5,10-methenyltetrahydrofolate synthetase deficiency: An extreme rare defect of folate metabolism in two Dutch siblings.

Two siblings, presenting with a neurometabolic phenotype, were identified with 5, 10-methenyltetrahydrofolate synthetase (MTHFS) deficiency. Whole genome sequencing in both patients demonstrated an homozygous MTHFS variant NM_006441.3(MTHFS):c.434G > A, p.Arg145Gin, which has been described before. At baseline, both patients showed moderate hyperhomocysteinemia, decreased 5-methyltetrahydrofolate (5MTHF), and increased 5-formyltetrahydrofolate (5-FTHF) in whole blood. In CSF, 5MTHF levels were in the low-normal range and 5-FTHF was strongly increased. In our novel enzyme assay, MTHFS activity was deficient in cultured fibroblasts in both sisters. Oral treatment was initiated with escalating dose of 5-methyltetrahydrofolate (5MTHF) up to 12 mg and hydroxycobalamin 5 mg daily. Plasma homocysteine normalized and 5MTHF became elevated in the blood of both patients. The elevated 5FTHF levels increased further on treatment in blood and CSF. This regimen resulted in some clinical improvement of patient 1. In patient 2, the clinical benefits of 5MTHF supplementation were less obvious. It seems plausible that the alleviation of the deficient 5MTHF levels and normalization of homocysteine in blood are of some clinical benefit. On the other hand, the very high levels of 5FTHF may well be detrimental and may prompt us to decrease the dose of 5MTHF. In addition, we hypothesize that the crippled MTHFS enzyme may destabilize the purinosome, which is presumably not ameliorated by 5MTHF.

Functional properties of measles virus proteins derived from a subacute sclerosing panencephalitis patient who received repeated remdesivir treatments.

Subacute sclerosing panencephalitis (SSPE) is a rare but fatal late neurological complication of measles, caused by persistent measles virus (MeV) infection of the central nervous system. There are no drugs approved for the treatment of SSPE. Here, we followed the clinical progression of a 5-year-old SSPE patient after treatment with the nucleoside analog remdesivir, conducted a post-mortem evaluation of the patient's brain, and characterized the MeV detected in the brain. The quality of life of the patient transiently improved after the first two courses of remdesivir, but a third course had no further clinical effect, and the patient eventually succumbed to his condition. Post-mortem evaluation of the brain displayed histopathological changes including loss of neurons and demyelination paired with abundant presence of MeV RNA-positive cells throughout the brain. Next-generation sequencing of RNA isolated from the brain revealed a complete MeV genome with mutations that are typically detected in SSPE, characterized by a hypermutated M gene. Additional mutations were detected in the polymerase (L) gene, which were not associated with resistance to remdesivir. Functional characterization showed that mutations in the F gene led to a hyperfusogenic phenotype predominantly mediated by N465I. Additionally, recombinant wild-type-based MeV with the SSPE-F gene or the F gene with the N465I mutation was no longer lymphotropic but instead efficiently disseminated in neural cultures. Altogether, this case encourages further investigation of remdesivir as a potential treatment of SSPE and highlights the necessity to functionally understand SSPE-causing MeV.IMPORTANCEMeasles virus (MeV) causes acute, systemic disease and remains an important cause of morbidity and mortality in humans. Despite the lack of known entry receptors in the brain, MeV can persistently infect the brain causing the rare but fatal neurological disorder subacute sclerosing panencephalitis (SSPE). SSPE-causing MeVs are characterized by a hypermutated genome and a hyperfusogenic F protein that facilitates the rapid spread of MeV throughout the brain. No treatment against SSPE is available, but the nucleoside analog remdesivir was recently demonstrated to be effective against MeV in vitro. We show that treatment of an SSPE patient with remdesivir led to transient clinical improvement and did not induce viral escape mutants, encouraging the future use of remdesivir in SSPE patients. Functional characterization of the viral proteins sheds light on the shared properties of SSPE-causing MeVs and further contributes to understanding how those viruses cause disease.

Kohlschütter-Tönz syndrome: Case report with novel feature and detailed review of features associated with ROGDI variants.

Kohlschütter-Tönz syndrome (KTS) is a rare, autosomal recessive syndrome characterized by a triad of epilepsy, amelogenesis imperfecta and severe global developmental delay. It was first described in a Swiss family in 1974 by Alfried Kohlschütter and Otmar Tönz. It is caused by pathogenic variants in the ROGDI gene. To the best of our knowledge, there are currently 43 patients with a confirmed ROGDI gene pathogenic variant reported. Here, we review in detail the clinical manifestations of KTS, provide an overview of all reported genetically confirmed patients, and document an additional case of KTS-a 6-year-old Latvian girl-with a confirmed ROGDI gene pathogenic variant. In contrast to previous reports, we detected idiopathic bilateral nephrocalcinosis in this newly identified KTS patient. Perampanel proved an effective treatment for our patient with prolonged super-refractory status epilepticus. In order to better characterize this rare syndrome and its clinical course, it is important to report any additional symptoms and also the effectiveness of used therapies. Future research should focus on elucidating the mechanisms by which the absence/insufficiency of ROGDI-encoded protein causes the clinical manifestations of KTS. This knowledge could shape possible ways of influencing the disease's natural history with more effective therapies.

Alcohol-related seizures may be associated with more severe depression, alcohol dependence syndrome, and more pronounced alcohol-related problems.

Severe alcohol abuse and related medical and social functioning risks, as well as clinically significant depression, are common in patients who are admitted to hospital with alcohol-related seizures (ARS) and significantly affect the quality of life of the patient. Compared with studies involving patients with alcohol dependence, no large-scale studies with the aim of finding the prevalence and severity of depression and its most commonly affected aspects for patients with ARS have been carried out in Latvia yet. The habits and frequency of alcohol use in correlation to depression and its severity are also not known. One hundred ten patients were included in the study - 60 patients with ARS and 50 patients with alcohol use disorder (AUD) - without ARS. The research population consists mainly of working-age adults; however, most patients with ARS have significantly impaired daily activity and social life. Compared with patients who only have alcohol dependence, a more common problem in patients with ARS is having an alcohol dependence level that requires additional clinical examinations and consultations by a narcologist using the Alcohol Use Disorder Identification Test (AUDIT) scale, and this level is more often related to depression particularly characterized by pronounced suicidal thoughts (exhibited by almost 1 out of every 4 patients). According to the Hamilton Depression Rating Scale (HAM-D), depression has affected 81.7% of patients with ARS and 96% of patients with AUD. Seizures negatively affect patients' physical and emotional well-being in over 80% of cases; moreover, it is common for most patients to feel depressed after the seizures. Over half of the patients with ARS scored 20-40 points according to the AUDIT scale, indicating serious alcohol abuse disorder. Our research data can help bring awareness of the need to more carefully evaluate patients with ARS for an early detection of alcohol abuse disorder and depression with a risk of self-harm and unintentional harm to others as well as to decrease the burden on social care and healthcare. This article is part of the Special Issue "Individualized Epilepsy Management: Medicines, Surgery and Beyond".

Tick-borne encephalitis: A 43-year summary of epidemiological and clinical data from Latvia (1973 to 2016).

BACKGROUND: The incidence of tick-borne encephalitis (TBE) varies significantly over time. To better understand the annual incidence of all TBE cases in Latvia we investigated the disease burden in the country from 1973-2016 using several available sources and case definitions. METHODS: We identified cases of TBE from an electronic database (maintained by the Centre for Disease Prevention and Control of Latvia [CDPC]) by the use of ICD-10 diagnosis codes for TBE (A84; A84.0; A84.1; A84.8; A84.9). In addition, previously unreported TBE cases were found by review of TBE diagnoses according to ICD-10 codes in four hospital databases. RESULTS: From 1973 to 2016 a total of 15,193 TBE cases were reported to the CDPC, 2,819 of which were reported from January 2007 through December 2016, additionally for this time period, 104 cases were identified via hospital survey. From all 2,923 reported cases (2007-2016), 1,973 met TBE case definition criteria and were included in the TBE study analysis. The highest average 10 year incidence was observed from 1990-1999 (27.9 cases per 100,000; range 4.6-53.0), however, the average 10-year incidence from 2007-2016 using officially adopted TBE case definition was 9.6 cases per 100,000 (range 5.8-14.6). For this 10-year time period most cases were adults (95.1%) and male (52.2%). The most common clinical form of TBE was meningitis (90.6%). A tick bite prior to TBE onset was reported in 60.6% of TBE cases and 98.2% of cases were not vaccinated against TBE. CONCLUSION: The data demonstrate that the incidence of TBE varies by about one third based on the case definition used. TBE occurs almost entirely in the unvaccinated population. Regular TBE awareness campaigns could encourage the population in Latvia to use protective measures to further control TBE in the country, either via vaccination or tick avoidance.