Sodium Oxybate-Treated Familial Myoclonus-Dystonia Syndrome Due to Novel SGCE Variant.

Myoclonus-dystonia syndrome (MDS, OMIM #159900) is an autosomal-dominant movement disorder caused by heterozygous variants in the epsilon sarcoglycan gene (SGCE) and characterized by a combination of myoclonic jerks, dystonia, and psychiatric comorbidities. Patients with MDS have a normal life expectancy with markedly reduced quality of life. Here, we report four family members diagnosed with MDS of variable severity due to a novel heterozygous splicing variant in SGCE (c.

Experimentally validated modeling of dynamic drug-hERG channel interactions reproducing the binding mechanisms and its importance in action potential duration.

Background And Objective: Assessment of drug cardiotoxicity is critical in the development of new compounds and modeling of drug-binding dynamics to hERG can improve early cardiotoxicity assessment. We previously developed a methodology to generate Markovian models reproducing preferential state-dependent binding properties, trapping dynamics and the onset of I block using simple voltage clamp protocols. Here, we test this methodology with real I blockers and investigate the impact of drug dynamics on action potential prolongation.

Printed Silk Microelectrode Arrays for Electrophysiological Recording and Controlled Drug Delivery.

The use of soft and flexible bioelectronic interfaces can enhance the quality for recording cells' electrical activity by ensuring a continuous and intimate contact with the smooth, curving surfaces found in the physiological environment. This work develops soft microelectrode arrays (MEAs) made of silk fibroin (SF) films for recording interfaces that can also serve as a drug delivery system. Inkjet printing is used as a tool to deposit the substrate, conductive electrode, and insulator, as well as a drug-delivery nanocomposite film.

Periocular Pigmented Basal Cell Carcinomas: Clinicopathologic Features and Mutational Profile.

Purpose: Pigmented basal cell carcinomas (PBCC) is an uncommon variant of basal cell carcinoma of the periocular region with limited information in the literature. We highlight the clinicopathological profile and somatic mutations in periocular PBCC.

Methods: The clinicopathological features and somatic mutations in patients with periocular PBCC were examined and compared with periocular non-PBCC reported in the literature.

Molecular autopsy by proxy in preconception counseling.

Monogenic diseases that result in early pregnancy loss or neonatal death are genetically and phenotypically highly variable. This often poses significant challenges in arriving at a molecular diagnosis for reproductive planning. Molecular autopsy by proxy (MABP) refers to the genetic testing of relatives of deceased individuals to deduce the cause of death.

Inkjet-Printed and Electroplated 3D Electrodes for Recording Extracellular Signals in Cell Culture.

Recent investigations into cardiac or nervous tissues call for systems that are able to electrically record in 3D as opposed to 2D. Typically, challenging microfabrication steps are required to produce 3D microelectrode arrays capable of recording at the desired position within the tissue of interest. As an alternative, additive manufacturing is becoming a versatile platform for rapidly prototyping novel sensors with flexible geometric design.

Phenotypic and molecular spectrum of pyridoxamine-5'-phosphate oxidase deficiency: A scoping review of 87 cases of pyridoxamine-5'-phosphate oxidase deficiency.

Pyridoxamine-5'-phosphate oxidase (PNPO) deficiency is an autosomal recessive pyridoxal 5'-phosphate (PLP)-vitamin-responsive epileptic encephalopathy. The emerging feature of PNPO deficiency is the occurrence of refractory seizures in the first year of life. Pre-maturity and fetal distress, combined with neonatal seizures, are other associated key characteristics.

Fully Printed μ-Needle Electrode Array from Conductive Polymer Ink for Bioelectronic Applications.

Microelectrode arrays (MEAs) are widely used platforms in bioelectronics to study electrogenic cells. In recent years, the processing of conductive polymers for the fabrication of three-dimensional electrode arrays has gained increasing interest for the development of novel sensor designs. Here, additive manufacturing techniques are promising tools for the production of MEAs with three-dimensional electrodes.

Printed microfluidic filter for heparinized blood.

A simple lab-on-a-chip method for blood plasma separation was developed by combining stereolithographic 3D printing with inkjet printing, creating a completely sealed microfluidic device. In some approaches, one dilutes the blood sample before separation, reducing the concentration of a target analyte and increasing a contamination risk. In this work, a single drop (8 l) of heparinized whole blood could be efficiently filtered using a capillary effect without any external driving forces and without dilution.

Nanoscale Electrochemical Sensor Arrays: Redox Cycling Amplification in Dual-Electrode Systems.

Micro- and nanofabriation technologies have a tremendous potential for the development of powerful sensor array platforms for electrochemical detection. The ability to integrate electrochemical sensor arrays with microfluidic devices nowadays provides possibilities for advanced lab-on-a-chip technology for the detection or quantification of multiple targets in a high-throughput approach. In particular, this is interesting for applications outside of analytical laboratories, such as point-of-care (POC) or on-site water screening where cost, measurement time, and the size of individual sensor devices are important factors to be considered.

Influence of Self-Assembled Alkanethiol Monolayers on Stochastic Amperometric On-Chip Detection of Silver Nanoparticles.

We investigate the influence of self-assembled alkanethiol monolayers at the surface of platinum microelectrode arrays on the stochastic amperometric detection of citrate-stabilized silver nanoparticles in aqueous solutions. The measurements were performed using a microelectrode array featuring 64 individually addressable electrodes that are recorded in parallel with a sampling rate of 10 kHz for each channel. We show that both the functional end group and the total length of the alkanethiol influence the charge transfer.

Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.

Our knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS).

Ciliary genes TBC1D32/C6orf170 and SCLT1 are mutated in patients with OFD type IX.

Clinical syndromes caused by defects in the primary cilium are heterogeneous but there are recurrent phenotypic manifestations that define them as a collective group known as ciliopathies. Dozens of genes have been linked to various ciliopathies but large patient cohorts have clearly revealed the existence of additional genetic heterogeneity, which is yet to be fully appreciated. In our search for novel ciliopathy-linked genes through the study of unmapped ciliopathy phenotypes, we have identified two simplex cases with a severe ciliopathy phenotype consistent with oro-facio-digital syndrome type IX featuring midline cleft, microcephaly, and colobomatous microphathalmia/anophthalmia.

Mutations in LRPAP1 are associated with severe myopia in humans.

Myopia is an extremely common eye disorder but the pathogenesis of its isolated form, which accounts for the overwhelming majority of cases, remains poorly understood. There is strong evidence for genetic predisposition to myopia, but determining myopia genetic risk factors has been difficult to achieve. We have identified Mendelian forms of myopia in four consanguineous families and implemented exome/autozygome analysis to identify homozygous truncating variants in LRPAP1 and CTSH as the likely causal mutations.

Mutation in MPDZ causes severe congenital hydrocephalus.

Background: Congenital hydrocephalus is an important birth defect that is heterogeneous in aetiology and clinical presentation. Although genetics is believed to play an important role in the aetiology of non-syndromic congenital hydrocephalus, the overwhelming majority of cases lack mutations in L1CAM, the only disease gene identified to date. The purpose of this study is to identify a novel genetic cause of congenital hydrocephalus.

POC1A truncation mutation causes a ciliopathy in humans characterized by primordial dwarfism.

Primordial dwarfism (PD) is a phenotype characterized by profound growth retardation that is prenatal in onset. Significant strides have been made in the last few years toward improved understanding of the molecular underpinning of the limited growth that characterizes the embryonic and postnatal development of PD individuals. These include impaired mitotic mechanics, abnormal IGF2 expression, perturbed DNA-damage response, defective spliceosomal machinery, and abnormal replication licensing.

LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency.

Background: Clinical immunology has traditionally relied on accurate phenotyping of the patient's immune dysfunction for the identification of a candidate gene or genes for sequencing and molecular confirmation. Although this is also true for other branches of medicine, the marked variability in immune-related phenotypes and the highly complex network of molecules that confer normal host immunity are challenges that clinical immunologists often face in their quest to establish a specific genetic diagnosis.

Objective: We sought to identify the underlying genetic cause in a consanguineous family with chronic inflammatory bowel disease-like disorder and combined immunodeficiency.

Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome.

Adams-Oliver syndrome (AOS) is defined by the combination of aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). It is usually inherited as an autosomal-dominant trait, but autosomal-recessive inheritance has also been documented. In an individual with autosomal-recessive AOS, we combined autozygome analysis with exome sequencing to identify a homozygous truncating mutation in dedicator of cytokinesis 6 gene (DOCK6) which encodes an atypical guanidine exchange factor (GEF) known to activate two members of the Rho GTPase family: Cdc42 and Rac1.

A nullimorphic ERLIN2 mutation defines a complicated hereditary spastic paraplegia locus (SPG18).

Hereditary Spastic Paraplegia (HSP) is a clinically and genetically heterogeneous group of neurological disorders that are characterized by progressive spasticity of the lower extremities. We describe an extended consanguineous Saudi family in which HSP is linked to SPG18, a previously reported autosomal recessive locus, and show that it is associated with a nullimorphic deletion of ERLIN2, a component of endoplasmic reticulum associated degradation. This finding adds to the growing diversity of cellular functions that are now known to be involved in the maintenance of the corticospinal tract neurons.