The expanding clinical and genetic spectrum of DYNC1H1-related disorders.

Intracellular trafficking involves an intricate machinery of motor complexes including the dynein complex to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains as well as cytoplasmic light and intermediate chains have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy-chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life. We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0-59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders, and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy. Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies, and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross-River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of NDD manifestations, indicating a role of dynein in anti-viral immunity and neuronal health. In summary, our findings expand the clinical, imaging, and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients.

Prevalence of COVID-19 Among Children and Adolescents While Easing Lockdown Restrictions in Cologne, North Rhine-Westphalia, Germany.

BACKGROUND: In Germany, widespread full closures of schools and day care facilities were part of lockdown measures to control the spread of coronavirus disease 2019 (COVID-19). In the state of North Rhine-Westphalia closures took place on March 16, 2020 and were gradually eased from end of April 2020 until beginning of June 2020. OBJECTIVE: This study aims to evaluate the prevalence of COVID-19 among children and adolescents during the reopening period of schools and day care facilities in Cologne, North Rhine-Westphalia, Germany. It further depicts medical history and results of physical examinations of pediatric patients undergoing a test for severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2). METHODS: Testing for SARS-CoV-2 was carried out by a naso- and / or oropharyngeal swab by local pediatricians at the time of presentation. Samples were analyzed by real-time reverse transcription polymerase chain reaction (RT-PCR). Medical history and physical examination results were retrospectively analyzed. RESULTS: 525 children and adolescents presented mainly with mild upper respiratory tract infections. Three patients were diagnosed with COVID-19. Their medical history and examination results did not stand out from the other patients. CONCLUSION: A precautious stepwise opening of schools and day care facilities was not associated with the occurrence of a relevant prevalence of COVID-19 among children and adolescents. However, a low general prevalence of COVID-19 at the end of the observation period has to be taken into account. Systematic testing might enable adjusted regulations in favor of full closures, especially in the light of increasing evidence for pediatric patients constituting a low-risk group for COVID-19.

Atopy and Elevation of IgE, IgG3, and IgG4 May Be Risk Factors for Post COVID-19 Condition in Children and Adolescents.

SARS-CoV-2 infection causes transient cardiorespiratory and neurological disorders, and severe acute illness is rare among children. Post COVID-19 condition (PCC) may cause profound, persistent phenotypes with increasing prevalence. Its manifestation and risk factors remain elusive. In this monocentric study, we hypothesized that atopy, the tendency to produce an exaggerated immunoglobulin E (IgE) immune response, is a risk factor for the manifestation of pediatric PCC. We present a patient cohort (n = 28) from an early pandemic period (2021-2022) with comprehensive evaluations of phenotypes, pulmonary function, and molecular investigations. PCC predominantly affected adolescents and presented with fatigue, dyspnea, and post-exertional malaise. Sensitizations to aeroallergens were found in 93% of cases. We observed elevated IgE levels (mean 174.2 kU/L, reference < 100 kU/L) regardless of disease severity. Concurrent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) was found in 29% of patients that also faced challenges in school attendance. ME/CFS manifestation was significantly associated with elevated immunoglobulin G subclasses IgG3 (p < 0.05) and IgG4 (p < 0.05). A total of 57% of patients showed self-limiting disease courses with mean recovery at 12.7 months (range 5-25 months), 29% at 19.2 months (range 12-30 months), and the rest demonstrated overall improvement. These findings offer additional insights into immune dysregulation as a risk factor for pediatric PCC.

Severe human bocavirus infection, Germany.

Human bocavirus (HBoV), discovered in 2005, can cause respiratory disease or no symptoms at all. We confirmed HBoV infection in an 8-month-old girl with hypoxia, respiratory distress, wheezing, cough, and fever. This case demonstrates that lower respiratory tract infection caused by HBoV can lead to severe and life-threatening disease.

Determination of thiamin diphosphate in whole blood samples by high-performance liquid chromatography--a method suitable for pediatric diagnostics.

An improved and easy to use method for the determination of thiamin diphosphate (TDP) in 100 microl of whole blood was developed. The small sample volume makes it possible to assess the nutritional status of vitamin B(1) in infants and even in preterm infants. Sample preparation comprises the extraction of TDP from whole blood by hemolysis, protein precipitation with trichloroacetic acid, and subsequent centrifugation. Potassium ferricyanide is used for pre-column derivatization of TDP to its fluorescent thiochrome derivative. Chromatographic separation was carried out using a reversed-phase column and an isocratic elution which consisted of a phosphate buffer and acetonitrile. TDP was detected fluorimetrically and quantified by external standardization. Method validation showed a high precision, almost complete recovery, and a high sensitivity. The lower limit of detection and the lower limit of quantification were 0.2 ng/ml and 4 ng/ml, respectively. Linearity was demonstrated over the expected concentration range of 4-400 ng/ml. In conclusion, we present a convenient HPLC method for the determination of TDP which is precise, sensitive and suitable for pediatric diagnostics.