Newborn infant screening for spinal muscular atrophy: Chances and challenges

With the development of causally oriented therapies for 5q-associated spinal muscular atrophy (SMA), the disease course has changed dramatically. However, the results of available studies clearly indicate that the timing at which therapy is initiated is critical to therapeutic success. It is also apparent that high-grade motor neuron loss cannot be reversed by any of these therapies. Since the disease in most cases starts in early infancy, it is obvious to include 5q-associated SMA in general newborn infant screening (NBS). In recent years, pilot programs like those in Germany, Belgium, and the USA, as well as SMA screening, have been included in routine care in numerous countries. In other countries, however, the discussion process about ethical and financial aspect of NBS has not yet been completed. The data available from screening projects clearly show that NBS and thus early treatment dramatically improves the prognosis compared to the natural disease course.1 Although there is no doubt about the usefulness of NBS, problems in its implementation must be proactively addressed. These problems range from possible negative influences on the acceptance of previously established screening programs; logistical problems in the timely shipment of samples; difficulties in laboratory analysis; limitation of available therapy due to economic reasons; to the complex needs of identified children and their families. The paper by D’Silva et al.2 describes in detail the experience and difficulties in a large pilot project that began in 2018. It was found that overall readiness for NBS was not adversely affected. Similar experiences have been found in other pilot studies. A survey in Japan showed that the acceptance of NBS for SMA in the general population was 95%.3 This was due to the respondents' belief that early therapy is definitely more effective than late therapy, regardless of the respondents' specific knowledge of the disease. The methodology used in the study by D'Silva et al. was able to identify all affected children correctly. The fact that laboratory analysis for confirmation was inadvertently omitted in one child highlights the need for a tracking system to ensure that such errors are avoided whenever possible. Because the laboratory diagnostics in the study were performed in only one laboratory, it cannot be ruled out that additional technical errors may occur when similar programs are rolled out in larger countries with several different laboratories involved. What is unusual is the extremely low number of children with four copies of SMN2 in the Australian population compared with data found in other countries. The question arises whether this can be explained by a peculiarity of the Australian population compared with other populations or whether it can be explained by methodological problems in the precise determination of copy number.4 This problem has been addressed in several studies. Incorrect copy number determination may lead to therapeutic errors in countries where therapeutic decisions are based on SMN2 copy number. Thus, early therapy may not be initiated in cases where four instead of three SMN2 copies were erroneously detected.5 The Australian study clearly demonstrates the need to standardize procedures and to involve the various stakeholders (such as healthcare providers and payers) in the screening process in a structured way, to thus create a functioning network in order to enable timely therapy. In about a quarter of the patients, first symptoms were already visible within the first 4 weeks of life; in other studies, signs of SMA were already found at the first presentation after screening.1 This emphasizes the reality that successful NBS for SMA is a race against time

Molekulare Therapien bei neuromuskulären Erkrankungen im Kindesalter — Große Hoffnungen und unbekannte Risiken

Spinal muscular atrophy and muscular dystrophy Duchenne belong to the group of rare neuromuscular diseases manifesting in early childhood. Therapeutic options for some of these rare monogenic diseases have changed significantly in recent years. Molecular therapies such as direct gene transfer or alternative processing of the disease-specific gene play an important role in this transformation.In particular, the course of 5q-associated spinal muscle atrophy has changed significantly due to the availability of such causal therapies, while the results of ongoing studies are still pending for most muscle diseases. In the area of neuromuscular diseases, an achievable therapeutic goal is to slow the progression, but not complete healing. Currently, only limited data are available. In particular, the long-term effectiveness and the possible risks are still unknown. Therefore, these therapies should be used under strictly monitored conditions

Myofascial Trigger Points in Children With Tension-Type Headache: A New Diagnostic and Therapeutic Option

The goal of this pilot study was to evaluate the effect of a trigger point–specific physiotherapy on headache frequency, intensity, and duration in children with episodic or chronic tension-type headache. Patients were recruited from the special headache outpatient clinic. A total of 9 girls (mean age 13.1 years; range, 5-15 years) with the diagnosis of tension-type headache participated in the pilot study from May to September 2006 and received trigger point–specific physiotherapy twice a week by a trained physiotherapist. After an average number of 6.5 therapeutic sessions, the headache frequency had been reduced by 67.7%, intensity by 74.3%, and duration by 77.3%. No side effects were noted during the treatment. These preliminary findings suggest a role for active trigger points in children with tension-type headache. Trigger point–specific physiotherapy seems to be an effective therapy in these children. Further prospective and controlled studies in a larger cohort are warranted

Determinants of Plasma Docosahexaenoic Acid Levels and Their Relationship to Neurological and Cognitive Functions in PKU Patients: A Double Blind Randomized Supplementation Study

Children with phenylketonuria (PKU) follow a protein restricted diet with negligible amounts of docosahexaenoic acid (DHA). Low DHA intakes might explain subtle neurological deficits in PKU. We studied whether a DHA supply modified plasma DHA and neurological and intellectual functioning in PKU. In a double-blind multicentric trial, 109 PKU patients were randomized to DHA doses from 0 to 7 mg/kg&day for six months. Before and after supplementation, we determined plasma fatty acid concentrations, latencies of visually evoked potentials, fine and gross motor behavior, and IQ. Fatty acid desaturase genotypes were also determined. DHA supplementation increased plasma glycerophospholipid DHA proportional to dose by 0.4% DHA per 1 mg intake/kg bodyweight. Functional outcomes were not associated with DHA status before and after intervention and remained unchanged by supplementation. Genotypes were associated with plasma arachidonic acid levels and, if considered together with the levels of the precursor alpha-linolenic acid, also with DHA. Functional outcomes and supplementation effects were not significantly associated with genotype. DHA intakes up to 7 mg/kg did not improve neurological functions in PKU children. Nervous tissues may be less prone to low DHA levels after infancy, or higher doses might be required to impact neurological functions. In situations of minimal dietary DHA, endogenous synthesis of DHA from alpha-linolenic acid could relevantly contribute to DHA status.This work was supported by the Commission of the European Communities, the Sixth Framework Programme NUTRIMENTHE (Grant Agreement No. 212652). Additional support was provided by Nutricia (Liverpool, UK)

Analyse der Spontanmotorik im 1. Lebensjahr: Markerlose 3-D-Bewegungserfassung zur Früherkennung von Entwicklungsstörungen

Children with motor development disorders benefit greatly from early interventions. An early diagnosis in pediatric preventive care (U2–U5) can be improved by automated screening. Current approaches to automated motion analysis, however, are expensive, require lots of technical support, and cannot be used in broad clinical application. Here we present an inexpensive, marker-free video analysis tool (KineMAT) for infants, which digitizes 3‑D movements of the entire body over time allowing automated analysis in the future. Three-minute video sequences of spontaneously moving infants were recorded with a commercially available depth-imaging camera and aligned with a virtual infant body model (SMIL model). The virtual image generated allows any measurements to be carried out in 3‑D with high precision. We demonstrate seven infants with different diagnoses. A selection of possible movement parameters was quantified and aligned with diagnosis-specific movement characteristics. KineMAT and the SMIL model allow reliable, three-dimensional measurements of spontaneous activity in infants with a very low error rate. Based on machine-learning algorithms, KineMAT can be trained to automatically recognize pathological spontaneous motor skills. It is inexpensive and easy to use and can be developed into a screening tool for preventive care for children.Kinder mit motorischer Entwicklungsstörung profitieren von einer frühen Entwicklungsförderung. Eine frühe Diagnosestellung in der kinderärztlichen Vorsorge (U2–U5) kann durch ein automatisiertes Screening verbessert werden. Bisherige Ansätze einer automatisierten Bewegungsanalyse sind jedoch teuer und aufwendig und nicht in der Breite anwendbar. In diesem Beitrag soll ein neues System zur Videoanalyse, das Kinematic Motion Analysis Tool (KineMAT) vorgestellt werden. Es kann bei Säuglingen angewendet werden und kommt ohne Körpermarker aus. Die Methode wird anhand von 7 Patienten mit unterschiedlichen Diagnosen demonstriert. Mit einer kommerziell erhältlichen Tiefenbildkamera (RGB-D[Red-Green-Blue-Depth]-Kamera) werden 3‑minütige Videosequenzen von sich spontan bewegenden Säuglingen aufgenommen und mit einem virtuellen Säuglingskörpermodell (SMIL[Skinned Multi-infant Linear]-Modell) in Übereinstimmung gebracht. Das so erzeugte virtuelle Abbild erlaubt es, beliebige Messungen in 3‑D mit hoher Präzision durchzuführen. Eine Auswahl möglicher Bewegungsparameter wird mit diagnosespezifischen Bewegungsauffälligkeiten zusammengeführt. Der KineMAT und das SMIL-Modell erlauben eine zuverlässige, dreidimensionale Messung der Spontanaktivität bei Säuglingen mit einer sehr niedrigen Fehlerrate. Basierend auf maschinellen Lernalgorithmen kann der KineMAT trainiert werden, pathologische Spontanmotorik automatisiert zu erkennen. Er ist kostengünstig und einfach anzuwenden und soll als Screeninginstrument für die kinderärztliche Vorsorge weiterentwickelt werden

LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood.

International audienceAutosomal recessive LPIN1 mutations have been recently described as a novel cause of rhabdomyolysis in a few families. The purpose of the study was to evaluate the prevalence of LPIN1 mutations in patients exhibiting severe episodes of rhabdomyolysis in infancy. After exclusion of primary fatty acid oxidation disorders, LPIN1 coding sequence was determined in genomic DNA and cDNA. Among the 29 patients studied, 17 (59%) carried recessive nonsense or frameshift mutations, or a large scale intragenic deletion. In these 17 patients, episodes of rhabdomyolysis occurred at a mean age of 21 months. Secondary defect of mitochondrial fatty oxidation or respiratory chain was found in skeletal muscle of two patients. The intragenic deletion, c.2295-866_2410-30del, was identified in 8/17 patients (47%), all Caucasians, and occurred on the background of a common haplotype, suggesting a founder effect. This deleted human LPIN1 form was unable to complement ∆pah1 yeast for growth on glycerol, in contrast to normal LPIN1. Since more than 50% of our series harboured LPIN1 mutations, LPIN1 should be regarded as a major cause of severe myoglobinuria in early childhood. The high frequency of the intragenic LPIN1 deletion should provide a valuable criterion for fast diagnosis, prior to muscle biopsy

Guideline for the management of myasthenic syndromes

Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare chronic diseases. MG and LEMS have an autoimmune-mediated etiology, while CMS are genetic disorders. A (strain dependent) muscle weakness due to neuromuscular transmission disorder is a common feature. Generalized MG requires increasingly differentiated therapeutic strategies that consider the enormous therapeutic developments of recent years. To include the newest therapy recommendations, a comprehensive update of the available German-language guideline ‘Diagnostics and therapy of myasthenic syndromes’ has been published by the German Neurological society with the aid of an interdisciplinary expert panel. This paper is an adapted translation of the updated and partly newly developed treatment guideline. It defines the rapid achievement of complete disease control in myasthenic patients as a central treatment goal. The use of standard therapies, as well as modern immunotherapeutics, is subject to a staged regimen that takes into account autoantibody status and disease activity. With the advent of modern, fast-acting immunomodulators, disease activity assessment has become pivotal and requires evaluation of the clinical course, including severity and required therapies. Applying MG-specific scores and classifications such as Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Foundation of America allows differentiation between mild/moderate and (highly) active (including refractory) disease. Therapy decisions must consider age, thymic pathology, antibody status, and disease activity. Glucocorticosteroids and the classical immunosuppressants (primarily azathioprine) are the basic immunotherapeutics to treat mild/moderate to (highly) active generalized MG/young MG and ocular MG. Thymectomy is indicated as a treatment for thymoma-associated MG and generalized MG with acetylcholine receptor antibody (AChR-Ab)-positive status. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status. Specific treatment for myasthenic crises requires plasmapheresis, immunoadsorption, or IVIG. Specific aspects of ocular, juvenile, and congenital myasthenia are highlighted. The guideline will be further developed based on new study results for other immunomodulators and biomarkers that aid the accurate measurement of disease activity

Development of practice and consensus-based strategies including a treat-to-target approach for the management of moderate and severe juvenile dermatomyositis in Germany and Austria

Background: Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy in childhood and a major cause of morbidity among children with pediatric rheumatic diseases. The management of JDM is very heterogeneous. The JDM working group of the Society for Pediatric Rheumatology (GKJR) aims to define consensus- and practice-based strategies in order to harmonize diagnosis, treatment and monitoring of JDM. Methods: The JDM working group was established in 2015 consisting of 23 pediatric rheumatologists, pediatric neurologists and dermatologists with expertise in the management of JDM. Current practice patterns of management in JDM had previously been identified via an online survey among pediatric rheumatologists and neurologists. Using a consensus process consisting of online surveys and a face-to-face consensus conference statements were defined regarding the diagnosis, treatment and monitoring of JDM. During the conference consensus was achieved via nominal group technique. Voting took place using an electronic audience response system, and at least 80% consensus was required for individual statements. Results: Overall 10 individual statements were developed, finally reaching a consensus of 92 to 100% regarding (1) establishing a diagnosis, (2) case definitions for the application of the strategies (moderate and severe JDM), (3) initial diagnostic testing, (4) monitoring and documentation, (5) treatment targets within the context of a treat-totarget strategy, (6) supportive therapies, (7) explicit definition of a treat-to-target strategy, (8) various glucocorticoid regimens, including intermittent intravenous methylprednisolone pulse and high-dose oral glucocorticoid therapies with tapering, (9) initial glucocorticoid-sparing therapy and (10) management of refractory disease. Conclusion: Using a consensus process among JDM experts, statements regarding the management of JDM were defined. These statements and the strategies aid in the management of patients with moderate and severe JDM

Распространенность болезни Помпе у пациентов с идиопатической гиперкреатинкиназемией и слабостью поясно-конечностных мышц (анализ 3076 случаев)*

.Проведен проспективный скрининг дефицита фермента кислой α-глюкозидазы (GAA) европейской когорты пациентов с гиперкреатинкиназемией (гиперКК) и / или слабостью поясно-конечностных мышц (СПКМ) неустановленной этиологии с помощью метода сухого пятна крови (dry blood spot, DBS).Материалы и методы. Образцы DBS были собраны у 3076 взрослых пациентов, проходивших обследование в 7 немецких и британских нервно-мышечных центрах. Все образцы были исследованы на дефицит GAA методом флуорометрии. При выявлении пониженной ферментативной активности определяли наличие мутации гена GAA.Результаты. Из 3076 образцов DBS в 232 (7,6 %) случаях обнаружена низкая ферментативная активность GAA. У 55 (24 %) из 232 пациентов наблюдали изолированную гиперКК, а у 176 (76 %) – гиперКК и СПКМ. При комбинации 2 признаков у 94 % больных активность GAA была снижена. Мутационный анализ выявил мутации гена GAA у 74 (2,4 %) пациентов, при этом 70 больных были гетерозиготными по распространенной мутации сайта сплайсинга гена GAA c.-32-13T>G. У пациентов с подтвержденной болезнью Помпе основной симптомокомплекс состоял из СПКМ (85,3 %) в сочетании с дыхательной недостаточностью (61 %). У 12,0 % больных наблюдали изолированную гиперКК, а у 2,7 % – гиперКК и дыхательную недостаточность.Заключение. В большой когорте пациентов с гиперКК и / или СПКМ  распространенность болезни Помпе с поздним началом составляет 2,4 %, что требует проведения целевого скрининга активности GAA у пациентов с гиперКК и / или СПКМнеустановленной этиологии

Effect and safety of treatment with ACE-inhibitor Enalapril and β-blocker metoprolol on the onset of left ventricular dysfunction in Duchenne muscular dystrophy - a randomized, double-blind, placebo-controlled trial

Background: X-linked Duchenne muscular dystrophy (DMD), the most frequent human hereditary skeletal muscle myopathy, inevitably leads to progressive dilated cardiomyopathy. We assessed the effect and safety of a combined treatment with the ACE-inhibitor enalapril and the β-blocker metoprolol in a German cohort of infantile and juvenile DMD patients with preserved left ventricular function. Methods, Trial design: Sixteen weeks single-arm open run-in therapy with enalapril and metoprolol followed by a two-arm 1:1 randomized double-blind placebo-controlled treatment in a multicenter setting. Inclusion criteria: DMD boys aged 10–14 years with left ventricular fractional shortening [LV-FS] ≥ 30% in echocardiography. Primary endpoint: time from randomization to first occurrence of LV-FS < 28%. Secondary: changes of a) LV-FS from baseline, b) blood pressure, c), heart rate and autonomic function in ECG and Holter-ECG, e) cardiac biomarkers and neurohumeral serum parameters, f) quality of life, and g) adverse events. Results: From 3/2010 to 12/2013, 38 patients from 10 sites were centrally randomized after run-in, with 21 patients continuing enalapril and metoprolol medication and 17 patients receiving placebo. Until end of study 12/2015, LV-FS < 28% was reached in 6/21 versus 7/17 patients. Cox regression adjusted for LV-FS after run-in showed a statistically non-significant benefit for medication over placebo (hazard ratio: 0.38; 95% confidence interval: 0.12 to 1.22; p = 0.10). Analysis of secondary outcome measures revealed a time-dependent deterioration of LV-FS with no statistically significant differences between the two study arms. Blood pressure, maximal heart rate and mean-NN values were significantly lower at the end of open run-in treatment compared to baseline. Outcome analysis 19 months after randomization displayed significantly lower maximum heart rate and higher noradrenalin and renin values in the intervention group. No difference between treatments was seen for quality of life. As a single, yet important adverse event, the reversible deterioration of walking abilities of one DMD patient during the run-in period was observed. Conclusions: Our analysis of enalapril and metoprolol treatment in DMD patients with preserved left ventricular function is suggestive to delay the progression of the intrinsic cardiomyopathy to left ventricular failure, but did not reach statistical significance, probably due to insufficient sample size. Clinical trial registration: DRKS-number 00000115, EudraCT-number 2009–009871-36