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Background We recently described the genotype/phenotype features of all Spanish patients diagnosed with McArdle disease as of January 2011 ( n  = 239, prevalence of ~1/167,000) ( J Neurol Neurosurg Psychiatry 2012;83:322–8). Several caveats were however identified suggesting that the prevalence of the disease is actually higher. Methods We have now updated main genotype/phenotype data, as well as potential associations within/between them, of all Spanish individuals currently diagnosed with McArdle disease (December 2016). Results Ninety-four new patients (all Caucasian) have been diagnosed, yielding a prevalence of ~1/139,543 individuals. Around 55% of the mutated alleles have the commonest PYGM pathogenic mutation p.R50X, whereas p.W798R and p.G205S account for 10 and 9% of the allelic variants, respectively. Seven new mutations were identified: p.H35R, p.R70C, p.R94Q, p.L132WfsX163, p.Q176P, p.R576Q, and c.244-3_244-2CA. Almost all patients show exercise intolerance, the second wind phenomenon and high serum creatine kinase activity. There is, however, heterogeneity in clinical severity, with 8% of patients being asymptomatic during normal daily life, and 21% showing limitations during daily activities and fixed muscle weakness. A major remaining challenge is one of diagnosis, which is often delayed until the third decade of life in 72% of new patients despite the vast majority (86%) reporting symptoms before 20 years. An important development is the growing proportion of those reporting a 4-year improvement in disease severity (now 34%) and following an active lifestyle (50%). Physically active patients are more likely to report an improvement after a 4-year period in the clinical course of the disease than their inactive peers (odds ratio: 13.98; 95% confidence interval: 5.6, 34.9; p  < 0.001). Peak oxygen uptake is also higher in the former (20.7 ± 6.0 vs. 16.8 ± 5.3 mL/kg/min, p  = 0.0013). Finally, there is no association between PYGM genotype and phenotype manifestation of the disease. Conclusions The reported prevalence of McArdle disease grows exponentially despite frequent, long delays in genetic diagnosis, suggesting that many patients remain undiagnosed. Until a genetic cure is available (which is not predicted in the near future), current epidemiologic data support that adoption of an active lifestyle is the best medicine for these patients.

Neutrophils are the most abundant, short lived, and terminally differentiated leukocytes with distinct tiers of arsenals to counter pathogens. Neutrophils were traditionally considered transcriptionally inactive cells, but recent researches in the field led to a paradigm shift in neutrophil biology and revealed subpopulation heterogeneity, and functions pivotal to immunity and inflammation. Furthermore, recent unfolding of metabolic plasticity in neutrophils has challenged the long-standing concept of their sole dependence on glycolytic pathway. Metabolic adaptations and distinct regulations have been identified which are critical for neutrophil differentiation and functions. The metabolic reprogramming of neutrophils by inflammatory mediators or during pathologies such as sepsis, diabetes, glucose-6-phosphate dehydrogenase deficiency, glycogen storage diseases (GSDs), systemic lupus erythematosus (SLE), rheumatoid arthritis, and cancer are now being explored. In this review, we discuss recent developments in understanding of the metabolic regulation, that may provide clues for better management and newer therapeutic opportunities for neutrophil centric immuno-deficiencies and inflammatory disorders.

Pompe disease and Mucopolysaccharidoses Type I (MPS-I) are lysosomal disorders caused by a deficiency of [alpha]-glucosidase and alpha-L-iduronidase, respectively. The mainstay of treatment is enzyme replacement therapy (ERT), a life-long treatment that requires regular I.V. infusions. Hospital-based therapy can, however, negatively impact quality of life over time. The purpose of the HomERT study (Home infusions of ERT) was to evaluate the safety, treatment compliance, and treatment satisfaction related to home therapy of Pompe disease patients with Myozyme.sup.® (alglucosidase alfa) and MPS-I patients with Aldurazyme.sup.® (laronidase). The final results are presented in this paper. The HomERT study was a multicenter, non-interventional, minimum 12-month prospective observational, double-cohort study that analyzed 56 patients from 14 sites in Italy from October 2021 to February 2024: cohort A (Pompe disease - 47 patients) and cohort B (MPS-I - 9 patients: 6 Hurler/Scheie, 3 Scheie). During the observation period, the mean (SD) number of missed infusions was 5.8 (3.92) in cohort A and 3.0 (3.52) in cohort B, corresponding to a mean (SD) of missed infusions of 19.8 (32.7)% and 4.1 (4.2)%, respectively, versus the number of planned infusions. Only 2 patients in cohort A returned to the hospital setting due to \"adverse event\" and \"other\" reasons. A total of 13 Adverse Drug Reactions (ADR) were reported during the home-care setting before and after enrollment. The average number of ADRs per patient was 0.2 (1.46) in cohort A and 0.2 (0.67) in group B, and the rate of ADRs/year was 0.15 (95% CI: 0.06; 0.34) in cohort A and 0.06 (95% CI: 0.01; 0.38) in cohort B. The majority of patients preferred home-based infusions (cohort A: 93.6%; cohort B: 88.9%), and the main reason was attributed to treatment convenience (cohort A: 93.6%; cohort B: 100%). Despite the underlying conditions, most patients self-evaluated their health as \"Fair\" in cohort A (36.2%) and \"Good\" in cohort B (44.5%). The use of ERT with [alpha]-glucosidase and alpha-L-iduronidase alfa remains a strong candidate for home therapy, with favorable safety profile, improved treatment ERT compliance, and patient satisfaction. NCT05073783.

Glycogen plays a central role in glucose homeostasis and is abundant in several types of tissue. We report an MRI method for imaging glycogen noninvasively with enhanced detection sensitivity and high specificity, using the magnetic coupling between glycogen and water protons through the nuclear Overhauser enhancement (NOE). We show in vitro that the glycogen NOE (glycoNOE) signal is correlated linearly with glycogen concentration, while pH and temperature have little effect on its intensity. For validation, we imaged glycoNOE signal changes in mouse liver, both before and after fasting and during glucagon infusion. The glycoNOE signal was reduced by 88 ± 16% (n = 5) after 24 h of fasting and by 76 ± 22% (n = 5) at 1 h after intraperitoneal (i.p.) injection of glucagon, which is known to rapidly deplete hepatic glycogen. The ability to noninvasively image glycogen should allow assessment of diseases in which glucose metabolism or storage is altered, for instance, diabetes, cardiac disease, muscular disorders, cancer, and glycogen storage diseases.

Two brothers with an undefined congenital disorder of glycosylation were found to have phosphoglucomutase 1 deficiency, which has previously been described as a glycogen storage disorder. Supplementation with galactose improves protein glycosylation in this disease. Protein N-glycosylation is a ubiquitous process in all organ systems. During N-glycosylation, glycan precursors are assembled from monosaccharide units and then covalently attached to asparagine residues in the nascent peptide chain of a protein (Figure 1). The protein-bound glycans undergo further processing to generate mature glycoproteins. Genetic defects in protein N-glycosylation, designated as congenital disorders of glycosylation, lead to multisystem disorders. Mutations of genes involved in N-glycosylation may affect either the biosynthesis of the glycan precursor (congenital disorder of glycosylation type I [CDG-I]) or the processing of the glycan after its attachment to the protein (congenital disorder of glycosylation type . . .

The liver is a major store of glycogen and is essential in maintaining systemic glucose homeostasis. In healthy individuals, glycogen synthesis and breakdown in the liver are tightly regulated. Abnormal glycogen metabolism results in prominent pathological changes in the liver, often manifesting as hepatic glycogenosis or glycogen inclusions. This can occur in genetic glycogen storage disease or acquired conditions with insulin dysregulation such as diabetes mellitus and non-alcoholic fatty liver disease or medication effects. Some primary hepatic tumors such as clear cell hepatocellular carcinoma also demonstrate excessive glycogen accumulation. This review provides an overview of the pathological manifestations and molecular mechanisms of liver diseases associated with abnormal glycogen accumulation.

Glycogen storage disease type 1a (GSD1a) is caused by a congenital deficiency of glucose-6-phosphatase-[alpha] (G6Pase-[alpha], encoded by G6PC), which is primarily associated with life-threatening hypoglycemia. Although strict dietary management substantially improves life expectancy, patients still experience intermittent hypoglycemia and develop hepatic complications. Emerging therapies utilizing new modalities such as adeno- associated virus and mRNA with lipid nanoparticles are under development for GSD1a but potentially require complicated glycemic management throughout life. Here, we present an oligonucleotide-based therapy to produce intact G6Pase-[alpha] from a pathogenic human variant, G6PC c.648G>T, the most prevalent variant in East Asia causing aberrant splicing of G6PC. DS-4108b, a splice-switching oligonucleotide, was designed to correct this aberrant splicing, especially in liver. We generated a mouse strain with homozygous knockin of this variant that well reflected the pathophysiology of patients with GSD1a. DS-4108b recovered hepatic G6Pase activity through splicing correction and prevented hypoglycemia and various hepatic abnormalities in the mice. Moreover, DS-4108b had long-lasting efficacy of more than 12 weeks in mice that received a single dose and had favorable pharmacokinetics and tolerability in mice and monkeys. These findings together indicate that this oligonucleotide- based therapy could provide a sustainable and curative therapeutic option under easy disease management for GSD1a patients with G6PC c.648G>T.

Clinical pathway recommendations (CPR) are based on existing guidelines and deliver a short overview on how to deal with a specific diagnosis, resulting therapy and follow-up. In this paper we propose a methodology for developing CPRs for Pompe disease, a metabolic myopathy caused by deficiency of lysosomal acid alpha-glucosidase. The CPR document was developed within the activities of the MetabERN, a non-profit European Reference Network for Metabolic Diseases established by the European Union. A working group was selected among members of the MetabERN lysosomal storage disease subnetwork, with specific expertise in the care of Pompe disease, and patient support group representatives. The working strategy was based on a systematic literature search to develop a database, followed by quality assessment of the studies selected from the literature, and by the development of the CPR document according to a matrix provided by MetabERN. Quality assessment of the literature and collection of citations was conducted according to the AGREE II criteria and Grading of Recommendations, Assessment, Development and Evaluation methodology. General aspects were addressed in the document, including pathophysiology, genetics, frequency, classification, manifestations and clinical approach, laboratory diagnosis and multidisciplinary evaluation, therapy and supportive measures, follow-up, monitoring, and pregnancy. The CPR document that was developed was intended to be a concise and easy-to-use tool for standardization of care for patients among the healthcare providers that are members of the network or are involved in the care for Pompe disease patients.

Pompe's disease, glycogen-storage disease type II, and acid maltase deficiency are alternative names for the same metabolic disorder. It is a pan-ethnic autosomal recessive trait characterised by acid α-glucosidase deficiency leading to lysosomal glycogen storage. Pompe's disease is also regarded as a muscular disorder, but the generalised storage of glycogen causes more than mobility and respiratory problems. The clinical spectrum is continuous and broad. First symptoms can present in infants, children, and adults. Cardiac hypertrophy is a key feature of classic infantile Pompe's disease. For a long time, there was no means to stop disease progression, but the approval of enzyme replacement therapy has substantially changed the prospects for patients. With this new development, the disease is now among the small but increasing number of lysosomal storage disorders, for which treatment has become a reality. This review is meant to raise general awareness, to present and discuss the latest insights in disease pathophysiology, and to draw attention to new developments about diagnosis and care. We also discuss the developments that led to the approval of enzyme replacement therapy with recombinant human α-glucosidase from Chinese hamster ovary cells (alglucosidase alfa) by the US Food and Drug Administration and European Medicines Agency in 2006, and review clinical practice. [PUBLICATION ABSTRACT]

Mauriac syndrome is a rare complication of type 1 diabetes mellitus (T1D) with chronically elevated hemoglobin A1C (HbA1c) that is characterized by short stature, delayed puberty, cushingoid features, and hepatic glycogenosis. We report a 14-year-old male patient with T1D managed with multiple daily insulin injections who presented with growth failure and delayed puberty in the setting of several years of HbA1c > 12% (SI: > 108 mmol/mol) (reference range, < 5.7% [SI: < 39 mmol/mol]). He was initially suspected to have growth hormone deficiency, failed a growth hormone stimulation test and received growth hormone treatment without an increase in height velocity. After several months, he presented with abdominal distention due to new hepatomegaly. Laboratory evaluation revealed transaminitis with normal synthetic function and absence of cholestasis. Liver biopsy confirmed hepatic glycogenosis. Treatment included T1D management re-education, psychosocial support, and transition to automated insulin delivery (AID). AID resulted in decreased HbA1c level, normalized liver enzymes, resolution of hepatomegaly, puberty progression, and increased linear growth in line with his mid-parental height. This patient demonstrated that growth failure and delayed puberty can precede hepatic glycogenosis and that AID is a safe and effective treatment option for patients with Mauriac syndrome.