Objective:
KCNQ2 and KCNQ3 mutations are known to be responsible for benign familial neonatal seizures (BFNS). A few reports on patients with a KCNQ2 mutation with a more severe outcome exist, but a ...definite relationship has not been established. In this study we investigated whether KCNQ2/3 mutations are a frequent cause of epileptic encephalopathies with an early onset and whether a recognizable phenotype exists.
Methods:
We analyzed 80 patients with unexplained neonatal or early‐infantile seizures and associated psychomotor retardation for KCNQ2 and KCNQ3 mutations. Clinical and imaging data were reviewed in detail.
Results:
We found 7 different heterozygous KCNQ2 mutations in 8 patients (8/80; 10%); 6 mutations arose de novo. One parent with a milder phenotype was mosaic for the mutation. No KCNQ3 mutations were found. The 8 patients had onset of intractable seizures in the first week of life with a prominent tonic component. Seizures generally resolved by age 3 years but the children had profound, or less frequently severe, intellectual disability with motor impairment. Electroencephalography (EEG) at onset showed a burst‐suppression pattern or multifocal epileptiform activity. Early magnetic resonance imaging (MRI) of the brain showed characteristic hyperintensities in the basal ganglia and thalamus that later resolved.
Interpretation:
KCNQ2 mutations are found in a substantial proportion of patients with a neonatal epileptic encephalopathy with a potentially recognizable electroclinical and radiological phenotype. This suggests that KCNQ2 screening should be included in the diagnostic workup of refractory neonatal seizures of unknown origin. ANN NEUROL 2012;71:15–25
Absence epilepsies of childhood are heterogeneous with most cases following complex inheritance. Those cases with onset before 4 years of age represent a poorly studied subset. We screened 34 ...patients with early‐onset absence epilepsy for mutations in SLC2A1, the gene encoding the GLUT1 glucose transporter. Mutations leading to reduced protein function were found in 12% (4/34) of patients. Two mutations arose de novo, and two were familial. These findings suggest GLUT1 deficiency underlies a significant proportion of early‐onset absence epilepsy, which has both genetic counseling and treatment implications because the ketogenic diet is effective in GLUT1 deficiency. Ann Neurol 2009;66:415–419
Abstract
Current dyslipidemia management in patients with atherosclerotic cardiovascular disease (ASCVD) is based on traditional serum lipids. Yet, there is some indication from basic research that ...serum apolipoproteins A-I, (a), B, C-I, C-II, C-III, and E may give better pathophysiological insight into the root causes of dyslipidemia. To facilitate the future adoption of clinical serum apolipoprotein (apo) profiling for precision medicine, strategies for accurate testing should be developed in advance.
Recent discoveries in basic science and translational medicine set the stage for the IFCC Working Group on Apolipoproteins by Mass Spectrometry. Main drivers were the convergence of unmet clinical needs in cardiovascular disease (CVD) patients with enabling technology and metrology. First, the residual cardiovascular risk after accounting for established risk factors demonstrates that the current lipid panel is too limited to capture the full complexity of lipid metabolism in patients. Second, there is a need for accurate test results in highly polymorphic and atherogenic apolipoproteins such as apo(a). Third, sufficient robustness of mass spectrometry technology allows reproducible protein quantification at the molecular level. Fourth, several calibration hierarchies in the revised ISO 17511:2020 guideline facilitate metrological traceability of test results, the highest achievable standard being traceability to SI.
This article outlines the conceptual approach aimed at achieving a novel, multiplexed Reference Measurement System (RMS) for seven apolipoproteins based on isotope dilution mass spectrometry and peptide-based calibration. This RMS should enable standardization of existing and emerging apolipoprotein assays to SI, within allowable limits of measurement uncertainty, through a sustainable network of Reference Laboratories.
•Overview of analytical challenges of the faecal immunochemical test for haemoglobin.•Harmonisation study underway.•Summary included of key pre-analytical variables.•Analytical evaluation of external ...quality assurance schemes complete.•Four potential third party internal quality assurance materials available.
Quantitative faecal immunochemical tests for haemoglobin (FIT) are being used increasingly around the world in colorectal cancer screening programmes, and in patients presenting with lower bowel symptoms to determine who should proceed to further bowel visualisation investigations, usually colonoscopy. The clinical utility of FIT is well reported. There are a number of analytical challenges including pre-analytical variation, difficulty setting up external quality assessment schemes, access to third party internal quality control material and a lack of standardisation or harmonisation of FIT methods. Here we report the work of the International Federation of Clinical Chemistry FIT Working Group. We provide an overview of the main pre-analytical variables; discuss different approaches to external quality assurance of FIT; propose a solution to third party internal quality assurance materials and summarise the challenges of standardisation and harmonisation of FIT.
Abstract
Background
Elevated concentrations of lipoprotein(a) Lp(a) are directly related to an increased risk of cardiovascular diseases, making it a relevant biomarker for clinical risk assessment. ...However, the lack of global standardization of current Lp(a) measurement procedures (MPs) leads to inconsistent patient care. The International Federation for Clinical Chemistry and Laboratory Medicine working group on quantitating apolipoproteins by mass spectrometry (MS) aims to develop a next-generation SI (International system of units)-traceable reference measurement system consisting of a MS-based, peptide-calibrated reference measurement procedure (RMP) and secondary serum-based reference materials (RMs) certified for their apolipoprotein(a) apo(a) content. To reach measurement standardization through this new measurement system, 2 essential requirements need to be fulfilled: a sufficient correlation among the MPs and appropriate commutability of future serum-based RMs.
Methods
The correlation among the candidate RMP (cRMP) and immunoassay-based MPs was assessed by measuring a panel of 39 clinical samples (CS). In addition, the commutability of 14 different candidate RMs was investigated.
Results
Results of the immunoassay-based MPs and the cRMPs demonstrated good linear correlations for the CS but some significant sample-specific differences were also observed. The results of the commutability study show that RMs based on unspiked human serum pools can be commutable with CS, whereas human pools spiked with recombinant apo(a) show different behavior compared to CS.
Conclusions
The results of this study show that unspiked human serum pools are the preferred candidate secondary RMs in the future SI-traceable Lp(a) Reference Measurement System.
Abstract
Background
Medical results generated by European CE Marking for In Vitro Diagnostic or in-house tests should be traceable to higher order reference measurement systems (RMS), such as ...International Federation of Clinical Chemistry and Laboratory Medicine (IFCC)-endorsed reference measurement procedures (RMPs) and reference materials. Currently, serum apolipoprotein (a) apo(a) is recognized as a novel risk factor for cardiovascular risk assessment and patient management. The former RMS for serum apo(a) is no longer available; consequently, an International System of Units (SI)-traceable, ideally multiplexed, and sustainable RMS for apo(a) is needed.
Methods
A mass spectrometry (MS)-based candidate RMP (cRMP) for apo(a) was developed using quantitative bottom-up proteomics targeting 3 proteotypic peptides. The method was provisionally validated according to ISO 15193 using a single human serum based calibrator traceable to the former WHO-IFCC RMS.
Results
The quantitation of serum apo(a) was by design independent of its size polymorphism, was linear from 3.8 to 456 nmol/L, and had a lower limit of quantitation for apo(a) of 3.8 nmol/L using peptide LFLEPTQADIALLK. Interpeptide agreement showed Pearson Rs of 0.987 and 0.984 for peptides GISSTVTGR and TPENYPNAGLTR, and method comparison indicated good correspondence (slopes 0.977, 1.033, and 1.085 for LFLEPTQADIALLK, GISSTVTGR, and TPENYPNAGLTR). Average within-laboratory imprecision of the cRMP was 8.9%, 11.9%, and 12.8% for the 3 peptides.
Conclusions
A robust, antibody-independent, MS-based cRMP was developed as higher order RMP and an essential part of the apo(a) traceability chain and future RMS. The cRMP fulfils predefined analytical performance specifications, making it a promising RMP candidate in an SI-traceable MS-based RMS for apo(a).
Incidence rates of epilepsy in children are highest during the first year of life. Most frequently, epilepsy results from a metabolic or structural defect in the brain. However, some infants have ...clearly delineated epilepsy syndromes for which no underlying etiology can be identified except for a genetic predisposition.
We reviewed the current knowledge on the genetics of epilepsy syndromes starting in the first year of life. We focus on those epilepsy syndromes without a clear structural or metabolic etiology.
Recent molecular studies have led to the identification of the responsible gene defects for several of the monogenetic epilepsy syndromes with onset in the first year of life.
This knowledge has consequences for clinical practice as it opens new perspectives for genetic testing, improving early diagnosis, and facilitating genetic counseling. This overview of epilepsy syndromes and associated gene defects might serve as a basis for the selection of patients in whom genetic testing can be helpful.
Many idiopathic epilepsy syndromes have a characteristic age dependence, the underlying molecular mechanisms of which are largely unknown. Here we propose a mechanism that can explain that epileptic ...spells in benign familial neonatal-infantile seizures occur almost exclusively during the first days to months of life. Benign familial neonatal-infantile seizures are caused by mutations in the gene SCN2A encoding the voltage-gated Na+ channel NaV1.2. We identified two novel SCN2A mutations causing benign familial neonatal-infantile seizures and analysed the functional consequences of these mutations in a neonatal and an adult splice variant of the human Na+ channel NaV1.2 expressed heterologously in tsA201 cells together with beta1 and beta2 subunits. We found significant gating changes leading to a gain-of-function, such as an increased persistent Na+ current, accelerated recovery from fast inactivation or altered voltage-dependence of steady-state activation. Those were restricted to the neonatal splice variant for one mutation, but more pronounced for the adult form for the other, suggesting that a differential developmental splicing does not provide a general explanation for seizure remission. We therefore analysed the developmental expression of NaV1.2 and of another voltage-gated Na+ channel, NaV1.6, using immunohistochemistry and real-time reverse transcription–polymerase chain reaction in mouse brain slices. We found that NaV1.2 channels are expressed early in development at axon initial segments of principal neurons in the hippocampus and cortex, but their expression is diminished and they are gradually replaced as the dominant channel type by NaV1.6 during maturation. This finding provides a plausible explanation for the transient expression of seizures that occur due to a gain-of-function of mutant NaV1.2 channels.
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