by the combination of congenital scalp defects and terminal transverse limb defects. In some instances, cardiovascular malformations and orofacial malformations have been observed. Little is written with regards to the anesthetic management and airway concerns of patients with Adams-Oliver syndrome. Case presentation A five-year-old female with Adams-Oliver syndrome presented for repeat lower extremity surgery. Airway exam was significant for dysmorphic features, such as hypertelorism, deviated jaw, and retrognathia. Video laryngoscope was utilized for intubation due to the patients retrognathic jaw, cranial deformities, and facial dysmorphism. A vein finder with ultrasound guidance was needed to place the peripheral intravenous line due to her history of difficult intravenous access. The patient was successfully intubated with slight cricoid pressure applied to direct the endotracheal tube smoothly. Surgery and recovery were both unremarkable. Conclusions Due to varying presentations of Adams-Oliver syndrome, anesthetic and airway management considerations should be carefully assessed prior to surgery. Anesthesiologists must take into consideration possible orofacial abnormalities that may make intubation difficult. Amniotic band syndrome and other limb defects could potentially impact intravenous access as well.

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Epileptic Encephalopathy in Adams–Oliver Syndrome Associated to a New DOCK6 Mutation: A Peculiar Behavioral Phenotype

Cited by 7 publications

References 18 publications

Expanding the phenotype in Adams–Oliver syndrome correlating with the genotype

Expanding the phenotype in Adams–Oliver syndrome correlating with the genotype

Quantitative proteomic analysis of Rett iPSC-derived neuronal progenitors

Case report and review of literature of a rare congenital disorder: Adams-Oliver syndrome

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