Background Alterations in the MYH7 gene can cause cardiac and skeletal myopathies. MYH7 -related skeletal myopathies are extremely rare, and the vast majority of causal variants in the MYH7 gene are predicted to alter the rod domain of the of ß-cardiac myosin molecule, resulting in distal muscle weakness as the predominant manifestation. Here we describe two unrelated patients harboring an in-frame deletion in the MYH7 gene that is predicted to result in deletion of a single amino acid (p.Glu500del) in the head domain of ß-cardiac myosin. Both patients display an unusual skeletal myopathy phenotype with congenital axial stiffness and muscular hypertonus, but no cardiac involvement. Results Clinical data, MRI results and histopathological data were collected retrospectively in two unrelated boys (9 and 3.5 years old). Exome sequencing uncovered the same 3-bp in-frame deletion in exon 15 (c.1498_1500delGAG) of the MYH7 gene of both patients, a mutation which deletes a highly conserved glutamate residue (p.Glu500del) in the relay loop of the head domain of the ß-cardiac myosin heavy chain. The mutation occurred de novo in one patient, whereas mosaicism was detected in blood of the father of the second patient. Both boys presented with an unusual phenotype of prenatal polyhydramnios, congenital axial stiffness and muscular hypertonus. In one patient the phenotype evolved into an axial/proximal skeletal myopathy without distal involvement or cardiomyopathy, whereas the other patient exhibited predominantly stiffness and respiratory involvement. We review and compare all patients described in the literature who possess a variant predicted to alter the p.Glu500 residue in the ß-cardiac myosin head domain, and we provide in-silico analyses of potential effects on polypeptide function. Conclusion The data presented here expand the phenotypic spectrum of mutations in the MYH7 gene and have implications for future diagnostics and therapeutic approaches.

Background: Data on pediatric DBS is still limited because of small numbers in single center series and lack of systematic multi-center trials. Objectives: We evaluate short- and long-term adverse events (AEs) of patients undergoing deep brain stimulation (DBS) during childhood and adolescence. Methods: Data collected by the German registry on pediatric DBS (GEPESTIM) were analyzed according to reversible and irreversible AEs and time of occurrence with relation to DBS-surgery: Intraoperative, perioperative (<4 weeks), postoperative (4 weeks <6 months) and long term AEs (>6 months). Results: 72 patients with childhood-onset dystonia from 10 DBS-centers, who received 173 DBS electrodes and 141 implantable pulse generators (IPG), were included in the registry. Mean time of postoperative follow-up was 4.6 +/- 4 years. In total, 184 AEs were documented in 53 patients (73.6%). 52 DBS-related AEs in 26 patients (36.1%) required 45 subsequent surgical interventions 4.7 +/- 4.1 years (range 3 months-15 years) after initial implantation. The total risk of an AE requiring surgical intervention was 7.9% per electrode-year. Hardware-related AEs were the most common reason for surgery. There was a tendency of a higher rate of AEs in patients aged 7-9 years beyond 6 months after implantation. Discussion: The intraoperative risk of AEs in pediatric patients with dystonia undergoing DBS is very low, whereas the rate of postoperative hardware-related AEs is a prominent feature with a higher occurrence compared to adults, especially on long-term follow-up. Conclusion: Factors leading to such AEs must be identified and patient management has to be focused on risk minimization strategies in order to improve DBS therapy and maximize outcome in pediatric patients. (C) 2019 Elsevier Inc. All rights reserved.

Background/Purpose: Essential tremor (ET) is one of the most common pediatric movement disorders. Assessing tremor severity can be done using various methods such as tremor-rating scales and visual spiral analysis. Digital spiral analysis (DSA) is a relatively new method that has only been used in adults so far. In this study in pediatric patients, severity of ET was assessed using DSA as well as longer-established exams. The aim of the study was to validate DSA as an instrument for further studies in pediatric tremor.

In this study, we performed a survey of infantile and late-onset Pompe disease (IOPD and LOPD) in Austria. Paediatric and neuromuscular centres were contacted to provide a set of anonymized clinical and genetic data of patients with IOPD and LOPD. The number of patients receiving enzyme replacement therapy (ERT) was obtained from the pharmaceutical company providing alglucosidase alfa. We found 25 patients in 24 families, 4 IOPD and 21 LOPD with a resulting prevalence of 1:350,914. The most frequent clinical manifestation in LOPD was a lower limb-girdle phenotype combined with axial weakness. Three patients were clinically pauci- or asymptomatic and were diagnosed because of persistent hyperCKemia. Diagnostic delay in LOPD was 7.4 ± 9.7 years. The most common mutation was c.-32-13T > G. All IOPD and 17 symptomatic LOPD patients are receiving ERT. Standardized follow-up was only available in six LOPD patients for the 6-min walk test (6minWT) and in ten for the forced vital capacity (FVC). Mean FVC did not decline (before ERT; 63.6 ± 39.7%; last evaluation during ERT: 61.9 ± 26.9%; P = 0.5) while there was a trend to decline in the mean distance covered by the 6minWT (before ERT: 373.5 ± 117.9 m; last evaluation during ERT: 308.5 ± 120.8 m; P = 0.077). The study shows a lower prevalence of Pompe disease in Austria than in other European countries and corroborates a limb-girdle phenotype with axial weakness as the most common clinical presentation, although asymptomatic hyperCKemia may be the first indication of LOPD.

Background: The coexistence of myasthenia gravis and an antibody-associated neuropathy syndrome is a rare phenomenon.

Objective Herpes simplex encephalitis (HSE) is the most common single cause of viral encephalitis in children. In some cases, secondary neurological decline occurs within weeks after HSE mimicking early relapse. Symptoms in this phase often include extrapyramidal choreo-athetotic movement disorders. An autoimmune component has long been suspected in these relapses. Aim of this study was to assess whether antibodies against N-methyl-D-aspartate receptors (NMDARs) may be part of this mechanism. Methods We present a case series of 3 pediatric patients treated with immunomodulation and plasmapheresis for choreo-athetotic movement disorder after HSE. Clinical and serological data were evaluated retrospectively. Anti-neuronal antibodies were assessed from frozen serum and CSF samples using tissue-based and cell-based assays. Results Childrens' median age was 8 months (range 6–11; 3 male). The extrapyramidal choreo-athetotic movement disorder developed 15 to 35 days after onset of encephalitis. All three patients were in need of tube feeding because of pharyngeal dyskinesias. Corticosteroids were administered in 2 cases. All patients received intravenous immunoglobulins and plasmapheresis. The treatment with plasmapheresis started 6–16 days after the onset of the movement disorder and was performed 7–9 times in a period of 14–22 days. In two cases a remission was achieved and in one case only a slight symptom relief was noticed. Two out of three patients revealed positive NMDAR antibodies. In one patient antineuronal antibodies were not detectable. Conclusion Increasing reports on NMDAR antibody related symptoms after HSE strengthen the importance of analyzing anti-neuronal antibodies at earliest clinical clues and to treat with immune modulatory agents. Interestingly, one of our patients with extrapyramidal movement disorder was negative for NMDAR Abs in spite of striking clinical similarities with NMDAR positive patients. This finding might either suggest insufficient sensitivity of anti-neuronal antibody screening methods or indicate presence of currently unknown antibodies causing similar clinical presentation. Herpes simplex encephalitis (HSE) is the most common single cause of viral encephalitis in children. In some cases, secondary neurological decline occurs within weeks after HSE mimicking early relapse. Symptoms in this phase often include extrapyramidal choreo-athetotic movement disorders. An autoimmune component has long been suspected in these relapses. Aim of this study was to assess whether antibodies against N-methyl-D-aspartate receptors (NMDARs) may be part of this mechanism. We present a case series of 3 pediatric patients treated with immunomodulation and plasmapheresis for choreo-athetotic movement disorder after HSE. Clinical and serological data were evaluated retrospectively. Anti-neuronal antibodies were assessed from frozen serum and CSF samples using tissue-based and cell-based assays. Childrens' median age was 8 months (range 6–11; 3 male). The extrapyramidal choreo-athetotic movement disorder developed 15 to 35 days after onset of encephalitis. All three patients were in need of tube feeding because of pharyngeal dyskinesias. Corticosteroids were administered in 2 cases. All patients received intravenous immunoglobulins and plasmapheresis. The treatment with plasmapheresis started 6–16 days after the onset of the movement disorder and was performed 7–9 times in a period of 14–22 days. In two cases a remission was achieved and in one case only a slight symptom relief was noticed. Two out of three patients revealed positive NMDAR antibodies. In one patient antineuronal antibodies were not detectable. Increasing reports on NMDAR antibody related symptoms after HSE strengthen the importance of analyzing anti-neuronal antibodies at earliest clinical clues and to treat with immune modulatory agents. Interestingly, one of our patients with extrapyramidal movement disorder was negative for NMDAR Abs in spite of striking clinical similarities with NMDAR positive patients. This finding might either suggest insufficient sensitivity of anti-neuronal antibody screening methods or indicate presence of currently unknown antibodies causing similar clinical presentation.

ZusammenfassungDas Verständnis um das Krankheitsbild des Pseudotumor cerebri hat sich in den letzten Jahren insbesondere im pädiatrischen Be-reich sehr erweitert und geändert, dennoch ist die Ätiologie des nun als idiopathische, intrakranielle Hypertension (IIH) bezeichneten Krankheitsbildes unklar. Das Risiko eines permanenten Visusverlustes erfordert speziell im Kindesalter eine rasche und erfahrene inter-disziplinäre Abklärung und ein konsistentes Management von Therapie und Verlaufsevaluation. Prospektive, kollektive Daten sollen das Verständnis der Pathophysiologie, Epidemiologie und der Risikofaktoren der pädiatrischen IIH verbessern und einen Konsens zu diagnostischen und therapeutischen Empfehlungen ermöglichen.

Case Report: Mitochondrial DNA mutations of ATP6 affect a subunit of ATP synthase (complex V of the oxidative phosphorylation) and present mostly as severe neurologic diseases with neuropathy, ataxia, retinitis pigmentosa [NARP] or as maternal inherited Leigh syndrome (MILS). Only recently, patients with hypertrophic CMP and ATP6 mutations have been described.

Aims: The primary aim of this study was to investigate quality of life (QoL) and mental issues in neurologically ill children and adolescents.

Background: Mutations within the DMD gene leading to the absence or vast reduction of dystrophin cause Duchenne muscular dystrophy (DMD). The majority of female heterozygous carriers of X-linked recessive DMD mutations are asymptomatic or mildly affected due to the balanced X-inactivation. However, in rare cases of female DMD carriers skewed X-inactivation leads to clinical symptoms.

The incidence of herpes simplex virus type 1 (HSV-1) encephalitis represents 1 of 250.000 to 500.000. Despite antiviral treatment, the rate of mortality and neurological sequelae is high. Secondary extrapyramidale, choreo-athetotic movements are a rare, but severe sequela after HSV-1 encephalitis with unknown pathogenesis. Beside the resumption of viral replication and the primary involvement of the basal ganglia, an immune- mediated pathogenesis is incremental up for discussion, due to the fact that immune modulating treatment yields symptom relief. To the best of our knowledge this is the first case series of patients treated with plasmapheresis for choreo-athetotic movement disorder after HSV-1 encephalitis.

Rett syndrome, first described by the Austrian neurologist Andreas Rett (1966), is a profoundly disabling neurodevelopmental disorder that is almost entirely confined to females. The mutations in the X-linked gene MECP2, which were identified as the main cause for Rett syndrome, span a broad spectrum of phenotypes - from classic Rett to milder variants with better speech, language and motor abilities (preserved speech variant; PSV). On the other hand, there are also patients with Rett syndrome caused by mutations in other genes (e.g., FOXG1, CDKL5) as well as patients with MECP2 mutations who show no clinical signs. Therefore, the clinical criteria of this disorder are of utmost importance for its early identification and delineation. Although an apparently normal early development had initially been regarded as one of the criteria for classic Rett syndrome, various scientists considered the disorder to be a developmental disorder that manifests shortly after birth. Affected girls usually follow a four-stage developmental trajectory, with most of them undergoing a profound deterioration of neurofunctions (pre-regression period, regression period/rapid destructive stage, the pseudo-stationary stage, and the late deterioration stage). Our aim is to give an insight into the delineation of early signs of this developmental disorder as well as its various neurophysiological correlates. It is thus a contribution to early detection for early clinical trials, and is based on the detailed longitudinal research that we have been conducting so far.