Methylation of the 4q35 D4Z4 repeat defines disease status in facioscapulohumeral muscular dystrophy.

Genetic diagnosis of facioscapulohumeral muscular dystrophy (FSHD) remains a challenge in clinical practice as it cannot be detected by standard sequencing methods despite being the third most common muscular dystrophy. The conventional diagnostic strategy addresses the known genetic parameters of FSHD: the required presence of a permissive haplotype, a size reduction of the D4Z4 repeat of chromosome 4q35 (defining FSHD1) or a pathogenic variant in an epigenetic suppressor gene (consistent with FSHD2). Incomplete penetrance and epistatic effects of the underlying genetic parameters as well as epigenetic parameters (D4Z4 methylation) pose challenges to diagnostic accuracy and hinder prediction of clinical severity. In order to circumvent the known limitations of conventional diagnostics and to complement genetic parameters with epigenetic ones, we developed and validated a multistage diagnostic workflow that consists of a haplotype analysis and a high-throughput methylation profile analysis (FSHD-MPA). FSHD-MPA determines the average global methylation level of the D4Z4 repeat array as well as the regional methylation of the most distal repeat unit by combining bisulphite conversion with next-generation sequencing and a bioinformatics pipeline and uses these as diagnostic parameters. We applied the diagnostic workflow to a cohort of 148 patients and compared the epigenetic parameters based on FSHD-MPA to genetic parameters of conventional genetic testing. In addition, we studied the correlation of repeat length and methylation level within the most distal repeat unit with age-corrected clinical severity and age at disease onset in FSHD patients. The results of our study show that FSHD-MPA is a powerful tool to accurately determine the epigenetic parameters of FSHD, allowing discrimination between FSHD patients and healthy individuals, while simultaneously distinguishing FSHD1 and FSHD2. The strong correlation between methylation level and clinical severity indicates that the methylation level determined by FSHD-MPA accounts for differences in disease severity among individuals with similar genetic parameters. Thus, our findings further confirm that epigenetic parameters rather than genetic parameters represent FSHD disease status and may serve as a valuable biomarker for disease status.

[Molecular therapies in muscular dystrophies]. / Molekulare Therapien von Muskeldystrophien.

Muscular dystrophies (MD) are a clinically and genetically heterogeneous group of skeletal muscle-wasting diseases with progressive muscle weakness and atrophy, while disease severity depends on the subtype of the disease. Tremendous progress in basic research and an improved understanding of the pathophyisology of the disease have led to various molecular pipeline therapies for MD. Within the last years, promising new molecular therapies have been developed facilitating causative therapy in the near future. New developments of personalized gene therapy aim at genetically defined disease subgroups of MD, based on the underlying molecular mechanism and the resulting phenotype, and set an example for other hereditary diseases. We have learned tremendously within the last decade; however, there is still a long way to go until these therapeutic strategies will be able to finally cure MD, and not just modify the phenotype and pathology of DMD patients.

Analysis and occurrence of biallelic pathogenic repeat expansions in RFC1 in a German cohort of patients with a main clinical phenotype of motor neuron disease.

Biallelic pathogenic repeat expansions in RFC1 were recently identified as molecular origin of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) as well as of one of the most common causes of adult-onset ataxia. In the meantime, the phenotypic spectrum has expanded massively and now includes mimics of multiple system atrophy or parkinsonism. After identifying a patient with a clinical diagnosis of amyotrophic lateral sclerosis (ALS) as a carrier of biallelic pathogenic repeat expansions in RFC1, we studied a cohort of 106 additional patients with a clinical main phenotype of motor neuron disease (MND) to analyze whether such repeat expansions are more common in MND patients. Indeed, two additional MND patients (one also with ALS and one with primary lateral sclerosis/PLS) have been identified as carrier of biallelic pathogenic repeat expansions in RFC1 in the absence of another genetic alteration explaining the phenotype, suggesting motor neuron disease as another extreme phenotype of RFC1 spectrum disorder. Therefore, MND might belong to the expanding phenotypic spectrum of pathogenic RFC1 repeat expansions, particularly in those MND patients with additional features such as sensory and/or autonomic neuropathy, vestibular deficits, or cerebellar signs. By systematically analyzing the RFC1 repeat array using Oxford nanopore technology long-read sequencing, our study highlights the high intra- and interallelic heterogeneity of this locus and allows the identification of the novel repeat motif 'ACAAG'.

Patients' and caregivers' perception of multidimensional and palliative care in amyotrophic lateral sclerosis - protocol of a German multicentre study.

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is an inevitably fatal condition that leads to a progressive loss of physical functioning, which results in a high psychosocial burden and organizational challenges related to medical care. Multidimensional and multiprofessional care is advised to meet the complex needs of patients and their families. Many healthcare systems, including Germany, may not be able to meet these needs because non-medical services such as psychological support or social counselling are not regularly included in the care of patients with ALS (pwALS). Specialised neuropalliative care is not routinely implemented nor widely available. Caregivers of pwALS are also highly burdened, but there is still a lack of support services for them. METHODS: This project aims to assess the perceptions and satisfaction with ALS care in Germany in pwALS and their caregivers. This will be achieved by means of a cross-sectional, multicentre survey. The examination will assess, to which extend the patients' needs in the six domains of physical, psychological, social, spiritual, practical and informational are being met by current care structures. This assessment will be linked to mental well-being, subjective quality of life, attitudes toward life-sustaining measures and physician-assisted suicide, and caregiver burden. The study aims to recruit 500 participants from nationwide ALS centres in order to draw comprehensive conclusions for Germany. A total of 29 centres, mostly acquired via the clinical and scientific German Network for Motor Neuron Diseases (MND-NET), will take part in the project, 25 of which have already started recruitment. PERSPECTIVE: It is intended to provide data-based starting points on how current practice of care in Germany is perceived pwALS and their caregivers and how it can be improved according to their needs. Planning and initiation of the study has been completed. TRIAL REGISTRATION: The study is registered at ClinicalTrails.gov; NCT06418646.

Effects of tofersen treatment in patients with SOD1-ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program.

Background: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated. Methods: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events. Findings: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported. Interpretation: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction. Funding: No funding was received towards this study.

Primary headache in children and adolescents: update on pharmacotherapy of migraine and tension-type headache.

Primary headache disorders are frequently encountered in the pediatric population. The therapeutic approach consists of a multimodal program, including lifestyle modification, psychotherapeutic intervention, pharmacotherapy, and complementary measures. This systematic review focuses on the pharmacotherapy of pediatric migraine and tension-type headache (TTH). In addition to the general treatment principles, the results of 33 clinical reports published on the topic since 2008 are outlined in detail. Furthermore, a tabular summary of previously investigated agents not studied since 2008 is given, as is an overview of promising pharmacologic approaches so far only evaluated in adults. A variety of pharmacologic options is available, but high-quality evidence is limited to single agents. At this time, approval is restricted to four triptans and flupirtine for the symptomatic treatment of pediatric acute migraine and TTH, respectively. No agent has been approved for the prevention of pediatric primary headaches. This review does not grade the drugs hierarchically because the complex profiles of many agents differ only slightly or even overlap. However, a detailed expert opinion is provided. On the basis of the outlined facts, the team of physician, patient, and parents has to decide on the most appropriate regimen for the individual situation in the sense of personalized medicine.

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.

Closing the Gap - Detection of 5q-Spinal Muscular Atrophy by Short-Read Next-Generation Sequencing and Unexpected Results in a Diagnostic Patient Cohort.

BACKGROUND: The importance of early diagnosis of 5q-Spinal muscular atrophy (5q-SMA) has heightened as early intervention can significantly improve clinical outcomes. In 96% of cases, 5q-SMA is caused by a homozygous deletion of SMN1. Around 4 % of patients carry a SMN1 deletion and a single-nucleotide variant (SNV) on the other allele. Traditionally, diagnosis is based on multiplex ligation probe amplification (MLPA) to detect homozygous or heterozygous exon 7 deletions in SMN1. Due to high homologies within the SMN1/SMN2 locus, sequence analysis to identify SNVs of the SMN1 gene is unreliable by standard Sanger or short-read next-generation sequencing (srNGS) methods. OBJECTIVE: The objective was to overcome the limitations in high-throughput srNGS with the aim of providing SMA patients with a fast and reliable diagnosis to enable their timely therapy. METHODS: A bioinformatics workflow to detect homozygous SMN1 deletions and SMN1 SNVs on srNGS analysis was applied to diagnostic whole exome and panel testing for suggested neuromuscular disorders (1684 patients) and to fetal samples in prenatal diagnostics (260 patients). SNVs were detected by aligning sequencing reads from SMN1 and SMN2 to an SMN1 reference sequence. Homozygous SMN1 deletions were identified by filtering sequence reads for the ,, gene-determining variant" (GDV). RESULTS: 10 patients were diagnosed with 5q-SMA based on (i) SMN1 deletion and hemizygous SNV (2 patients), (ii) homozygous SMN1 deletion (6 patients), and (iii) compound heterozygous SNVs in SMN1 (2 patients). CONCLUSIONS: Applying our workflow in srNGS-based panel and whole exome sequencing (WES) is crucial in a clinical laboratory, as otherwise patients with an atypical clinical presentation initially not suspected to suffer from SMA remain undiagnosed.

Clinical and genetic features of amyotrophic lateral sclerosis patients with C9orf72 mutations.

An expansion of the GGGGCC hexanucleotide in the non-coding region of C9orf72 represents the most common cause of familial amyotrophic lateral sclerosis. The objective was to describe and analyse the clinical and genetic features of amyotrophic lateral sclerosis patients with C9orf72 mutations in a large population. Between November 2011 and December 2020, clinical and genetic characteristics of n = 248 patients with amyotrophic lateral sclerosis carrying C9orf72 mutations were collected from the clinical and scientific network of German motoneuron disease centres. Clinical parameters included age of onset, diagnostic delay, family history, neuropsychological examination, progression rate, phosphorylated neurofilament heavy chain levels in CSF and survival. The number of repeats was correlated with the clinical phenotype. The clinical phenotype was compared to n = 84 patients with SOD1 mutations and n = 2178 sporadic patients without any known disease-related mutations. Patients with C9orf72 featured an almost balanced sex ratio with 48.4% (n = 120) women and 51.6% (n = 128) men. The rate of 33.9% patients (n = 63) with bulbar onset was significantly higher compared to sporadic (23.4%, P = 0.002) and SOD1 patients (3.1%, P < 0.001). Of note, 56.3% (n = 138) of C9orf72, but only 16.1% of SOD1 patients reported a negative family history (P < 0.001). The GGGGCC hexanucleotide repeat length did not influence the clinical phenotypes. Age of onset (58.0, interquartile range 52.0-63.8) was later compared to SOD1 (50.0, interquartile range 41.0-58.0; P < 0.001), but earlier compared to sporadic patients (61.0, interquartile range 52.0-69.0; P = 0.01). Median survival was shorter (38.0 months) compared to SOD1 (198.0 months, hazard ratio 1.97, 95% confidence interval 1.34-2.88; P < 0.001) and sporadic patients (76.0 months, hazard ratio 2.34, 95% confidence interval 1.64-3.34; P < 0.001). Phosphorylated neurofilament heavy chain levels in CSF (2880, interquartile range 1632-4638 pg/ml) were higher compared to sporadic patients (1382, interquartile range 458-2839 pg/ml; P < 0.001). In neuropsychological screening, C9orf72 patients displayed abnormal results in memory, verbal fluency and executive functions, showing generally worse performances compared to SOD1 and sporadic patients and a higher share with suspected frontotemporal dementia. In summary, clinical features of patients with C9orf72 mutations differ significantly from SOD1 and sporadic patients. Specifically, they feature a more frequent bulbar onset, a higher share of female patients and shorter survival. Interestingly, we found a high proportion of patients with negative family history and no evidence of a relationship between repeat lengths and disease severity.

Spectrum and frequency of genetic variants in sporadic amyotrophic lateral sclerosis.

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.

Cutaneous T-cell lymphoma mimicking myopathy with lipoatrophy.

Mycosis fungoides (MF) is the most common form of primary cutaneous T-cell lymphoma. Classic MF usually follows a rather benign course over many years or decades, rarely ever leading to fatal extracutaneous organ involvement. Single cases of muscular involvement have been reported. Here we describe a 42-year-old male patient with hair loss and lipoatrophy since six months diagnosed as follicular MF and with a two months history of progressive distal leg weakness. Muscle biopsy and whole body muscle MRI showed an extensive muscular and subcutaneous fatty tissue infiltration. After therapy with topical steroids and acitretin/PUVA, systemic chemotherapy (CHOP) was initiated. The patient suffered from a rapid disease progression with fatal outcome 2.5 years after the first skin lesions, displaying progressive cachexia, muscular atrophy and weakness with scapuloperoneal distribution and cardiac dysfunction. So far, extensive muscular involvement by MF mimicking a distinct muscular phenotype has not been reported.

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.

ALSFRS-R-SE: an adapted, annotated, and self-explanatory version of the revised amyotrophic lateral sclerosis functional rating scale.

BACKGROUND: The ALS Functional Rating Scale in its revised version (ALSFRS-R) is a disease-specific severity score that reflects motor impairment and functional deterioration in people with amyotrophic lateral sclerosis (ALS). It has been widely applied in both clinical practice and ALS research. However, in Germany, several variants of the scale, each differing slightly from the others, have developed over time and are currently in circulation. This lack of uniformity potentially hampers data interpretation and may decrease item validity. Furthermore, shortcomings within the standard ALSFRS-R questions and answer options can limit the quality and conclusiveness of collected data. METHODS: In a multistage consensus-building process, 18 clinical ALS experts from the German ALS/MND network analyzed the ALSFRS-R in its current form and created an adapted, annotated, and revised scale that closely adheres to the well-established standardized English version. RESULTS: Ten German-language variants of the ALSFRS-R were collected, three of which contained instructions for self-assessment. All of these variants were compiled and a comprehensive linguistic revision was undertaken. A short introduction was added to the resulting scale, comprising general instructions for use and explanations for each of the five reply options per item. This adapted version of the scale, named ALSFRS-R-SE (with the "SE" referring to "self-explanatory"), was carefully reviewed for language and comprehensibility, in both German and English. CONCLUSION: An adapted and annotated version of the ALSFRS-R scale was developed through a multistage consensus process. The decision to include brief explanations of specific scale items and reply options was intended to facilitate ALSFRS-R-SE assessments by both healthcare professionals and patients. Further studies are required to investigate the accuracy and utility of the ALSFRS-R-SE in controlled trials and clinical real-world settings.

Effect of Discontinuation of Nusinersen Treatment in Long-Standing SMA3.

BACKGROUND: Spinal muscular atrophy is an autosomal recessive neuromuscular disease leading to ongoing degeneration of anterior horn cells in the spinal cord. Nusinersen is the first approved treatment for the condition, an intrathecally administered antisense oligonucleotide. It modulates pre-RNA splicing of the SMN2 gene and increases full-length SMN protein expression, thereby increasing SMN protein levels. The benefit of Nusinersen for patients with spinal muscular atrophy type 3 (SMA3) has recently been shown in several real-world cohorts. OBJECTIVE: We aim to elucidate not only the effect of therapy with Nusinersen, but the development of the disease course after discontinuation of treatment. To our knowledge, there are so far no reports on the effects of Nusinersen discontinuation. METHODS: We report on a 45-year-old female patient with genetically confirmed SMA3 and a disease duration of 40 years prior to treatment onset. RESULTS: The patient was non-ambulantory, best motor function at treatment onset was holding arms with support, reflected in MRC of 3/5 in upper limbs. After having received Nusinersen for 11 months without complications, the patient showed improvement in motor functions, as measured by hand grip measurement (HGS), Hammersmith Functional Rating Scale Expanded (HFMSE), and Revised Upper Limb Module (RULM). Due to worsening of a pre-existing anxiety disorder, treatment was discontinued after six injections. Sixteen months later, progression of the disease became evident with worsening of HFMSE and RULM scores, while hand strength remained stable. CONCLUSION: Treatment with Nusinersen in SMA3 improves motor function in longstanding disease even in clinically advanced stages; however, after discontinuation of treatment, further progression mirroring the natural history of the disease is anticipated.

Congenital myopathy and epidermolysis bullosa due to PLEC variant.

We report on an adult Turkish patient with mild myopathy with a fiber-type disproportion and mitochondrial disorganization caused by genetic variants in the plectin gene (PLEC). Molecular genetic panel testing revealed two homozygous variants in PLEC (NM_000445.4): c.8306C>G (p.Pro2769Arg) and c.7506 + 5C>G (p. ?) that were classified as variants of unknown significance (class 3) following ACMG guidelines for variant classification in genetic diagnostics. A thorough reassessment of the patient revealed mild skin blistering (epidermolysis bullosa simplex, EBS). This illustrates the importance of deep phenotyping of neuromuscular patients.

Location matters - Genotype-phenotype correlation in LRSAM1 mutations associated with rare Charcot-Marie-Tooth neuropathy CMT2P.

More than 80 genes are known to be associated with Charcot-Marie-Tooth disease (CMT). Mutations of LRSAM1 were identified as a rare cause and define the subgroup of axonal neuropathy CMT2P. We identified additional 14 patients out of 12 families. Clinical and electrophysiological data confirm a late-onset axonal neuropathy with a predominance of sensorimotor impairment. The patients harbored ten different variants in LRSAM1, seven of which were novel. Due to variable inheritance patterns and clustering of pathogenic variants in 3´-prime exons, interpretation of genetic variants in LRSAM1 is challenging. The majority follows dominant inheritance, whereas recessive inheritance has been described for one variant. Variants at the 3`end may or may not escape from nonsense-mediated decay, thereby defining the pattern of inheritance. Our data emphasize the importance of the C-terminal RING domain, which exerts a dominant-negative effect on protein function, whenever affected by an altered or truncated protein. In conclusion, CMT2P is a rare, but nevertheless relevant cause of adult-onset axonal and painful neuropathy. ACMG (American College of Medical Genetics and genomics) criteria should be carefully applied in variant interpretation, with special attention to premature termination codon-introducing variants and their location within the gene.

Lower limb radiology of distal myopathy due to the S60F myotilin mutation.

Distal myopathies are a clinically and genetically heterogenous group of disorders in which the distal limb musculature is selectively or disproportionately affected. Precisely defining specific categories is a challenge because of overlapping clinical phenotypes, making it difficult to decide which of the many known causative genes to screen in individual cases. In this study we define the distinguishing magnetic resonance imaging findings in myotilin myopathy by studying 8 genealogically unrelated cases due to the same point mutation in TTID. Proximally, the vastii, biceps femoris and semimembranosus were involved with sparing of gracilis and sartorius. Distally, soleus, gastrocnemius, tibialis anterior, extensor hallicus and extensor digitorum were involved. This pattern contrasts with other distal myopathies and provides further support for the role of imaging in the clinical investigation of muscle disease.

Charcot-Marie-Tooth disease type 2CC due to a frameshift mutation of the neurofilament heavy polypeptide gene in an Austrian family.

Neurofilaments are structural components of motor axons. Recently different variants resulting in translation of a cryptic amyloidogenic element of the neurofilament-heavy polypeptide (NEFH) gene have been described to cause Charcot-Marie-Tooth disease type 2CC (CMT2CC) by forming amyloidogenic toxic protein aggregation. Until now only few CMT2CC patients have been described. Clinical features include progressive muscle weakness and atrophy mainly affecting the lower limbs, hyporeflexia and distal sensory impairment. In addition to classic CMT features, some patients were reported to have increased serum creatine kinase levels, an electrophysiologic pattern suggestive for myopathies, and pyramidal signs. Ambulation is progressively impaired, most patients are non-ambulant in the 5th decade. Nerve conduction testing shows a symmetrical, distal and proximal sensorimotor axonal neuropathy. Here we describe the first Austrian pedigree suffering from CMT2CC and give an overview on the phenotype of CMT2CC described so far.