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Background and purpose: Two novel enzyme replacement therapies (ERTs), studied in phase 3 trials in late‐onset Pompe patients, reached marketing authorization by the European Medicines Agency in 2022 and 2023. The European Pompe Consortium (EPOC) updates and extends the scope of the 2017 recommendations for starting, switching and stopping ERT. Methods: The European Pompe Consortium consists of 25 neuromuscular and metabolic experts from eight European countries. This update was performed after an in‐person meeting, three rounds of discussion and voting to provide a consensus recommendation. Results: The patient should be symptomatic, that is, should have skeletal muscle weakness or respiratory muscle involvement. Muscle magnetic resonance imaging findings showing substantial fat replacement can support the decision to start in a patient‐by‐patient scenario. Limited evidence supports switching ERT if there is no indication that skeletal muscle and/or respiratory function have stabilized or improved during standard ERT of 12 months or after severe infusion‐associated reactions. Switching of ERT should be discussed on a patient‐by‐patient shared‐decision basis. If there are severe, unmanageable infusion‐associated reactions and no stabilization in skeletal muscle function during the first 2 years after starting or switching treatment, stopping ERT should be considered. After stopping ERT for inefficacy, restarting ERT can be considered. Six‐monthly European Pompe Consortium muscle function assessments are recommended. Conclusions: The triple‐S criteria on ERT start, switch and stop include muscle magnetic resonance imaging as a supportive finding and the potential option of home infusion therapy. Six‐monthly long‐term monitoring of muscle function is highly recommended to cover insights into the patient's trajectory under ERT. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Respiratory status is a key determinant of prognosis in patients with Duchenne muscular dystrophy (DMD). We aimed to evaluate the determinants of diaphragm ultrasound and its performance in predicting restrictive respiratory patterns in DMD. Methods: This was a retrospective study of DMD patients followed in our center and admitted for an annual checkup from 2015 to 2018. We included DMD patients who underwent diaphragm ultrasound and pulmonary functional tests. Results: This study included 74 patients with DMD. The right diaphragm thickening fraction (TF) was significantly associated with age (P =.001), Walton score (P =.012), inspiratory capacity (IC) (P =.004), upright forced vital capacity (FVC) (P <.0001), supine FVC (P =.038), and maximal inspiratory pressure (MIP) (P =.002). Right diaphragm excursion was significantly associated with age (P <.0001), steroid use (P =.008), history of spinal fusion (P <.0001), body mass index (BMI) (P =.002), Walton score (P <.0001), IC (P <.0001), upright FVC (P <.0001), supine FVC (P <.0001), and MIP (P <.0001). A right diaphragm TF >28% and a right diaphragm excursion>25.4 mm were associated with an FVC >50% with, respectively, an area under the curve (AUC) of 0.95 (P =.001) and 0.93 (P <.001). A left diaphragm TF >26.8% and a left diaphragm excursion >21.5 mm were associated with an FVC >50% with, respectively, an AUC of 0.95 (P =.011) and 0.97 (P <.001). Discussion Diaphragm excursion and diaphragm TF can predict restrictive pulmonary insufficiency in DMD. [ABSTRACT FROM AUTHOR]

Introduction: Hereditary inclusion body myopathy (hIBM) refers to a group of clinically and genetically heterogeneous diseases. The overlapping histochemical features of hIBM with other genetic disorders lead to low diagnostic rates with targeted single-gene sequencing. This is true for the most prevalent form of hIBM, GNEpathy. Therefore, we used whole-exome sequencing (WES) to determine whether a cohort of clinically suspected GNEpathy patients undiagnosed by targeted GNE analysis could be genetically characterized.Methods: Twenty patients with hIBM but undiagnosed by targeted GNE sequencing were analyzed by WES before data filtering on 306 genes associated with neuromuscular disorders.Results: Seven patients out of 20 were found to have disease-causing mutations in genes associated with hIBM or genes allowing for hIBM in the differential diagnosis or associated with unexpected diagnosis.Discussion: Next-generation sequencing is an efficient strategy in the context of hIBM, resulting in a molecular diagnosis for 35% of the patients initially undiagnosed by targeted GNE analysis. Muscle Nerve 56: 993-997, 2017. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Duchenne muscular dystrophy (DMD) is characterized by respiratory and heart involvements. In the context of permanently wheelchair bound and on mechanical ventilation (MV) patients, the clinical presentation of acute heart failure (AHF) syndrome may be atypical. We sought to describe clinical and genetic profiles and to determine prognosis of DMD and Becker muscular dystrophy (BMD) patients on home MV (HMV), hospitalized for AHF. Methods and results: We included genetically proven DMD and BMD patients on HMV admitted for AHF. A total of 13 patients (11 DMD and 2 BMD) fulfilled the inclusion criteria. Median age was 34.0 [interquartile range (IQR) 26.0; 40.0] years. Median pulmonary vital capacity was 9.0% (6.0; 15.0) of predicted value. Long‐term invasive ventilation was performed in 69% of patients. All the 11 DMD patients carried out‐of‐frame DMD gene mutations. At admission, dyspnoea was present in 46%, lipothymia in 23%, and abdominal discomfort in 38.4% of patients. A total of 53.8% of patients showed anasarca. Cardiogenic shock presentation was found in six patients (46%). Ejection fraction was severely altered [median 25% (IQR 20; 30)]. Intra‐hospital mortality rate was 30%, reaching 53.8 % after 1 year. Previous episodes of AHF ≥ 2 were associated with intra‐hospital mortality (P = 0.025). In patients with cardiogenic shock, intra‐hospital mortality rate was 66.6%, reaching 83.3% after 1 year. Conclusions: In adult DMD and BMD patients with severe ejection fraction alteration and on HMV, admitted for AHF, right cardiac signs are frequent. The intra‐hospital and 1 year mortality rate was high and was associated with previous episodes of AHF ≥ 2. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: Acid α-glucosidase deficiency, that is, Pompe disease, is a glycogenosis for which enzyme replacement therapy (ERT) is available. It is not known whether patients diagnosed at an asymptomatic stage should be treated to prevent progression of the disease. Methods: We investigated 7 patients with asymptomatic Pompe disease identified from the French Pompe registry. Results: The patients had a mean age of 45 (range 24-75) years, a median follow-up duration of 2 (range 1-22) years, and normal clinical examination, pulmonary function tests (PFTs), and echocardiography. All presented with at least 1 subclinical abnormality, including hyperCKemia, vacuolar myopathy, and muscle MRI abnormalities, suggesting that subclinical myopathy was present in all cases. Conclusions: Asymptomatic Pompe disease may remain clinically silent for decades, and affected patients should be monitored closely for overt myopathy using clinical examination, PFTs, and muscle MRI to determine when to start ERT. Muscle Nerve 51: 884-889, 2015 [ABSTRACT FROM AUTHOR]

Background: Glycogen storage disease type III (GSDIII) is a rare autosomal recessive disorder due to glycogen debranching enzyme (GDE) deficiency. It results in a multisystemic disease with predominant hepatic and myopathic symptoms. While frequent social maladjustment has been observed in our clinical practice, cognitive and psychological disturbances have never been assessed. The aim of this pilot study was to examine and characterize the cognitive profile of patients with GSDIII. Methods: Seven patients (six women and one man, mean age: 38.7 ± 11.6 years) with GSDIII underwent a neuropsychological set of tests assessing global cognitive efficiency, executive functions, social cognition, apathy, and episodic memory. Results: All patients presented previous psychopathological history. We observed attention fluctuations for each patient, and impaired global cognitive efficiency with deficiencies in executive functions in 5/7 patients. Emotional skills (social cognition) were impaired in five patients. Memory was mostly preserved. Conclusion: The impairment in social cognition (recognition of emotions and ability to attribute mental states to others) and executive functions observed could be a consequence of orbito-frontal dysfunction due to the abnormal glycogen metabolism characteristic of the underlying disease. These results are consistent with the hypothesis of a central nervous system involvement in patients with GSDIII, but need to be confirmed in future research. This could explain the social and economic difficulties, and the lack of compliance to the medical follow-up presented by these patients. It suggests that these disturbances need to be taken into account when planning the medical management of patients with GSDIII. [ABSTRACT FROM AUTHOR]

Glycogen storage diseases are important causes of myopathy and cardiomyopathy. We describe 10 patients from 8 families with childhood or juvenile onset of myopathy, 8 of whom also had rapidly progressive cardiomyopathy, requiring heart transplant in 4. The patients were homozygous or compound heterozygous for missense or truncating mutations in RBCK1, which encodes for a ubiquitin ligase, and had extensive polyglucosan accumulation in skeletal muscle and in the heart in cases of cardiomyopathy. We conclude that RBCK1 deficiency is a frequent cause of polyglucosan storage myopathy associated with progressive muscle weakness and cardiomyopathy. Ann Neurol 2013;74:914-919 [ABSTRACT FROM AUTHOR]

Background: Recessive LPIN1 mutations were identified as a cause of severe rhabdomyolysis in pediatric patients. The human lipin family includes two other closely related members, lipin-2 and 3, which share strong homology and similar activity. The study aimed to determine the involvement of the LPIN family genes in a cohort of pediatric and adult patients (n = 171) presenting with muscular symptoms, ranging from severe (CK >10 000 UI/L) or moderate (CK <10 000 UI/L) rhabdomyolysis (n = 141) to exercise-induced myalgia (n = 30), and to report the clinical findings in patients harboring mutations. Methods: Coding regions of LPIN1, LPIN2 and LPIN3 genes were sequenced using genomic or complementary DNAs. Results: Eighteen patients harbored two LPIN1 mutations, including a frequent intragenic deletion. All presented with severe episodes of rhabdomyolysis, starting before age 6 years except two (8 and 42 years). Few patients also suffered from permanent muscle symptoms, including the eldest ones (≥40 years). Around 3/4 of muscle biopsies showed accumulation of lipid droplets. At least 40% of heterozygous relatives presented muscular myalgia. Nine heterozygous SNPs in LPIN family genes were identified in milder phenotypes (mild rhabdomyolysis or myalgia). These variants were non-functional in yeast complementation assay based on respiratory activity, except the LPIN3-P24L variant. Conclusion: LPIN1-related myolysis constitutes a major cause of early-onset rhabdomyolysis and occasionally in adults. Heterozygous LPIN1 mutations may cause mild muscular symptoms. No major defects of LPIN2 or LPIN3 genes were associated with muscular manifestations. [ABSTRACT FROM AUTHOR]

The objective of this 12-month study was to describe the clinical features of late-onset Pompe disease and identify appropriate outcome measures for use in clinical trials. Assessments included quantitative muscle testing (QMT), functional activities (FAA), 6-min walk test (6MWT), and pulmonary function testing (PFT). Percent predicted values indicated quantifiable upper and lower extremity weakness, impaired walking ability, and respiratory muscle weakness. Significant declines in arm and leg strength and pulmonary function were observed during the study period. The outcome measures were demonstrated to be safe and reliable. Symptom duration was identified as the best predictor of the extent of skeletal and respiratory muscle weakness. Muscle Nerve 38: 1236-1245, 2008 [ABSTRACT FROM AUTHOR]

Background Chronic respiratory failure and heart involvement may occur in Duchenne muscular dystrophy. We aimed to assess the prognostic value of the right ventricular (RV) systolic dysfunction in patients with Duchenne muscular dystrophy. Methods and Results We studied 90 genetically proven patients with Duchenne muscular dystrophy from 2010 to 2019, to obtain respiratory function and Doppler echocardiographic RV systolic function. Prognostic value was assessed in terms of death and cardiac events. The median age was 27.5 years, and median forced vital capacity was at 10% of the predicted value: 83 patients (92%) were on home mechanical ventilation. An RV systolic dysfunction was found in 46 patients (51%). In patients without RV dysfunction at inclusion, a left ventricular systolic dysfunction at inclusion was associated with a higher risk of developing RV dysfunction during follow-up with an odds ratio of 4.5 ( P =0.03). RV systolic dysfunction was significantly associated with cardiac events, mainly acute heart failure (62%) and cardiogenic shock (23%). In a multivariable Cox model, the adjusted hazard ratio was 4.96 (95% CI [1.09-22.6]; P =0.04). In terms of death, we found a significant difference between patients with RV dysfunction versus patients without RV dysfunction in the Kaplan-Meier curves (log-rank P =0.045). Conclusions RV systolic dysfunction is frequently present in patients with Duchenne muscular dystrophy and is associated with increased risk of cardiac events, irrespective of left ventricular dysfunction and mechanical ventilation. Registration URL: https://www.clinicaltrials.org; unique identifier: NCT02501083.

Defining disease severity in patients with Pompe disease is important for prognosis and monitoring the response to therapies. Current approaches include qualitative and quantitative assessments of the disease burden, and clinical measures of the impact of the disease on affected systems. The aims of this manuscript were to review a noninvasive urinary glucose tetrasaccharide biomarker of glycogen storage, and to discuss advances in imaging techniques for determining the disease burden in Pompe disease. The glucose tetrasaccharide, Glcα1-6Glcα1-4Glcα1-4Glc (Glc(4) ), is a glycogen-derived limit dextrin that correlates with the extent of glycogen accumulation in skeletal muscle. As such, it is more useful than traditional biomarkers of tissue damage, such as CK and AST, for monitoring the response to enzyme replacement therapy in patients with Pompe disease. Glc(4) is also useful as an adjunctive diagnostic test for Pompe disease when performed in conjunction with acid alpha-glucosidase activity measurements. Review of clinical records of 208 patients evaluated for Pompe disease by this approach showed Glc(4) had 94% sensitivity and 84% specificity for Pompe disease. We propose Glc(4) is useful as an overall measure of disease burden, but does not provide information on the location and distribution of excess glycogen accumulation. In this manuscript we also review magnetic resonance spectroscopy and imaging techniques as alternative, noninvasive tools for quantifying glycogen and detailing changes, such as fibrofatty muscle degeneration, in specific muscle groups in Pompe disease. These techniques show promise as a means of monitoring disease progression and the response to treatment in Pompe disease. © 2012 Wiley Periodicals, Inc., (Copyright © 2012 Wiley Periodicals, Inc.)