A recurrent single-amino acid deletion (p.Glu500del) in the head domain of ß-cardiac myosin in two unrelated boys presenting with polyhydramnios, congenital axial stiffness and skeletal myopathy.

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.

Qualitative and quantitative muscle ultrasound in patients with Duchenne muscular dystrophy: Where do sonographic changes begin?

OBJECTIVE: The number of studies investigating and understanding the disease mechanisms of Duchenne muscular dystrophy (DMD) in human clinical trials have increased substantially over the last decade. Suitable clinical instruments for the measurement of disease progress and drug efficiency are mandatory, but currently not available, especially in the youngest patients. The aim of this study was to detect a reproducible pattern of muscle involvement in early stages potentially preceding evidence of motor regression. MATERIAL AND METHODS: A cohort of 25 DMD patients aged 1-6 years at the first presentation were examined at multiple timepoints and compared with age-matched healthy controls. Muscle ultrasound was quantified using computer-analyzed gray scale levels (GSL) and blinded visual rating, using a modified Heckmatt scale. RESULTS: Changes in muscle echogenicity in DMD patients occurred very early, clearly preceding motor regression and in some cases, even before the motor plateau phase was reached. Visual rating and GSL identified the earliest changes in the proximal adductor magnus muscle. CONCLUSION: Muscle ultrasound can be used as an additional method to assess the disease progression and for decision-making in paucisymptomatic DMD patients. Sonographic changes in the ad-ductor magnus muscle seem to be the first detectable changes with a recognisable pattern.

Rare intronic mutation between Exon 62 and 63 (c.9225-285A>G) of the dystrophin gene associated with atypical BMD phenotype.

Dystrophinopathies are predominantly caused by deletions, duplications and point mutations in the coding regions of the dystrophin gene with less than 1% of all pathogenic mutations identified within intronic sequences. We describe a 17-year-old male with a Becker muscular dystrophy diagnosis and mental disability due to an intron mutation that led to aberrant splicing and formation of an additional exon. Histopathological analysis of muscle tissue revealed signs of muscular dystrophy and reduced signal for dystrophin, alpha-sarcoglycan, and alpha-dystroglycan. Multiplex ligation-dependent probe amplification screening and total sequencing of the dystrophin gene did not identify a mutation in the coding regions. However, next generation sequencing revealed an intron mutation between exons 62 and 63 of the dystrophin gene known for pseudoexon formation and disruption of the reading frame. We report a functional consequence of this mutation as an increased intracellular-weighted sodium signal (assessed by 23Na-magnetic resonance imaging) in leg muscles.

Diagnosis and treatment of Guillain-Barré Syndrome in childhood and adolescence: An evidence- and consensus-based guideline.

This evidence- and consensus-based practical guideline for the diagnosis and treatment of Guillain-Barré Syndrome (GBS) in childhood and adolescence has been developed by a group of delegates from relevant specialist societies and organisations; it is the result of an initiative by the German-Speaking Society of Neuropediatrics (GNP), and is supported by the Association of Scientific Medical Societies (AWMF, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften). A systematic analysis of the literature revealed that only a few adequately-controlled studies exist for this particular age group, while none carries a low risk of bias. For this reason, the diagnostic and therapeutic recommendations largely rely on findings in adult patients with GBS, for which there are a higher number of suitable studies available. Consensus was established using a written, multi-step Delphi process. A high level of consensus could be reached for the crucial steps in diagnosis and treatment. We recommend basing the diagnostic approach on the clinical criteria of GBS and deriving support from CSF and electrophysiological findings. Repetition of invasive procedures that yield ambiguous results is only recommended if the diagnosis cannot be ascertained from the other criteria. For severe or persistently-progressive GBS treatment with intravenous immunoglobulin (IVIG) is recommended, whereas in cases of IVIG intolerance or inefficacy we recommended treatment with plasmapheresis. Corticosteroids are ineffective for GBS but can be considered when acute onset chronic inflammatory demyelinating polyneuropathy (A-CIDP) is suspected due to a prolonged disease course. The full German version of the Guideline is available on the AWMF website (https://www.awmf.org/leitlinien/detail/ll/022-008.html).

Are national suicide prevention programs effective? A comparison of 4 verum and 4 control countries over 30 years.

BACKGROUND: Suicide and non-fatal suicidal behavior are significant public health issues worldwide requiring effective preventive interventions. METHODS: The aim of the present study was to analyze the effectiveness of national suicide prevention programs taking a statistical approach involving the segmented regression analysis of interrupted time series data. RESULTS: This study demonstrates that National Suicide Prevention Programs are effective, but this effect seems to correlate with age and sex. Our data have shown a statistical significant decline in suicide rates in the verum countries in males, with the strongest effects in groups aged 25-to-44 years and 45-to-64 years. CONCLUSION: Our study implies that the implementation of a national strategy is an effective tool to reduce suicide rates.

Novel SBF2 mutations and clinical spectrum of Charcot-Marie-Tooth neuropathy type 4B2.

Biallelic SBF2 mutations cause Charcot-Marie-Tooth disease type 4B2 (CMT4B2), a sensorimotor neuropathy with autosomal recessive inheritance and association with glaucoma. Since the discovery of the gene mutation, only few additional patients have been reported. We identified seven CMT4B2 families with nine different SBF2 mutations. Revisiting genetic and clinical data from our cohort and the literature, SBF2 variants were private mutations, including exon-deletion and de novo variants. The neuropathy typically started in the first decade after normal early motor development, was predominantly motor and had a rather moderate course. Electrophysiology and nerve biopsies indicated demyelination and excess myelin outfoldings constituted a characteristic feature. While neuropathy was >90% penetrant at age 10 years, glaucoma was absent in ~40% of cases but sometimes developed with age. Consequently, SBF2 mutation analysis should not be restricted to individuals with coincident neuropathy and glaucoma, and CMT4B2 patients without glaucoma should be followed for increased intraocular pressure. The presence of exon-deletion and de novo mutations demands comprehensive mutation scanning and family studies to ensure appropriate diagnostic approaches and genetic counseling.

[Spinal muscular atrophy : Time for newborn screening?] / Spinale Muskelatrophie : Zeit für das Neugeborenenscreening?

The most common neurodegenerative disease in childhood is spinal muscular atrophy (SMA). The severe infantile type 1 (Werdnig-Hoffman disease) makes 60% of SMA in total. These children usually die within 18 months without ventilation. New therapeutic approaches have led from the theoretical concept to randomized controlled clinical trials in patients. For the first time, a pharmacological treatment of SMA has been approved. The early detection of the disease is decisive for the success of therapy. All previous data suggest starting treatment early and when possible prior to the onset of symptoms considerably improves the outcome in comparison to a delayed start. The goal must be the presymptomatic diagnosis in order to initiate treatment before motor neuron degeneration. Technical and ethical prerequisites for a molecular genetic newborn screening are given.

Early-Onset Myopathies: Clinical Findings, Prevalence of Subgroups and Diagnostic Approach in a Single Neuromuscular Referral Center in Germany.

BACKGROUND: Early-onset myopathies are a heterogeneous group of neuromuscular diseases with broad clinical, genetic and histopathological overlap. The diagnostic approach has considerably changed since high throughput genetic methods (next generation sequencing, NGS) became available. OBJECTIVE: We present diagnostic subgroups in a single neuromuscular referral center and describe an algorithm for the diagnostic work-up. METHODS: The diagnostic approach of 98 index patients was retrospectively analysed. In 56 cases targeted sequencing of a known gene was performed, in 44 patients NGS was performed using large muscle specific panels, and in 12 individuals whole exome sequencing (WES) was undertaken. One patient was diagnosed via array CGH. Clinical features of all patients are provided. RESULTS: The final diagnosis could be found in 63 out of 98 patients (64%) with molecular genetic analysis. In 55% targeted gene sequencing could establish the genetic diagnosis. However, this rate largely depended on the presence of distinct histological or clinical features. NGS (large myopathy-related panels and WES) revealed genetic diagnosis in 58.5% (52% and 67%, respectively). The genes detected by WES in our cohort of patients were all covered by the panels. Based on our findings we propose an algorithm for a practical diagnostic approach.Prevalences:MTM1- and LAMA2-patients are the two biggest subgroups, followed by SEPN1-, RYR1- and Collagen VI-related diseases. 31% of genetically confirmed cases represents a group with overlap between "congenital myopathies (CM)" and "congenital muscular dystrophies (CMD)". In 36% of the patients a specific genetic diagnosis could not be assigned. CONCLUSIONS: A final diagnosis can be confirmed by high throughput genetic analysis in 58.5% of the cases, which is a higher rate than reported in the literature for muscle biopsy and should in many cases be considered as a first diagnostic tool. NGS cannot replace neuromuscular expertise and a close discussion with the geneticists on NGS is mandatory. Targeted candidate gene sequencing still plays a role in selected cases with highly suspicious clinical or histological features. There is a relevant clinical and genetic overlap between the entities CM and CMD.

[Multiple sclerosis in childhood and adolescence : Complex, chronic and differentiated]. / Multiple Sklerose im Kindes- und Jugendalter : Komplex, chronisch, differenziert.

Pediatric multiple sclerosis (MS) is one of the most important acquired neurological disorders in childhood and adolescence. A timely recognition, diagnosis and treatment are of utmost importance. This article highlights the current state of knowledge on the etiology, pathogenesis, diagnosis, clinical presentation and treatment in childhood. Although the rate of progression of disability in the early years is slower in younger patients compared to adults, a disease-modifying therapy should be started once MS is diagnosed.

Proximal muscular atrophy and weakness: An unusual adverse effect of deferasirox iron chelation therapy.

Deferasirox is a standard treatment for chronic transfusional iron overload. Adverse effects of deferasirox have been reported in large prospective studies. We report two cases of monozygotic twins manifesting with proximal muscular atrophy and weakness under deferasirox. Discontinuation of deferasirox resulted in symptom improvement and ultimately in complete remission five months after successful haematopoietic stem cell transplantation. Broad diagnostic work-up could not bring evidence of another aetiology of muscular weakness. Iron overload or beta thalassemia itself as a cause is considered unlikely in our patients because the chronological coincidence of muscular symptoms was contra-directional to serum ferritin levels and significant clinical improvement was observed promptly after cessation of deferasirox even before transplantation. These observations suggest that the development of muscular weakness in patients on deferasirox should be recognised as a possible adverse effect of the drug.

Diagnostic algorithms in Charcot-Marie-Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients.

We present clinical features and genetic results of 1206 index patients and 124 affected relatives who were referred for genetic testing of Charcot-Marie-Tooth (CMT) neuropathy at the laboratory in Aachen between 2001 and 2012. Genetic detection rates were 56% in demyelinating CMT (71% of autosomal dominant (AD) CMT1/CMTX), and 17% in axonal CMT (24% of AD CMT2/CMTX). Three genetic defects (PMP22 duplication/deletion, GJB1/Cx32 or MPZ/P0 mutation) were responsible for 89.3% of demyelinating CMT index patients in whom a genetic diagnosis was achieved, and the diagnostic yield of the three main genetic defects in axonal CMT (GJB1/Cx32, MFN2, MPZ/P0 mutations) was 84.2%. De novo mutations were detected in 1.3% of PMP22 duplication, 25% of MPZ/P0, and none in GJB1/Cx32. Motor nerve conduction velocity was uniformly <38 m/s in median or ulnar nerves in PMP22 duplication, >40 m/s in MFN2, and more variable in GJB1/Cx32, MPZ/P0 mutations. Patients with CMT2A showed a broad clinical severity regardless of the type or position of the MFN2 mutation. Out of 75 patients, 8 patients (11%) with PMP22 deletions were categorized as CMT1 or CMT2. Diagnostic algorithms are still useful for cost-efficient mutation detection and for the interpretation of large-scale genetic data made available by next generation sequencing strategies.

Muscle ultrasound in classic infantile and adult Pompe disease: a useful screening tool in adults but not in infants.

A cohort of 4 infantile and 15 adult Pompe patients has been investigated regarding correlation between strength and ultrasound of skeletal musculature. In adults, muscle ultrasound is useful to assess clinical and subclinical involvement of muscles. In this study, visible sonographic changes were found in every clinically affected muscle, using a modified Heckmatt scale. In some muscles morphologic changes preceded weakness. Regarding the anatomical pattern of involvement, our findings do not support the hypothesis of a specific pattern with a higher vulnerability of vastus intermedius than rectus femoris, which has been postulated before. A frequent sparing of triceps brachii could be confirmed. Intramuscular abnormalities occurred in a focal, a diffuse, or an intermediate pattern, with characteristics of both. In contrast to muscular dystrophies, bone echogencity was not markedly decreased in Pompe disease even in an advanced stage. In infants, muscle ultrasound showed no distinct pathology even in clinically severely affected children and should not be used as a screening method for infantile Pompe disease.

Somatropin treatment of spinal muscular atrophy: a placebo-controlled, double-blind crossover pilot study.

In preclinical studies growth hormone and its primary mediator IGF-1 have shown potential to increase muscle mass and strength. A single patient with spinal muscular atrophy reported benefit after compassionate use of growth hormone. Therefore we evaluated the efficacy and safety of growth hormone treatment for spinal muscular atrophy in a multicenter, randomised, double-blind, placebo-controlled, crossover pilot trial. Patients (n = 19) with type II/III spinal muscular atrophy were randomised to receive either somatropin (0.03 mg/kg/day) or placebo subcutaneously for 3 months, followed by a 2-month wash-out phase before 3 months of treatment with the contrary remedy. Changes in upper limb muscle strength (megascore for elbow flexion and hand-grip in Newton) were assessed by hand-held myometry as the primary measure of outcome. Secondary outcome measures included lower limb muscle strength, motor function using the Hammersmith Functional Motor Scale and other functional tests for motor function and pulmonary function. Somatropin treatment did not significantly affect upper limb muscle strength (point estimate mean: 0.08 N, 95% confidence interval (CI:-3.79;3.95, p = 0.965), lower limb muscle strength (point estimate mean: 2.23 N, CI:-2.19;6.63, p = 0.302) or muscle and pulmonary function. Side effects occurring during somatropin treatment corresponded with well-known side effects of growth hormone substitution in patients with growth hormone deficiency. In this pilot study, growth hormone treatment did not improve muscle strength or function in patients with spinal muscular atrophy type II/III.

[Quality of life after brachial plexus lesions in adults]. / Lebensqualität bei posttraumatischen Paresen des Plexus brachialis im Erwachsenenalter.

Brachial plexus lesions are among the most severe injuries of the upper extremity. Despite intensive conservative and surgical treatment efforts, patients frequently suffer from serious impairments in the quality of life. This contribution presents the results of a retrospective clinical survey on the quality of life after brachial plexus injuries. Out of 38 treated patients, 25 patients could be included in the study. The disability of arm, shoulder and hand was evaluated by the DASH score and the quality of life by the FLZm, a questionnaire on life satisfaction. In addition, demographic data, work situation and mechanism and type of injury were recorded. The examined patients were mainly young males who were injured in traffic, in particular motorcycle accidents. The DASH score analysis revealed that plexus injuries are among the most disabling injuries of the upper extremity. The associated restrictions in the different sections of the quality of life involve not only the health-related section but also partnership, family and leisure time activities. A strong relation between the possibility to return to work and the quality of life was found. We recommend the use of the DASH score and the FLZm questionnaire on life satisfaction as routine tools for the evaluation of the therapeutic outcome after brachial plexus injuries.

Early white matter changes in childhood multiple sclerosis: a diffusion tensor imaging study.

BACKGROUND AND PURPOSE: Loss of integrity in nonlesional white matter occurs as a fundamental feature of multiple sclerosis in adults. The purpose of our study was to evaluate DTI-derived measures of white matter microstructure in children with MS compared with age- and sex-matched controls by using tract-based spatial statistics. MATERIALS AND METHODS: Fourteen consecutive pediatric patients with MS (11 female/3 male; mean age, 15.1 ± 1.6 years; age range, 12-17 years) and age- and sex-matched healthy subjects (11 female/3 male; mean age, 14.8 ± 1.7 years) were included in the study. After we obtained DTI sequences, data processing was performed by using tract-based spatial statistics. RESULTS: Compared with healthy age- and sex-matched controls, children with multiple sclerosis showed a global decrease in mean fractional anisotropy (P ≤ .001), with a concomitant increase in mean (P < .001), radial (P < .05), and axial diffusivity (P < .001). The most pronounced fractional anisotropy value decrease in patients with MS was found in the splenium of the corpus callosum (P < .001). An additional decrease in fractional anisotropy was identified in the right temporal and right and left parietal regions (P < .001). Fractional anisotropy of the white matter skeleton was related to disease duration and may, therefore, serve as a diagnostic marker. CONCLUSIONS: The microstructure of white matter is altered early in the disease course in childhood multiple sclerosis.

[Anti-suicidal effect of lithium: current state of research and its clinical implications for the long-term treatment of affective disorders]. / Suizidprophylaktische Wirkung von Lithium : Aktueller Forschungsstand und Implikationen für die Therapie affektiver Störungen.

Treatment of patients with suicidal behaviour is one of the most challenging tasks for health care professionals. Due to the high mortality, morbidity and costs related to suicide, the development of treatment and preventive strategies for suicidal behaviour have been a focus of psychiatric research. For lithium, one of the oldest pharmacological agents used in psychiatry, anti-suicidal effects have been found since the early 90s in many international studies. Despite this unambiguous evidence and corresponding recommendations in national and international guidelines for the acute and maintenance therapy of affective disorders, the use of lithium is still underrepresented. The following article provides a review of studies investigating the anti-suicidal effects of lithium in affective disorders. Clinical implications for the treatment of affective disorders are discussed.

Completed suicides in 47 psychiatric hospitals in Germany--results from the AGATE-study.

INTRODUCTION: There is an ongoing debate about a possibly enhanced risk of suicidal behaviour in some psychiatric patients due to psychopharmacotherapy. Our retrospective study aimed at analyzing the psychopharmacotherapy of 133 inpatient suicides and 133 controls by a matched pair design. METHODS: We analyzed all suicides (n = 133) reported in the AGATE study from 1991 to 2008. Besides evaluation of sociodemographic variables and suicide methods, we compared psychopharmacotherapy of suicides with schizophrenia (n = 59) and affective disorders (n = 59) to that of a matched control group. RESULTS: Most suicides (n = 102, 76.7%) were judged not to be related to psychopharmacotherapy. In general, more psychopharmacological drugs were prescribed for suicides than for controls. Schizophrenic suicides received more low potency FGAs than their controls. More suicides with affective disorders than controls were treated with NASSAs, SNRIs, and high or low potency FGAs. In contrast to their controls, none of the suicides with affective disorders received lithium. NASSAs, SNRIs, and high or low potency FGAs predicted suicide in regression analysis for inpatients with affective disorders. DISCUSSION: Differences in psychopharmacotherapy might mainly result from a recognized risk of suicide or a more severe degree of illness. However, the underrepresentation of lithium in the suicide groups is noticeable.

[Splints in birth-related brachial plexus injuries]. / Zur Schienenbehandlung bei geburtstraumatischen Läsionen des Plexus brachialis.

Most cases of obstetrical brachial plexus palsies are mild traction injuries which resolve under physical therapy within several weeks or months. Severe ruptures or avulsion injuries of the plexus can lead to lifelong impairment of the upper extremities. Hence, in severe brachial plexus injuries the indications for brachial plexus reconstruction should be evaluated, early. At the age of about 3 months, the infant should be presented in a centre specialised in obstetrical brachial plexus palsies. In almost all cases intensive physical therapy is performed. In addition, many patients require splinting in order to gain function as part of the conservative therapy or for postoperative fixation. Depending on the type of splint, different demands are made on design, material and strategy of adjustment. Many different natural and synthetic materials are available for orthopaedic constructions. Because of its good adjustment options, the use of low temperature thermoplastic is steadily increasing. This contribution presents an overview of our currently used splints, new technical developments in our experience with more than 200 patients with obstetrical brachial plexus palsy. We present our experience with the most common splints for the use in fixation after birth-related brachial plexus surgery, subscapularis release, trapezius muscle transfer and functional improvement of hands with a lack of wrist extension.

Mitochondrial DNA depletion and fatal infantile hepatic failure due to mutations in the mitochondrial polymerase γ (POLG) gene: a combined morphological/enzyme histochemical and immunocytochemical/biochemical and molecular genetic study.

Combined morphological, immunocytochemical, biochemical and molecular genetic studies were performed on skeletal muscle, heart muscle and liver tissue of a 16-months boy with fatal liver failure. The pathological characterization of the tissues revealed a severe depletion of mtDNA (mitochondrial DNA) that was most pronounced in liver, followed by a less severe, but still significant depletion in skeletal muscle and the heart. The primary cause of the disease was linked to compound heterozygous mutations in the polymerase γ (POLG) gene (DNA polymerase γ; A467T, K1191N). We present evidence, that compound heterozygous POLG mutations lead to tissue selective impairment of mtDNA replication and thus to a mosaic defect pattern even in the severely affected liver. A variable defect pattern was found in liver, muscle and heart tissue as revealed by biochemical, cytochemical, immunocytochemical and in situ hybridization analysis. Functionally, a severe deficiency of cytochrome-c-oxidase (cox) activity was seen in the liver. Although mtDNA depletion was detected in heart and skeletal muscle, there was no cox deficiency in these tissues. Depletion of mtDNA and microdissection of cox-positive or negative areas correlated with the histological pattern in the liver. Interestingly, the mosaic pattern detected for cox-activity and mtDNA copy number fully aligned with the immunohistologically revealed defect pattern using Pol γ, mtSSB- and mtTFA-antibodies, thus substantiating the hypothesis that nuclear encoded proteins located within mitochondria become unstable and are degraded when they are not actively bound to mtDNA. Their disappearance could also aggravate the mtDNA depletion and contribute to the non-homogenous defect pattern.

Concurrent TNFRSF1A R92Q and pyrin E230K mutations in a child with multiple sclerosis.

We report a 16-year-old female patient with a severe course of multiple sclerosis and concomitant symptoms suggestive of a hereditary autoinflammatory disease. Genetic analyses revealed that she inherited a TNFRSF1A R92Q mutation from her mother and a pyrin E230K mutation from her father. To our knowledge, this is the first report of a patient with severe childhood multiple sclerosis and mutations in two genes which predispose to hereditary autoinflammatory disorders. We speculate that these mutations contribute to early multiple sclerosis manifestation and enhance the inflammatory damage inflicted by the autoimmune response.