Clinical manifestation of juvenile and pediatric HD patients

Background: Studies on the clinical manifestation and course of disease in children suffering from Huntington’s disease (HD) are rare. Case reports of juvenile HD (onset $\leq$ 20 years) describe heterogeneous motoric and non-motoric symptoms, often accompanied with a delay in diagnosis. We aimed to describe this rare group of patients, especially with regard to socio-medical aspects and individual or common treatment strategies. In addition, we differentiated between juvenile and the recently defined pediatric HD population (onset $\leq$ 18 years). Methods: Out of 2593 individual HD patients treated within the last 25 years in the Huntington Centre, North Rhine-Westphalia (NRW), 32 subjects were analyzed with an early onset younger than 21 years (1.23%, juvenile) and 18 of them younger than 18 years of age (0.69%, pediatric). Results: Beside a high degree of school problems, irritability or aggressive behavior (62.5% of pediatric and 31.2% of juvenile cases), serious problems concerning the social and family background were reported in 25% of the pediatric cohort. This includes an attempted rape and robbery at the age of 12, as problems caused by the affected children, but also alcohol-dependency in a two-year-old induced by a non-HD affected stepfather. A high degree of suicidal attempts and ideations (31.2% in pediatric and 33.3% in juvenile group) was reported, including drinking of solvents, swallowing razor blades or jumping from the fifth floor with following incomplete paraparesis. Beside dopaminergic drugs for treatment of bradykinesia, benzodiazepines and tetrabenazine for treatment of dystonia, cannabinoids, botulinum toxin injection and deep brain stimulation were used for the improvement of movement disorders, clozapine for the treatment of tremor, and dopa-induced hallucinations and zuclopenthixole for the treatment of severe aggressive behavior. Conclusions: Beside abnormalities in behavior from an early age due to HD pathology, children seem to have higher socio-medical problems related to additional burden caused by early affected parents, instable family backgrounds including drug abuse of a parent or multiple changes of partners. Treatment required individualized strategies in many cases

A new perspective on meals as part of an Optimized Mixed Diet for children and adolescents

$\bf Objectives:$ To show by the example of the Optimized Mixed Diet (OMD) for children and adolescents in Germany, how the different food and nutrient profiles of the traditional daily meals complement each other to achieve daily nutrient intakes that meet the Dietary References V. $\bf Methods:$ The 7-day menu plan of the OMD with the usual 5 daily meals in Germany was used. The total nutrient intake from all meals was compared with the nutrient references. Then the composition of the meals was optimized. $\bf Results:$ Although the cooked meal (lunch) provides only 25% of the daily energy intake, it is relatively rich (>25% of the daily intake) in most vitamins and minerals, which distinguishes it from the other meals. The cold main meals (breakfast, dinner) are rich in calcium and vitamin B2, due to the preferential use of milk in these meals. The two snacks each provide 12.5% of the daily energy intake. $\textbf {Discussion and conclusion:}$ People eat foods but not nutrients and they eat foods as meals; this holds especially true for children and adolescents. A well-calculated menu plan can assure the nutrient adequacy of an OMD where the different food and nutrient profiles of the meals complement each other in a modular system. Guidelines for meals could facilitate flexible coordination of family meals and meals in childcare centers and schools. Different meal types set varied stimulus patterns at different levels (neurocognition, emotion, digestion), which may open up long-term health benefits

Somatosensory abnormalities after infection with SARS-CoV-2

$\bf Background:$ Long-term neurological complaints after SARS-CoV-2 infection occur in 4–66% of children and adolescents. Controlled studies on the integrity of the peripheral nerve system are scarce. Therefore, we examined the somatosensory function in children and adolescents after SARS-CoV-2 infection in a case-control study compared with age-matched individuals. $\textbf {Materials and Methods:}$ Eighty-one subjects after SARS-CoV-2 infection ($\it n$ = 44 female, 11.4 $\pm$ 3.5 years, $\it n$ = 75 SARS-CoV-2 seropositive, $\it n$ = 6 PCR positive during infection and SARS-CoV-2 seronegative at the time point of study inclusion, $\it n$ = 47 asymptomatic infection) were compared to 38 controls without SARS-CoV-2 infection (26 female, 10.3 $\pm$ 3.4 years, $\it n$ = 15 with other infection within last 6 months). After standardised interviews and neurological examinations, large fibre (tactile and vibration detection thresholds) and small fibre (cold and warm detection thresholds, paradoxical heat sensation) functions were assessed on both feet following a validated protocol. After z-transformation of all values, all participants were compared to published reference values regarding the number of abnormal results. Additionally, the mean for all sensory parameters values of both study groups were compared to an ideal healthy population (with $\it z$-value 0 $\pm$ 1), as well as with each other, as previously described. Statistical analyses: $\it t$-test, Chi-squared test, and binominal test. $\bf Findings:$ None of the controls, but 27 of the 81 patients (33%, $\it p$ < 0.001) reported persistent complaints 2.7 $\pm$ 1.9 (0.8–8.5) months after SARS-CoV-2 infection, most often reduced exercise capacity (16%), fatigue (13%), pain (9%), or paraesthesia (6%). Reflex deficits or paresis were missing, but somatosensory profiles showed significantly increased detection thresholds for thermal (especially warm) and vibration stimuli compared to controls. Approximately 36% of the patients after SARS-CoV-2, but none of the controls revealed an abnormal sensory loss in at least one parameter ($\it p$ < 0.01). Sensory loss was characterised in 26% by large and 12% by small fibre dysfunction, the latter appearing more frequently in children with prior symptomatic SARS-CoV-2 infection. Myalgia/paraesthesia was indicative of somatosensory dysfunction. In all eight re-examined children, the nerve function recovered after 2–4 months. $\bf Interpretation:$ This study provides evidence that in a subgroup of children and adolescents previously infected with SARS-CoV-2, regardless of their complaints, the function of large or small nerve fibres is presumably reversibly impaired

Pulmonary function and long-term respiratory symptoms in children and adolescents after COVID-19

$\bf Background:$ Persistent respiratory symptoms after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in adults are frequent, and there can be long-term impairment of pulmonary function. To date, only preliminary evidence is available on persistent respiratory sequelae of SARS-CoV-2 in children and adolescents. Our objective was to examine the long-term effects of symptomatic and asymptomatic SARS-CoV-2 infections on pulmonary function in this age group in a single-center, controlled, prospective study. $\bf Methods:$ Participants with serological or polymerase chain reaction-based evidence of SARS-CoV-2 infection were recruited from a population-based study of seroconversion rates. Multiple-breath washout (MBW), body plethysmography, and diffusion capacity testing were performed for children and adolescents. Participants were interviewed about their symptoms during the acute phase of infection and long-lasting symptoms. Cases were compared with SARS-CoV-2 seronegative controls from the same population-based study with and without history of respiratory infection within 6 months prior to assessment. Primary endpoints were differences in pulmonary function, including diffusion capacity and MBW, between participants with and without evidence of SARS-CoV-2 infection. Secondary endpoints included correlation between lung function and long-lasting symptoms as well as disease severity. $\bf Findings:$ In total, 73 seropositive children and adolescents (5–18 years) were recruited after an average of 2.6 months (range 0.4–6.0) following SARS-CoV-2 infection. Among 19 patients (27.1%) who complained of persistent or newly emerged symptoms since SARS-CoV-2, 8 (11.4%) reported respiratory symptoms. No significant differences were detected in frequency of abnormal pulmonary function when comparing cases with 45 controls, including 14 (31.1%) with a history of previous infection (SARS-CoV-2: 12, 16.4%; controls: 12, 27.7%; odds ratio 0.54, 95% confidence interval 0.22–1.34). Only two patients with persistent respiratory symptoms showed abnormal pulmonary function. Multivariate analysis revealed reduced forced vital capacity ($\it p$ = 0.012) in patients with severe SARS-CoV-2 infection. $\bf Interpretation:$ Pulmonary function is rarely impaired in children and adolescents after SARS-CoV-2 infection, except from those with severe infection, and did not differ between SARS-CoV-2 and other previous infections, suggesting that SARS-CoV-2 is not more likely to cause pulmonary sequelae than other infections. The discrepancy between persisting respiratory symptoms and normal pulmonary function suggests a different underlying pathology such as dysfunctional breathing

Novel variants in a patient with late-onset hyperprolinemia type II

$\bf Background$ Hyperprolinemia type 2 (HPII) is a rare autosomal recessive disorder of the proline metabolism, that affects the ALDH4A1 gene. So far only four different pathogenic mutations are known. The manifestation is mostly in neonatal age, in early infancy or early childhood. $\bf Case presentation$ The 64-years female patient had a long history of abdominal pain, and episode of an acute neuritis. Ten years later she was admitted into the neurological intensive-care-unit with acute abdominal pain, multiple generalized epileptic seizures, a vertical gaze palsy accompanied by extensive lactic acidosis in serum 26.0 mmol/l (reference: 0.55–2.2 mmol/l) and CSF 12.01 mmol/l (reference: 1.12–2.47 mmol/l). Due to repeated epileptic seizures and secondary complications a long-term sedation with a ventilation therapy over 20 days was administered. A diagnostic work-up revealed up to 400-times increased prolin-level in urine CSF and blood. Furthermore, a low vitamin-B$_6$ serum value was found, consistent with a HPII causing secondary pyridoxine deficiency and seizures. The $\it ALDH4A1$ gene sequencing confirmed two previously unknown compound heterozygous variants ($\it ALDH4A1$ gene (NM_003748.3) Intron 1: c.62 + 1G > A - heterozygous and $\it ALDH4A1$ gene (NM_003748.3) Exon 5 c.349G > C, p.(Asp117His) - heterozygous). Under high-dose vitamin-B$_6$ therapy no further seizures occurred. $\bf Conclusion$ We describe two novel $\it ALDH4A1$-variants in an adult patient with hyperprolinemia type II causing secondary pyridoxine deficiency and seizures. Severe and potentially life-threatening course of this treatable disease emphasizes the importance of diagnostic vigilance and thorough laboratory work-up including gene analysis even in cases with atypical late manifestation

Erucic acid exposure during the first year of life

Recently, the European Food Safety Authority (EFSA) issued a tolerable daily intake (TDI) for erucic acid, which is mainly found in rapeseed oil. Infants may be exposed to erucic acid from rapeseed oil indirectly through maternal consumption via breastmilk or the fat component in formula, and directly as a part of complementary feeding (CF). To check the safety of infant nutrition, scenarios for erucic acid exposure were calculated based on the daily food amounts of the German dietary guidelines. Information on erucic acid concentrations in foods was obtained from European studies for breastmilk, from EFSA samples for formula powder, and from a representative analysis of rapeseed oil samples in the German retail market. 6 scenarios were calculated for the early milk feeding phase (4 formula feeding, 2 breastfeeding) and 8 scenarios for the later CF phase (5 CF +formula feeding, 3 CF +breastfeeding). Out of the 14 scenarios, only 3 resulted in exposures that were definitively below the TDI (range 4.4.–6.0 mg/kg bodyweight; BW). Assuming either high consumption or high concentration led to high exceedances (range 7.5–26.2 mg/kg BW), especially in case of the new EU limits for formula or vegetable oils (33.6 and 43.2 mg/kg BW, respectively). In our scenarios, high erucic acid exposures occurred during a particularly sensitive developmental period. To definitively weigh the potential risks from erucic acid in infants against nutritional benefits of the dietary recommendations, reliable, timely data on erucic acid in breast milk and formula are needed, similar to those from rapeseed oil in Germany

Exhaled aerosols among PCR-confirmed SARS-CoV-2-infected children

$\bf Background:$ Available data on aerosol emissions among children and adolescents during spontaneous breathing are limited. Our aim was to gain insight into the role of children in the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and whether aerosol measurements among children can be used to help detect so-called superspreaders—infected individuals with extremely high numbers of exhaled aerosol particles. $\bf Methods:$ In this prospective study, the aerosol concentrations of SARS-CoV-2 PCR-positive and SARS-CoV-2 PCR-negative children and adolescents (2–17 years) were investigated. All subjects were asked about their current health status and medical history. The exhaled aerosol particle counts of PCR-negative and PCR-positive subjects were measured using the Resp-Aer-Meter (Palas GmbH, Karlsruhe, Germany) and compared using linear regression. $\bf Results:$ A total of 250 children and adolescents were included in this study, 105 of whom were SARS-CoV-2 positive and 145 of whom were SARS-CoV-2 negative. The median age in both groups was 9 years (IQR 7–11 years). A total of 124 (49.6%) participants were female, and 126 (50.4%) participants were male. A total of 81.9% of the SARS-CoV-2-positive group had symptoms of viral infection. The median particle count of all individuals was 79.55 particles/liter (IQR 44.55–141.15). There was a tendency for older children to exhale more particles (1–5 years: 79.54 p/L; 6–11 years: 77.96 p/L; 12–17 years: 98.63 p/L). SARS-CoV-2 PCR status was not a bivariate predictor ($\it t$ = 0.82, $\it p$ = 0.415) of exhaled aerosol particle count; however, SARS-CoV-2 status was shown to be a significant predictor in a multiple regression model together with age, body mass index (BMI), COVID-19 vaccination, and past SARS-CoV-2 infection ($\it t$ = 2.81, $\it p$ = 0.005). COVID-19 vaccination status was a highly significant predictor of exhaled aerosol particles ($\it p$ < .001). $\bf Conclusion:$ During SARS-CoV-2 infection, children and adolescents did not have elevated aerosol levels. In addition, no superspreaders were found

Endocannabinergic modulation of central serotonergic activity in healthy human volunteers

$\bf Background$ The serotonergic and the endocannabinoid system are involved in the etiology of depression. Depressive patients exhibit low serotonergic activity and decreased level of the endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2AG). Since the cannabinoid (CB) 1 receptor is activated by endogenous ligands such as AEA and 2AG, whose concentration are controlled by the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase, respectively, we investigated the effects on serotonergic utilization. In this study, we investigated the impact of the rs1049353 single-nucleotide polymorphism (SNP) of the cannabinoid receptor 1 $\it (CNR1)$ gene, which codes the endocannabinoid CB1 receptor, and the rs324420 SNP of the $\it FAAH$ gene on the serotonergic and endocannabinoid system in 59 healthy volunteers. $\bf Methods$ Serotonergic activity was measured by loudness dependence of auditory-evoked potentials (LDAEP). Plasma concentrations of AEA, 2AG and its inactive isomer 1AG were determined by mass spectrometry. Genotyping of two SNPs $\textit {(rs1049353, rs344420)}$ was conducted by polymerase chain reaction (PCR) and differential enzymatic analysis with the PCR restriction fragment length polymorphism method. $\bf Results$ Genotype distributions by serotonergic activity or endocannabinoid concentration showed no differences. However, after detailed consideration of the $\it CNR1$-A-allele-carriers, a reduced AEA (A-allele-carrier $\textit {M = 0.66}$, SD = $\it 0.24$; GG genotype $\textit {M = 0.72}$, SD = $\it 0.24$) and 2AG (A-allele-carriers $\textit {M = 0.70}$, SD = $\it 0.33$; GG genotype M = 1.03, SD = $\it 0.83$) plasma concentration and an association between the serotonergic activity and the concentrations of AEA and 2AG has been observed. $\bf Conclusions$ Our results suggest that carriers of the CNR1-A allele may be more susceptible to developing depression

Stress-mediated abnormalities in regional myocardial wall motion in young women with a history of psychological trauma

$\bf Background:$ Psychosocial stress has been associated with the development and progression of atherosclerotic cardiovascular disease (CVD). Previously, we reported subtle differences in global longitudinal strain in somatically healthy women with a psychiatric diagnosis of borderline personality disorder (BPD). This study aimed to investigate the impact of BPD on segmental myocardial wall motion using speckle tracking echocardiography (STE) analysis. $\bf Methods:$ A total of 100 women aged between 18 and 38 years were included in this study. Fifty patients meeting the diagnostic criteria for BPD were recruited from the Department of Psychiatry (LWL-University Hospital Bochum) and compared with fifty age-matched healthy control subjects without previous cardiac disease. Laboratory tests and STE were performed with segmental wall motion analysis. $\bf Results:$ The BPD group had a higher prevalence of risk factors for CVD, with smoking and obesity being predominant, when compared with the control group. Other cardiovascular parameters such as blood pressure, glucose, and cholesterol levels were also elevated, even though not to pathological values. Moreover, in the STE analysis, the BPD group consistently exhibited decreased deformation in nine myocardial wall regions compared with the control group, along with a shift toward higher values in the distribution of peak pathological segments. Additionally, significantly higher values of free thyroxine concentration and thyroid’s secretory capacity were observed in the BPD group, despite falling within the (high-) normal range. $\bf Conclusions:$ BPD is associated with chronic stress, classical risk factors, and myocardial wall motion abnormalities. Further exploration is warranted to investigate the relationship between high-normal thyroid metabolism, these risk factors, and myocardial function in BPD patients. Long-term follow-up studies would be valuable in confirming the potential for predicting adverse events