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Cerebral foreign body reaction (CFBR) due to hydrophilic polymer embolization is a rarely diagnosed complication of cerebral endovascular procedures. Despite the considerable use of endovascular treatment in the literature, few cases of CFBR have been described so far. Our main objective is to describe three patients who were diagnosed at our center with CFBR and provide an overview of the existing literature. In these three cases, cerebral aneurysms were treated with different endovascular techniques as Contour device implantation, coil embolization, and flow diversion stent. Only one patient manifested focal neurological signs characterized by contralateral strength deficit, dysarthria, and headache. In the other two cases, the lesions were asymptomatic and were found at follow-up imaging. Brain MRI showed hyperintense lesions in FLAIR sequences in subcortical white matter without diffusivity restriction on diffusion-weighted imaging (DWI) corresponding to contrast-enhancing foci in T1-weighted images, suggestive of CFBR. Pathophysiology and predisposing factors are still unclear. Corticosteroid therapy led to marked improvement at neuroimaging in all cases and to a clinical remission in the first case. Our data confirm that CFBR is an underestimated complication to be aware of, in both neurological and neuroradiological practice., Competing Interests: Declarations. Conflicts of interest: The authors declared they have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical approval: The study was approved by the local Ethic Commitee (University Hospital of Messina)., (© 2025. Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: Declarations. Ethics approval and consent to participate: The manuscript does not contain clinical studies or patient data. All people will give their informed consent prior to their inclusion in the registry. Conflict of interest: The authors declare that they have no conflict of interest.

Late-onset Pompe disease (LOPD) includes patients from 1 year of age to adulthood. The vast heterogeneity in clinical manifestations and disease progression is not fully explained; however, a short disease duration and a young age seem to be good predictors of a better response to treatment. For this purpose, we investigated and followed up a cohort of 13 juvenile patients with LOPD from the clinical and therapeutic point of view, mainly pointing out the transition from presymptomatic to symptomatic status. We retrospectively collected clinical, morphological, biochemical and molecular data from 13 juvenile LOPD patients. Motor and respiratory functional data, obtained during annual follow-up visits, were analyzed. The data included serial evaluations of the Medical Research Council (MRC) scale, the 6-Minute Walking Test (6MWT), the Gait, Stairs, Gower, and Chair (GSGC) score, and seated and supine Forced Vital Capacity (FVC). Muscle Magnetic Resonance Imaging (MRI) was also included, although it was not performed in all cases. Currently, patients mean age is 18 years. All patients but one were diagnosed because of an isolated hyperCKemia: the mean age at diagnosis was 6.8 years (range 1-18). The onset of symptoms occurred from 6 months to 12 years after the diagnosis. The mean clinical follow-up duration was 9 years (range 2-18). From the genetic point of view, the most shared mutation was c.32-13T>G, found in twelve patients as compound heterozygosis. Seven patients underwent muscle biopsy, which showed vacuolar myopathy with glycogen accumulation in four of them with unspecific changes in the other three cases. Five patients developed proximal muscle weakness during the follow-up with a mild waddling gait and a positive Gowers manoeuver. Muscle MRI revealed mild hypotrophy of the thighs at the development of symptoms in four out of five cases. Four patients started alglucosidase alfa, and one avalglucosidase alfa. These five patients on Enzyme Replacement Therapy (ERT) showed motor and respiratory stability in the following years. Timely identification of emerging clinical manifestations in presymptomatic LOPD patients, as a result of careful follow-up, is essential to start prompt treatment to modify the disease natural course., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: OM and AT received honoraria from Sanofi Genzyme., (Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.)

Late-onset Pompe disease (LOPD) is a rare genetic disorder caused by the deficiency of acid alpha-glucosidase leading to progressive cellular dysfunction owing to the accumulation of glycogen in the lysosome. The mechanism of relentless muscle damage (a classic manifestation of the disease) has been studied extensively by analysing the whole-muscle tissue; however, little, if anything, is known about transcriptional heterogeneity among nuclei within the multinucleated skeletal muscle cells. This is the first report of application of single-nucleus RNA sequencing to uncover changes in the gene expression profile in muscle biopsies from eight patients with LOPD and four muscle samples from age- and sex-matched healthy controls. We matched these changes with histological findings using GeoMx spatial transcriptomics to compare the transcriptome of control myofibres from healthy individuals with non-vacuolated (histologically unaffected) and vacuolated (histologically affected) myofibres of LODP patients. We observed an increase in the proportion of slow and regenerative muscle fibres and macrophages in LOPD muscles. The expression of the genes involved in glycolysis was reduced, whereas the expression of the genes involved in the metabolism of lipids and amino acids was increased in non-vacuolated fibres, indicating early metabolic abnormalities. Additionally, we detected upregulation of autophagy genes and downregulation of the genes involved in ribosomal and mitochondrial function leading to defective oxidative phosphorylation. Upregulation of genes associated with inflammation, apoptosis and muscle regeneration was observed only in vacuolated fibres. Notably, enzyme replacement therapy (the only available therapy for the disease) showed a tendency to restore dysregulated metabolism, particularly within slow fibres. A combination of single-nucleus RNA sequencing and spatial transcriptomics revealed the landscape of the normal and diseased muscle and highlighted the early abnormalities associated with disease progression. Thus, the application of these two new cutting-edge technologies provided insight into the molecular pathophysiology of muscle damage in LOPD and identified potential avenues for therapeutic intervention., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: This case study aimed to evaluate the safety and efficacy of sleeve gastrectomy surgery in an obese patient with Late-onset Pompe disease (LOPD) and to explore the potential role of bariatric surgery in improving clinical outcomes and promoting a more physiological body composition when dietary and physical interventions fail., Methods: We describe a case of an obese LOPD patient who underwent sleeve gastrectomy, with clinical follow-up conducted to monitor motor and respiratory functions, as well as patient-reported outcome measures (PROMs), over time., Results: The surgery was well-tolerated without significant complications, and prolonged stability in motor and respiratory functions was observed. Furthermore, the patient reported improvements in quality of life and PROMs following weight loss., Conclusion: This case suggests that bariatric surgery, specifically sleeve gastrectomy, may be a safe and effective complementary strategy for weight loss in LOPD patients, offering benefits in functional stability, and quality of life., (Copyright © 2024 Gaetano Conte Academy - Mediterranean Society of Myology.)

Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) and disease spectrum is an autosomal recessive disorder associated with biallelic repeat expansion (RE) in the RFC1 gene. A high carrier frequency in the healthy population determines the possibility of having affected members in two consecutive generations. We describe pseudodominance in two families affected with RFC1 disorder (10 affected, 5 oligo/asymptomatic individuals). In Family A, after the 75-year-old index case was diagnosed with CANVAS, the 73-year-old wife decided to undergo screening for carrier testing. Although she did not report any symptoms, she resulted positive for the biallelic AAGGG RE thus leading to a diagnosis in the asymptomatic offspring as well and revealing a pseudodominant pattern of inheritance. In Family B pseudodominance was suspected after the identification of the RFC1 RE in the proband affected by sensitive neuropathy because of a positive family history for undetermined polyneuropathy in the mother. The post-mortem identification of the RFC1 RE in a sample specimen from the deceased mother, who had been under our care, allowed the solution of a "cold case". Our report suggests that pseudodominance is a confounding phenomenon to consider in RFC1-spectrum disorder and genetic counselling is instrumental in families with affected individuals., Competing Interests: Declarations. Ethical Approval: This study was approved by the ethics committee of Policlinico G. Martino, Messina and was performed in line with the principles of the Declaration of Helsinki. Consent to Participate: All included patients or their deputies provided written informed consent. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: The Rasch-Built Pompe-Specific Activity (R-PAct) scale is a patient-reported outcome measure specifically designed to quantify the effects of Pompe disease on daily life activities, developed for use in Dutch- and English-speaking countries. This study aimed to validate the R-PAct for use in other countries., Methods: Four other language versions (German, French, Italian, and Spanish) of the R-PAct were created and distributed among Pompe patients (≥16 years old) in Germany, France, Spain, Italy, and Switzerland and pooled with data of newly diagnosed patients from Australia, Belgium, Canada, the Netherlands, New Zealand, the USA, and the UK and the original validation cohort (n = 186). The psychometric properties of the scale were assessed by exploratory factor analysis and Rasch analysis., Results: Data for 520 patients were eligible for analysis. Exploratory factor analysis suggested that the items separated into two domains: Activities of Daily Living and Mobility. Both domains independently displayed adequate Rasch model measurement properties, following the removal of one item ("Are you able to practice a sport?") from the Mobility domain, and can be added together to form a "higher order" factor as well. Differential item functioning (DIF)-by-language assessment indicated DIF for several items; however, the impact of accounting for DIF was negligible. We recalibrated the nomogram (raw score interval-level transformation) for the updated 17-item R-PAct scale. The minimal detectable change value was 13.85 for the overall R-PAct., Conclusions: After removing one item, the modified-R-PAct scale is a valid disease-specific patient-reported outcome measure for patients with Pompe disease across multiple countries., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objectives: Focal myositis (FM) is a rare and restricted skeletal muscle inflammation, presenting as a solid mass with a typical lower leg localization and benign prognosis. In most cases the process solves spontaneously or after immunosuppressant therapy, but sometimes it recurs or progresses to a systemic inflammation. The basis of the disease are mostly unknown., Methods: Hence, we provide an update of histopathological features of FM, in order to better define the underlying pathomechanisms of this disorder. A PubMed literature search was focused on the case reports published in English from July 1977 to December 2023., Results: FM and other myositis may show similar morphological features. Emerging studies on MMP molecules and future eventual research on microRNAs (miRNAs) could help in differential diagnosis., Conclusions: Clinical, laboratory, neurophysiological and imaging findings can allow a correct diagnosis. However, muscle biopsy seems to be the only diagnostic tool to differentiate among FM and other localized soft tissue masses., (Copyright © 2024 Gaetano Conte Academy - Mediterranean Society of Myology.)

Background: Autosomal-dominant spinocerebellar ataxia (ADCA) due to intronic GAA repeat expansion in FGF14 (SCA27B) is a recent, relatively common form of late-onset ataxia., Objective: Here, we aimed to: (1) investigate the relative frequency of SCA27B in different clinically defined disease subgroups with late-onset ataxia collected among 16 tertiary Italian centers; (2) characterize phenotype and diagnostic findings of patients with SCA27B; (3) compare the Italian cohort with other cohorts reported in recent studies., Methods: We screened 396 clinically diagnosed late-onset cerebellar ataxias of unknown cause, subdivided in sporadic cerebellar ataxia, ADCA, and multisystem atrophy cerebellar type. We identified 72 new genetically defined subjects with SCA27B. Then, we analyzed the clinical, neurophysiological, and imaging features of 64 symptomatic cases., Results: In our cohort, the prevalence of SCA27B was 13.4% (53/396) with as high as 38.5% (22/57) in ADCA. The median age of onset of SCA27B patients was 62 years. All symptomatic individuals showed evidence of impaired balance and gait; cerebellar ocular motor signs were also frequent. Episodic manifestations at onset occurred in 31% of patients. Extrapyramidal features (17%) and cognitive impairment (25%) were also reported. Brain magnetic resonance imaging showed cerebellar atrophy in most cases (78%). Pseudo-longitudinal assessments indicated slow progression of ataxia and minimal functional impairment., Conclusion: Patients with SCA27B in Italy present as an adult-onset, slowly progressive cerebellar ataxia with predominant axial involvement and frequent cerebellar ocular motor signs. The high consistency of clinical features in SCA27B cohorts in multiple populations paves the way toward large-scale, multicenter studies., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Autosomal recessive pathogenetic variants in the DGUOK gene cause deficiency of deoxyguanosine kinase activity and mitochondrial deoxynucleotides pool imbalance, consequently, leading to quantitative and/or qualitative impairment of mitochondrial DNA synthesis. Typically, patients present early-onset liver failure with or without neurological involvement and a clinical course rapidly progressing to death. This is an international multicentre study aiming to provide a retrospective natural history of deoxyguanosine kinase deficient patients. A systematic literature review from January 2001 to June 2023 was conducted. Physicians of research centres or clinicians all around the world caring for previously reported patients were contacted to provide followup information or additional clinical, biochemical, histological/histochemical, and molecular genetics data for unreported cases with a confirmed molecular diagnosis of deoxyguanosine kinase deficiency. A cohort of 202 genetically confirmed patients, 36 unreported, and 166 from a systematic literature review, were analyzed. Patients had a neonatal onset (≤ 1 month) in 55.7% of cases, infantile (>1 month and ≤ 1 year) in 32.3%, pediatric (>1 year and ≤18 years) in 2.5% and adult (>18 years) in 9.5%. Kaplan-Meier analysis showed statistically different survival rates ( P < 0.0001) among the four age groups with the highest mortality for neonatal onset. Based on the clinical phenotype, we defined four different clinical subtypes: hepatocerebral (58.8%), isolated hepatopathy (21.9%), hepatomyoencephalopathy (9.6%), and isolated myopathy (9.6%). Muscle involvement was predominant in adult-onset cases whereas liver dysfunction causes morbidity and mortality in early-onset patients with a median survival of less than 1 year. No genotype-phenotype correlation was identified. Liver transplant significantly modified the survival rate in 26 treated patients when compared with untreated. Only six patients had additional mild neurological signs after liver transplant. In conclusion, deoxyguanosine kinase deficiency is a disease spectrum with a prevalent liver and brain tissue specificity in neonatal and infantile-onset patients and muscle tissue specificity in adult-onset cases. Our study provides clinical, molecular genetics and biochemical data for early diagnosis, clinical trial planning and immediate intervention with liver transplant and/or nucleoside supplementation., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Hereditary spastic paraparesis (HSP) is a group of central nervous system diseases primarily affecting the spinal upper motor neurons, with different inheritance patterns and phenotypes. SPG46 is a rare, early-onset and autosomal recessive HSP, linked to biallelic GBA2 mutations. About thirty families have been described worldwide, with different phenotypes like complicated HSP, recessive cerebellar ataxia or Marinesco-Sjögren Syndrome. Herein, we report five SPG46 patients harbouring five novel GBA2 mutations, the largest series described in Italy so far. Probands were enrolled in five different centres and underwent neurological examination, clinical cognitive assessment, column imaging for scoliosis assessment, ophthalmologic examination, brain imaging, GBA2 activity in peripheral blood cells and genetic testing. Their phenotype was consistent with HSP, with notable features like upper gaze palsy and movement disorders. We review demographic, genetic, biochemical and clinical information from all documented cases in the existing literature, focusing on the global distribution of cases, the features of the syndrome, its variable presentation, new potential identifying features and the significance of measuring GBA2 enzyme activity., (© 2024. The Author(s).)

Pompe disease (PD) is a rare metabolic disorder with progressive neuromuscular consequences that negatively impact a child's development and quality of life (QoL). Despite an improved prognosis with treatment, the risk for early death due cardiorespiratory crisis remains. Parents not only face physical fatigue and family distress in coping with the child's special needs but also experience emotions, worries, and unexpressed needs (a "humanistic burden") that require supportive interventions. Fourteen parents of children with PD completed an online self-report questionnaire assessing their child's QoL, their own parental burden of care, and disease-related issues. The aim was to estimate the associations between the child's QoL and the caregiver's burden levels. Three mothers were also interviewed. A total of 57.1% of parents lived with moderate/severe burden conditions; worse QoL for the child was associated with higher levels of caregiver burden ( r S [ N = 14] = -0.67, p < 0.01). Uncertainty about the child's future was a state commonly described by mothers. However, the child's resilience, normalization of disease, and coping strategies (primarily positive appraisal and focusing on the present) alleviated suffering and helped mothers maintain family functioning. Finally, dissatisfaction with communication in relationships with professionals emerged. In conclusion, a typical pediatric palliative care approach is recommended since it manages to guarantee parents empathetic and supportive communication from healthcare professionals, alleviating feelings of isolation and loneliness in parents.

Background: The Italian Medicines Agency (AIFA) demands precise information on benefit/risk profile of home-based enzyme replacement therapy (ERT) for the treatment of patients with Pompe disease and Mucopolysaccharidosis type I (MPS I). This passage is necessary to obtain the authorization for ERT home therapy, even after the coronavirus disease-19 (COVID-19) pandemic period. This research intends to evaluate the safety, treatment satisfaction, and compliance of MPS I patients treated with laronidase (Aldurazyme®) and Pompe Disease patients treated with alglucosidase alfa (Myozyme®) in a homecare setting., Results: We report herein an early interim analysis of the HomERT (Home infusions of ERT) study, a multicenter, non-interventional, double-cohort study that retrospectively analyzed 38 patients from 14 sites in Italy: cohort A (Pompe disease - 32 patients) and cohort B (MPS I - 6 patients). Among the selected patients who started home therapy before enrollment, the average number of missed home-based infusions was 0.7 (1.3) in cohort A and 3.8 (6.4) in cohort B with no return to the hospital setting. Irrespective of the treatment location, 3 prior ADRs per cohort were reported. The majority of patients preferred home-based infusions (cohort A: 96.9%; cohort B: 100%): the main reason was attributed to treatment convenience (cohort A: 81.3%; cohort B: 83.3%). Despite the underlying conditions, most patients self-evaluated their health as "good" (cohort A: 50%; cohort B: 83.3%)., Conclusions: Evidence of favorable safety profile, improved treatment compliance and personal satisfaction validates the use of ERT with laronidase and alglucosidase alfa as a strong candidate for home therapy., (© 2023. The Author(s).)

Background: Paraneoplastic neurological syndromes (PNSs) are nonmetastatic complications of malignancy, defined by the presence of onconeural antibodies (ONAs). ONAs may be found in 60% of patients with central nervous system (CNS) involvement, and they are directed against intraneuronal antigens or channels, receptors or associated proteins located at the synaptic or extra-synaptic neuronal cell membrane. Given its rare incidence, there are few epidemiological case series on CNS-PNS. We aim to discuss the variability of CNS-PNSs etiology, clinical features, management and outcome, highlighting the importance of early recognition and appropriate treatment, leading to significant reduction of mortality and morbidity., Methods: We retrospectively reviewed our 7-years single-center experience, and specifically discussed the underlying etiology, parenchymal CNS involvement, and the acute treatment response. Only cases fulfilling PNS Euronetwork criteria for definitive PNS were included., Results: A total of 26 probable PNSs cases involving CNS were identified. We reported medical records of eleven (42.3%) illustrative cases, meeting the criteria of definite PNS and presenting variable clinical spectrum and different radiological appearances. Our series has a relative paucity of the most common syndromes and larger portion of clinical diagnosis with ONAs. Well-characterized ONAs had been detected in CSF of six patients., Conclusions: Our case series supports the utmost importance of early recognition of CNS-PNSs. Screening for occult malignancies should not be limited to patients with classical CNS syndrome. Empiric immunomodulatory therapy may be considered before the diagnostic evaluation is completed, in order to prevent unfavorable outcome. Late presentations should not discourage initiation of treatment., (© 2023. The Author(s) under exclusive licence to Belgian Neurological Society.)

Background: The European registry for individuals with GSD5 and other muscle glycogenosis (EUROMAC) was launched to register rare muscle glycogenosis in Europe, to facilitate recruitment for research trials and to learn about the phenotypes and disseminate knowledge about the diseases. A network of twenty collaborating partners from eight European countries and the US contributed data on rare muscle glycogenosis in the EUROMAC registry., Methods: Following the initial report on demographics, neuromuscular features and comorbidity (2020), we here present the data on social participation, previous and current treatments (medication, supplements, diet and rehabilitation) and limitations. Furthermore, the following questionnaires were used: Fatigue severity scale (FSS), WHO Disability Assessment Scale (DAS 2.0), health related quality of life (SF36) and International Physical Activity Questionnaire (IPAQ)., Results: Of 282 participants with confirmed diagnoses of muscle glycogenosis, 269 had GSD5. Of them 196 (73%) completed all questionnaires; for the others, the data were incomplete. The majority, 180 (67%) were currently working. Previous medical treatments included pain medication (23%) and rehabilitation treatment (60%). The carbohydrate-rich diet was reported to be beneficial for 68%, the low sucrose diet for 76% and the ketogenic diet for 88%. Almost all participants (93%) reported difficulties climbing stairs. The median FSS score was 5.22, indicating severe fatigue. The data from the WHODAS and IPAQ was not of sufficient quality to be interpreted., Conclusions: The EUROMAC registry have provided insight into the functional and social status of participants with GSD5: most participants are socially active despite limitations in physical and daily life activities. Regular physical activity and different dietary approaches may alleviate fatigue and pain., (© 2023. The Author(s).)

Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype-phenotype correlation has been extensively discussed, and caution is recommended when interpreting the clinical significance of any mutation in a single patient. As there is no evidence that environmental factors can modulate the phenotype, the observed clinical variability in PD suggests that genetic variants other than pathogenic GAA mutations influence the mechanisms of muscle damage/repair and the overall clinical picture. Genes encoding proteins involved in glycogen synthesis and catabolism may represent excellent candidates as phenotypic modifiers of PD. The genes analyzed for glycogen synthesis included UGP2, glycogenin ( GYG1 -muscle, GYG2 , and other tissues), glycogen synthase ( GYS1 -muscle and GYS2 -liver), GBE1 , EPM2A, NHLRC1 , GSK3A, and GSK3B. The only enzyme involved in glycogen catabolism in lysosomes is α-glucosidase, which is encoded by GAA , while two cytoplasmic enzymes, phosphorylase ( PYGB -brain, PGL -liver, and PYGM -muscle) and glycogen debranching ( AGL ) are needed to obtain glucose 1-phosphate or free glucose. Here, we report the potentially relevant variants in genes related to glycogen synthesis and catabolism, identified by whole exome sequencing in a group of 30 patients with late-onset Pompe disease (LOPD). In our exploratory analysis, we observed a reduced number of variants in the genes expressed in muscles versus the genes expressed in other tissues, but we did not find a single variant that strongly affected the phenotype. From our work, it also appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact the phenotype.

Acute hospitalisation may be required to support patients with Neuromuscular disorders (NMDs) mainly experiencing respiratory complications, swallowing difficulties, heart failure, urgent surgical procedures. As NMDs may need specific treatments, they should be ideally managed in specialized hospitals. Nevertheless, if urgent treatment is required, patients with NMD should be managed at the closest hospital site, which may not be a specialized centre where local emergency physicians have the adequate experience to manage these patients. Although NMDs are a group of conditions that can differ in terms of disease onset, progression, severity and involvement of other systems, many recommendations are transversal and apply to the most frequent NMDs. Emergency Cards (EC), which report the most common recommendations on respiratory and cardiac issues and provide indications for drugs/treatments to be used with caution, are actively used in some countries by patients with NMDs. In Italy, there is no consensus on the use of any EC, and a minority of patients adopt it regularly in case of emergency. In April 2022, 50 participants from different centres in Italy met in Milan, Italy, to agree on a minimum set of recommendations for urgent care management which can be extended to the vast majority of NMDs. The aim of the workshop was to agree on the most relevant information and recommendations regarding the main topics related to emergency care of patients with NMD in order to produce specific ECs for the 13 most frequent NMDs., (©2022 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy.)

Objectives: To assess natural history and 12-month change of a series of scales and functional outcome measures in a cohort of 117 patients with primary mitochondrial myopathy (PMM)., Methods: Twelve months follow-up data of 117 patients with PMM were collected. We analysed the 6-min walk test (6MWT), timed up-and-go test (× 3) (3TUG), five-times sit-to-stand test (5XSST), timed water swallow test (TWST), and test of masticating and swallowing solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional pain inventory as patient-reported outcome measures. PMM patients were divided into three phenotypic categories: mitochondrial myopathy (MiMy) without extraocular muscles involvement, pure chronic progressive external ophthalmoplegia (PEO) and PEO&MiMy. As 6MWT is recognized to have significant test-retest variability, we calculated MCID (minimal clinically important difference) as one third of baseline 6 min walking distance (6MWD) standard deviation., Results: At 12-month follow-up, 3TUG, 5XSST and FSS were stable, while TWST and the perceived pain severity (WHYMPI) worsened. 6MWD significantly increased in the entire cohort, especially in the higher percentiles and in PEO patients, while was substantially stable in the lower percentile (< 408 m) and MiMy patients. This increase in 6MWD was considered not significant, as inferior to MCID (33.3 m). NMDAS total score showed a slight but significant decline at 12 months (0.9 point). The perceived pain severity significantly worsened. Patients with PEO performed better in functional measures than patients with PEO&MiMy or MiMy, and had lower values of NMDAS., Conclusions: PMM patients showed a slow global decline valued by NMDAS at 12 months; 6MWT was a more reliable measurement below 408 m, substantially stable at 12 months. PEO patients had better motor performance and lower NMDAS than PEO&MiMy and MiMy also at 12 months of follow-up., (© 2022. The Author(s).)

Background and Objectives: Glycogen storage disease type V (GSDV) or McArdle disease is a muscle glycogenosis that classically manifests with exercise intolerance and exercise-induced muscle pain. Muscle weakness and wasting may occur, but it is typically mild and described as located around the shoulder girdle in elderly patients. Paraspinal muscle involvement has received little attention in the literature. This study aimed to quantify fat replacement of paraspinal, shoulder, and lower limb muscles by magnetic resonance imaging in a European cohort of patients with GSDV., Methods: This observational study included patients with verified GSDV and healthy controls (HCs). Whole-body MRIs and clinical data were collected. The degree of muscle fat replacement was evaluated on T1-weighted images with the semiquantitative visual Mercuri scale and on Dixon images where individual muscle fat fractions (FFs) were quantitatively calculated., Results: MRIs and clinical data from a total of 57 patients with GSDV (age 44.3 ± 15.2 years) from 5 European centers were assessed and compared with findings in 30 HCs (age 42.4 ± 14.8 years). Patients with GSDV had significantly more fat replacement of the paraspinal muscles compared with HCs on all levels investigated, detected by both the Mercuri and the Dixon method (Dixon, paraspinal composite FF [GSDV vs HC] at the cervical level: 31.3 ± 13.1 vs 15.4 ± 7.8; thoracic level: 34.5±19.0 vs 16.9±8.6; and lumbar level: 43.9 ± 19.6 vs 21.8 ± 10.2 [ p < 0.0001]). Patients with GSDV also had significantly more fat replacement of the shoulder muscles (evaluated by the Mercuri scale), along with significantly, but numerically less, fat replacement of thigh and calf muscles compared with HC (Dixon, lower limb composite FF [GSDV vs HC] at the thigh level: 12.0 ± 5.6 vs 8.8 ± 2.7 and calf level: 13.1 ± 6.7 vs 9.1 ± 2.9 [ p ≤ 0.05])., Discussion: The primary findings are that patients with GSDV exhibit severe fat replacement of the paraspinal muscles, which can have important implications for the future management of patients with GSDV, and also significant fat replacement of shoulder girdle muscles as previously described. The clinical relevance of the discrete increases in lower limb FF is uncertain. The changes were found to be age-related in both groups, but an accelerated effect was found in GSDV, probably due to continuous muscle damage., (© 2022 American Academy of Neurology.)

Statins are drugs widely prescribed in high-risk patients for cerebrovascular or cardiovascular diseases and are, usually, safe and well tolerated. However, these drugs sometimes may cause neuromuscular side effects that represent about two-third of all adverse events. Muscle-related adverse events include cramps, myalgia, weakness, immune-mediated necrotizing myopathy and, more rarely, rhabdomyolysis. Moreover, they may lead to peripheral neuropathy and induce or unmask a preexisting neuromuscular junction dysfunction. A clinical follow up of patients assuming statins could reveal early side effects that may cause neuromuscular damage and suggest how to better modulate their use. In fact, statin dechallenge or cessation, or the alternative use of other lipid-lowering agents, can avoid adverse events. This review summarizes the current knowledge on statin-associated neuromuscular adverse effects, diagnosis, and management. It is conceivable that the incidence of neuromuscular complications will increase because, nowadays, use of statins is even more diffused than in the past. On this purpose, it is expected that pharmacogenomic and environmental studies will help to timely predict neuromuscular complications due to statin exposure, leading to a more personalized therapeutic approach.

Muscle Glycogenosis type 0 (GSD0B) is an extremely rare disorder first recognized in 2007 in three siblings with childhood onset and severe cardiomyopathy. Since then, a few cases with severe cardiac involvement and premature death have been reported. We describe two unrelated cases presenting with an adult-onset myopathy with no heart involvement. Clinical features were quite similar in both patients, mainly characterized by early fatigability, myalgia and muscle weakness. Muscle biopsy revealed marked glycogen depletion in nearly all myofibers. Biochemical assay demonstrated a marked reduction of Glycogen Synthase (GS) activity. Sequence analysis of GYS1 revealed two new variants: a homozygous G to C substitution in the splice donor consensus site (c.678+1G>C) in patient1 and a homozygous missense variant c.630G>C in exon 3 (p. Asp145His) in patient 2. This study describes a new phenotype of muscle GSD0B presenting with adult onset, proximal myopathy, no cardiac abnormalities and a quite benign disease course. This report highlights the importance of a systematic diagnostic approach that includes muscle morphology and enzymatic assay to facilitate the identification of adult patients with GSD0B., Competing Interests: Declaration of competing interest All other authors report no disclosures., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Mitochondrial DNA (mtDNA) maintenance disorders embrace a broad range of clinical syndromes distinguished by the evidence of mtDNA depletion and/or deletions in affected tissues. Among the nuclear genes associated with mtDNA maintenance disorders, RNASEH1 mutations produce a homogeneous phenotype, with progressive external ophthalmoplegia (PEO), ptosis, limb weakness, cerebellar ataxia, and dysphagia. The encoded enzyme, ribonuclease H1, is involved in mtDNA replication, whose impairment leads to an increase in replication intermediates resulting from mtDNA replication slowdown. Here, we describe two unrelated Italian probands (Patient 1 and Patient 2) affected by chronic PEO, ptosis, and muscle weakness. Cerebellar features and severe dysphagia requiring enteral feeding were observed in one patient. In both cases, muscle biopsy revealed diffuse mitochondrial abnormalities and multiple mtDNA deletions. A targeted next-generation sequencing analysis revealed the homozygous RNASEH1 mutations c.129-3C>G and c.424G>A in patients 1 and 2, respectively. The c.129-3C>G substitution has never been described as disease-related and resulted in the loss of exon 2 in Patient 1 muscle RNASEH1 transcript. Overall, we recommend implementing the use of high-throughput sequencing approaches in the clinical setting to reach genetic diagnosis in case of suspected presentations with impaired mtDNA homeostasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer RH declared a past co-authorship with the author OM to the handling editor., (Copyright © 2022 Manini, Caporali, Meneri, Zanotti, Piga, Arena, Corti, Toscano, Comi, Musumeci, Carelli and Ronchi.)

Background and Objectives: Hereditary spastic paraplegias (HSPs) are a group of inherited rare neurologic disorders characterized by length-dependent degeneration of the corticospinal tracts and dorsal columns, whose prominent clinical feature is represented by spastic gait. Spastic paraplegia type 4 (SPG4, SPAST-HSP) is the most common form. We present both clinical and molecular findings of a large cohort of patients, with the aim of (1) defining the clinical spectrum of SPAST-HSP in Italy; (2) describing their molecular features; and (3) assessing genotype-phenotype correlations to identify features associated with worse disability., Methods: A cross-sectional retrospective study with molecular and clinical data collected in an anonymized database was performed., Results: A total of 723 Italian patients with SPAST-HSP (58% men) from 316 families, with a median age at onset of 35 years, were included. Penetrance was 97.8%, with men showing higher Spastic Paraplegia Rating Scale (SPRS) scores (19.67 ± 12.58 vs 16.15 ± 12.61, p = 0.009). In 26.6% of patients with SPAST-HSP, we observed a complicated phenotype, mainly including intellectual disability (8%), polyneuropathy (6.7%), and cognitive decline (6.5%). Late-onset cases seemed to progress more rapidly, and patients with a longer disease course displayed a more severe neurologic disability, with higher SPATAX (3.61 ± 1.46 vs 2.71 ± 1.20, p < 0.001) and SPRS scores (22.63 ± 11.81 vs 12.40 ± 8.83, p < 0.001). Overall, 186 different variants in the SPAST gene were recorded, of which 48 were novel. Patients with SPAST-HSP harboring missense variants displayed intellectual disability (14.5% vs 4.4%, p < 0.001) more frequently, whereas patients with truncating variants presented more commonly cognitive decline (9.7% vs 2.6%, p = 0.001), cerebral atrophy (11.2% vs 3.4%, p = 0.003), lower limb spasticity (61.5% vs 44.5%), urinary symptoms (50.0% vs 31.3%, p < 0.001), and sensorimotor polyneuropathy (11.1% vs 1.1%, p < 0.001). Increasing disease duration (DD) and abnormal motor evoked potentials (MEPs) were also associated with increased likelihood of worse disability (SPATAX score>3)., Discussion: The SPAST-HSP phenotypic spectrum in Italian patients confirms a predominantly pure form of HSP with mild-to-moderate disability in 75% of cases, and slight prevalence of men, who appeared more severely affected. Early-onset cases with intellectual disability were more frequent among patients carrying missense SPAST variants, whereas patients with truncating variants showed a more complicated disease. Both longer DD and altered MEPs are associated with worse disability., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an autosomal recessive disorder of fatty acid oxidation due to deficiency of the mitochondrial electron transfer chain. The late-onset form is characterized by exercise intolerance, muscle weakness, and lipid storage in myofibers. Most MADD patients greatly benefit from riboflavin supplementation., Patients and Methods: A retrospective study was conducted on patients with a diagnosis of vacuolar myopathy with lipid storage followed in our neuromuscular unit in the last 20 years. We selected 10 unrelated patients with the diagnosis of MADD according to clinical, morphological, and biochemical aspects. Clinical features, blood tests including serum acylcarnitines, EMG, and ENG were revised. Muscle biopsy was performed in all, and one individual underwent also a sural nerve biopsy. Gene sequencing of ETFA, ETFB , and ETFDH was performed as a first-tier genetic analysis followed by next-generation sequencing of an hyperCKemia gene panel in patients with undefined genotypes., Results: Clinical evaluation at onset in all our patients showed fatigue and muscle weakness; four patients showed difficulties in chewing, three patients complained of dysphagia, two patients had a dropped head, and a patient had an unexpected ataxia with numbness and dysesthesia. Laboratory blood tests revealed a variable increase in serum CK (266-6,500) and LDH levels (500-2,000). Plasma acylcarnitine profile evidenced increased levels of different chains intermediates. EMG was either normal or showed myogenic or neurogenic patterns. NCS demonstrated sensory neuropathy in two patients. Muscle biopsies showed a vacuolar myopathy with a variable increase in lipid content. Nerve biopsy evidenced an axonal degeneration with the loss of myelinated fibers. ETFDH genetic analysis identifies 14 pathogenic variants. Patients were treated with high doses of riboflavin (400 mg/die). All of them showed a rapid muscle strength improvement and normalization of abnormal values in laboratory tests. Neuropathic symptoms did not improve., Conclusion: Our data confirmed that clinical features in MADD patients are extremely variable in terms of disease onset and symptoms making diagnosis difficult. Laboratory investigations, such as serum acylcarnitine profile and muscle biopsy evaluation, may strongly address to a correct diagnosis. The favorable response to riboflavin supplementation strengthens the importance of an early diagnosis of these disorders among the spectrum of metabolic myopathies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer CA declared a shared affiliation, with no collaboration, with one of the authors, SV, to the handling editor at the time of the review., (Copyright © 2022 Lupica, Oteri, Volta, Ghezzi, Drago, Rodolico, Musumeci and Toscano.)

Introduction: Both prevalence and clinical features of the various movement disorders in adults with primary mitochondrial diseases are unknown., Methods: Based on the database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases", we reviewed the clinical, genetic, neuroimaging and neurophysiological data of adult patients with primary mitochondrial diseases (n = 764) where ataxia, myoclonus or other movement disorders were part of the clinical phenotype., Results: Ataxia, myoclonus and movement disorders were present in 105/764 adults (13.7%), with the onset coinciding or preceding the diagnosis of the mitochondrial disease in 49/105 (46.7%). Ataxia and parkinsonism were the most represented, with an overall prevalence at last follow-up of 59.1% and 30.5%, respectively. Hyperkinetic movement disorders were reported in 15.3% at last follow-up, being the less common reported movement disorders. The pathogenic m.8344A > G and POLG variants were always associated with a movement disorder, while LHON variants and mtDNA single deletions were more commonly found in the subjects who did not present a movement disorder. The most common neuroimaging features were cortical and/or cerebellar atrophy, white matter hyperintensities, basal ganglia abnormalities and nigro-striatal degeneration. Almost 70% of patients with parkinsonism responded to dopaminergic therapy, mainly levodopa, and 50% with myoclonus were successfully treated with levetiracetam., Conclusion: Movement disorders, mainly ataxia and parkinsonism, are important findings in adult primary mitochondrial diseases. This study underlies the importance of looking for a mitochondrial etiology in the diagnostic flowchart of a movement disorder and may help direct genetic screening in daily practice., (© 2021. The Author(s).)

The nuclear gene TK2 encodes the mitochondrial thymidine kinase, an enzyme involved in the phosphorylation of deoxycytidine and deoxythymidine nucleosides. Biallelic TK2 mutations are associated with a spectrum of clinical presentations mainly affecting skeletal muscle and featuring muscle mitochondrial DNA (mtDNA) instability. Current classification includes infantile- ( ≤ 1 year), childhood- (1-12 years), and late-onset (≥12 years) forms. In addition to age at onset, these forms differ for progression, life expectancy, and signs of mtDNA instability (mtDNA depletion vs. accumulation of multiple mtDNA deletions). Childhood-onset TK2 deficiency typically causes a rapidly progressive proximal myopathy, which leads to wheelchair-bound status within 10 years of disease onset, and severe respiratory impairment. Muscle biopsy usually reveals a combination of mitochondrial myopathy and dystrophic features with reduced mtDNA content. Here we report the case of an Italian patient presenting childhood-onset, slowly progressive mitochondrial myopathy, ptosis, hypoacusis, dysphonia, and dysphagia, harboring the TK2 variants c.278A>G and c.543del, the latter unreported so far. Compared to other childhood-onset TK2 -patients, our case displays atypical features, including slowly progressive muscle weakness and absence of respiratory failure, which are usually observed in late-onset forms. This report extends the genetic background of TK2-related myopathy, highlighting the clinical overlap among different forms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Manini, Meneri, Rodolico, Corti, Toscano, Comi, Musumeci and Ronchi.)

Mitochondrial disorders are the most common inherited conditions, characterized by defects in oxidative phosphorylation and caused by mutations in nuclear or mitochondrial genes. Due to its high energy request, skeletal muscle is typically involved. According to the International Workshop of Experts in Mitochondrial Diseases held in Rome in 2016, the term Primary Mitochondrial Myopathy (PMM) should refer to those mitochondrial disorders affecting principally, but not exclusively, the skeletal muscle. The clinical presentation may include general isolated myopathy with muscle weakness, exercise intolerance, chronic ophthalmoplegia/ophthalmoparesis (cPEO) and eyelids ptosis, or multisystem conditions where there is a coexistence with extramuscular signs and symptoms. In recent years, new therapeutic targets have been identified leading to the launch of some promising clinical trials that have mainly focused on treating muscle symptoms and that require populations with defined genotype. Advantages in next-generation sequencing techniques have substantially improved diagnosis. So far, an increasing number of mutations have been identified as responsible for mitochondrial disorders. In this review, we focused on the principal molecular genetic alterations in PMM. Accordingly, we carried out a comprehensive review of the literature and briefly discussed the possible approaches which could guide the clinician to a genetic diagnosis.

Objectives: Treatment approach of myasthenia gravis (MG) is still debated; corticosteroids alone or in combination with immunosuppressive agents are the most used drugs. Azathioprine (AZA) has been shown to be effective for MG with a significant steroid-sparing activity, although burdened by side effects. Few studies on methotrexate (MTX) administration showed controversial results. In this cohort, we evaluated the role of MTX as a effective steroid-sparing agent., Methods: Fifteen MG patients treated with MTX, previously treated with AZA for at least 12 months, with poor benefits and uncomfortable side effects AZA related, have been selected. Each patient was evaluated through MG-Activity of Daily Living and Quantitative MG scores 5 times/yr., Results: Patients treated with MTX had a significant improvement of MG-Activity of Daily Living and Quantitative MG scores. Furthermore, all patients reduced prednisone dosage, and none complained of side effects., Conclusions: We suggest MTX is effective and well tolerated and could be considered as a steroid-sparing agent in MG treatment., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1 , PRKCG , and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.

Background: Pompe disease is one of the few neuromuscular diseases with an approved drug therapy, which has been available since 2006. Our study aimed to determine the real-world long-term efficacy and safety of alglucosidase alfa., Methods: This multicenter retrospective study (NCT02824068) collected data from adult Pompe disease patients receiving ERT for at least 3 years. Demographics and baseline characteristics, muscle strength, lung function (FVC), walking capability (6MWT), and safety were assessed once a year. Evaluation was done on the group and individual levels, using quantitative linear models (t test) and general univariate linear models (ANOVA)., Findings: Sixty-eight adult Pompe disease patients from four countries (Spain, Taiwan, Italy, Germany (STIG)) participated. The mean follow-up was 7.03 years ± 2.98. At group level in all outcome measures, an initial improvement followed by a secondary decline was observed. After 10 years, the 6MWT %pred showed the most sustained positive effect (p = 0.304). The MRC %max remained stable with a mild decline (p = 0.131), however, FVC %pred deteriorated significantly (p < 0.001) by 14.93% over 10 years of ERT. The progression rate of FVC %pred under ERT could be explained in most of the patients (83.5%) by the disease severity at baseline. Furthermore, our study shows a decline in the FVC combined with an increase in non-invasive and invasive ventilation requirements in adult Pompe disease patients over time., Conclusions: The STIG real-world study confirms an initial efficacy of ERT in the first years with a secondary sustained decline in multiple outcome measures. Further efforts are required to establish a more valid long-term monitoring and improved therapies.

Aim: To investigate the in vivo skeletal muscle metabolism in patients with β-enolase deficiency (GSDXIII) during exercise, and the effect of glucose infusion., Methods: Three patients with GSDXIII and 10 healthy controls performed a nonischemic handgrip test as well as an incremental cycle ergometer test measuring maximal oxidative consumption (VO 2max ) and a 1-hour submaximal cycle test at an intensity of 65% to 75% of VO 2max . The patients repeated the submaximal exercise after 2 days, where they received a 10% iv-glucose supplementation., Results: Patients had lower VO 2max than healthy controls, and two of three patients had to stop prematurely during the intended 1-hour submaximal exercise test. During nonischemic forearm test, all patients were able to produce lactate in normal amounts. Glucose infusion had no effect on patients' exercise capacity., Conclusions: Patients with GSDXIII experience exercise intolerance and episodes of myoglobinuria, even to the point of needing renal dialysis, but still retain an almost normal anaerobic metabolic response to submaximal intensity exercise. In accordance with this, glucose supplementation did not improve exercise capacity. The findings show that GSDXIII, although causing episodic rhabdomyolysis, is one of the mildest metabolic myopathies affecting glycolysis., Competing Interests: The authors declare no potential conflict of interest., (© 2021 The Authors. JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

Pompe disease is a rare hereditary metabolic disorder caused by α-glucosidase (GAA) deficiency. The late-onset form of the disease (LOPD) is considered a multisystemic disorder which could involve vascular system with cerebrovascular abnormalities such as intracranial aneurysms or dolichoectasia. Intracranial aneurysm rupture may represent a life-threatening emergency. A possible treatment of unruptured intracranial aneurysms (UIAs) should consider both aneurysm-related (aneurysmal size, shape, localization, numbers and hemodynamic factors) and patient-related risk factors (patient's age and sex, hypertension, smoke exposure). Moreover, UIAs management of LOPD patients needs also to take into account the altered blood vessels integrity and elasticity, whose consistency is likely weakened by the deficient GAA activity as a further potential risk factor. We herein present our approach for of UIAs management in three patients with LOPD. Among them, only one patient with a left saccular UIA of the anterior communicating artery, after careful consideration of risk factors, underwent the endovascular treatment. The other two patients were scheduled for a 1-year follow-up, according to radiological, clinical, and risk evaluation features. Finally, we would like to suggest some general recommendations for UIAs management. In particular, if no risk factors are identified, a cautious yearly follow-up is suggested; otherwise, if risk factors are present, endovascular treatment should be considered.