Pathogenic missense variants in
GRIN2A
and
GRIN2B
may result in gain or loss of function (GoF/LoF) of the N-methyl-D-aspartate receptor (NMDAR). This observation gave rise to the hypothesis of ...successfully treating GRIN-related disorders due to LoF variants with co-agonists of the NMDAR. In this respect, we describe a retrospectively collected series of ten individuals with
GRIN2A
- or
GRIN2B
-related disorders who were treated with L-serine, each within an independent
n-of-1
trial. Our cohort comprises one individual with a LoF missense variant with clinical improvements confirming the above hypothesis and replicating a previous
n-of-1
trial. A second individual with a GoF missense variant was erroneously treated with L-serine and experienced immediate temporary behavioral deterioration further supporting the supposed functional pathomechanism. Eight additional individuals with null variants (that had been interpreted as
loss-of-function
variants despite not being missense) again showed clinical improvements. Among all nine individuals with LoF missense or null variants, L-serine treatment was associated with improvements in behavior in eight (89%), in development in four (44%), and/or in EEG or seizure frequency in four (44%). None of these nine individuals experienced side effects or adverse findings in the context of L-serine treatment. In summary, we describe the first evidence that L-serine treatment may not only be associated with clinical improvements in GRIN-related disorders due to LoF missense but particularly also null variants.
Variants in several potassium channel genes, including KCNA1 and KCNA2, cause Developmental and Epileptic Encephalopathies (DEEs). We investigated whether variants in KCNA3, another mammalian ...homologue of the Drosophila shaker family and encoding for Kv1.3 subunits, can cause DEE.
Genetic analysis of study individuals was performed by routine exome or genome sequencing, usually of parent-offspring trios. Phenotyping was performed via a standard clinical questionnaire. Currents from wild-type and/or mutant Kv1.3 subunits were investigated by whole-cell patch-clamp upon their heterologous expression.
Fourteen individuals, each carrying a de novo heterozygous missense variant in KCNA3, were identified. Most (12/14; 86%) had DEE with marked speech delay with or without motor delay, intellectual disability, epilepsy, and autism spectrum disorder. Functional analysis of Kv1.3 channels carrying each variant revealed heterogeneous functional changes, ranging from "pure" loss-of-function (LoF) effects due to faster inactivation kinetics, depolarized voltage-dependence of activation, slower activation kinetics, increased current inactivation, reduced or absent currents with or without dominant-negative effects, to "mixed" loss- and gain-of-function (GoF) effects. Compared to controls, Kv1.3 currents in lymphoblasts from 1 of the proband displayed functional changes similar to those observed upon heterologous expression of channels carrying the same variant. The antidepressant drug fluoxetine inhibited with similar potency the currents from wild-type and 1 of the Kv1.3 GoF variant.
We describe a novel association of de novo missense variants in KCNA3 with a human DEE, and provide evidence that fluoxetine might represent a potential targeted treatment for individuals carrying variants with significant GoF effects. ANN NEUROL 2024;95:365-376.
Pathogenic missense variants in GRIN2A and GRIN2B may result in gain or loss of function (GoF/LoF) of the N-methyl-D-aspartate receptor (NMDAR). This observation gave rise to the hypothesis of ...successfully treating GRIN-related disorders due to LoF variants with co-agonists of the NMDAR. In this respect, we describe a retrospectively collected series of ten individuals with GRIN2A- or GRIN2B-related disorders who were treated with L-serine, each within an independent n-of-1 trial. Our cohort comprises one individual with a LoF missense variant with clinical improvements confirming the above hypothesis and replicating a previous n-of-1 trial. A second individual with a GoF missense variant was erroneously treated with L-serine and experienced immediate temporary behavioral deterioration further supporting the supposed functional pathomechanism. Eight additional individuals with null variants (that had been interpreted as loss-of-function variants despite not being missense) again showed clinical improvements. Among all nine individuals with LoF missense or null variants, L-serine treatment was associated with improvements in behavior in eight (89%), in development in four (44%), and/or in EEG or seizure frequency in four (44%). None of these nine individuals experienced side effects or adverse findings in the context of L-serine treatment. In summary, we describe the first evidence that L-serine treatment may not only be associated with clinical improvements in GRIN-related disorders due to LoF missense but particularly also null variants.
It is essential to carry out a clinical assessment of dry body weight in dialysis-dependent children in order to develop a suitable dialysis prescription. Bioimpedance analysis and inferior vena cava ...diameter (IVCD) have been evaluated and utilized in adults as noninvasive parameters for the assessment of dry weight and extracellular volume. Since there are no data available for normal children, we performed a prospective study to establish reference standards for a pediatric population (111 females and 95 males, aged 6.8-16 years). We found strong correlations of both resistance and IVCD with age, height, weight, and, in particular, with body surface area. IVCD and resistance also correlated with each other. We also investigated 28 pediatric dialysis patients who showed growth retardation and delayed puberty. Applying age-related reference intervals to pediatric dialysis patients resulted in an underestimation of overhydration. The combination of both methods using body surface area-related reference limits with the clinical features of deviation of dry weight will serve as an adjunct to the assessment of post-dialysis dry weight.
Der Wasserhaushalt von Dialysepatienten bewegt sich ondulierend zwischen Überwässerung vor der Behandlung und gezielter Dehydratation nach der Dialyse. Das Ziel der Behandlung ist ein e ...Flüssigkeitsbalance. Das Gewicht nach der Dialyse bei dem dieser Zustand erreicht ist, wird als Trockengewicht oder Dialysezielgewicht bezeichnet. Zur Zeit ist kein einzelner Parameter verfügbar, von dem sich ein adäquates Trockengewicht der Dialysepatienten ableiten ließe. Die Einschätzung des Trockengewichtes von dialysepflichtigen Kindern stützt sich auf die sorgfältige klinische Untersuchung. Die Bioimpedanzanalyse und die Messung des Durchmessers der Vena cava inferior sind zwei nicht invasive Verfahren, die bereits an erwachsenen Dialysepatienten untersucht und zur Beurteilung des Trockengewichtes sowie des Extrazellulärvolumens angewandt werden. Für Kinder sind keine Referenzwerte für beide Verfahren verfügbar. Aus diesen Grund entschlossen wir uns, Normalwerte für diese Altersgruppe (6,8 bis 16 Jahre) zu erheben. Es zeigte sich ein enger Zusammenhang zwischen Resistanz (BIA) und Durchmesser der Vena cava inferior auf der einen und Werten wie z.B. Alter, Gewicht und Körperoberfläche auf der andren Seite. Resistanz und Durchmesser stehen ebenfalls in enger Beziehung zueinander. Bei der Untersuchung von 31 Dialysepatienten zeigten sich Wachstumsverzögerung und verspätete Pubertät. Daraus wird deutlich das altersbezogene Referenzwerte zu einer falschen Einschätzung des Wasserhaushaltes führen würden. Die kombinierte Anwendung beider Verfahren mit der Körperoberfläche als Bezugswert, kann im Vergleich zu den Veränderungen des Körpergewichtes wertvolle Informationen zur Optimierung des Trockengewichtes geben.
The hydration state of a dialysis patient reflects the balance between fluid overload, normovolemia and underhydration. The goal of the treatment is a fluid balance that is close to normal. The weight after dialysis in which this is achieved is the so called "dry weight". However, there is no single parameter to define the adequate dry body weight of a dialysis patient. In the assessment of dry body weight in dialysis-dependent children one must rely on careful and repeated clinical observation. Bioimpedance analysis and inferior vena cava diameter (IVCD) have been evaluated and utilized in adults as noninvasive parameters for the assessment of dry weight and extracellular volume. Since there are no data available for normal children, we performed a prospective study to establish reference standards for a pediatric population (111 females and 95 males, aged 6.8-16 years). We found strong correlations of both resistance (BIA) and IVCD with age, height, weight, and, in particular, with body surface area. IVCD and resistance also correlated with each other. We also investigated 31 pediatric dialysis patients who showed growth retardation and delayed puberty. Applying age-related reference intervals to pediatric dialysis patients resulted in an underestimation of overhydration. The combination of both methods using body surface area-corrected values with the clinical features of deviation of dry weight will serve as an adjunct to the assessment of post-dialysis dry weight.
Zusammenfassung
Die reibungslose Transition von Kindern und Jugendlichen mit Epilepsie in die Erwachsenenmedizin stellt eine Herausforderung dar. Die Patienten sind oft noch nicht in der Lage, ihre ...Krankheit allein zu bewältigen, und ihre Eltern zögern, die Dreiecksbeziehung zwischen ihnen, ihren Kindern und dem Arzt zu verlassen. Besonders schwierig ist die Transition für Kinder und Jugendliche mit kognitiven und körperlichen Beeinträchtigungen. Mangelnde Kommunikation zwischen Neuropädiater und Neurologen kann den Transitionsprozess zusätzlich behindern. Aus diesem Grund haben Neuropädiater, Neurologen und Psychologen aus ganz Deutschland einen Epilepsie-spezifischen Leitfaden zur Transition (ESLi-Trans) für einen einfachen, breit umsetzbaren und erfolgreichen Transitionsprozess erarbeitet. Die Empfehlungen und Materialien sollen dazu beitragen, einen geordneten, strukturierten Wechsel aus der kinderärztlichen Sprechstunde in die Erwachsenenbehandlung zu vollziehen und Behandlungsunsicherheiten sowie ggf. damit verbundene Krankheitsverschlechterungen zu vermeiden.
Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2,
have been identified as the cause for an evolving spectrum of neurological disorders. Affected
individuals show ...early-onset developmental and epileptic encephalopathy, intellectual disability, and
movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder
course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported.
By analyzing phenotypic, functional, and genetic data from published reports and novel cases,
we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated
disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated
with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities
and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-
function. We describe seven additional individuals harboring three known and the novel KCNA2
variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the
importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as
a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical
spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum,
genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.
Apart from genetic alterations, development and progression of colorectal cancer has been linked to influences from nutritional intake, hyperalimentation, and cellular metabolic changes that may be ...the basis for new diagnostic and therapeutic approaches. However, in contrast to genomics and proteomics, comprehensive metabolomic investigations of alterations in malignant tumors have rarely been conducted.
In this study we investigated a set of paired samples of normal colon tissue and colorectal cancer tissue with gas-chromatography time-of-flight mass-spectrometry, which resulted in robust detection of a total of 206 metabolites. Metabolic phenotypes of colon cancer and normal tissues were different at a Bonferroni corrected significance level of p=0.00170 and p=0.00005 for the first two components of an unsupervised PCA analysis. Subsequent supervised analysis found 82 metabolites to be significantly different at p<0.01. Metabolites were connected to abnormalities in metabolic pathways by a new approach that calculates the distance of each pair of metabolites in the KEGG database interaction lattice. Intermediates of the TCA cycle and lipids were found down-regulated in cancer, whereas urea cycle metabolites, purines, pyrimidines and amino acids were generally found at higher levels compared to normal colon mucosa.
This study demonstrates that metabolic profiling facilitates biochemical phenotyping of normal and neoplastic colon tissue at high significance levels and points to GC-TOF-based metabolomics as a new method for molecular pathology investigations.
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