[Principles of translational gene therapy for neuromuscular diseases]. / Prinzipien der translationalen Gentherapie für neuromuskuläre Erkrankungen.

BACKGROUND: In recent years the theoretical hope has become reality and the first hereditary neuromuscular diseases have become causally treatable. Neuromuscular diseases have thus become the pacemaker of this form of therapy for the whole of neurology. AIMS: This article describes the principles of precision gene therapy for neurogenetic diseases using examples of neuromuscular diseases. DISCUSSION: Various strategies of gene therapy have become established and are being tested in preclinical and clinical trials and evaluated as approved forms for long-term efficacy. The aim of every gene therapy is the modification or introduction of the target gene with initiation of a degradation of dysfunctional proteins. Various techniques, such as gene transfer, gene substitution or gene editing in vivo and ex vivo are now usable. For example, a modification of the pre-mRNA using antisense oligonucleotides or RNA interference (siRNA) can be used for exon skipping. An initiation of gene expression to produce the target protein can be based on a modification of the DNA by means of gene replacement, cell-based therapy (iPS cells), regulation by compensatory proteins or pharmacological treatment with so-called small molecules. Each method has advantages and complex disadvantages that must be individually evaluated. Phenotypic peculiarities of a rare disease often only become apparent through specific translational therapy. It is already becoming obvious that a very early point in timing of gene therapy is probably the most effective. Newborn screening is therefore gaining additional importance as early diagnosis can achieve the best possible success of therapies, possibly even preventively.

An integrative correlation of myopathology, phenotype and genotype in late onset Pompe disease.

AIMS: Pompe disease is caused by pathogenic mutations in the alpha 1,4-glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype-phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability. METHODS: Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology-score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule-associated protein 1A/1B-light chain 3, p62 and Bcl2-associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies. RESULTS: The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology-score. High morphology-scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology-score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine-kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.-32-13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type. CONCLUSIONS: Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy.

[Innovative therapeutic approaches for hereditary neuromuscular diseases]. / Innovative Therapieansätze bei hereditären neuromuskulären Erkrankungen.

Advances in the understanding of the genetic mechanisms and pathophysiology of neuromuscular diseases have recently led to the development of new, innovative and often mutation-specific therapeutic approaches. Methods used include splicing modification by antisense oligonucleotides, read-through of premature stopcodons, use of viral vectors to introduce genetic information, or optimizing the effectiveness of enzyme replacement therapies. The first drugs have already been approved for the treatment of Duchenne muscular dystrophy and spinal muscular atrophy. For other diseases, such as myotubular myopathy, myotonic dystrophy, facioscapulohumeral muscular dystrophy and Pompe disease, new promising approaches are in preclinical or clinical development. As these are rare diseases with a broad spectrum of clinical severity, drug approval is often based on a limited amount of evidence. Therefore, systematic follow-up in the postmarketing period is particularly important to assess the safety and efficacy of these new and often high-priced orphan drugs.

European consensus for starting and stopping enzyme replacement therapy in adult patients with Pompe disease: a 10-year experience.

BACKGROUND AND PURPOSE: Pompe disease is a rare inheritable muscle disorder for which enzyme replacement therapy (ERT) has been available since 2006. Uniform criteria for starting and stopping ERT in adult patients were developed and reported here. METHODS: Three consensus meetings were organized through the European Pompe Consortium, a network of experts from 11 European countries in the field of Pompe disease. A systematic review of the literature was undertaken to determine the effectiveness of ERT in adult patients on a range of clinical outcome measures and quality of life. A narrative synthesis is presented. RESULTS: Consensus was reached on how the diagnosis of Pompe disease should be confirmed, when treatment should be started, reasons for stopping treatment and the use of ERT during pregnancy. This was based on expert opinion and supported by the literature. One clinical trial and 43 observational studies, covering a total of 586 individual adult patients, provided evidence of a beneficial effect of ERT at group level. At individual patient level, the response to treatment varied, but factors associated with a patient's response to ERT were not described in many studies. Eleven observational studies focused on more severely affected patients, suggesting that ERT can also be beneficial in these patients. There are no studies on the effects of ERT in pre-symptomatic patients. CONCLUSIONS: This is the first European consensus recommendation for starting and stopping ERT in adult patients with Pompe disease, based on the extensive experience of experts from different countries.

[Educational and Professional Qualifications of Adults With Myotonic Dystrophies - A Misleading Perception by the Myopathic Face?]. / Ausbildung und berufliche Qualifikation von Erwachsenen mit Myotonen Dystrophien - eine fehlgeleitete Wahrnehmung durch die Facies myopathica?

BACKGROUND: Myotonic dystrophies types 1 and 2 (DM1 / DM2) are the most frequent inherited progressive, segmental progeroid, multisystemic neuromuscular diseases in adulthood. The executive impairment is one of the key disease features. The myopathic face triggers the general perception of DM1 patients being associated with a low educational level. METHODS: We used a standardized questionnaire to evaluate educational levels in adults with genetically confirmed DM1 and DM2 in comparison to data of the general population. Investigated topics included the level of education, e. g. the highest university degree aquired. RESULTS: Out of a total cohort of 546 DM patients, 125 DM1 and 156 DM2 patients (51 %) participated in this study. There was no statistically significant difference between the two collectives as far as high school levels are concerned. 50.4 % of DM1 and 48.3 % of DM2 patients obtained the higher education entrance qualification compared to 29.6 % of the normal German population. However, there were significant differences between the two collectives in "spelling problems" (DM1 cohort: p = 0.039), "difficulty in mental arithmetic" (p = 0.043), and classification of patients "with learning difficulties" (p = 0.012). DISCUSSION: Misled by a myopathic face, many physicians associate myotonic dystrophy with cognitive deficiency. Based on our study, the minimal deviation between DM1 and DM2 and the normal German population indicates that the multisystemic disease does not significantly influence the maximum attainable level of education in adults with DM1. CONCLUSION: In summary, physicians should be aware that the general educational levels are rather normal in patients with myotonic dystrophy type 1 and rethink their perception of DM1 patients.

Sleep-related symptoms and sleep-disordered breathing in adult Pompe disease.

BACKGROUND AND PURPOSE: Respiratory muscle weakness is the major cause of early death in patients with adult Pompe disease. It first manifests as nocturnal hypercapnia, eventually leading to sleep disruption. Sleep-related symptoms along with motor performance, forced vital capacity (FVC) and respiratory symptoms were investigated in 65 adult patients with Pompe disease. METHODS: Patients answered the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale, the Fatigue Severity Scale, the Rotterdam Nine-item Handicap Scale, the SF-36 health-related quality of life questionnaire, and a respiratory symptom questionnaire. In all patients, the 6-min walk test was performed and FVC was obtained. Polysomnography and oxycapnometry results were available in 31 patients. RESULTS: Sixty patients received enzyme replacement therapy, and 32 individuals were on home ventilatory support. Reduced sleep quality was highly prevalent (PSQI > 5; 43.1%) and correlated with both excessive daytime sleepiness (Epworth Sleepiness Scale > 10; 24.6%) and fatigue (Fatigue Severity Scale > 4; 72.3%). The SF-36 health-related quality of life questionnaire was reduced in the physical domains, and was inversely correlated with sleep quality, FVC and motor performance. In 11 out of 17 non-ventilated patients with polysomnography records, sleep-disordered breathing was present, and duration of nocturnal oxygen desaturation (SaO2 < 90%) was significantly correlated to the PSQI global score. CONCLUSIONS: In adult Pompe disease, sleep disturbances are a common cause of excessive daytime sleepiness and fatigue. Sleep-related symptoms may be indicative of respiratory muscle weakness and should give rise to further work-up of sleep-disordered breathing.

[The Spectrum of Neuromyotonia: Clinics, Therapy and Outcome]. / Das Spektrum der Neuromyotonie: Klinik, Therapie und Langzeitverlauf.

BACKGROUND: Neuromyotonia (NM), Isaacs-Zschoke-Mertens syndrome or continuous muscle fiber activity (CMFA), is a rare condition associated with VGKC-antibodies. Clinically, fasciculations, myokymias, muscle stiffness and a myotonic appearance of movements after contraction are typical findings. In addition, CNS-symptoms vary from moderate fatigue, poor concentration and autonomic symptoms to severe encephalopathy in Morvan's syndrome. In electromyography, spontaneous irregular discharges can be found frequently with typical di-, tri- or multiplet single motor unit discharges. In up to 60 %, serum antibodies against VGKC-complexes can be detected. METHODS: Patients with neuromyotonia were evaluated for clinical symptoms, response to treatment and outcome over a five-year period of follow-up. For evaluation, we used video recording of clinical symptoms, electroneurography, electromyography and myosonography as well as immunological tests (VGKC-complex antibody including CASPR2 and IGL1). Furthermore, cerebral fluid and screening for neoplasias were done. Patients with evidence for neuropathy, myopathy or motor neuron disease, even if diagnosed in the follow-up, were excluded. RESULTS: In 3 of 5 patients, neuromyotonia was diagnosed by electromyography and positive VGKC antibodies. In two patients, diagnosis was based on typical clinical symptoms and electromyographical changes. Anticonvulsants (carbamazepine) for symptomatic treatment were moderately effective in four patients; treatment with i. v. immunoglobulins was highly successful in one patient with high positive VGKC-complex antibody titers. In one patient with low-titer VGKC antibodies, neither anticonvulsants nor i. v. immunoglobulins nor prednisone was a successful treatment. CONCLUSIONS: Neuromyotonia is a rare, treatable condition. However, due to the high variability of symptoms, response to therapy and outcome, neuromyotonia treatment needs to be highly individualized.

Pain in adult patients with Pompe disease: a cross-sectional survey.

BACKGROUND: Pompe disease is a rare hereditary metabolic myopathy caused by a deficiency of acid-α-glucosidase. We investigated the presence and severity of pain and its interference with daily activities in a large group of adults with Pompe disease, who we compared with an age-matched control group. METHODS: Data were collected in a cross-sectional survey in Germany and The Netherlands. Pain was assessed using the short-form brief pain inventory (BPI). Patients also completed the Short Form-36 item (SF-36v2), the Hospital Anxiety and Depression Scale (HADS) and the Rotterdam Handicap Scale (RHS). RESULTS: Forty-five percent of the 124 adult Pompe patients reported having had pain in the previous 24h, against 27% of the 111 controls (p=0.004). The median pain severity score in Pompe patients reporting pain was 3.1 (on a scale from 0 to 10), indicating mild pain; against 2.6 amongst controls (p=0.06). The median score of pain interference with daily activities in patients who reported pain was 3.3, against 1.3 in controls (p=0.001). Relative to patients without pain, those with pain had lower RHS scores (p=0.02), lower SF-36 Physical and Mental component summary scores (p<0.001 and p=0.049), and higher levels of depression and anxiety (p=0.005 and p=0.003). CONCLUSIONS: To date, this is one of the largest studies on pain in a specific neuromuscular disorder. Nearly one in two Pompe patients had experienced pain in the previous 24h. Although pain severity and its interference with daily life were mild, pain was related to a reduced quality of life, less participation in daily life, and greater depression and anxiety. Its management should therefore be seen as part of clinical practice involving Pompe patients.

Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease.

Hereditary rippling muscle disease (RMD) is an autosomal dominant human disorder characterized by mechanically triggered contractions of skeletal muscle. Genome-wide linkage analysis has identified an RMD locus on chromosome 3p25. We found missense mutations in positional candidate CAV3 (encoding caveolin 3; ref. 5) in all five families analyzed. Mutations in CAV3 have also been described in limb-girdle muscular dystrophy type 1C (LGMD1C; refs. 6,7), demonstrating the allelism of dystrophic and non-dystrophic muscle diseases.

[Diagnosis and therapy of late onset Pompe disease]. / Diagnose und Therapie des Late-onset-Morbus-Pompe.

As Pompe disease glycogen storage disease type 2 with a severely reduced life expectancy is now a treatable disorder, accurate diagnostic procedures and evidence-based indications for therapy are mandatory. We screened the literature for consensus reports and published trial data of late-onset Pompe disease. These data were summarized in a Delphi consensus method approach. The clinical suspicion of late-onset Pompe disease should be substantiated by the validated dry blood spot test measurement for acid α-glucosidase activity. Alternatively, enzyme activity analysis in lymphocytes is also feasible. Glucosidase α gene sequencing for verifying the diagnosis is recommended. A muscle biopsy including measurements of acid α-glucosidase activity and glycogen concentration is warranted for differential diagnosis in selected cases. The confirmed diagnosis should lead to a multidisciplinary treatment approach, possibly including enzyme replacement therapy.

[Congenital and endogenous endocrine myopathy]. / Angeborene und Endogene Endokrine Myopathien.

Disorders in endocrinological pathways rarely lead to manifest acquired or endogenous myopathy so that an interdisciplinary evaluation between neurology and endocrinology is essential for these disorders. Asymptomatic or forme fruste variants may be more common and even underdiagnosed in these circumstances. Dysbalance disorders of protein synthesis, electrolytes and carbohydrates can lead to several rare forms of myopathy due to the dependence on hormonal metabolism. In general, the main neuromuscular symptom is proximal weakness, sometimes in addition to myalgia and muscle atrophy. Endocrine myopathies are usually reversible by treatment of the underlying disease. The severity of the endocrinopathy is of fundamental importance for the long-term clinical outcome.

[Neuromuscular signal transmission in adulthood. Current facets of acquired and hereditary disorders]. / Neuromuskuläre Signalübertragung im Erwachsenenalter. Aktuelle Facetten erworbener und angeborener Störungen.

The availability of early diagnosis and modern effective therapies has reduced mortality and disability linked to late-onset acquired or hereditary neuromuscular transmission disorders. Nevertheless, identification of the pathogenesis of these diseases remains a challenge. In addition to non-specific and fluctuating presenting symptoms current diagnostic work-up strategies include electrophysiology, antibody measurements and less frequently molecular genetics. For differential diagnostic purposes there is an increasing demand for improving awareness concerning late-onset congenital myasthenic syndromes (CMS) which are rare but nevertheless symptomatically treatable diseases. Especially in seronegative myasthenic syndromes, molecular genetic analyses of CMS genes should be integrated into the differential diagnostic work-up. Therefore, some facets of neuromuscular synaptogenesis in the context of seronegative acquired myasthenic syndromes and recently uncovered congenital myasthenic syndromes are reviewed.

Dyslexia and cognitive impairment in adult patients with myotonic dystrophy type 1: a clinical prospective analysis.

BACKGROUND: Cognitive impairments in patients with myotonic dystrophy type 1 (DM1) have often been described, however, there are only few studies differentiating between partial performance disorders and mental retardation in common. This study focused on the evaluation of reading performance and the frequency of dyslexia in adult DM1 patients. METHODS: We performed a prospective cohort study including genetically confirmed adult DM1 patients registered in the DM registry of Germany or the internal database of the Friedrich-Baur-Institute, Munich, Germany. For the assessment of the patients' reading and spelling performance, we used the standardized and validated test 'Salzburger Lese- und Rechtschreibtest' (SLRT II). The 'CFT-20 R Grundintelligenztest Skala 2' in revised ("R") version (CFT 20-R), determining the intelligence level, was appropriate to differentiate between dyslexia and general mental retardation. The diagnosis of dyslexia, the combined reading and spelling disorder, was based on the guidelines for diagnosis and therapy of children and adolescents with dyslexia 2015 (S3-guideline) providing (1) the criterion of the divergence from age level and (2) the criterion of IQ-divergence. RESULTS: Fifty-seven DM1 patients participated in our study. Evaluating the reading performance, 16 patients fulfilled the divergence criteria of the age level and 2 patients the IQ-divergence criteria. In total, the diagnosis of a reading disorder was given in 18 DM1 patients (31.6 %). In 11 out of these 18 patients with a reading disorder, a relevant impairment of spelling performance was observed with at least three spelling errors. As there are no normative values for adults in spelling performance, we assume a combined reading disorder and dyslexia, in those 11 DM1 patients (19.3 %). Regarding the separate analyses of the test procedures, in the SLRT II the performance was below average in 40.4 % of all patients for 'word reading' and in 61.4 % of all patients for 'pseudoword reading'. There was a significant positive correlation between the CTG expansion size and a reading disorder (p=0.027). The average IQ of 17 examined DM1 patients was in the lower normal range (86.1 ± 19.1). 54.5 % of patients with reading disorder had a normal IQ. CONCLUSION: The calculated prevalence of dyslexia in the DM1 study cohort was 19.3 % and thus considerably increased compared to the normal German population. As dyslexia is not equivalent to a general cognitive impairment, it is important not to miss dyslexic features in cognitive inconspicuous DM1 patients. Case-by-case one should consider a differential diagnostic approach, as individualized therapies can be offered to support dyslexic patients in their performance.

Side effects of anesthesia in DM2 as compared to DM1: a comparative retrospective study.

BACKGROUND AND PURPOSE: Myotonic dystrophy type 2 (DM2) is an adult-onset progressive multisystem disease. There have been no reported risks for anesthesia in DM2. METHODS: We assess the frequency, type, and severity of peri-operative complications under general and local anesthesia in genetically proven DM2. A retrospective multicenter study was conducted. RESULTS: Out of 320 DM2 patients, 134 participated by completing questionnaires (41, 88%), which were delivered by mail, and their clinical records were reviewed (class III evidence). A total of 121 patients had 340 operations in general anesthesia at an average age of 40.5 years (range 18-82); 132 (38.8%) general anesthesia were performed prior to DM2 onset, 187 (55.9%) after disease onset. A total of 212 (62.4%) of the interventions were performed without known DM2 diagnosis. In 120 (35.3%) interventions, DM2 was already diagnosed. The locations of surgery were lower abdomen (47%), peripheral extremities (46.8%), upper abdomen (3.8%), thorax (1.8%), and brain (0.6%). The overall frequency of severe complications was 0.6% (2 of 340). One incident was a post-operative development of rhabdomyolysis, hyperthermia, muscle weakness and renal failure; the others, prolonged muscular weakness and renal failure. Minor complications related to a general anesthesia were reported by 27 participants (20.2%). In 116 patients (86.6%), 342 interventions were performed in regional anesthesia. Minor complications were reported by 20.2% participants such as nausea (6.7%), muscular weakness and pain (5.9%), prolonged anesthesia (5.2%), circulatory insufficiency (2.9%), and shortness of breath (2.9%). CONCLUSION: The overall lower risk seems to be predominantly related to the minor respiratory involvement in DM2, than in myotonic dystrophy type 1 (DM1).

[Lipid storage myopathies. A clinical and pathobiochemical challenge]. / Lipidspeichermyopathien. Eine klinische und pathobiochemische Herausforderung.

Lipid storage myopathies are a clinically and genetically heterogeneous group of muscle diseases characterized by an accumulation of lipid in skeletal muscle. Currently four different groups of lipid storage myopathies are described: primary carnitine deficiency (PCD), multiple acyl-CoA dehydrogenase deficiency, primary and secondary coenzyme Q10 deficiency and neutral lipid storage diseases. It might be due to their rareness and considerable clinical variability that these disorders are frequently disregarded in neurological differential diagnosis. This article provides a synopsis of several new aspects of pathophysiology, symptoms, diagnostic tools and current therapeutic approaches of lipid storage myopathies.

Physiology, pathophysiology and diagnostic significance of autophagic changes in skeletal muscle tissue--towards the enigma of rimmed and round vacuoles.

Autophagic vacuoles are the morphological hallmark in a wide variety of human skeletal muscle disorders. The present review summarizes recent novel insights in the physiology and pathophysiology of autophagic vacuole formation in skeletal muscle. Special emphasis will be given to the relationship between vacuolar changes and lysosomal and non-lysosomal protein degradation pathways, the diagnostic significance of rimmed and round vacuoles and novel therapeutic options related to autophagic pathways.

[Metabolic myopathies - an overview]. / Metabolische Myopathien - ein Uberblick.

Metabolic disorders of energy production characterise the group of rare, mainly autosomal recessively inherited metabolic muscular diseases which are often associated with multi-systemic symptoms. In this report, an update on the clinics, pathophysiology, pathomorphology and current treatment options of metabolic myopathies will be given. Beyond classic phenotypes of these disorders, one should be aware of oligosymptomatic patients who can be easily missed. The relevant gene mutations and the pathophysiology and pathomorphology they cause are now known for almost all these metabolic diseases. Establishing the correct diagnosis has become even more important since highly specific therapy options are now available for at least some of these inherited disorders, e.g. enzyme replacement therapy in Pompe disease.

[Inflammatory myopathies]. / Inflammatorische Myopathien.

Inflammatory myopathies cover infectious, focal and immunogenic myopathies. This review focuses on the clinical features, diagnostic techniques, pathogenesis and therapy of immunogenic myopathies. Besides myositis associated with other autoimmune disorders, dermatomyositis is the most common immunogenic myopathy. The independent diagnosis of polymyositis has come under debate, since within this group of patients some are now diagnosed as having either hereditary muscular dystrophy with inflammatory signs or inclusion body myositis (IBM). Even more strikingly, patients diagnosed with sporadic IBM may now be diagnosed with either a form of hereditary IBM or with a form belonging to the group of protein aggregate myopathies or myofibrillar myopathies. This re-classification reflects the well-known and clinically evident therapeutic dilemma in many of these patients. Thus the indication for muscle biopsy or rebiopsy requires new consideration and attention.