The continuously evolving phenotype of succinic semialdehyde dehydrogenase deficiency.

The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long-term follow-up. Longitudinal clinical and biochemical data of 22 pediatric and 9 adult individuals with SSADHD from the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD) were studied with in silico analyses, pathogenicity scores and molecular modeling of ALDH5A1 variants. Leading initial symptoms, with onset in infancy, were developmental delay and hypotonia. Year of birth and specific initial symptoms influenced the diagnostic delay. Clinical phenotype of 26 individuals (median 12 years, range 1.8-33.4 years) showed a diversifying course in follow-up: 77% behavioral problems, 76% coordination problems, 73% speech disorders, 58% epileptic seizures and 40% movement disorders. After ataxia, dystonia (19%), chorea (11%) and hypokinesia (15%) were the most frequent movement disorders. Involvement of the dentate nucleus in brain imaging was observed together with movement disorders or coordination problems. Short attention span (78.6%) and distractibility (71.4%) were the most frequently behavior traits mentioned by parents while impulsiveness, problems communicating wishes or needs and compulsive behavior were addressed as strongly interfering with family life. Treatment was mainly aimed to control epileptic seizures and psychiatric symptoms. Four new pathogenic variants were identified. In silico scoring system, protein activity and pathogenicity score revealed a high correlation. A genotype/phenotype correlation was not observed, even in siblings. This study presents the diversifying characteristics of disease phenotype during the disease course, highlighting movement disorders, widens the knowledge on the genotypic spectrum of SSADHD and emphasizes a reliable application of in silico approaches.

ACOX1 Gain-of-Function Variant in Two German Pediatric Patients, in One Case Mimicking Autoimmune Inflammatory Disease.

Mitchell syndrome is a very rare genetic disorder due to a specific de novo gain-of-function variant in acyl-CoA oxidase 1 (ACOX1). So far, only five patients with this disease have been described worldwide. We present here two additional unrelated German patients found to carry the same heterozygous ACOX1 N237S variant through exome sequencing (ES). Both patients showed neurodegenerative clinical features starting from ∼4 to 5 years of age including progressive hearing loss, ataxia, ichthyosis, as well as progressive visual impairment leading to amaurosis, and died at the ages of 16 and 8 years, respectively. The first patient was clinically suspected to have anti-myelin oligodendrocyte glycoprotein-antibody-associated myelitis, but the disease course overall deteriorated despite extensive immunomodulatory therapy. The second patient was originally suspected to have a mitochondrial disorder due to intermittent elevated blood lactate. Since Mitchell syndrome has only been identified in 2020, the diagnosis in this second patient was only established through re-evaluation of ES data years after the original analysis. Comparison of all seven reported patients suggests that Mitchell syndrome often (but not always) clinically mimics autoimmune-inflammatory disease. Therefore, in patients with autoimmune central nervous system disease who do not respond adequately to standard therapies, re-evaluation of this diagnosis is needed and genetic analyses such as trio ES should be considered.

Cognitive development in children with new-onset Rolandic epilepsy and Rolandic discharges without seizures: Focusing on intelligence, visual perception, working memory and the role of parents' education.

PURPOSE: Our aim was to assess intelligence, visual perception and working memory in children with new-onset Rolandic epilepsy (RE) and children with Rolandic discharges without seizures (RD). METHODS: The participants in the study were 12 children with RE and 26 children with RD aged 4 to 10 years (all without medication and shortly after diagnosis) and 31 healthy controls. Their cognitive performance was assessed using the German versions of the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III), the Wechsler Intelligence Scale for Children (WISC-IV), the Developmental Test of Visual Perception-2 (DTVP-2), the Developmental Test of Visual Perception-Adolescent and Adult (DTVP-A) (each according to age) and the Word Order, Hand Movements and Spatial Memory subtests of the German version of the Kaufman Assessment Battery for Children (K-ABC). RESULTS: The comparison of the entire group of children with RE/RD and the control group conducted in the first step of our analysis revealed a weaker performance of the children with RE/RD in all cognitive domains. Significant deficits, however, were found exclusively in the RD group. Compared to the controls, they performed significantly weaker regarding IQ (full scale IQ: p < 0.001; verbal IQ: p < 0.001; performance IQ: p = 0.002; processing speed: p = 0.005), visual perception (general visual perception: p = 0.005; visual-motor integration: p = 0.002) and working memory (WISC working memory: p = 0.002 and K-ABC Word Order (p = 0.010) and Hand Movements (p = 0.001) subtests. Also, the children without seizures scored significantly lower than those with seizures on the WISC Working Memory Index (p = 0.010) and on the K-ABC Word Order (p = 0.021) and Hand Movements (p = 0.027) subtests. Further analysis of our data demonstrated the particular importance of the family context for child development. Significant cognitive deficits were found only in children with RD from parents with lower educational levels. This group consistently scored lower compared to the control group regarding IQ (full scale IQ: p < 0.001; verbal IQ: p < 0.001; performance IQ: p = 0.012; processing speed: p = 0.034), visual perception (general visual perception: p = 0.018; visual-motor integration: p = 0.010) and auditory working memory (WISC working memory: p = 0.014). Furthermore, compared to the children with RE, they performed significantly weaker on verbal IQ (p = 0.020), auditory working memory consistently (WISC working memory: p = 0.027; K-ABC: Word Order: p = 0.046) as well as in one of the K-ABC spatial working memory subtests (Hand Movements: p = 0.029). Although we did not find significant deficits in children with new-onset RE compared to healthy controls, the performance of this group tended to be weaker more often. No statistically significant associations were observed between selected clinical markers (focus types: centrotemporal/other foci/laterality of foci and spread of Rolandic discharges) and cognitive test results. Except for spatial working memory, we also found no evidence that the age of our patients at the time of study participation was of significant importance to their cognitive performance. CONCLUSIONS: Our study provides some evidence that children with Rolandic discharges, with and without seizures, may be at higher risk of cognitive impairment. In addition to medical care, we emphasise early differentiated psychosocial diagnostics to provide these children and their families with targeted support if developmental problems are present.

[Diagnosis and Management of Late-Onset Pompe Disease]. / Diagnostik, Therapie und psychosoziale Aspekte bei late-onset Morbus Pompe.

Pompe disease is a lysosomal storage disorder, with onset between the first weeks after birth and adulthood, depending on its phenotype. It can affect multiple organ systems and presents itself with a wide variety of symptoms. Thus, recognizing Pompe disease is difficult. Especially since enzyme replacement therapy for Pompe disease was introduced (in Germany in 2006), early diagnosis by means of enzyme activity determination from dried blood spot analysis and genetic verification has become important for outcome and quality of life. When facing an obscure muscular disorder, it is crucial to consider Pompe disease. This article provides an overview about Pompe disease and focuses on the diagnosis of the late onset type. The most important aspects of interdiciplinary care for patients with Pompe disease are presented. Additionally, it contains a section focusing on psychosocial challenges for children with Pompe disease and their families, which may include mental disorders and social retreat, and gives advice on how to support parents of affected children.

l-Arginine/nitric oxide pathway and oxidative stress in adults with ADHD: Effects of methylphenidate treatment.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a mental disorder that was once thought to occur only in children. Meanwhile, it is known that adults can also be affected. The first-line drug in children and adults to treat symptoms of inattention, impulsivity, lack of self-regulation, and hyperactivity is methylphenidate (MPH). Known adverse effects of MPH include cardiovascular problems, such as elevated blood pressure and heart rate. Therefore, biomarkers to monitor potential cardiovascular side effects of MPH are needed. The l-Arginine/Nitric oxide (Arg/NO) pathway is involved in noradrenaline and dopamine release as well as in normal cardiovascular functioning and is therefore a prime candidate for the search of biomarkers. The aim of the present study was to investigate the Arg/NO pathway as well as oxidative stress in adult ADHD patients in plasma and urine and the potential influence of MPH medication. METHODS: In plasma and urine samples of 29 adults with ADHD (39.2 ± 10.9 years) and 32 healthy adults serving as controls (CO) (38.0 ± 11.6 years) the major NO metabolites nitrite and nitrate, Arg, the NO synthesis inhibitor asymmetric dimethylarginine (ADMA) and its major urinary metabolite dimethylamine (DMA) as well as malondialdehyde (MDA) were measured by gas chromatography-mass spectrometry. RESULTS: Of the 29 patients with ADHD 14 were currently without MPH treatment (-MPH) and 15 were treated with MPH (+MPH). Plasma nitrate concentrations were significantly higher in patients not treated with MPH vs. CO (-MPH 60.3 µM [46.2-76.0] vs. CO 44.4 µM [35.0-52.7]; p = 0.002), while plasma nitrite tended to be higher in -MPH patients (2.77 µM [2.26-3.27]) vs. CO (2.13 µM [1.50-2.93]; p = 0.053). Additionally, plasma creatinine concentrations were significantly different, with -MPH showing significantly higher concentrations than the other two groups (-MPH 141 µM [128-159]; +MPH 96.2 µM [70.2-140]; Co 75.9 µM [62.0-94.7]; p < 0.001). Urinary creatinine excretion tended to be lowest in -MPH group vs. +MPH and CO (-MPH 11.4 ± 8.88 mM; +MPH 20.7 ± 9.82 mM; 16.6 ± 7.82 mM; p = 0.076). None of the other metabolites, including MDA, a marker of oxidative stress, showed a difference between the groups. CONCLUSION: Adult patients with ADHD, who are not treated with MPH (-MPH), showed varied Arg/NO pathway, but Arg bioavailability seemed to be consistent over the groups. Our findings imply that urinary reabsorption may be increase and/or excretion of nitrite and nitrate may be decreased in ADHD, resulting in an increase in the plasma concentration of nitrite. MPH seems to partially reverse these effects by not yet known mechanisms, and does not affect oxidative stress.

Endocannabinergic modulation of central serotonergic activity in healthy human volunteers.

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 (CNR1) gene, which codes the endocannabinoid CB1 receptor, and the rs324420 SNP of the FAAH gene on the serotonergic and endocannabinoid system in 59 healthy volunteers. 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 (rs1049353, rs344420) was conducted by polymerase chain reaction (PCR) and differential enzymatic analysis with the PCR restriction fragment length polymorphism method. RESULTS: Genotype distributions by serotonergic activity or endocannabinoid concentration showed no differences. However, after detailed consideration of the CNR1-A-allele-carriers, a reduced AEA (A-allele-carrier M = 0.66, SD = 0.24; GG genotype M = 0.72, SD = 0.24) and 2AG (A-allele-carriers M = 0.70, SD = 0.33; GG genotype M = 1.03, SD = 0.83) plasma concentration and an association between the serotonergic activity and the concentrations of AEA and 2AG has been observed. CONCLUSIONS: Our results suggest that carriers of the CNR1-A allele may be more susceptible to developing depression.

Exome Sequencing and Optical Genome Mapping in Molecularly Unsolved Cases of Duchenne Muscular Dystrophy: Identification of a Causative X-Chromosomal Inversion Disrupting the DMD Gene.

Duchenne muscular dystrophy (DMD) is a severe progressive muscle disease that mainly affects boys due to X-linked recessive inheritance. In most affected individuals, MLPA or sequencing-based techniques detect deletions, duplications, or point mutations in the dystrophin-encoding DMD gene. However, in a small subset of patients clinically diagnosed with DMD, the molecular cause is not identified with these routine methods. Evaluation of the 60 DMD patients in our center revealed three cases without a known genetic cause. DNA samples of these patients were analyzed using whole-exome sequencing (WES) and, if unconclusive, optical genome mapping (OGM). WES led to a diagnosis in two cases: one patient was found to carry a splice mutation in the DMD gene that had not been identified during previous Sanger sequencing. In the second patient, we detected two variants in the fukutin gene (FKTN) that were presumed to be disease-causing. In the third patient, WES was unremarkable, but OGM identified an inversion disrupting the DMD gene (~1.28 Mb) that was subsequently confirmed with long-read sequencing. These results highlight the importance of reanalyzing unsolved cases using WES and demonstrate that OGM is a useful method for identifying large structural variants in cases with unremarkable exome sequencing.

Altered Left Ventricular Myocardial Deformation in Young Women With Borderline Personality Disorder: An Echocardiographic Study.

OBJECTIVE: Borderline personality disorder (BPD) is characterized by intense mood swings, impulsivity, self-injurious behavior, poor anger control, fear of abandonment, and unstable interpersonal relationships. BPD is also associated with a heightened risk of cardiovascular disease, whereby the underlying mechanisms are insufficiently understood. Accordingly, the present study set out to examine whether individuals with BPD would show abnormal myocardial deformation and to explore the role of potential risk factors, including maladaptive stress responsivity, childhood trauma, and current stress exposure. METHODS: Fifty female patients diagnosed with BPD and 50 controls matched for sex and age underwent echocardiography to determine the global longitudinal strain (GLS) of the left ventricle. In addition, childhood trauma, chronic stress, and "allostatic load" were determined, as well as borderline symptom severity and common risk factors for cardiovascular disease. RESULTS: Aside from a significantly greater GLS in BPD patients, a multivariable regression analysis revealed that allostatic load (ß = 0.225, p = .048) was significantly associated with GLS, with childhood trauma (ß = 0.279, p = .062) approaching significance. Conversely, smoking (p = .867), chronic stress (p = .193), and borderline symptom severity (p = .342) were not associated with GLS, even though bivariate correlations were significant. CONCLUSIONS: Somatically healthy women with BPD display subtle signs of increased GLS, which is associated with allostatic load as an indicator of the "wear-and-tear" of the body. The association between childhood trauma with GLS was of similar strength but did not reach the threshold for statistical significance. This finding may support the need for primary prevention of somatic consequences of maladaptive stress responsivity in psychiatric patients.

Impact of lunch with carbohydrates differing in glycemic index on children's cognitive functioning in the late postprandial phase: a randomized crossover study.

PURPOSE: Studies about effects of lunch dietary Glycemic Index (GI) on cognition of schoolchildren are scarce. Our previous CogniDo GI study found no changes of cognition in the early postprandial phase after consumption of two rice types with medium vs. high dietary GI for lunch (i.e., 45 min after starting lunch). This study investigated whether the dietary GI of lunch has an impact on cognition of schoolchildren in the late postprandial phase, 90 min after lunch. METHODS: A randomized, 2 × 2 crossover intervention study was conducted at a comprehensive school with 5th and 6th grade students. Participants (n = 212) were randomly assigned to either sequence 1 or 2. In the first period, participants of sequence 1 received a dish with high GI rice (GI: 79), those of sequence 2 with medium GI rice (GI: 64)-in the second period, 1 week later, vice versa. Computer-based cognitive testing was performed 90 min after lunch examining tonic alertness, visual search and task switching, and working memory. Treatment effects and treatment effects adjusted for estimated lunch glycemic load (GL) were analyzed using a linear mixed model. RESULTS: The selected cognitive parameters were not affected by the GI of lunch 90 min after lunch, neither after intention-to-treat nor in the per-protocol analysis. Adjustment for GL also did not change results. CONCLUSION: The present study revealed no notable differences after the consumption of two rice types with medium vs. high dietary GI for lunch in children's cognitive function in the late postprandial phase, 90 min after lunch. CLINICAL TRIAL REGISTRATION: German Clinical Trials Register (DRKS00013597); date of registration: 16/04/2018, retrospectively registered.

Seroconversion rate and socio-economic and ethnic risk factors for SARS-CoV-2 infection in children in a population-based cohort, Germany, June 2020 to February 2021.

IntroductionSocio-economic and ethnic background have been discussed as possible risk factors for SARS-CoV-2 infections in children. Improved knowledge could lead to tailored prevention strategies and help improve infection control.AimWe aimed to identify risk factors for SARS-CoV-2 infections in children in the first and second wave of the pandemic.MethodsWe performed an observational population-based cohort study in children (6 months-18 years) scheduled for legally required preventive examination and their parents in a metropolitan region in Germany. Primary endpoint was the SARS-CoV-2 seroconversion rate during the study period. Risk factors assessed included age, pre-existing medical conditions, socio-economic factors and ethnicity.ResultsWe included 2,124 children and their parents. Seroconversion rates among children in all age groups increased 3-4-fold from June 2020 to February 2021. Only 24 of 58 (41%) seropositive children reported symptoms. In 51% of infected children, at least one parent was also SARS-CoV-2-positive. Low level of parental education (OR = 3.13; 95% CI: 0.72-13.69) non-significantly increased the risk of infection. Of the total cohort, 38.5% had a migration background, 9% of Turkish and 5% of Middle Eastern origin, and had the highest risk for SARS-CoV-2 infections (OR = 6.24; 95% CI: 1.38-28.12 and OR = 6.44 (95% CI: 1.14-36.45) after adjustment for other risk factors.ConclusionIn the second half of 2020, seroprevalence for SARS-CoV-2 in children increased especially in families with lower-socioeconomic status. Culture-sensitive approaches are essential to limit transmission and could serve as a blueprint for vaccination strategies.

Characterization of the L-Arginine/Nitric Oxide Pathway and Oxidative Stress in Pediatric Patients with Atopic Diseases.

INTRODUCTION: L-Arginine (Arg) is a semi-essential amino acid. Constitutive and inducible nitric oxide synthase (NOS) isoforms convert Arg to nitric oxide (NO), a potent vaso- and bronchodilator with multiple biological functions. Atopic dermatitis (AD) and bronchial asthma (BA) are atopic diseases affecting many children globally. Several studies analyzed NO in airways, yet the systemic synthesis of NO in AD and BA in children with BA, AD or both is elusive. METHODS: In a multicenter study, blood and urine were obtained from 130 of 302 participating children for the measurement of metabolites of the Arg/NO pathway (BA 31.5%; AD 5.4%; AD + BA 36.1%; attention deficit hyperactivity disorder (ADHD) 12.3%). In plasma and urine amino acids Arg and homoarginine (hArg), both substrates of NOS, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), both inhibitors of NOS, dimethylamine (DMA), and nitrite and nitrate, were measured by gas chromatography-mass spectrometry. Malondialdehyde (MDA) was measured in plasma and urine samples to evaluate possible effects of oxidative stress. RESULTS: There were no differences in the Arg/NO pathway between the groups of children with different atopic diseases. In comparison to children with ADHD, children with AD, BA or AD and BA had higher plasma nitrite (p < 0.001) and nitrate (p < 0.001) concentrations, suggesting higher systemic NO synthesis in AD and BA. Urinary excretion of DMA was also higher (p = 0.028) in AD and BA compared to patients with ADHD, suggesting elevated ADMA metabolization. DISCUSSION/CONCLUSION: The Arg/NO pathway is activated in atopic diseases independent of severity. Systemic NO synthesis is increased in children with an atopic disease. Plasma and urinary MDA levels did not differ between the groups, suggesting no effect of oxidative stress on the Arg/NO pathway in atopic diseases.

Desmin Knock-Out Cardiomyopathy: A Heart on the Verge of Metabolic Crisis.

Desmin mutations cause familial and sporadic cardiomyopathies. In addition to perturbing the contractile apparatus, both desmin deficiency and mutated desmin negatively impact mitochondria. Impaired myocardial metabolism secondary to mitochondrial defects could conceivably exacerbate cardiac contractile dysfunction. We performed metabolic myocardial phenotyping in left ventricular cardiac muscle tissue in desmin knock-out mice. Our analyses revealed decreased mitochondrial number, ultrastructural mitochondrial defects, and impaired mitochondria-related metabolic pathways including fatty acid transport, activation, and catabolism. Glucose transporter 1 and hexokinase-1 expression and hexokinase activity were increased. While mitochondrial creatine kinase expression was reduced, fetal creatine kinase expression was increased. Proteomic analysis revealed reduced expression of proteins involved in electron transport mainly of complexes I and II, oxidative phosphorylation, citrate cycle, beta-oxidation including auxiliary pathways, amino acid catabolism, and redox reactions and oxidative stress. Thus, desmin deficiency elicits a secondary cardiac mitochondriopathy with severely impaired oxidative phosphorylation and fatty and amino acid metabolism. Increased glucose utilization and fetal creatine kinase upregulation likely portray attempts to maintain myocardial energy supply. It may be prudent to avoid medications worsening mitochondrial function and other metabolic stressors. Therapeutic interventions for mitochondriopathies might also improve the metabolic condition in desmin deficient hearts.

The role of breastfeeding promotion in German hospitals for exclusive breastfeeding duration.

Breastfeeding promotion and support in hospitals is expected to have a positive impact on maternal breastfeeding outcomes. The objective of this study is to examine the association between breastfeeding promotion in maternity hospitals in Germany and exclusive breastfeeding (EBF) rates during the first 4 months. Thus, a nationwide cross-sectional web-based survey of breastfeeding promotion was conducted in 103 hospitals. Mother-infant pairs (n = 962) were recruited at these hospitals for a prospective web-based survey of breastfeeding status at five-time points, that is, during a hospital stay, at discharge as well as after 0.5, 2, and 4 months. The hospital analysis was based on the "10 Steps to Successful Breastfeeding" of the World Health Organization and the United Nations Children's Fund, adapted for Germany. Their degree of implementation was stratified by a breastfeeding promotion index (BPI) as low (≤5 steps), medium (6-8 steps), and high (≥9 steps). The association between the BPI and the odds of EBF at each of the five-time points was estimated by multivariable regression models, adjusting for various maternal factors. At all time points, the proportion of EBF among mothers from high BPI hospitals exceeded the proportion of those from medium or low BPI hospitals. A high BPI was associated with higher odds of EBF during the hospital stay and at discharge, while maternal factors for EBF such as breastfeeding experience and no early use of a pacifier persisted beyond. The high commitment of hospitals and tailored support of mothers is essential for EBF.

Age-dependent favorable visual recovery despite significant retinal atrophy in pediatric MOGAD: how much retina do you really need to see well?

BACKGROUND: To investigate age-related severity, patterns of retinal structural damage, and functional visual recovery in pediatric and adult cohorts of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) optic neuritis (ON). METHODS: All MOGAD patients from the 5 participating centers were included. Patients with initial manifestation <18 years were included in the pediatric (MOGADped) cohort and patients with ≥18 years in the adult (MOGADadult) cohort. For patients with MOGAD ON, examinations at least ≥6 months after ON onset were included in the analyses. Using spectral domain optical coherence tomography (SD-OCT), we acquired peripapillary retinal nerve fiber layer thickness (pRNFL) and volumes of combined ganglion cell and inner plexiform layer (GCIPL). High- and 2.5% low-contrast visual acuity (HCVA, LCVA) and visual-evoked potentials (VEP) were obtained. RESULTS: Twenty MOGADped (10.3±3.7 years, 30 MOGAD ON eyes) and 39 MOGADadult (34.9±11.6 years, 42 MOGAD ON eyes) patients were included. The average number of ON episodes per ON eye was similar in both groups (1.8±1.3 and 2.0±1.7). In both pediatric and adult MOGAD, ON led to pronounced neuroaxonal retinal atrophy (pRNFL: 63.1±18.7 and 64.3±22.9 µm; GCIPL: 0.42±0.09 and 0.44±0.13 mm3, respectively) and moderate delay of the VEP latencies (117.9±10.7 and 118.0±14.5 ms). In contrast, visual acuity was substantially better in children (HCVA: 51.4±9.3 vs. 35.0±20.6 raw letters, p=0.001; LCVA: 22.8±14.6 vs. 13.5±16.4, p=0.028). Complete visual recovery (HCVA-logMAR 0.0) occurred in 73.3% of MOGADped and 31% MOGADadults ON eyes, while 3.3% and 31% demonstrated moderate to severe (logMAR > 0.5) visual impairment. Independent of retinal atrophy, age at ON onset significantly correlated with visual outcome. CONCLUSION: Pediatric MOGAD ON showed better visual recovery than adult MOGAD ON despite profound and almost identical neuroaxonal retinal atrophy. Age-related cortical neuroplasticity may account for the substantial discrepancy between structural changes and functional outcomes.

Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry.

Inherited disorders of neurotransmitter metabolism are a group of rare diseases, which are caused by impaired synthesis, transport, or degradation of neurotransmitters or cofactors and result in various degrees of delayed or impaired psychomotor development. To assess the effect of neurotransmitter deficiencies on intelligence, quality of life, and behavior, the data of 148 patients in the registry of the International Working Group on Neurotransmitter Related Disorders (iNTD) was evaluated using results from standardized age-adjusted tests and questionnaires. Patients with a primary disorder of monoamine metabolism had lower IQ scores (mean IQ 58, range 40-100) within the range of cognitive impairment (<70) compared to patients with a BH4 deficiency (mean IQ 84, range 40-129). Short attention span and distractibility were most frequently mentioned by parents, while patients reported most frequently anxiety and distractibility when asked for behavioral traits. In individuals with succinic semialdehyde dehydrogenase deficiency, self-stimulatory behaviors were commonly reported by parents, whereas in patients with dopamine transporter deficiency, DNAJC12 deficiency, and monoamine oxidase A deficiency, self-injurious or mutilating behaviors have commonly been observed. Phobic fears were increased in patients with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals with sepiapterin reductase deficiency frequently experienced communication and sleep difficulties. Patients with BH4 deficiencies achieved significantly higher quality of life as compared to other groups. This analysis of the iNTD registry data highlights: (a) difference in IQ and subdomains of quality of life between BH4 deficiencies and primary neurotransmitter-related disorders and (b) previously underreported behavioral traits.

Breast-feeding promotion in hospitals and prospective breast-feeding rates during the first year of life in two national surveys 1997-1998 and 2017-2019 in Germany.

OBJECTIVES: The present study aimed to assess the current state of breast-feeding promotion in hospitals and the prevalence of breast-feeding during the first year of life in Germany and to compare the results with a study 20 years earlier. DESIGN: In the studies on 'breast-feeding and infant nutrition in Germany' named 'SuSe', a cross-sectional survey in hospitals was combined with a subsequent prospective survey of breast-feeding and infant nutrition during the first year of life (0·5, 2, 4, 6 and 12 months after birth) in mother-infant pairs who were recruited in the hospitals. Written questionnaires and phone calls were used in SuSe I and web-based questionnaires in SuSe II. Breast-feeding promotion and prevalence were evaluated using recommendations from the WHO and the UNICEF. SETTING: Two nationwide surveys SuSe I (1997-1998) and SuSe II (2017-2019). PARTICIPANTS: In SuSe I, 177 hospitals and 1717 mother-infant pairs and in SuSe II 109 hospitals and 962 mother-infant pairs were included. RESULTS: In SuSe II, hospitals implemented seven of the WHO 'Ten Steps to Successful Breastfeeding' to a greater extent than the hospitals in SuSe I. More mothers exclusively breastfed for 4 months (57 % v. 33 %) and continued breast-feeding until 6 (78 % v. 48 %) and 12 months (41 % v. 13 %). In both studies, exclusive breast-feeding decreased between 4 and 6 months of age due to the introduction of complementary feeding. CONCLUSIONS: In Germany, breast-feeding habits have come closer to the recommendations over the last 20 years.

AADC deficiency from infancy to adulthood: Symptoms and developmental outcome in an international cohort of 63 patients.

Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal recessive neurodevelopmental disorder characterized by impaired synthesis of dopamine, noradrenaline, adrenaline and serotonin, leading to a complex syndrome of motor, behavioral, and autonomic symptoms. This retrospective study assessed the symptoms and developmental outcome of a large international cohort of patients with AADCD via physician and/or caregiver responses to a detailed, standardized questionnaire. Sixty-three patients (60% female; ages 6 months-36 years, median 7 years; 58 living) from 23 individual countries participated. Common symptoms at onset (median age 3 months, range 0-12 months) were hypotonia, developmental delay, and/or oculogyric crises. Oculogyric crises were present in 97% of patients aged 2 to 12 years, occurred in the majority of patients in all age groups, and tended to be most severe during early childhood. Prominent non-motor symptoms were sleep disturbance, irritable mood, and feeding difficulties. The majority of subjects (70%) had profound motor impairment characterized by absent head control and minimal voluntary movement, while 17% had mild motor impairment and were able to walk independently. Dopamine agonists were the medications most likely to produce some symptomatic benefit, but were associated with dose-limiting side effects (dyskinesia, insomnia, irritability, vomiting) that led to discontinuation 25% of the time. The age distribution of our cohort (70% of subjects under age 13 years) and the observation of a greater proportion of patients with a more severe disease phenotype in the younger compared to the older patients, both suggest a significant mortality risk during childhood for patients with severe disease.

Translation of EU Food Law and Nutrient Reference Values Into Practice: the German Dietary Scheme for the First Year of Life.

OBJECTIVES: European dietary regulations affect national dietary guidelines for child nutrition. The update of the German Dietary Scheme for the first year of life is used to examine the translation of European nutrient references into food-based guidelines while maintaining traditional habits. METHODS: Within the Dietary Scheme, intake of energy and nutrients was calculated in the complementary feeding period for each of the 3 daily recommended complementary meals (a vegetable-potato-meat meal, a milk-cereal meal, a cereal-fruit meal) in addition to the daily liquid-milk servings (breast milk or follow-on formula). Pureed-home-made complementary meals were assumed. The adequacy of nutrient intake was evaluated by comparison with the European Food Safety Authority (EFSA) Dietary Reference Values. Macronutrient content of meals was compared to the European complementary food directive. RESULTS: Daily intake of most nutrients following the scheme was well in line with EFSA values, whereas the commonly 'critical' nutrients iron and iodine remained far below EFSA values. Substituting breast milk or whole cow's milk with follow-on formula had only a small impact on nutrient supply. Although the different nutrient profiles of meals were not fully in line with European regulations, they add up to an overall balanced daily diet. CONCLUSIONS: Taken together, European dietary reference values for energy and nutrients can mostly be met by the modular system of the Dietary Scheme as a total diet concept for infant nutrition in Germany. The different proposed meals generally agree with EU regulations for complementary food.

[Huntington's disease with childhood and adolescent onset: course of disease, clinical presentation and diagnostic challenges]. / Zur Huntington-Erkrankung im Kindes- und Jugendalter ­ Erkrankung, klinische Präsentation und Probleme der Diagnostik.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a gene mutation in chromosome 4 that leads to an expansion of CAG - triplet repeats. It occurs mainly between the age of 30 and 50. Only less than 10 % of HD patients are younger than 20 years. In contrast to adult patients young HD patients show more often psychiatric and cognitive symptoms at disease onset than chorea. One third of the children with HD develops an epilepsy.We present 6 children diagnosed with HD in different stages of childhood. We describe first symptoms as well as genetic characteristics and other distinctive features.Both, the clinical presentation and the course of HD in childhood differ from HD in adults. In adolescents the clinical symptoms at onset are often psychiatric (like depression or attention deficit disorder). Choreatic movements typical for adult HD patients are missing.Due to the low prevalence of HD in childhood and the variability of clinical symptoms the process of diagnosing HD in children is difficult. Very often the diagnosis is made years after the first symptoms. Early diagnosis, however, is often important for managing social problems and problems in school.

Novel variants in a patient with late-onset hyperprolinemia type II: diagnostic key for status epilepticus and lactic acidosis.

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. 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-B6 serum value was found, consistent with a HPII causing secondary pyridoxine deficiency and seizures. The ALDH4A1 gene sequencing confirmed two previously unknown compound heterozygous variants (ALDH4A1 gene (NM_003748.3) Intron 1: c.62 + 1G > A - heterozygous and ALDH4A1 gene (NM_003748.3) Exon 5 c.349G > C, p.(Asp117His) - heterozygous). Under high-dose vitamin-B6 therapy no further seizures occurred. CONCLUSION: We describe two novel 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.