Klinik für Neuropädiatrie und Muskelerkrankungen

We performed a clinical and molecular genetic analysis in members of five families with dopa-responsive dystonia. Four mutations were detected in the gene GCH1 that codes for GTP cyclohydrolase I. Two of these mutations, a delG309 in exon 1 and a C544T transition in exon 5, have not been described before. They result in inactivation of the enzyme by truncation. The remaining two mutations, both A to G transitions, a(-2)g in intron 1 and a(-2)g in intron 2, cause truncation by abnormal splicing. The genotype of family members was correlated to their clinical phenotype (obtained before molecular analysis). Clinical symptoms observed in the families included generalized and focal dystonia, abnormal gait, and subtle signs such as an abnormal writing test. High penetrance (0.8-1.0) was observed in four of five families if minor symptoms and signs were considered. A given mutation was more likely to cause symptoms in females than in males, thus confirming the well-established higher incidence of dopa-responsive dystonia in females than in males.

Analysis of the gene GCH1 in 58 patients with dystonia and a positive response to L-dopa revealed mutations in 30 individuals from 22 families. Thirteen of the mutations observed were familial, three occurred de novo, and inheritance could not be determined in six cases. There was no mutation in the promoter region of GCH1 in any patient. The doses of L-dopa given to members of the two groups were not significantly different.

Giant axonal neuropathy (GAN) is a severe early onset neurodegenerative disorder affecting both the peripheral nerves and the central nervous system. The diagnosis is based on the presence of characteristic giant axons on nerve biopsy. In GAN, the integrity of the intermediate filament network is altered. Indeed, abnormal accumulation of the intermediate filaments has been reported in different cell types, including in the swollen axons, which are filled with neurofilaments. We identified the defective protein, gigaxonin, of unknown function, and reported fourteen distinct mutations in twelve families of various origins. Two additional mutations have been recently reported. In the present study, we analysed the GAN gene in 6 families, and identified seven novel mutations: three nonsense and two missense mutations and two deletions. In addition, the molecular result for an already reported family was re-evaluated. In this family, the R269Q "polymorphism" is in fact the pathogenic mutation.

BACKGROUND: Spinal muscular atrophy (SMA) is a severe, life-limiting neurodegenerative disease. A disease-modifying and approved therapy with nusinersen has been available in Germany since July 2017. Gene therapies offer another promising treatment option through a once in a lifetime administration. In May 2019 a gene replacement therapy for the treatment of SMA was approved for the first time by the U.S. Food and Drug Administration (FDA). An application for approval in Europe has been submitted and is currently pending. OBJECTIVE: This consensus paper was compiled at the invitation of the German Society for Muscular Diseases (DGM) with the participation of all potential German neuromuscular treatment centers, the German section of the Society for Pediatric Neurology (GNP) and with the involvement of the medical scientific advisory board of the DGM. The aim was to define and establish the necessary prerequisites for a safe and successful application of the new gene replacement therapy in clinical practice. CONCLUSION: Gene replacement therapy with onasemnogene abeparvovec has the potential to significantly influence the course of SMA. Long-term data on sustainability of effects and possible adverse effects of gene replacement therapy are not yet available. The application of this innovative therapy must be carried out in specialized and appropriately qualified treatment centers under strict safety conditions. This article makes suggestions for the necessary framework conditions and gives recommendations for a systematic pretreatment and posttreatment assessment schedule under gene therapy. The effectiveness and safety of the therapy should be systematically documented in an industry-independent and disease-specific register.

L-2-hydroxyglutaric aciduria (L-2-HGA) is a metabolic disease with an autosomal recessive mode of inheritance. It was first reported in 1980. Patients with this disease have mutations in both alleles of the L2HDGH gene. The clinical presentation of individuals with L-2-HGA is somewhat variable, but affected individuals typically suffer from progressive neurodegeneration. Analysis of urinary organic acids reveals an increased signal of 2-hydroxyglutaric acid, mainly as the L-enantiomer. L-2-HGA is known to occur in individuals of various ethnic backgrounds, but up to now mutation analysis has been mainly focused on patients of Turkish and Portuguese origin. This led us to confirm the diagnosis on the DNA level and undertake the corresponding mutation analysis in individuals of diverse ethnicity previously diagnosed with L-2-HGA on the basis of urinary metabolites and clinical/neuroimaging data. In 24 individuals from 17 families with diverse ethnic and geographic origins, 13 different mutations were found, 10 of which have not been reported previously. At least eight of the patients were compound heterozygotes. The identification of two mutations (c.751C > T and c.905C > T in exon 7) in patients with different origins supports the view that they occurred independently in different families. In contrast, the mutation c.788C > T was detected in all six Venezuelan patients originating from the same Caribbean island of Margarita, but not in other patients, thus rendering a founder effect likely. None of the mutations was found in the control population, indicating that they are most probably causative. Mutation analysis may improve the quality of diagnosis and prenatal diagnosis of L-2-HGA.

OBJECTIVE: Many patients with epilepsy have both focal and bilateral tonic-clonic seizures (BTCSs), but it is largely unclear why ictal activity spreads only sometimes. Previous work indicates that interictal high-frequency oscillations (HFOs), traditionally subdivided into ripples (80-250 Hz) and fast ripples (250-500 Hz), are a promising biomarker of epileptogenicity. We aimed to investigate whether HFOs correlate with the emergence of seizure activity and whether they differ between focal seizures (FSs) with impaired awareness and BTCSs. METHODS: We retrospectively analyzed 15 FSs and 13 BTCSs from seven patients with mesial temporal lobe epilepsy, each of them with at least one BTCS and at least one FS. Representative intervals of intracranial electroencephalography from the seizure onset zone (SOZ) and remote non-SOZ areas were selected to compare pre-ictal, complex focal, tonic-clonic, and postictal periods. Ripples and fast ripples were visually identified and their density, that is, percentage of time occupied by the respective events, computed. RESULTS: Ripple and fast ripple densities increased inside the SOZ after seizure onset (P < 0.01) and in remote areas after progression to BTCSs (P < 0.01). Postictal SOZ ripple density dropped below pre-ictal levels (P < 0.001). Prior to onset of bilateral tonic-clonic movements, ripple density inside the SOZ is higher in BTCSs than in FSs (P < 0.05). INTERPRETATION: Ripples and fast ripples correlate with onset and spread of ictal activity. Abundant ripples inside the SOZ may reflect the activation of specific neuronal networks related to imminent spread of seizure activity.

Two cases of oculomotor palsy with cyclic spasms are reported. Case 1, a 25-year-old woman, was unable to elicit contractions of her right oculomotor muscles at will. Her right pupil was unresponsive to light and to near stimuli. Accommodation could not be elicited by approaching visual objects. During cyclic spasms, the lid rose to the upper limbus of the cornea, the pupil constricted from 5 to 3 mm, and the eye accommodated 7 diopters. The electromyogram of the levator showed polyphasic units of 8 ms duration instead of the normal 2 ms. To eliminate the conspicuous twitching and intermittent ptosis of the lid, the levator was excised and the lid suspended from the brow by a fascia lata sling. Light- and electron microscopy of the levator revealed a pattern of neurogenic muscular atrophy with secondary myopathic changes. The intramuscular nerves showed signs of ongoing remyelination of axons and recent reinnervation of muscle cells. - In Case 2, slow progression of an oculomotor palsy was documented from birth until the age of seven, when signs of cyclic spasms appeared. The authors suggest that chronic rather than acute damage to the oculomotor nerve, exerted for instance by pressure of a vessel, might have caused the syndrome of oculomotor palsy with cyclic spasms in both of these patients.

Serum creatine kinase isoenzymes were studied in 41 patients suffering from Duchenne type muscular dystrophy and 20 mothers of patients (carriers) by cellulose acetate electrophoresis. Both the MM and MB types were found in all cases of Duchenne type dystrophy patients, and in carriers with highly elevated total creatine kinase activity BB was not observed above the detection limits of the methods used. However, a so-called atypical CK--BB band has been demonstrated.

Background and Objectives: Olesoxime (TRO19622) was identified as a potential treatment of spinal muscular atrophy (SMA) based on its beneficial effects in multiple preclinical neurodegeneration models. Olesoxime promotes neuron survival, neurite outgrowth, recovery from nerve injury and accelerates myelination or remyelination in models of demyelinating diseases. Maintaining motor neuron architecture and survival is highly relevant to SMA, a disease associated with progressive motor neuron compromise mainly affecting neuromuscular function. A clinical study has been performed to evaluate the effects of olesoxime treatment in patients with SMA.

Zusammenfassung Epilepsien zählen zu den häufigsten neurologischen Erkrankungen mit etwa 600 000 Betroffenen in Deutschland. Symptome epileptischer Anfälle, die Vielzahl möglicher Epilepsieursachen und die unterschiedlichen Krankheitsverläufe erschweren sowohl die korrekte Diagnosestellung als auch die Auswahl einer geeigneten Therapie (Antikonvulsiva, epilepsiechirurgische Eingriffe, Neurostimulationsverfahren, ketogene Ernährungstherapien, Verhaltensstrategien u. a.). Zudem haben krankheitsspezifische Risiken sowie häufig auftretende Komorbiditäten nicht selten gravierende psychosoziale Konsequenzen. Daher wird bei der Versorgung von Menschen mit Epilepsie neben der vollständigen Anfallskontrolle ohne Nebenwirkungen und der Lebensqualität auch die Kontrolle bzw. Linderung typischer Begleiterkrankungen und Risiken angestrebt. Um diese Behandlungsziele zu erreichen, sind spezifische Fachkenntnisse und Untersuchungsmöglichkeiten erforderlich, die von spezialisierten Zentren vorgehalten werden. Epilepsiezentren sind als überregionale Kompetenzzentren definiert, die über spezielle Expertise und eine besondere Ausstattung zur ambulanten und stationären Versorgung von Patienten mit Epilepsien und verwandten Erkrankungen verfügen. Zu ihren Aufgaben zählen u. a. die umfassende Diagnostik, Differenzialdiagnostik und Therapie von Epilepsiepatienten sowie die multiprofessionelle und interdisziplinäre Beratung von Angehörigen und Eltern. Dieser Artikel fasst die diagnostischen und therapeutischen Herausforderungen bei der Versorgung von Menschen mit Epilepsien zusammen, beschreibt die personellen, apparativen und institutionellen Voraussetzungen von Epilepsiezentren und gibt eine Übersicht über die Vergütung epileptologischer Spezialleistungen nach G-DRG. Darüber hinaus werden Merkmale einzelner Epilepsiezentren in Deutschland skizziert sowie Perspektiven und Möglichkeiten zur Verbesserung der Versorgung von Epilepsiepatienten diskutiert.

Zusammenfassung Ziel der Studie Der Anteil von Kindern mit Migrationshintergrund unter 5 Jahren liegt bundesweit bei 35%, in Nordrhein-Westfalen (NRW) bei 43%. Häufig sind mit dem Migrationshintergrund unzureichende Deutschkenntnisse bei einem oder beiden Elternteilen verbunden. Kommunikationsbarrieren durch Sprachdifferenzen haben einen negativen Einfluss auf die Behandlungsqualität, Patientensicherheit und Behandlungskosten. Es wird untersucht, wie Kinder- und Jugendkliniken auf die Herausforderung durch Sprachbarrieren vorbereitet sind. Methodik Wir führten eine Querschnittsbefragung aller Kinderkliniken in NRW durch und luden dazu die Klinikdirektoren schriftlich und per email zur Teilnahme ein. Der Fragebogen orientierte sich an den „Standards for Culturally and Linguistically Appropriate Services in Health and Health Care“ (CLAS) und wurde an die deutschen Verhältnisse angepasst. Ergebnisse 38 Kliniken nahmen teil (51%). Sprachbarrieren kommen häufig vor (bei 75% der Antwortenden mehr als 10% der Patienten). 82% der Antwortenden sehen ihre Klinik schlechter als „gut“ auf die Überwindung von Sprachbarrieren vorbereitet. Die Feststellung des Dolmetscherbedarfs erfolgt bei der Mehrheit (61%) „fall-abhängig“ und nicht einem Protokoll folgend. Zur Überwindung von Sprachbarrieren werden überwiegend mehrsprachige Mitarbeiter eingesetzt, wobei nur 38% eine Liste von mehrsprachigen Mitarbeitern als ausreichende Ressource bewerten. Die Kosten, die für professionelle Dolmetscher entstehen, waren 42% der Antwortenden nicht bekannt. In den übrigen Fällen betrugen sie weniger als € 500/Monat. Schlussfolgerung Die Überwindung von Sprachbarrieren erfolgt unter Einsatz lokaler Ressourcen, die aus Sicht der Mehrheit der Antwortenden nicht ausreichen. Die Entwicklung von Qualitätsstandards und Bereitstellung finanzieller Mittel sind notwendig, um das Verbesserungspotenzial zu mobilisieren. Hierfür sind Untersuchungen in anderen Disziplinen und Sektoren notwendig, um in einen Dialog mit Entscheidungsträgern aus Politik und Krankenkassen zu treten.

The incidence of the GBS in childhood is significantly lower than in adults. The clinical course may be equally severe, 10-25% of the affected children requiring artificial ventilation. Besides respiratory insufficiency, cardial arrhythmias are a major threat to the patients' lives. However, eventually more than 90% of the children recover completely. Controlled studies on the efficacy of therapeutic measures have been performed only in adults. To children their results should be transferred with caution. Steroids are of no value in the acute disease. However, they should be tried when progression for more than 4 weeks suggests the diagnosis of CIDP. Plasmapheresis is beneficial in CIDP and severe GBS; in GBS the time for weaning from the respirator and for achieving independent ambulation is significantly reduced. Recent studies have demonstrated that intravenous immunoglobulins can be equally effective. However, the administration of immunoglobulins in less severe cases should at present be reserved to a controlled study.

Zusammenfassung Eine barrierefreie Teilnahme am alltäglichen Leben stellt für Menschen mit aktiver Epilepsie häufig eine Herausforderung dar. Epileptische Anfälle können in Kindergarten, Schule und am Arbeitsplatz sowie im häuslichen Umfeld Unsicherheit und Überforderung hervorrufen. Individuell erstellte Pläne für Betreuende, Angehörige, Aufsichtspersonen und den Rettungsdienst sollen im Falle eines akuten Anfalls geeignete Handlungsanweisungen geben. Bisher gibt es hierfür im deutschsprachigen Raum keine standardisierten Vorlagen. Mit den Handlungsplänen bei epileptischen Anfällen für Laien (HEAL) bzw. Therapeuten (HEAT) werden hier 2 Formulare vorgestellt, die zum einen eine standardisierte Grundlage bieten und andererseits leicht auf den individuellen Bedarf angepasst werden können.

This paper deals with signs, symptoms and course in spasmodic torticollis (ST). Two hundred and fifty-six patients were included in the study, 59.3% women, 40.7% men. The mean age was 49.1 years. Rotating torticollis out-numbered latero- and antero-retrocollis. A family history of ST occurred in 3.1% of the total sample. First degree relatives were affected in 2.3%. Thirty-four per cent of the patients had additional dystonic symptoms. Most frequently these affected the upper extremities (13%), and less often the legs. Of the patients 19.1% had experienced a period of complete remission. The correlations between the severity of the signs and the neurological symptoms are surprisingly weak.

Abstract Introduction In an earlier experiment with rabbits after a single injection of depot steroid various pathological changes in the hearty skeletal and thoracic muscle cells could be observed ( Freund-Molbert et al., 1973 ). The multiplicity of the ultrastructural changes could not be traced back to a single cellular organelle where the steroids first attack. After an injection of steroids electrophysiological investigations showed changes in the plasmalemma of muscle cells ( Gruener and Stern , 1972 ). For this reason, the experiment was repeated using the freeze etch method in order to demonstrate possible macromolecular changes in the plasmalemma of the skeletal and cardiac muscle cells and to bring this into relation to intracellular reactions. Material and method Male and female rabbits weighing from 1800 to 2200 grams were used. The animals were given a single injection of depot methylprednisolone (60 mg) or depot triamcinolone (66 mg) into the right hind leg (vehicle solvent see Freund-Molbert et al., 1973 ). Three animals served as controls. The biopsies were taken under chloroform anesthesia. After the 3rd and 6th day pieces of the musculature were removed from both hind legs, after the 9th, 12th, 19th and 60th day from both hind legs and cardiac muscle and after the 35 th day only from the cardiac muscle. The weight of the animals was checked daily. The tissue was fixed for ultrathin sectioning in an ice-cold mixture of 3% glutaraldehyde immediately after the removal, postfixed with 1% OsO4 and embedded in Epon. Semithin sections were prepared for light microscopic examination. The ultrathin sections were stained with uranyl acetate and lead citrate and viewed in a Zeiss electron microscope (EM 9 a). For freeze etch electron microscopy the tissue was prefixed for two hours with a veronal acetate buffered solution of 3% glutaraldehyde (pH: 7.3; temperature: 4°C; normal control 4°C and 38°C). The tissue was then washed in buffer and incubated in a solution of 30% glycerol (veronal acetate buffer) for 2 hours. The pieces of tissue were frozen on golden grids in liquid Freon 22. Fracturing, etching and replicating was carried out using a Balzers machine. The replicas were viewed in a Zeiss electron microscope (EM 9 a). The micrographs of fractured plasma membranes were evaluated under a binocular microscope. The particles of 15–20 membranes (inner fracture face) per day of testing were counted. The standard deviation was determined mathematically. In thin sections calcium was determined by x-ray microanalyses. Results and discussion Both depot-steroids lead to general changes in the skeletal muscle. Serious changes in the cardiac muscle occur as well. However, skeletal and cardiac muscles show various pathological reactions which are dependent on time. In ultrathin sections skeletal muscle cells show vacuolated mitochondria 3 days after the injection which is followed by an increase of the intracellular glycogen on the 6th day. On the 12th day the percentage of glycogen has usually decreases to the amount of glycogen in the control animals. In numerous skeletal muscle cells the myofibrils have degenerated within a circumscribed area. Other cells show pronounced accumulation of lipid droplets. On the 19th day all stages of muscle cell degeneration, including calcification, are found. On the 60th day after the injection both muscle cellular necroses and calcification have been completely dissolved. With the help of the freeze etch method, macromolecular changes in the plasma membrane of the skeletal muscle cell are shown in relation to the results of the ultrathin section. A significant increase of membrane particles (inner fracture face) is observed 9 days after the injection of depot steroid. This increase is followed by the degeneration of the skeletal muscle cells. On the 19th day the number of particles has already decreased and increased only slightly up to the 60th day of the experiment. In the cardiac muscle pathological changes appeared at a later time than in the skeletal muscle. This difference in the pattern of damage between the skeletal and cardiac muscle cells becomes distinct during a later phase of the experiment on the 35 th and 60th day. On these days the cardiac muscle shows greater pathological changes in the cellular organelles than on the 19th day. On the 60th day the myofibrils still remain extremely small. Giant mitochondria with glycogen invaginations and myelin-like degeneration of the mitochondrial cristae are observed. As in the skeletal muscle the macromolecular changes in the plasma-lemma (inner fracture face) in the form of an increase of membrane particles precede the intracellular changes. This increase reaches two peaks on the 12th and 35 th day. The result shows that the state of specific metabolism and the membrane structure of the skeletal and cardiac muscle cell determine the degree of the pathological reaction at various times by means of an interaction. From the morphologically recognizable time-dependent relationship between the membrane changes and the intracellular degeneration it can be infered that through long-acting membrane changes and the disturbance of the intracellular metabolism the latter decompensates and the cell then degenerates.

Seit Anfang der 80er Jahre wird Botulinumtoxin A therapeutisch eingesetzt. Es gilt als Medikament der ersten Wahl zur Behandlung fokaler Dystonien in der Erwachsenenneurologie und wird zunehmend auch zur Behandlung muskulärer Hyperaktivität bei spastischen Bewegungsstörungen im Kindesalter eingesetzt. Als Hauptindikationen gelten der Pes equinus und der Adduktorenspasmus. Zahlreiche, auch plazebokontrollierte, doppelblinde Studien belegen den lokalen und funktionellen Gewinn bei der Behandlung des Pes equinus. Wenige offene Studien weisen auf die Verbesserung des Gangbildes und des Sitzens sowie auf pflegerische Gewinne nach der Behandlung des Adduktorenspasmus mit Botulinumtoxin A hin. Zahlreiche weitere Erfolg versprechende therapeutische Ansätze wie die Behandlung der oberen Extremität und die Multilevelbehandlung bedürfen der weiteren Evaluation. Als temporäres hocheffektives Therapieverfahren mit geringer Invasivität öffnet Botulinumtoxin A ein therapeutisches Fenster für Kinder, die für operative Therapieverfahren aufgrund ihres Alters noch nicht infrage kommen.

Introduction: Use of botulinum neurotoxin type A (BoNT/A), preparation Xeomin®, free of complexing proteins in (1) bilateral spastic cerebral palsy (BS-CP), (2) lower limb dystonia and (3) sialorrhea: efficacy and safety of the application in three patients in complex neuropaediatric supply.

Histopathological changes of the external eye muscles and of the peripheral skeletal muscles of 2 patients with Kearns-Sayre syndrome are demonstrated histochemically and electron microscopically. In one case the progression of the mitochondrial anomalies in this disease was documented through ultrastructural investigations of muscle biopsies over a period of 17 years. By freeze-fracture the membrane fracture faces of the transformed mitochondrial were examined in both patients. Biochemical results of one patient show that energy production by glycolysis is distinctly decreased with respect to oxydation. Clinical, morphological and biochemical results support the hypothesis that the Kearns-Sayre syndrome is caused by a primary mitochondriopathy which is not limited to the musculature.

INTRODUCTION: The prevalence of post-viral olfactory dysfunction has increased significantly during the COVID-19 pandemic, posing a major challenge for patients and practitioners. While olfactory training (OT) is a common approach to therapy, there has been increasing interest in supplementing therapy with a combination of palmitoylethanolamide (PEA) and luteolin (LUT), which are known for their anti-inflammatory properties. In this study, their efficacy in the treatment of patients with olfactory loss following upper respiratory tract infections, mainly COVID-19, was investigated in an outpatient clinic. METHODS: Fifty patients with persistent olfactory dysfunction were randomized to two groups: one receiving OT and PEA-LUT, the other OT alone. Olfactory function was evaluated before and after treatment. RESULTS: The study group showed significant improvements in odor discrimination and overall olfactory function (TDI score) after treatment with PEA-LUT and OT, while the control group did not. However, when clinically meaningful improvements were considered, there was no significant difference between the groups. CONCLUSION: The present study suggests that while PEA-LUT may have the potential to improve olfactory function in post-viral dysfunction, the additional benefit over OT alone may be limited. These results contrast with some previous studies.

Background: The estimation of incidences in neuromuscular diseases is challenging due to unspecific and incomplete coding and recording systems. Patient- and health care provider-driven data collections often tend to be fragmented and incomplete as the provision of patient identifying information is limited due to privacy regulations. As duplicated records cannot easily be identified, aggregation of data from different data sources leads to further inaccuracy. We here report about a novel approach to evaluate the incidences of Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) in Germany.