Biallelic variants in SNUPN cause a limb girdle muscular dystrophy with myofibrillar-like features.

Alterations in RNA-splicing are a molecular hallmark of several neurological diseases, including muscular dystrophies where mutations in genes involved in RNA metabolism or characterised by alterations in RNA splicing have been described. Here, we present five patients from two unrelated families with a limb-girdle muscular dystrophy (LGMD) phenotype carrying a biallelic variant in SNUPN gene. Snurportin-1, the protein encoded by SNUPN, plays an important role in the nuclear transport of small nuclear ribonucleoproteins (snRNPs), essential components of the spliceosome. We combine deep phenotyping, including clinical features, histopathology and muscle magnetic resonance image (MRI), with functional studies in patient-derived cells and muscle biopsies to demonstrate that variants in SNUPN are the cause of a new type of LGMD according to current definition. Moreover, an in vivo model in Drosophila melanogaster further supports the relevance of Snurportin-1 in muscle. SNUPN patients show a similar phenotype characterised by proximal weakness starting in childhood, restrictive respiratory dysfunction and prominent contractures, although interindividual variability in terms of severity even in individuals from the same family was found. Muscle biopsy showed myofibrillar-like features consisting of myotilin deposits and Z-disc disorganisation. MRI showed predominant impairment of paravertebral, vasti, sartorius, gracilis, peroneal and medial gastrocnemius muscles. Conservation and structural analyses of Snurportin-1 p.Ile309Ser variant suggest an effect in nuclear-cytosol snRNP trafficking. In patient-derived fibroblasts and muscle, cytoplasmic accumulation of snRNP components is observed, while total expression of Snurportin-1 and snRNPs remains unchanged, which demonstrates a functional impact of SNUPN variant in snRNP metabolism. Furthermore, RNA-splicing analysis in patients' muscle showed widespread splicing deregulation, in particular in genes relevant for muscle development and splicing factors that participate in the early steps of spliceosome assembly. In conclusion, we report that SNUPN variants are a new cause of limb girdle muscular dystrophy with specific clinical, histopathological and imaging features, supporting SNUPN as a new gene to be included in genetic testing of myopathies. These results further support the relevance of splicing-related proteins in muscle disorders.

Health-related quality of life of adults with spinal muscular atrophy: insights from a nationwide patient registry in Germany.

PURPOSE: Spinal muscular atrophy (SMA) is a rare, autosomal-recessive disease characterized by progressive muscular atrophy and weakness resulting in substantial disability and short life expectancy. The objective of this cross-sectional study was to assess health-related quality of life (HRQoL) of adults with SMA in Germany in the era of disease-modifying therapy. METHODS: Adults with SMA were recruited via the German national TREAT-NMD SMA patient registry. HRQoL was measured using the EQ-5D-5L, the Health Utilities Index Mark III (HUI), and the Short Form (36) Health Survey (SF-36). Estimates were stratified by current best motor function of the lower limb and trunk (i.e., non-sitter, sitter, and walker) and SMA type (i.e., type I, II, and III). RESULTS: A total of 82 adults with SMA (mean age: 42 years, 51% female) self-completed the study questionnaire. The mean EQ-5D-5L utility was estimated at 0.5135 (range across subgroups: 0.31-0.99), mean EQ-VAS at 69.71 (64.67-90.00), mean HUI-derived utility at 0.3171 ( - 0.02-0.96), mean SF-6D utility at 0.6308 (0.58-0.65), and mean SF-36 Physical Component Summary and Mental Health Component Summary scores at 33.78 (9.92-53.10) and 53.49 (21.02-72.25), respectively. CONCLUSIONS: We show that adults with SMA experience considerable impairment across a wide range of health dimensions, including mobility, dexterity, pain, and emotional well-being. However, our results exhibit non-trivial variability across clinical subgroups and HRQoL measures. These data contribute to our understanding of the subjective impact of living with a severely debilitating neuromuscular disease, such as SMA.

Inclusion body myositis-health-related quality of life and care situation during phases of the "patience journey" in Germany: results from a qualitative study.

BACKGROUND: To understand the health-related quality of life (HRQoL) in inclusion body myositis (IBM) from a holistic perspective on the background of a complex care situation. The focus was on how the patient journey may be structured over the course of this rare disease. METHODS: An exploratory qualitative study was performed via in-depth semi-structured interviews. Seven patients (males n = 5) with 2011 European Neuromuscular Centre (ENMC) IBM criteria from the German IBM patient registry were interviewed for this study. The dynamic network approach of resilience and the throughput-model of health services research were used to structure the qualitative analysis. RESULTS: Our results suggest that IBM patients experience the holistic HRQoL and care situation typically in four phases: (1) uncertainty about physical vulnerability until diagnosis, (2) promising treatment approaches, (3) self-management and dyadic coping, (4) weak body, busy mind and caregiver burden. The homophonous in-vivo code "patience journey" describes the frequently reported emotional perspective of the patient journey. Although the overarching theme of perceived social support varied throughout these phases, a reliable patient-partner-dyad may lead to improved HRQoL in the long-term. CONCLUSIONS: New hypotheses for future quantitative research were generated to better understand the IBM patients' burden in the long term. The identified relevance of social support emphasizes the patients' need to handle IBM as manageable in medical settings. During exhausting phases of IBM progression, more effective care elements for patients and their partners could disclose varying needs. Strengthening multi-professional healthcare services via individualised informational, practical, or emotional support could improve HRQoL, especially since there is no curative treatment available so far.

[Physiotherapeutic Care of Adults with Neuromuscular Diseases - an Online Survey of Physiotherapists in the City Area of Munich]. / Physiotherapeutische Versorgung von Erwachsenen mit Neuromuskulären Erkrankungen ­ Online-Befragung von Physiotherapeut*innen im Stadtgebiet München.

BACKGROUND AND AIM: Physiotherapy has a key role in the symptomatic treatment of neuromuscular disorders (NMD). In the health care of adults with NMD, there may be intransparency of physiotherapy processes due, among other factors, to disciplinary interfaces. This study describes the current state of physiotherapeutic care for adults with NMD and examines the needs of physiotherapists in improving the quality of physiotherapeutic care. METHODS: An online survey of physiotherapists in the city area of Munich was carried out using Lime Survey. The survey link was distributed in both inpatient and outpatient settings and with use of the snowball principle. The data on the closed and open questions were accordingly evaluated quantitatively descriptively and content-analytically. RESULTS: A total of 137 physiotherapists participated in the online survey, and information from 124 survey participants was included in the analyses. 62.4% (n=58) of them were involved in the treatment of adults with NMD. The most common physiotherapy prescription was "Physiotherapy for the treatment of central movement disorders" (KG-ZNS) (82.9%; n=34). Home visits and assistive devices were ranked as the most effective interventions. 69.1% (n=56) of survey participants would like more information on NMD, primarily in the form of e-learning (24.0%; n=37) and professional articles (21.4%; n=33). In addition to the identified need for information, there were requests for more in-depth interprofessional communication and increased time resources in physiotherapeutic treatment. CONCLUSION: The wide range of physiotherapeutic measures applied pursues, among other things, the goal of helping patients maintain their independence and is considered to be of great benefit in the care of adult patients with NMD. It is important to address the identified desire and need for information expressed by physiotherapists on the subject of NMD in the preferred form by means of low-threshold offers. The interprofessional communication should be intensified and time-related aspects should be considered in the issuing of prescriptions as well as with regard to a possible blank prescription option in the future, in order to achieve positive effects in the physiotherapeutic care of adult patients with NMD.

Assessing Dysferlinopathy Patients Over Three Years With a New Motor Scale.

OBJECTIVE: Dysferlinopathy is a muscular dystrophy with a highly variable clinical presentation and currently unpredictable progression. This variability and unpredictability presents difficulties for prognostication and clinical trial design. The Jain Clinical Outcomes Study of Dysferlinopathy aims to establish the validity of the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) scale and identify factors that influence the rate of disease progression using NSAD. METHODS: We collected a longitudinal series of functional assessments from 187 patients with dysferlinopathy over 3 years. Rasch analysis was used to develop the NSAD, a motor performance scale suitable for ambulant and nonambulant patients. Generalized estimating equations were used to evaluate the impact of patient factors on outcome trajectories. RESULTS: The NSAD detected significant change in clinical progression over 1 year. The steepest functional decline occurred during the first 10 years after symptom onset, with more rapid decline noted in patients who developed symptoms at a younger age (p = 0.04). The most rapidly deteriorating group over the study was patients 3 to 8 years post symptom onset at baseline. INTERPRETATION: The NSAD is the first validated limb girdle specific scale of motor performance, suitable for use in clinical practice and clinical trials. Longitudinal analysis showed it may be possible to identify patient factors associated with greater functional decline both across the disease course and in the short-term for clinical trial preparation. Through further work and validation in this cohort, we anticipate that a disease model incorporating functional performance will allow for more accurate prognosis for patients with dysferlinopathy. ANN NEUROL 2021;89:967-978.

Mutations in INPP5K, Encoding a Phosphoinositide 5-Phosphatase, Cause Congenital Muscular Dystrophy with Cataracts and Mild Cognitive Impairment.

Phosphoinositides are small phospholipids that control diverse cellular downstream signaling events. Their spatial and temporal availability is tightly regulated by a set of specific lipid kinases and phosphatases. Congenital muscular dystrophies are hereditary disorders characterized by hypotonia and weakness from birth with variable eye and central nervous system involvement. In individuals exhibiting congenital muscular dystrophy, early-onset cataracts, and mild intellectual disability but normal cranial magnetic resonance imaging, we identified bi-allelic mutations in INPP5K, encoding inositol polyphosphate-5-phosphatase K. Mutations impaired phosphatase activity toward the phosphoinositide phosphatidylinositol (4,5)-bisphosphate or altered the subcellular localization of INPP5K. Downregulation of INPP5K orthologs in zebrafish embryos disrupted muscle fiber morphology and resulted in abnormal eye development. These data link congenital muscular dystrophies to defective phosphoinositide 5-phosphatase activity that is becoming increasingly recognized for its role in mediating pivotal cellular mechanisms contributing to disease.

Long-term whole-body vibration training in two late-onset Pompe disease patients.

The treatment of late-onset Pompe disease (LOPD) relies on enzyme replacement therapy (ERT) and physiotherapy but the most appropriate exercise program is not yet established. Whole-body vibration training (WBVT) has showed promising results, improving motor performances in various populations. Our aim is to assess the effects of WBVT performed by two LOPD patients in addition to ERT and physiotherapy. A side-alternating WBVT lasting 2 years; clinical assessments included: manual muscle testing (MRC sumscore), knee extension and arm flection isometric strength (multi-muscle tester M3diagnos), timed function tests (10 m walking, standing-up from chair, ascending 4-steps), 6 min walking (6 MWT), motor disability (Walton Gardner-Medwin scale), pulmonary function. Follow-up evaluations performed for 9 years since ERT start (pre-WBVT and post-WBVT) are reported for comparison. MRC sumscore improved in both patients (Pt.1:41 â†’ 48, Pt.2:42 â†’ 47) as isometric strength of knee extension (Pt.1: + 62 %, Pt.2: + 26 %) and arm flection (Pt.1: + 88 %, Pt.2: + 66 %), 6 MWT improved in Pt.1 (+75 m). Timed function tests did not greatly change. Patients reported no significant CK elevation or WBVT-related complaints. WBVT may be safely used in LOPD and seems to moderately boost muscle strength in patients receiving ERT and physiotherapy for more than 3 years. Larger cohorts should be studied to better assess WBVT potential as adjunctive exercise tool in LOPD.

Influence of macular oedema on the measurement of macular pigment optical density.

INTRODUCTION: The purpose of this study was to determine macular pigment optical density (MPOD) in patients with macular degeneration as well as in patients with non-proliferative diabetic retinopathy. METHODS: Fifty-one phakic patients with either age-related macular degeneration (60 eyes of 30 patients; average age, 70.9 years) or non-proliferative diabetic retinopathy (42 eyes of 21 patients; average age, 61.7 years) were included in this cross-sectional study. Within the groups, patients were divided into those suffering from macular oedema and those with no oedema. An intra-subject comparison between eyes was carried out in both groups. Data were investigated on the basis of the coefficient of determination (R (2)). Macular pigment optical density was measured by fundus reflectometry using the one-wavelength reflection method (Visucam 500; Carl Zeiss Meditec AG, Jena, Germany), in conformity with the method described by Schweitzer et al. (2010). We evaluated the maximum optical density in the measurement area (max OD) and the average optical density across the reference area in the measurement area (mean OD). Specifically, the influence of macular oedema on macular pigment optical density was examined. The subsequent measurement of retinal thickness was carried out by spectral-domain optical coherence tomography (Spectralis SD-OCT, Heidelberg Engineering GmbH, Heidelberg, Germany). RESULTS: The current study included two groups. The first group consisted of patients with non-proliferative diabetic retinopathy, as follows: no macular oedema on either side (max OD: R (2) = 43.2 %, p = 0.16; mean OD: R (2) = 68.7 %, p = 0.04); one-sided macular oedema (max OD: R(2) = 16 %, p = 0.60; mean OD: R(2) = 100 %, p = 0.04); or macular oedema in both eyes (max OD: R(2) = 79.7 %, p < 0.01; mean OD: R(2) = 81.4 %, p < 0.01). The second group comprised patients with age-related macular degeneration (AMD), as follows: non-exudative changes on both sides (max OD: R(2) = 64.0 %, p = 0.20; mean OD: R (2) = 16 %, p = 0.60); one-sided exudative macular changes (max OD: R (2) = 50.6 %, p < 0.01; mean OD: R (2) = 20.8 %, p = 0.04); or exudative macular degeneration on both sides (max OD: 3 R (2) = 6.0 %, p = 0.29; mean OD: R (2)= 81.0 %, p = 0.04). The data available presented a correlation of MPOD values of both eyes of an individual within the groups investigated. In this respect, the data of the partner eyes within the group of patients with diabetic retinopathy were more highly correlated with each other than the values of both eyes of patients suffering from age-related macular degeneration. CONCLUSIONS: The present study showed that macular oedema did not seem to have an influence on a valid measurement of MPOD by one-wavelength fundus reflectometry. Thus, meaningful data could also be obtained on patients with exudative retinal changes.

Self-Reported Health-Related Quality of Life of Children with Spinal Muscular Atrophy: Preliminary Insights from a Nationwide Patient Registry in Germany.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare, severely debilitating neuromuscular disease characterized by a wide spectrum of progressive muscular atrophy and weakness. OBJECTIVES: The objective of this pilot study was to estimate self-assessed health-related quality of life (HRQoL) of children with SMA. METHODS: Children with SMA were recruited via the German national TREAT-NMD SMA patient registry and asked to self-complete the following rating-scales: KIDSCREEN-27, KINDL, the PedsQL 3.0 Neuromuscular Module (PedsQL 3.0 NMM), EQ-5D-5L, and the Health Utilities Index (HUI). Estimates were stratified by current best motor function of the lower limb and trunk (i.e., non-sitter, sitter, and walker) and SMA type (i.e., type I, II, and III). RESULTS: In total, 17 children with SMA (mean age: 9.88 years, SD: 4.33 years, range: 5-16 years; 59% female) participated in the study. Across examined strata, the mean KIDSCREEN-27 total score was estimated at between 48.24 and 83.81; the mean KINDL total score at between 60.42 and 76.73; the mean PedsQL 3.0 NMM total score at between 58.00 and 83.83; the mean EQ-5D-5L utility at between 0.31 and 0.99; and the mean HUI-derived utility at between -0.02 and 0.96. CONCLUSIONS: The results from this pilot study show that German children with SMA, despite significant physical disability, have surprisingly good HRQoL as assessed using KIDSCREEN-27. Yet, many reside in health states associated with low utility. The disease burden was generally higher among non-sitters compared with walkers, and SMA type I compared with type III, but more research is needed to further delineate this variability. Our preliminary findings contribute to the understanding of HRQoL in pediatric patients with SMA and should be helpful to inform the design of future studies of this patient population.

Smartphone-Based Assessment of Mobility and Manual Dexterity in Adult People with Spinal Muscular Atrophy.

Background: More responsive, reliable, and clinically valid endpoints of disability are essential to reduce size, duration, and burden of clinical trials in adult persons with spinal muscular atrophy (aPwSMA). Objective: The aim is to investigate the feasibility of smartphone-based assessments in aPwSMA and provide evidence on the reliability and construct validity of sensor-derived measures (SDMs) of mobility and manual dexterity collected remotely in aPwSMA. Methods: Data were collected from 59 aPwSMA (23 walkers, 20 sitters and 16 non-sitters) and 30 age-matched healthy controls (HC). SDMs were extracted from five smartphone-based tests capturing mobility and manual dexterity, which were administered in-clinic and remotely in daily life for four weeks. Reliability (Intraclass Correlation Coefficients, ICC) and construct validity (ability to discriminate between HC and aPwSMA and correlations with Revised Upper Limb Module, RULM and Hammersmith Functional Scale - Expanded HFMSE) were quantified for all SDMs. Results: The smartphone-based assessments proved feasible, with 92.1% average adherence in aPwSMA. The SDMs allowed to reliably assess both mobility and dexterity (ICC > 0.75 for 15/22 SDMs). Twenty-one out of 22 SDMs significantly discriminated between HC and aPwSMA. The highest correlations with the RULM were observed for SDMs from the manual dexterity tests in both non-sitters (Typing, ρ= 0.78) and sitters (Pinching, ρ= 0.75). In walkers, the highest correlation was between mobility tests and HFMSE (5 U-Turns, ρ= 0.79). Conclusions: This exploratory study provides preliminary evidence for the usability of smartphone-based assessments of mobility and manual dexterity in aPwSMA when deployed remotely in participants' daily life. Reliability and construct validity of SDMs remotely collected in real-life was demonstrated, which is a pre-requisite for their use in longitudinal trials. Additionally, three novel smartphone-based performance outcome assessments were successfully established for aPwSMA. Upon further validation of responsiveness to interventions, this technology holds potential to increase the efficiency of clinical trials in aPwSMA.

Long-term efficacy and safety of nusinersen in adults with 5q spinal muscular atrophy: a prospective European multinational observational study.

Background: Evidence for the efficacy of nusinersen in adults with 5q-associated spinal muscular atrophy (SMA) has been demonstrated up to a period of 16 months in relatively large cohorts but whereas patients reach a plateau over time is still to be demonstrated. We investigated the efficacy and safety of nusinersen in adults with SMA over 38 months, the longest time period to date in a large cohort of patients from multiple clinical sites. Methods: Our prospective, observational study included adult patients with SMA from Germany, Switzerland, and Austria (July 2017 to May 2022). All participants had genetically-confirmed, 5q-associated SMA and were treated with nusinersen according to the label. The total Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores, and 6-min walk test (6 MWT; metres), were recorded at baseline and 14, 26, and 38 months after treatment initiation, and pre and post values were compared. Adverse events were also recorded. Findings: Overall, 389 patients were screened for eligibility and 237 were included. There were significant increases in all outcome measures compared with baseline, including mean HFMSE scores at 14 months (mean difference 1.72 [95% CI 1.19-2.25]), 26 months (1.20 [95% CI 0.48-1.91]), and 38 months (1.52 [95% CI 0.74-2.30]); mean RULM scores at 14 months (mean difference 0.75 [95% CI 0.43-1.07]), 26 months (mean difference 0.65 [95% CI 0.27-1.03]), and 38 months (mean difference 0.72 [95% CI 0.25-1.18]), and 6 MWT at 14 months (mean difference 30.86 m [95% CI 18.34-43.38]), 26 months (mean difference 29.26 m [95% CI 14.87-43.65]), and 38 months (mean difference 32.20 m [95% CI 10.32-54.09]). No new safety signals were identified. Interpretation: Our prospective, observational, long-term (38 months) data provides further real-world evidence for the continuous efficacy and safety of nusinersen in a large proportion of adult patients with SMA. Funding: Financial support for the registry from Biogen, Novartis and Roche.

Time to diagnosis of Duchenne muscular dystrophy in Austria and Germany.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder manifesting in early childhood with progressive muscular weakness and atrophy, and resulting in early loss of ambulation. The collection and evaluation of epidemiological data for this disease is crucial for an early diagnosis and disease management. In Germany, data are collected via the TREAT-NMD DMD patient registry ( www.dmd-register.de ). In contrast, data collection in Austria has not yet been performed systematically. For collecting data from Austrian DMD patients, an online survey of the patient's caregivers was conducted. Data of 57 patients were collected entailing initial symptoms, diagnosis and therapeutic measures. Comparable data has been collected for Germany via the TREAT-NMD DMD patient registry. 57 DMD patients aged 4-34 years completed the Austrian survey. On average, first symptoms of the disease appeared at the age of 3.1 years. As the most frequent first symptom, 46% of the patients described problems in climbing stairs. In 40% of the patients, DMD was diagnosed early due to an accidentally detected hyperCKemia in infancy or early childhood. Corticosteroids represented the main therapeutic option in our cohort. At the time of the survey, only 52% of the patients were treated with corticosteroids. Patients from Germany reported that first symptoms appeared at the age of 3.06 years. Diagnosis was established by genetic testing or muscle biopsy. 47% of the patients were treated with corticosteroids. Time between first symptoms and diagnosis was 7 months in Austria, and 4.7 months in Germany, respectively. Compared to earlier international studies, the Austrian data show encouraging results regarding earlier start of corticosteroid therapy in a larger percentage of patients. Austrian and German data show a trend towards an earlier diagnosis of DMD, while the age at symptom onset was similar to previous studies. The collection and evaluation of epidemiological data of DMD patients is important and will hopefully contribute to accelerate DMD diagnosis and treatment access for the patients.

Patient-Reported Health-Related Quality of Life, Anxiety and Depression in Patients with Inclusion Body Myositis: A Register-Based Cross-Sectional Study in Germany.

Inclusion body myositis (IBM) is a rare neuromuscular disease and the most prevalent idiopathic inflammatory myopathy (IIM) in patients aged older than 50 years. A systematic review has shown that no clear-cut conclusions can be drawn about the health-related quality of life (HRQoL) and mental health in IBM. We aimed to assess the HRQoL and mental health, to explore associated disease-related and socioeconomic factors as well as the utilization of psychological support in German IBM patients. This cross-sectional study included 82 patients registered in the German IBM patient registry. Patients had completed a survey battery including the EQ-5D-5L, the Individualized Neuromuscular Quality of Life (INQoL) and the Hospital Anxiety and Depression Scale German version (HADS-D). The physical HRQoL dimension was suggested to be most relevant. Most impaired life domains of HRQoL were mobility, independence, and activities. We identified significant differences in the total INQoL score for the degree of disability and care level as well as in depression for the degree of disability (p < 0.05), respectively. Most patients indicated no symptoms of anxiety (64.6%) and depression (62.2%). A more need-oriented psychological support in German IBM patients, reporting doubtful or definite anxiety or depression, could be suggested.

Cost of illness in inclusion body myositis: results from a cross-sectional study in Germany.

BACKGROUND: Inclusion body myositis (IBM) is the most frequent type of myositis in elder patients with a slow chronic progression and refractory to treatment. Previous cost of illness (COI) studies in IBM used claims data to estimate direct costs in the US. No evidence exists globally on both direct and indirect costs in IBM from a societal perspective. We conducted a survey in patients registered in the German IBM patient registry. Self-developed items were used to assess the utilized healthcare resources and estimate the cost. The German Self-Administered Comorbidity Questionnaire (SCQ-D), the sIBM Physical Functioning Assessment (sIFA) and patient-reported measures for satisfaction and improvements in healthcare were applied for an explorative analysis. RESULTS: In total, 82 patients completed the survey. We estimated the mean total annual per capita COI of US$102,682 (95% CI US$82,763-US$123,090) in 2021. 92.7% of the total COI were direct costs. Medical costs were similar to nonmedical costs, with substantial costs for pharmacotherapy and informal care. Depending on the prevalence estimate, the total national COI per year were US$42.7 million-US$213.7 million. Significant differences in total COI were identified for the degree of disability, marital and employment status (p < 0.05). CONCLUSIONS: We identified remarkable and heterogenous cost in IBM. As informal care costs represented the most relevant cost driver, caregiver burden is a major factor in the patient journey. For the first time, comprehensive economic potentials were identified as a basis to improve the actual care situations and prioritizing future activities for research, pharmaceutical and digital product development as well as health politics.

Areas of improvement in the medical care of SMA: evidence from a nationwide patient registry in Germany.

BACKGROUND: Management and treatment of spinal muscular atrophy (SMA) has changed in recent years due to the introduction of novel transformative and potentially curative therapies resulting in the emergence of new disease phenotypes. Yet, little is known about the uptake and impact of these therapies in real-world clinical practice. The objective of this study was to describe current motor function, need of assistive devices, and therapeutic and supportive interventions provided by the healthcare system, as well as the socioeconomic situation of children and adults with different SMA phenotypes in Germany. We conducted a cross-sectional, observational study of German patients with genetically confirmed SMA identified and recruited via a nationwide SMA patient registry ( www.sma-register.de ) within the TREAT-NMD network. Study data was recorded directly from patient-caregiver pairs through a study questionnaire administered online via a dedicated study website. RESULTS: The final study cohort consisted of 107 patients with SMA. Of these, 24 were children and 83 adults. In total, about 78% of all participants were taking medication for SMA (predominantly nusinersen and risdiplam). All children with SMA1 were able to sit and 27% of children with SMA2 were able to stand or walk. Impaired upper limb function, scoliosis and bulbar dysfunction were observed more frequently in patients with reduced lower limb performance. Physiotherapy, occupational therapy, and speech therapy, as well as the use of cough assists were less common than indicated by care guidelines. Family planning and educational and employment status appear to be related to motor skill impairment. CONCLUSIONS: We show that the natural history of disease has changed in Germany following improvements in SMA care and the introduction of novel therapies. Yet, a non-trivial proportion of patients remain untreated. We also identified considerable limitations in rehabilitation and respiratory care, as well as low labour-market participation among adults with SMA, calling for action to improve the current situation.

The health-related quality of life, mental health and mental illnesses of patients with inclusion body myositis (IBM): results of a mixed methods systematic review.

BACKGROUND: Inclusion body myositis (IBM) is a rare neuromuscular disease (NMD) and effective therapies are not available. Thus, it is relevant to determine the health-related quality of life (HRQoL) in IBM patients including aspects of mental health and illnesses. OBJECTIVES: To identify and summarize the assessment of HRQoL, mental health and illnesses in IBM, the major factors that determine and influence them as well as the respective influence of IBM in general and compared to other NMD as a systematic review. METHODS: We performed a mixed methods systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search was conducted within the databases PubMed, PsycINFO, LIVIVO and the Cochrane Database. Data were narratively summarized and categorized in the physical, psychological and social HRQoL dimensions. RESULTS: The systematic screening totalled 896 articles. Six studies were finally identified, comprising of 586 IBM patients. The applied patient reported outcome measures (PROMs) varied. Quantitatively, the main physical impairments (e.g. weakness, functioning, role perception) were assessed using the general population or other NMD as comparators. Results on social and psychological HRQoL were frequently inconsistent. Qualitatively, psychological and social limitations accompanied IBM related physical deteriorations. CONCLUSIONS: A research gap exists regarding rigour determinants of HRQoL and mental illness in IBM. In-depth qualitative studies could help to prepare the ground for the assessment of long-term HRQoL data combined with appropriately focussed psychological PROMs advancing the understanding of the HRQoL in IBM throughout the course of the disease from a patient perspective.

Health-related Quality of Life and Satisfaction with German Health Care Services in Patients with Charcot-Marie-Tooth Neuropathy.

BackgroundCharcot-Marie-Tooth (CMT) neuropathies entail a large group of diseases with different gene mutation patterns, which produce heterogeneous phenotypes. Although health-related quality of life (HRQOL) is significantly impaired, a comprehensive assessment of HRQOL in CMT patients in Germany considering phenotypical heterogeneity represented a research gap.ObjectiveThe aim was to assess HRQOL and the satisfaction with health care in CMT patients in Germany.MethodsCMT patients > 15 years with a genetically confirmed CMT subtype were recruited through a national CMT patient registry. HRQOL was assessed using the EQ-5D-5L questionnaire. Furthermore, subjective impairments in daily or work activities and satisfaction with health care were assessed using 4-point scales.ResultsHRQOL in CMT patients (n = 385) was impaired compared to the German population. Most patients reported problems in the dimension mobility (89.6%), pain/discomfort (89.4%) and usual activities (81.0%). Except for patients with hereditary neuropathy with liability to pressure palsy (HNPP), we found no differences in HRQOL between the CMT subtypes. 72.0%of CMT patients were satisfied with available health care services. However, patients reported to expect more CMT-specific knowledge and support as well as easier prescription and cost coverage procedures from health professionals and insurances.ConclusionsThe patient-reported outcomes in the assessed CMT cohort elucidate the need for more specific health care services that also address the heterogeneous phenotypes. Although the assessment has been limited to the German health services setting, insights may be applicable to CMT-specific care in other national settings.

Assessing the Relationship of Patient Reported Outcome Measures With Functional Status in Dysferlinopathy: A Rasch Analysis Approach.

Dysferlinopathy is a muscular dystrophy with a highly variable functional disease progression in which the relationship of function to some patient reported outcome measures (PROMs) has not been previously reported. This analysis aims to identify the suitability of PROMs and their association with motor performance.Two-hundred and four patients with dysferlinopathy were identified in the Jain Foundation's Clinical Outcome Study in Dysferlinopathy from 14 sites in 8 countries. All patients completed the following PROMs: Individualized Neuromuscular Quality of Life Questionnaire (INQoL), International Physical Activity Questionnaire (IPAQ), and activity limitations for patients with upper and/or lower limb impairments (ACTIVLIMs). In addition, nonambulant patients completed the Egen Klassifikation Scale (EK). Assessments were conducted annually at baseline, years 1, 2, 3, and 4. Data were also collected on the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) and Performance of Upper Limb (PUL) at these time points from year 2. Data were analyzed using descriptive statistics and Rasch analysis was conducted on ACTIVLIM, EK, INQoL. For associations, graphs (NSAD with ACTIVLIM, IPAQ and INQoL and EK with PUL) were generated from generalized estimating equations (GEE). The ACTIVLIM appeared robust psychometrically and was strongly associated with the NSAD total score (Pseudo R 2 0.68). The INQoL performed less well and was poorly associated with the NSAD total score (Pseudo R 2 0.18). EK scores were strongly associated with PUL (Pseudo R 2 0.69). IPAQ was poorly associated with NSAD scores (Pseudo R 2 0.09). This study showed that several of the chosen PROMs demonstrated change over time and a good association with functional outcomes. An alternative quality of life measure and method of collecting data on physical activity may need to be selected for assessing dysferlinopathy.

Utility of maximum inspiratory and expiratory pressures as a screening method for respiratory insufficiency in slowly progressive neuromuscular disorders.

The aim of this study was to assess whether different cut-offs of maximum inspiratory and/or expiratory pressure (MIP/MEP) are valuable screening parameters to detect restrictive respiratory insufficiency. Spirometry, MIP, MEP and capillary blood gas analysis were obtained from patients with confirmed neuromuscular disorders. We calculated regression analysis, sensitivity, specificity and predictive values. We enrolled 29 patients with myotonic dystrophy type 1 (DM1), 19 with late-onset Pompe disease (LOPD), and 24 with spinal muscular atrophy type 3. Moderate to high reduction in manometry was exclusively found in LOPD and DM1 patients. Significant associations were found between manometry and spirometry. Highest adjusted r2 was found for MIP % predicted and forced vital capacity (FVC) % predicted. Manometry predicted abnormal FVC and forced expiratory volume 1 s (FEV1). MEP > 80 cmH2O predicted normal FVC and FEV1, regardless of cut-off values. MIP and MEP did not positively predict alterations in capillary blood gas analysis. Disease-specific cut-offs of manometry did not increase the prediction rate of patients with abnormal FVC and FEV1. Predicted values should be calculated for a more comprehensive interpretation of manometry results. MIP and MEP can serve as a screening parameter for patients with neuromuscular disorders, but parallel testing of both MIP and MEP needs to be performed to increase the positive prediction probability across disease groups.

Coagulation disorders in Duchenne muscular dystrophy? Results of a registry-based online survey.

Different complications of hemostasis have been reported in patients with Duchenne Muscular Dystrophy (DMD). These comprise an increased rate of bleeding-symptoms during scoliosis surgery but also thromboembolic complications such as pulmonary embolism, cerebral infarction, deep vein thrombosis or cardiac thrombus. For this cross-sectional study, personalized online survey-links were forwarded to 682 registered patients with a genetically confirmed diagnosis of DMD via the German-Austrian DMD patient registry (www.dmd-register.de). The questionnaire enquired data regarding the degree of mobility, disposition to hematoma, epistaxis and gum bleeding, occurrence of peri- and postsurgical hemorrhage, stroke, deep vein thrombosis, and cardiac thromboembolism. Further data on regular medication and age were recorded. Three-hundred-fifty-one DMD-patients completed the questionnaire (response rate of 51.5%). Of those, 164 (46.7%) were ambulatory and 187 (53.3%) were non-ambulatory. Age distribution was homogeneous. Two participants had a history of thromboembolic events (0.6%). Correlations analysis revealed no coherence with the degree of mobility, age or regular medication. A bleeding tendency was reported by 76 participants (21.7%). No significant correlations with age or degree of mobility were found. We found no association with underlying genetic variants. Results of this patient registry-based survey do not indicate a distinct DMD-specific risk for thromboembolic events that exceeds the risk by typical comorbidities of chronic immobility and cardiac insufficiency in advanced stages of the disease. The results of this survey suggest a mild bleeding tendency in this DMD cohort, whereas a selection bias cannot be excluded.