Many patients with developmental and epileptic encephalopathies present with variants in genes coding for GABA
receptors. These variants are presumed to cause loss-of-function receptors leading to ...reduced neuronal GABAergic activity. Yet, patients with GABA
receptor variants have diverse clinical phenotypes and many are refractory to treatment despite the availability of drugs that enhance GABAergic activity. Here we show that 44 pathogenic GABRB3 missense variants segregate into gain-of-function and loss-of-function groups and respective patients display distinct clinical phenotypes. The gain-of-function cohort (n = 27 patients) presented with a younger age of seizure onset, higher risk of severe intellectual disability, focal seizures at onset, hypotonia, and lower likelihood of seizure freedom in response to treatment. Febrile seizures at onset are exclusive to the loss-of-function cohort (n = 47 patients). Overall, patients with GABRB3 variants that increase GABAergic activity have more severe developmental and epileptic encephalopathies. This paradoxical finding challenges our current understanding of the GABAergic system in epilepsy and how patients should be treated.
This is a systematic review of cases with Lemierre's syndrome (LS) in the past 5 years. LS is characterized by sepsis often evolving after a sore throat or tonsillitis and then complicated by various ...septic emboli and thrombosis of the internal jugular vein. Symptoms include sepsis, pain, and/or swelling in the throat or neck, as well as respiratory symptoms. Laboratory findings show elevated infectious parameters and radiological findings show thrombosis of the internal jugular vein and emboli in the lungs or other organs. The syndrome is often associated with an infection with
We found a total of 137 cases of LS, of which 47 were infected with
and others with
and
. Complications of this rare but severe disease included osteomyelitis, meningitis, and acute respiratory distress syndrome. Mortality was extremely high in the pre-antibiotic era but has diminished with the advent of antibiotics. This review showed a mortality rate of only 2% of which none of the cases involved fusobacteria. Duration of treatment varied; a 4-6-week course of carbapenem or piperacillin/tazobactam in combination with metronidazole was optimum. Other treatment options included anticoagulants in 46% of cases, which is unwarrantedly high, as to date, no evidence of the positive effects of anticoagulants in LS exists. Only two cases had ligation of the internal jugular vein performed. This review confirms the rare, but severe aspects of LS. Mortality from LS in this day and age appears to be low, however the syndrome is difficult to recognize, and still requires the full attention of the clinician.
Malfunctions of voltage-gated sodium and calcium channels (encoded by
and
family genes, respectively) have been associated with severe neurologic, psychiatric, cardiac, and other diseases. Altered ...channel activity is frequently grouped into gain or loss of ion channel function (GOF or LOF, respectively) that often corresponds not only to clinical disease manifestations but also to differences in drug response. Experimental studies of channel function are therefore important, but laborious and usually focus only on a few variants at a time. On the basis of known gene-disease mechanisms of 19 different diseases, we inferred LOF (
= 518) and GOF (
= 309) likely pathogenic variants from the disease phenotypes of variant carriers. By training a machine learning model on sequence- and structure-based features, we predicted LOF or GOF effects area under the receiver operating characteristics curve (ROC) = 0.85 of likely pathogenic missense variants. Our LOF versus GOF prediction corresponded to molecular LOF versus GOF effects for 87 functionally tested variants in
and
(ROC = 0.73) and was validated in exome-wide data from 21,703 cases and 128,957 controls. We showed respective regional clustering of inferred LOF and GOF nucleotide variants across the alignment of the entire gene family, suggesting shared pathomechanisms in the
family genes.
Many patients with epilepsy undergo exome or genome sequencing as part of a diagnostic workup; however, many remain genetically unsolved. There are various factors that account for negative results ...in exome/genome sequencing for patients with epilepsy: (1) the underlying cause is not genetic; (2) there is a complex polygenic explanation; (3) the illness is monogenic but the causative gene remains to be linked to a human disorder; (4) family segregation with reduced penetrance; (5) somatic mosaicism or the complexity of, for example, a structural rearrangement; or (6) limited knowledge or diagnostic tools that hinder the proper classification of a variant, resulting in its designation as a variant of unknown significance. The objective of this review is to outline some of the diagnostic options that lie beyond the exome/genome, and that might become clinically relevant within the foreseeable future. These options include: (1) re‐analysis of older exome/genome data as knowledge increases or symptoms change; (2) looking for somatic mosaicism or long‐read sequencing to detect low‐complexity repeat variants or specific structural variants missed by traditional exome/genome sequencing; (3) exploration of the non‐coding genome including disruption of topologically associated domains, long range non‐coding RNA, or other regulatory elements; and finally (4) transcriptomics, DNA methylation signatures, and metabolomics as complementary diagnostic methods that may be used in the assessment of variants of unknown significance. Some of these tools are currently not integrated into standard diagnostic workup. However, it is reasonable to expect that they will become increasingly available and improve current diagnostic capabilities, thereby enabling precision diagnosis in patients who are currently undiagnosed.
...a genetic diagnosis is no longer just an explanation for the epilepsy but has true clinical implications. The study also supports the notion that patients with genetic epilepsies not only present ...to intensive care units, albeit being most commonly treated there, but also might present to outpatient clinics. ...genetic testing should not be limited to intensive care settings only. Currently, the ability to predict whether any damage that has already occurred from the underlying genetic condition is reversible or not is difficult; nonetheless, the assumption must be that the earlier targeted treatment is initiated, the better the patient outcome. ...a well-run laboratory is necessary if rapid turnaround time is required on genetic testing. ...precise phenotypic information from the referring physician and a tight collaboration with the personnel interpreting the genetic results is required for optimal interpretation and conclusive results.
Adult phenotype of KCNQ2 encephalopathy Boets, Stephanie; Johannesen, Katrine M; Destree, Anne ...
Journal of medical genetics,
06/2022, Letnik:
59, Številka:
6
Journal Article
Recenzirano
Odprti dostop
BackgroundPathogenic KCNQ2 variants are a frequent cause of developmental and epileptic encephalopathy.MethodsWe recruited 13 adults (between 18 years and 45 years of age) with KCNQ2 encephalopathy ...and reviewed their clinical, EEG, neuroimaging and treatment history.ResultsWhile most patients had daily seizures at seizure onset, seizure frequency declined or remitted during childhood and adulthood. The most common seizure type was tonic seizures (early) infancy, and tonic-clonic and focal impaired awareness seizures later in life. Ten individuals (77%) were seizure-free at last follow-up. In 38% of the individuals, earlier periods of seizure freedom lasting a minimum of 2 years followed by seizure recurrence had occurred. Of the 10 seizure-free patients, 4 were receiving a single antiseizure medication (ASM, carbamazepine, lamotrigine or levetiracetam), and 2 had stopped taking ASM. Intellectual disability (ID) ranged from mild to profound, with the majority (54%) of individuals in the severe category. At last contact, six individuals (46%) remained unable to walk independently, six (46%) had limb spasticity and four (31%) tetraparesis/tetraplegia. Six (46%) remained non-verbal, 10 (77%) had autistic features/autism, 4 (31%) exhibited aggressive behaviour and 4 (31%) destructive behaviour with self-injury. Four patients had visual problems, thought to be related to prematurity in one. Sleep problems were seen in six (46%) individuals.ConclusionSeizure frequency declines over the years and most patients are seizure-free in adulthood. Longer seizure-free periods followed by seizure recurrence are common during childhood and adolescence. Most adult patients have severe ID. Motor, language and behavioural problems are an issue of continuous concern.
Objective
Genetic testing has become a routine part of the diagnostic workup in children with early onset epilepsies. In the present study, we sought to investigate a cohort of adult patients with ...epilepsy, to determinate the diagnostic yield and explore the gain of personalized treatment approaches in adult patients.
Methods
Two hundred patients (age span = 18‐80 years) referred for diagnostic gene panel testing at the Danish Epilepsy Center were included. The vast majority (91%) suffered from comorbid intellectual disability. The medical records of genetically diagnosed patients were mined for data on epilepsy syndrome, cognition, treatment changes, and seizure outcome following the genetic diagnosis.
Results
We found a genetic diagnosis in 46 of 200 (23%) patients. SCN1A, KCNT1, and STXBP1 accounted for the greatest number of positive findings (48%). More rare genetic findings included SLC2A1, ATP6A1V, HNRNPU, MEF2C, and IRF2BPL. Gene‐specific treatment changes were initiated in 11 of 46 (17%) patients (one with SLC2A1, 10 with SCN1A) following the genetic diagnosis. Ten patients improved, with seizure reduction and/or increased alertness and general well‐being.
Significance
With this study, we show that routine diagnostic testing is highly relevant in adults with epilepsy. The diagnostic yield is similar to previously reported pediatric cohorts, and the genetic findings can be useful for therapeutic decision‐making, which may lead to better seizure control, ultimately improving quality of life.
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