Search

The coronavirus disease 2019 (COVID-19) pandemic has heavily impacted medical care of patients with Parkinson's disease (PwP).ObjectiveTo assess the longitudinal impact of the COVID-19 pandemic on PwP and their relatives in Germany.MethodsTwo online, nationwide, cross-sectional surveys were conducted from December 2020 to March 2021 and from July to September 2021.ResultsA total of 342 PwP and 113 relatives participated. Despite partial resumption of social and group activities, healthcare was continuously disrupted during times of loosened restrictions. Respondents’ willingness to use telehealth infrastructure increased, yet the availability remained low. PwP reported worsened symptoms and further deterioration during the pandemic, resulting in an increase in new symptoms and relatives’ burden. We identified patients at particular risk: young patients and those with long disease duration.ConclusionsThe COVID-19 pandemic persistently disrupts the care and quality of life of PwP. Although willingness to use telemedicine services has increased, its availability needs to be improved.

The objective was to assess the performance of serum neurofilament light chain (sNfL) in amyotrophic lateral sclerosis (ALS) in a wide range of disease courses, in terms of progression, duration and tracheostomy invasive ventilation (TIV).A prospective cross-sectional study at 12 ALS centers in Germany was performed. sNfL concentrations were age adjusted using sNfL Z scores expressing the number of standard deviations from the mean of a control reference database and correlated to ALS duration and ALS progression rate (ALS-PR), defined by the decline of the ALS Functional Rating Scale.In the total ALS cohort (n = 1378) the sNfL Z score was elevated (3.04; 2.46-3.43; 99.88th percentile). There was a strong correlation of sNfL Z score with ALS-PR (p < 0.001). In patients with long (5-10 years, n = 167) or very long ALS duration (>10 years, n = 94) the sNfL Z score was significantly lower compared to the typical ALS duration of

GFPT1-related congenital myasthenic syndrome (CMS) is characterized by progressive limb girdle weakness, and less prominent involvement of facial, bulbar, or respiratory muscles. While tubular aggregates in muscle biopsy are considered highly indicative in GFPT1-associated CMS, excessive glycogen storage has not been described. Here, we report on three affected siblings with limb-girdle myasthenia due to biallelic pathogenic variants in GFPT1: the previously reported missense variant c.41G > A (p.Arg14Gln) and the novel truncating variant c.1265_1268del (p.Phe422TrpfsTer26). Patients showed progressive proximal atrophic muscular weakness with respiratory involvement, and a lethal disease course in adulthood. In the diagnostic workup at that time, muscle biopsy suggested a glycogen storage disease. Initially, Pompe disease was suspected. However, enzymatic activity of acid alpha-glucosidase was normal, and gene panel analysis including 38 genes associated with limb-girdle weakness (GAA included) remained unevocative. Hence, a non-specified glycogen storage myopathy was diagnosed. A decade later, the diagnosis of GFPT1-related CMS was established by genome sequencing. Myopathological reexamination showed pronounced glycogen accumulations, that were exclusively found in denervated muscle fibers. Only single fibers showed very small tubular aggregates, identified in evaluation of serial sections. This family demonstrates how diagnostic pitfalls can be addressed by an integrative approach including broad genetic analysis and re-evaluation of clinical as well as myopathological findings.

ZUSAMMENFASSUNGDie 5q-assoziierte spinale Muskelatrophie (SMA) ist eine autosomal-rezessiv vererbte Erkrankung, die durch biallelische Defekte im SMN1-Gen (survival of motor neuron 1) auf Chromosom 5q verursacht wird. Der Gendefekt bewirkt einen fortschreitenden Untergang motorischer Vorderhornzellen im Rückenmark, was zu progredienten atrophen Paresen führt. Manifestationsalter und Schweregrad können sehr unterschiedlich sein. Die Anzahl der SMN2-Genkopien ist der entscheidende Modifier, es werden jedoch auch andere Faktoren vermutet. Anhand zweier Brüder mit 5q-assoziierter SMA soll gezeigt werden, dass trotz gleicher SMN2-Genkopienzahl erhebliche Unterschiede im Manifestationsalter und klinischen Phänotyp vorliegen können. Dies hat Implikationen für die genetische Beratung von gesunden Geschwistern von SMA-Patienten, da es zeigt, dass auch ältere Geschwister von Betroffenen ein Erkrankungsrisiko haben. Eine genetische Testung von Geschwistern kann nicht nur die Frage der Anlageträgerschaft beantworten, sondern hat auch einen prädiktiven Charakter. Dies ist aufgrund der seit einigen Jahren verfügbaren Therapieoptionen der SMA, deren Wirksamkeit bei frühem Therapiebeginn besonders hoch ist, von besonderer Bedeutung.

Adult polyglucosan body disease (APBD) is a rare but probably underdiagnosed autosomal recessive neurodegenerative disorder due to pathogenic variants in GBE1. The phenotype is characterized by neurogenic bladder dysfunction, spastic paraplegia, and axonal neuropathy. Additionally, cognitive symptoms and dementia have been reported in APBD but have not been studied systematically. Using exome sequencing, we identified two previously unreported bi-allelic missense GBE1 variants in a patient with severe memory impairment along with the typical non-cognitive symptoms. We were able to confirm a reduction of GBE1 activity in blood lymphocytes. To characterize the neuropsychological profile of patients suffering from APBD, we conducted a systematic review of cognitive impairment in this rare disease. Analysis of 24 cases and case series (in total 58 patients) showed that executive deficits and memory impairment are the most common cognitive symptoms in APBD.

Therapy of motoneuron diseases entered a new phase with the use of intrathecal antisense oligonucleotide therapies treating patients with specific gene mutations predominantly in the context of familial amyotrophic lateral sclerosis. With the majority of cases being sporadic, we conducted a cohort study to describe the mutational landscape of sporadic amyotrophic lateral sclerosis. We analysed genetic variants in amyotrophic lateral sclerosis-associated genes to assess and potentially increase the number of patients eligible for gene-specific therapies. We screened 2340 sporadic amyotrophic lateral sclerosis patients from the German Network for motor neuron diseases for variants in 36 amyotrophic lateral sclerosis-associated genes using targeted next-generation sequencing and for the C9orf72 hexanucleotide repeat expansion. The genetic analysis could be completed on 2267 patients. Clinical data included age at onset, disease progression rate and survival. In this study, we found 79 likely pathogenic Class 4 variants and 10 pathogenic Class 5 variants (without the C9orf72 hexanucleotide repeat expansion) according to the American College of Medical Genetics and Genomics guidelines, of which 31 variants are novel. Thus, including C9orf72 hexanucleotide repeat expansion, Class 4, and Class 5 variants, 296 patients, corresponding to ∼13% of our cohort, could be genetically resolved. We detected 437 variants of unknown significance of which 103 are novel. Corroborating the theory of oligogenic causation in amyotrophic lateral sclerosis, we found a co-occurrence of pathogenic variants in 10 patients (0.4%) with 7 being C9orf72 hexanucleotide repeat expansion carriers. In a gene-wise survival analysis, we found a higher hazard ratio of 1.47 (95% confidence interval 1.02–2.1) for death from any cause for patients with the C9orf72 hexanucleotide repeat expansion and a lower hazard ratio of 0.33 (95% confidence interval 0.12–0.9) for patients with pathogenic SOD1 variants than for patients without a causal gene mutation. In summary, the high yield of 296 patients (∼13%) harbouring a pathogenic variant and oncoming gene-specific therapies for SOD1/FUS/C9orf72, which would apply to 227 patients (∼10%) in this cohort, corroborates that genetic testing should be made available to all sporadic amyotrophic lateral sclerosis patients after respective counselling.

TDP-43 is the primary or secondary pathological hallmark of neurodegenerative diseases, such as amyotrophic lateral sclerosis, half of frontotemporal dementia cases, and limbic age-related TDP-43 encephalopathy, which clinically resembles Alzheimer’s dementia. In such diseases, a biomarker that can detect TDP-43 proteinopathy in life would help to stratify patients according to their definite diagnosis of pathology, rather than in clinical subgroups of uncertain pathology. For therapies developed to target pathological proteins that cause the disease a biomarker to detect and track the underlying pathology would greatly enhance such undertakings. This article reviews the latest developments and outlooks of deriving TDP-43-specific biomarkers from the pathophysiological processes involved in the development of TDP-43 proteinopathy and studies using biosamples from clinical entities associated with TDP-43 pathology to investigate biomarker candidates.

Background Genetic variants are considered to have a crucial impact on the occurrence of ischemic stroke. In clinical routine, the diagnostic value of next-generation sequencing (NGS) in the medical clarification of acute juvenile stroke has not been investigated so far. Material and methods We analyzed an exome-based gene panel of 349 genes in 172 clinically well-characterized patients with magnetic resonance imaging (MRI)-proven, juvenile (age ≤ 55 years), ischemic stroke admitted to a single comprehensive stroke center. Results Monogenetic diseases causing ischemic stroke were observed in five patients (2.9%): In three patients with lacunar stroke (1.7%), we identified pathogenic variants in NOTCH3 causing cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Hence, CADASIL was identified at a frequency of 12.5% in the lacunar stroke subgroup. Further, in two male patients (1.2%) suffering from lacunar and cardioembolic stroke, pathogenic variants in GLA causing Fabry’s disease were present. Additionally, genetic variants in monogenetic diseases lacking impact on stroke occurrence, variants of unclear significance (VUS) in monogenetic diseases, and (cardiovascular-) risk genes in ischemic stroke were observed in a total of 15 patients (15.7%). Conclusion Genetic screening for Fabry’s disease in cardioembolic and lacunar stroke as well as CADASIL in lacunar stroke might be beneficial in routine medical work-up of acute juvenile ischemic stroke.

This article presents the case of a 74-year-old female patient who first developed a progressive disease with sensory neuropathy, cerebellar ataxia and bilateral vestibulopathy at the age of 60 years. The family history was unremarkable. Magnetic resonance imaging (MRI) showed atrophy of the cerebellum predominantly in the vermis and atrophy of the spinal cord. The patient was given the syndromic diagnosis of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). In 2019 the underlying genetic cause of CANVAS was discovered to be an intronic repeat expansion in the RFC1 gene with autosomal recessive inheritance. The patient exhibited the full clinical picture of CANVAS and was tested positive for this repeat expansion on both alleles. The CANVAS is a relatively frequent cause of late-onset hereditary ataxia (estimated prevalence 5‑13/100,000). In contrast to the present patient, the full clinical picture is not always present. Therefore, testing for the RFC1 gene expansion is recommended in the work-up of patients with otherwise unexplained late-onset sporadic ataxia. As intronic repeat expansions cannot be identified by next generation sequencing methods, specific testing is necessary.

Background Variants in genes of the nucleotide excision repair (NER) pathway have been associated with heterogeneous clinical presentations ranging from xeroderma pigmentosum to Cockayne syndrome and trichothiodystrophy. NER deficiencies manifest with photosensitivity and skin cancer, but also developmental delay and early‐onset neurological degeneration. Adult‐onset neurological features have been reported in only a few xeroderma pigmentosum cases, all showing at least mild skin manifestations. Objective The aim of this multicenter study was to investigate the frequency and clinical features of patients with biallelic variants in NER genes who are predominantly presenting with neurological signs. Methods In‐house exome and genome datasets of 14,303 patients, including 3543 neurological cases, were screened for deleterious variants in NER‐related genes. Clinical workup included in‐depth neurological and dermatological assessments. Results We identified 13 patients with variants in ERCC4 (n = 8), ERCC2 (n = 4), or XPA (n = 1), mostly proven biallelic, including five different recurrent and six novel variants. All individuals had adult‐onset progressive neurological deterioration with ataxia, dementia, and frequently chorea, neuropathy, and spasticity. Brain magnetic resonance imaging showed profound global brain atrophy in all patients. Dermatological examination did not show any skin cancer or pronounced ultraviolet damage. Conclusions We introduce NERDND as adult‐onset neurodegeneration (ND) within the spectrum of autosomal recessive NER disorders (NERD). Our study demonstrates that NERDND is probably an underdiagnosed cause of neurodegeneration in adulthood and should be considered in patients with overlapping cognitive and movement abnormalities. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: COQ4 codes for a mitochondrial protein required for coenzyme Q₁₀ (CoQ₁₀) biosynthesis. Autosomal recessive COQ4-associated CoQ₁₀ deficiency leads to an early-onset mitochondrial multi-organ disorder. Methods: In-house exome and genome datasets (n = 14,303) were screened for patients with bi-allelic variants in COQ4. Work-up included clinical characterization and functional studies in patient-derived cell lines. Results: Six different COQ4 variants, three of them novel, were identified in six adult patients from four different families. Three patients had a phenotype of hereditary spastic paraparesis, two sisters showed a predominant cerebellar ataxia, and one patient had mild signs of both. Studies in patient-derived fibroblast lines revealed significantly reduced amounts of COQ4 protein, decreased CoQ₁₀ concentrations, and elevated levels of the metabolic intermediate 6-demethoxyubiquinone. Conclusion: We report bi-allelic variants in COQ4 causing an adult-onset ataxia-spasticity spectrum phenotype and a disease course much milder than previously reported. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients’ informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers’ burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients’ CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients’ functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King’s Stages for ALS. The caregivers’ burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers’ burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients’ functional status (rp = −0.555, p < 0.001, n = 242). It was influenced by the CGs’ own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], p < 0.001), patients’ wheelchair dependency (+9.30, 95% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs’ depression (rp = 0.627, p < 0.001, n = 234), anxiety (rp = 0.550, p < 0.001, n = 234), and poorer physical condition (rp = −0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients’ impairment in daily routine (rs = −0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs’ lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs’ work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required., publishedVersion

Background and Objectives Our objective was to improve rare variant interpretation using statistical measures as well as publicly accessible annotation of expression levels and tissue specificity of different splice isoforms. We describe rare VPS16 variants observed in patients with dystonia and patients without dystonia, elaborate on our interpretation of VPS16 variants affecting different transcripts, and provide detailed clinical description of the movement disorder caused by VPS16 variants. Methods In-house exome and genome data sets (n = 11,539) were screened for rare heterozygous missense and putative loss-of-function (pLoF) variants in VPS16. Using pext (proportion expressed across transcripts) values from the Genome Aggregation Database (gnomAD), we differentiated variants affecting weakly and highly expressed exons/transcripts and applied statistical measures to systematically identify disease-associated genetic variation among patients with dystonia (n = 280). Results Six different heterozygous pLoFs in VPS16 transcripts were identified in 13 individuals. Three of these pLoFs occurred in 9 individuals with different phenotypes, and 3 pLoFs were identified in 4 unrelated individuals with early-onset dystonia. Although pLoFs were enriched in the dystonia cohort (n = 280; p = 2.04 × 10−4; 4/280 cases vs 9/11,259 controls; Fisher exact test), it was not exome-wide significant. According to the pext values in gnomAD, all 3 pLoFs observed in the patients with dystonia were located in the highly expressed canonical transcript ENST00000380445.3, whereas 2 of 3 pLoFs detected in 8 individuals without dystonia were located in the first exon of the noncanonical transcript ENST00000380443.3 that is weakly expressed across all tissues. Taking these biological implications into account, pLoFs involving the canonical transcript were exome-wide significantly enriched in patients with dystonia (p = 1.67 × 10−6; 4/280 cases vs 1/11,259 controls; Fisher exact test). All VPS16 patients showed mild progressive dystonia with writer's cramp as the presenting symptom between age 7 and 34 years (mean 20 years) that often progressed to generalized dystonia and was even accompanied by hyperkinetic movements and myoclonus in 1 patient. Discussion Our data provide strong evidence for VPS16 pLoFs to be implicated in dystonia and knowledge on exon resolution expression levels as well as statistical measures proved to be useful for variant interpretation.

Improving quality of life (QoL) is central to amyotrophic lateral sclerosis (ALS) treatment. This Germany-wide, multicenter cross-sectional study analyses the impact of different symptom-specific treatments and ALS variants on QoL. Health-related QoL (HRQoL) in 325 ALS patients was assessed using the Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 (ALSAQ-5) and EuroQol Five Dimension Five Level Scale (EQ-5D-5L), together with disease severity (captured by the revised ALS Functional Rating Scale (ALSFRS-R)) and the current care and therapies used by our cohort. At inclusion, the mean ALSAQ-5 total score was 56.93 (max. 100, best = 0) with a better QoL associated with a less severe disease status (β = −1.96 per increase of one point in the ALSFRS-R score, p < 0.001). “Limb-onset” ALS (lALS) was associated with a better QoL than “bulbar-onset” ALS (bALS) (mean ALSAQ-5 total score 55.46 versus 60.99, p = 0.040). Moreover, with the ALSFRS-R as a covariate, using a mobility aid (β = −7.60, p = 0.001), being tracheostomized (β = −14.80, p = 0.004) and using non-invasive ventilation (β = −5.71, p = 0.030) were associated with an improved QoL, compared to those at the same disease stage who did not use these aids. In contrast, antidepressant intake (β = 5.95, p = 0.007), and increasing age (β = 0.18, p = 0.023) were predictors of worse QoL. Our results showed that the ALSAQ-5 was better-suited for ALS patients than the EQ-5D-5L. Further, the early and symptom-specific clinical management and supply of assistive devices can significantly improve the individual HRQoL of ALS patients. Appropriate QoL questionnaires are needed to monitor the impact of treatment to provide the best possible and individualized care., publishedVersion

Background: Nusinersen was the first approved disease-modifying therapy for all 5q-spinal muscular atrophy (SMA) patients regardless of age or disease severity. Its efficacy in adults has recently been demonstrated in a large cohort by motor outcome measures, which were only partially suitable to detect changes in very mildly or severely affected patients. Patient-reported outcome measures (PROs) have been suggested as a valuable addition. Here, we aimed to assess treatment satisfaction and investigate whether it may be a useful PRO to monitor SMA patients. Methods: We enrolled 91 mainly adult 5q-SMA patients treated with nusinersen in a national, multicenter, cross-sectional observational study. 21 patients underwent longitudinal follow up. Patients’ satisfaction with treatment in four dimensions (global, effectiveness, convenience, side effects) was assessed by the Treatment Satisfaction Questionnaire for Medication German version 1.4 (TSQM-1.4©) and related to clinical parameters, motor scores, and treatment duration. Results: More than 90% of SMA patients were consistently satisfied over a median treatment duration of 10 months. Highest mean scores were observed in the dimensions ‘side effects,’ ‘global satisfaction,’ and ‘effectiveness’ (93.5 ± 14.8 versus 73.1 ± 21.0 and 64.8 ± 20.6, respectively). Patients’ satisfaction with the convenience of treatment was considerably lower (43.6 ± 20.2). Interestingly, satisfaction with the effectiveness was higher in ambulatory (p = 0.014) compared with non-ambulatory patients and directly correlated to motor outcome measures. Five non-ambulatory patients withdrew from therapy. All of them presented with a deterioration of motor outcome measures and reported dissatisfaction with treatment effectiveness and convenience. Conclusion: Most patients were satisfied with nusinersen treatment effectiveness. Less severely affected patients indicated higher satisfaction. The TSQM-1.4© helped to identify therapy non-responders, who mainly addressed dissatisfaction with effectiveness and convenience. We suggest introducing the TSQM-1.4© as an additional PRO in SMA into clinical practice., publishedVersion

This article presents the case of a 74-year-old female patient who first developed a progressive disease with sensory neuropathy, cerebellar ataxia and bilateral vestibulopathy at the age of 60 years. The family history was unremarkable. Magnetic resonance imaging (MRI) showed atrophy of the cerebellum predominantly in the vermis and atrophy of the spinal cord. The patient was given the syndromic diagnosis of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). In 2019 the underlying genetic cause of CANVAS was discovered to be an intronic repeat expansion in the RFC1 gene with autosomal recessive inheritance. The patient exhibited the full clinical picture of CANVAS and was tested positive for this repeat expansion on both alleles. The CANVAS is a relatively frequent cause of late-onset hereditary ataxia (estimated prevalence 5‑13/100,000). In contrast to the present patient, the full clinical picture is not always present. Therefore, testing for the RFC1 gene expansion is recommended in the work-up of patients with otherwise unexplained late-onset sporadic ataxia. As intronic repeat expansions cannot be identified by next generation sequencing methods, specific testing is necessary.

International audience; We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.

Progressive external ophthalmoplegia is typically associated with single or multiple mtDNA deletions but occasionally mtDNA single nucleotide variants within mitochondrial transfer RNAs (mt-tRNAs) are identified. We report a 34-year-old female sporadic patient with progressive external ophthalmoplegia accompanied by exercise intolerance but neither fixed weakness nor multisystemic involvement. Histopathologically, abundant COX-deficient fibres were present in muscle with immunofluorescence analysis confirming the loss of mitochondrial complex I and IV proteins. Molecular genetic analysis identified a rare heteroplasmic m.15990C>T mt-tRNAPro variant reported previously in a single patient with childhood-onset myopathy. The variant in our patient was restricted to muscle. Single muscle fibre analysis identified higher heteroplasmy load in COX-deficient fibres than COX-normal fibres, confirming segregation of high heteroplasmic load with a biochemical defect. Our case highlights the phenotypic variability typically observed with pathogenic mt-tRNA mutations, whilst the identification of a second case with the m.15990C>T mutation not only confirms pathogenicity but shows that de novo mt-tRNA point mutations can arise in multiple, unrelated patients.

Intrathecal administration of nusinersen in adult spinal muscular atrophy (SMA) patients with scoliosis and spondylodesis requires image guidance, which is preferably achieved with multi-detector computed tomography (MDCT). As long-term treatment is necessary and patients are young, radiation doses should be reduced to a minimum whilst a sufficient image quality for precise interventional performance should be kept. We compared 44 MDCT standard-dose scans (133.0–200.0 mA) with a hybrid iterative reconstruction (iDose4) to 20 low-dose scans (20.0–67.0 mA) with iterative model reconstruction (IMR), which were performed for procedure planning of intrathecal nusinersen administration in 13 adult patients with SMA and complex spinal conditions. Qualitative image evaluation, including confidence for intervention planning, was performed by two neuroradiologists for standard- and low-dose scans. All 64 MDCT-guided intrathecal administrations of nusinersen were successful. The dose length product (DLP) was significantly lower when using low-dose scanning with IMR (median DLP of standard-dose scans: 92.0 mGy•cm vs. low-dose scans: 34.5 mGy•cm; p

Background: 5q spinal muscular atrophy (SMA) is an autosomal recessive lower motoneuron disease caused by deletion or mutations in the survival motor neuron 1 gene (SMN1) which results in reduced expression of full-length SMN protein. The main symptoms are caused by spinal motor neuron demise leading to muscle atrophy, and medical care mostly refers to motor symptoms. However, new insights of recent studies in severe SMA type I revealed disease involvement of several non-motor regions, for example cardiac, vascular, sensory nerve involvement, and thalamic lesions. Non-motor symptoms (NMS) were previously described in many neurodegenerative diseases i.e., Parkinson's disease and, importantly, also amyotrophic lateral sclerosis. Methods: We screened for NMS in 70 adult patients with SMA type II (SMAII) and type III (SMAIII) and 59 age/sex-matched healthy controls (controls) in a multicenter cross-sectional study including 5 different centers with specialized expertise in medical health care of motoneuron diseases. We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is a validated tool in Parkinson's disease. Results: Total NMS burden was low in adult SMA (median: 3 items) and not significantly different compared to controls (median: 2 items). Total NMS of SMA patients did not correlate with disease severity scores. However, the items "swallowing difficulties," "falling," and particularly "swelling legs" were significantly more frequently reported in SMA. Neuropsychiatric symptoms were reported in a frequency comparable to controls and were not significantly increased in SMA. Conclusion: Patient-reported prevalence of NMS in adult SMA was low, which does not argue for a clinically relevant multisystemic disorder in SMAII/III. Importantly, adult SMA patients do not seem to suffer more frequently from symptoms of depression or adaptive disorders compared to controls. Our results yield novel information on previously underreported symptoms and will help to improve the medical guidance of these patients. peerReviewed

Motor neuron diseases (MNDs) encompass an extensive and heterogeneous group of upper and/or lower motor neuron degenerative disorders, in which the particular clinical outcomes stem from the specific neuronal component involved in each condition. While mutations in a large number of molecules associated with lipid metabolism are known to be implicated in MNDs, there remains a lack of clarity regarding the key functional pathways involved, and their inter-relationships. This review highlights evidence that defines defects within two specific lipid (cholesterol/oxysterol and phosphatidylethanolamine) biosynthetic cascades as being centrally involved in MND, particularly hereditary spastic paraplegia. We also identify how other MND-associated molecules may impact these cascades, in particular through impaired organellar interfacing, to propose 'subcellular lipidome imbalance' as a likely common pathomolecular theme in MND. Further exploration of this mechanism has the potential to identify new therapeutic targets and management strategies for modulation of disease progression in hereditary spastic paraplegias and other MNDs.

In autoimmune myasthenia gravis (MG), the identification of antibodies and characterization of serological subgroups is of great importance for diagnosis and management of the disease. Our aims were to study the frequency of antibodies against lipoprotein-related protein 4 (LRP4), agrin, and titin using the most recent techniques, and to characterize corresponding clinical features and autoimmune diseases (AID) in 100 MG-patients. The antibody frequencies in the 55 AChR-antibody positive patients were 7% LRP4, 5% agrin, 53% titin, and in the 45 AChR-antibody negative patients 2% MuSK, 2% LRP4, 2% agrin, and 27% titin. LRP4-MG presented late-onset age, mild symptoms, good therapeutic response, and no thymic changes. Agrin-MG showed early onset age, mild-to-severe symptoms, and moderate treatment response. The phenotype of titin-MG depended on AChR-antibodies: AChR-antibody negative patients presented with mostly mild limb muscle weakness, whereas AChR-antibody positive patients showed more frequently severe symptoms, including myasthenic crisis, bulbar predominance, and thymoma. Additional AID were detected in 32% of MG-patients, most frequently Hashimoto's thyroiditis (21%). Based on our data, we recommend the detection of LRP4-antibodies for at least AChR-antibody negative MG-patients and titin-antibodies for all MG-patients. We propose taking an accurate medical history for typical symptoms of Hashimoto's thyroiditis in MG-patients.

Myotonic dystrophy type 1 (DM1) is the most frequent muscular dystrophy worldwide with complex, multi-systemic, and progressively worsening symptoms. There is currently no treatment for this inherited disorder and research can be challenging due to the rarity and variability of the disease. The UK Myotonic Dystrophy Patient Registry is a patient self-enrolling online database collecting clinical and genetic information. For this cross-sectional “snapshot” analysis, 556 patients with a confirmed diagnosis of DM1 registered between May 2012 and July 2016 were included. An almost even distribution was seen between genders and a broad range of ages was present from 8 months to 78 years, with the largest proportion between 30 and 59 years. The two most frequent symptoms were fatigue and myotonia, reported by 79 and 78% of patients, respectively. The severity of myotonia correlated with the severity of fatigue as well as mobility impairment, and dysphagia occurred mostly in patients also reporting myotonia. Men reported significantly more frequent severe myotonia, whereas severe fatigue was more frequently reported by women. Cardiac abnormalities were diagnosed in 48% of patients and more than one-third of them needed a cardiac implant. Fifteen percent of patients used a non-invasive ventilation and cataracts were removed in 26% of patients, 65% of which before the age of 50 years. The registry’s primary aim was to facilitate and accelerate clinical research. However, these data also allow us to formulate questions for hypothesis-driven research that may lead to improvements in care and treatment. Electronic supplementary material The online version of this article (doi:10.1007/s00415-017-8483-2) contains supplementary material, which is available to authorized users.

Tubular aggregates are accumulations of densely packed tubules in muscle fibers, occurring in distinct hereditary and acquired disorders. We present a patient with tubular aggregates and autoimmune Lambert-Eaton myasthenic syndrome. Initially, he showed mild proximal weakness, borderline decrement on 3 Hz stimulation, and slightly elevated creatine kinase. Muscle biopsy revealed tubular aggregates in type II fibers. Due to a good response to pyridostigmine, a limb-girdle myasthenia with tubular aggregates was suspected, but genetic analyses of GFPT1, DPGAT1, and ALG2 were normal. Two years later, the patient presented with progressive weakness and autonomic dysfunction. 17% decrement on 3 Hz stimulation and 100% increment after brief exercise were revealed. Autoantibodies to voltage-gated calcium-channels confirmed the diagnosis of Lambert-Eaton myasthenic syndrome. Steroids, azathioprine, and 3,4-diaminopyridine significantly improved symptoms. No tumor was found during follow-up. This is the first report about tubular aggregates associated with an acquired myasthenic syndrome. Our findings are important because of the therapeutic implications.