Phosphorylase Deficiency Research Articles

IMAGING: EP.332 Patients with McArdle disease have increased fat replacement of paraspinal muscles on MRI: a European multicenter study

IMAGING: EP.332 Patients with McArdle disease have increased fat replacement of paraspinal muscles on MRI: a European multicenter study

METABOLIC MYOPATHIES: EP.205 High prevalence of paraspinal muscle involvement in McArdle disease

METABOLIC MYOPATHIES: EP.205 High prevalence of paraspinal muscle involvement in McArdle disease

METABOLIC MYOPATHIES: EP.206 No effect of oral ketone ester supplementation on exercise capacity in patients with McArdle disease: a randomized placebo-controlled cross-over study

METABOLIC MYOPATHIES: EP.206 No effect of oral ketone ester supplementation on exercise capacity in patients with McArdle disease: a randomized placebo-controlled cross-over study

METABOLIC MYOPATHIES: EP.208 Natural history of McArdle disease: a single centre study of a cohort of 220 patients

METABOLIC MYOPATHIES: EP.208 Natural history of McArdle disease: a single centre study of a cohort of 220 patients

Investigating the Variation of TREC/KREC in Combined Immunodeficiencies

T-cell receptor excision circles (TREC)/Kappa-deleting recombination excision circles (KREC) assay has been recently recognized for detecting patients with primary (T- and/or B-cell) immunodeficiency (PID). We aimed to investigate the alterations of these biomarkers in some combined immunodeficiency patients compared to the healthy controls in different age groups. TREC and KREC were assessed in a total of 82 PID patients, most of them with exact genetic diagnosis (3 months to 42 years); using quantitative real-time-polymerase chain reaction (PCR). Patients had a final diagnosis of common variable immunodeficiency (n=23), ataxia-telangiectasia (AT) (n=17), hyper-IgE syndrome (HIES) (7 with DOCK8 deficiency, 4 with signal transducer and activator of transcription 3 (STAT3) deficiency, and 8 children with unknown genetic defects), Wiskott-Aldrich syndrome (WAS) (n=20), purine nucleoside phosphorylase (PNP)deficiency(n=1), dedicator of cytokinesis2 (DOCK2) deficiency (n=1), recombinase activating gene1 (RAG1) deficiency (n=1). Very low to zero amounts of TREC and/or KREC were detected in 14 out of 23 cases of common variable immunodeficiency (CVID), 14 out of 17 cases of AT, 8 out of 20 cases of WAS, 6 out of 7 cases of DOCK8-deficiency patients, 4 out of 8 cases of HIES with unknown genetic defects and all patients with defects in DOCK2, PNP, and RAG1. STAT3-deficient patients were normal for both biomarkers. All patients showed a significant difference in both markers compared to age-matched healthy controls. Our findings highlight that apart from severe types of T/B cell defects, this assay can also be used for early diagnosis the patients with late-onset of disease and even PIDs without a positive family history.

Whole-body muscle MRI in McArdle disease

This study describes muscle involvement on whole-body MRI (WB-MRI) scans at different stages of McArdle disease. WB-MRI was performed on fifteen genetically confirmed McArdle disease patients between ages 25 to 80. The degree of fatty substitution was scored for 60 muscles using Mercuri's classification. All patients reported an intolerance to exercise and episodes of rhabdomyolysis. A mild fixed muscle weakness was observed in 13/15 patients with neck flexor weakness in 7/15 cases, and proximal muscle weakness in 6/15 cases. A moderate scapular winging was observed in five patients. A careful review of the MRI scans, as well as hierarchical clustering of patients by Mercuri scores, pointed out recurrent muscle changes particularly in the subscapularis, anterior serratus, erector spinae and quadratus femoris muscles. WB-MRI imaging provides clinically relevant information and is a useful tool to orient toward the diagnosis of McArdle disease.

The Phenotypic and Genetic Spectrum of Glycogen Storage Disease Type VI.

Glycogen storage disease type VI (GSD VI) is an autosomal recessive disorder of glycogen metabolism due to mutations in the glycogen phosphorylase gene (PYGL), resulting in a deficiency of hepatic glycogen phosphorylase. We performed a systematic literature review in order to collect information on the clinical phenotypes and genotypes of all published GSD VI patients and to compare the data to those for GSD IX, a biochemically and clinically very similar disorder caused by a deficiency of phosphorylase kinase. A total of 63 genetically confirmed cases of GSD VI with clinical information were identified (median age: 5.3 years). The age at presentation ranged from 5 weeks to 38 years, with a median of 1.8 years. The main presenting symptoms were hepatomegaly and poor growth, while the most common laboratory findings at initial presentation comprised elevated activity of liver transaminases, hypertriglyceridemia, fasting hypoglycemia and postprandial hyperlactatemia. Liver biopsies (n = 37) showed an increased glycogen content in 89.2%, liver fibrosis in 32.4% and early liver cirrhosis in 10.8% of cases, respectively. No patient received a liver transplant, and one successful pregnancy was reported. Our review demonstrates that GSD VI is a disorder with broad clinical heterogeneity and a small number of patients with a severe phenotype and liver cirrhosis. Neither clinical nor laboratory findings allow for a differentiation between GSD VI and GSD IX. Early biochemical markers of disease severity or clear genotype phenotype correlations are missing. Given the overall benign and unspecific phenotype and the need for enzymatic or genetic analyses for confirmation of the diagnosis, GSD VI is likely underdiagnosed. With new treatment approaches in sight, early, pre-symptomatic diagnosis, especially with respect to hepatic cirrhosis, will become even more important.

McArdle disease: an important consideration in atraumatic compartment syndrome

McArdle disease: an important consideration in atraumatic compartment syndrome

Molecular diagnosis of McArdle disease using whole-exome sequencing.

Whole-exome sequencing (WES) analysis has been used recently as a diagnostic tool for finding molecular defects. In the present study, researchers attempted to analyze molecular defects through WES in a 13-year-old female patient who had not been diagnosed through a conventional genetic approach. DNA was extracted and subjected to WES analysis to identify the genetic defect. A total of 106,728 exons and splicing variants were selected, and synonymous single nucleotide variants (SNVs) and general single nucleotide polymorphisms (SNPs) were filtered out. Finally, nonsynonymous SNVs (c.C415T and c.C389T) of the PYGM gene were identified in nine compound heterozygous mutations. PYGM encodes myophosphorylase and degrades glycogen in the muscle to supply energy to muscle cells. The present study revealed that the patient's father had a c.C389T mutation and the mother had a c.C415T mutation, resulting in A130V and R139W missense mutations, respectively. To the best of our knowledge, the A130V variant in PYGM has not been reported in the common variant databases. All variations of the patient's family detected using WES were verified by Sanger sequencing. Because the patient had compound heterozygous mutations in the PYGM gene, the patient was presumed to exhibit markedly decreased muscle phosphorylase activity. To assess the function of myophosphorylase, an ischemic forearm exercise test was performed. The blood ammonia level sharply increased and the lactate level maintained a flat curve shape similar to the typical pattern of McArdle disease. Therefore, the diagnosis of the patient was confirmed to be McArdle disease, a glycogen storage disease. Through WES analysis, accurate and early diagnosis could be made in the present study. This report describes a novel compound heterozygous mutation of the PYGM gene in a Korean patient.

International patient group harnesses social media to help inform rare disease research: use of a low carbohydrate ketogenic diet in McArdle disease.

To highlight the benefits of a partnership between patient advocacy organizations (PAO) and clinical researchers in order to clinically study the prior anecdotal patient experience of utilizing a low-carbohydrate ketogenic diet (LCKD) to manage McArdle disease. The bedside-to-bench and back again method of translational research is well suited to explore anecdotal patient experiences, particularly for rare diseases. In McArdle disease, patients have explored the use of a LCKD to address the ubiquitous occurrence of physical activity intolerance and minimize associated adverse events. The International Association for Muscle Glycogen Storage Disease harnessed the power of social media to better understand this patient-centric finding and has subsequently partnered with clinical researchers to convey patient-centered priorities for research. From this partnership, a series of clinical and survey studies have been initiated. Collaboration between PAOs and clinical researchers has the potential to foster patient empowerment, advance anecdotal experiences into scientific hypotheses, and ultimately guide the development of management guidelines that reflect the patient perspective.

P.125 McArdle’s disease: Case report of a rare condition in pregnancy

Introduction: McArdle’s disease (glycogen storage disease type V) is an inherited disorder of glycogen metabolism affecting only skeletal muscle. [1] Quinlivan R, Buckley J, James M, et al McArdle disease: a clinical review. J Neurol Neurosurg Psychiatry 2010;81:1182-8. Google Scholar Data on anaesthetic implications in pregnant women with this condition are scarce, thus posing a challenge to their management. We describe a case of a pregnant woman with McArdle’s disease presenting to our tertiary unit.

The phenotypic and genotypic features of a Scottish cohort with McArdle disease

This retrospective study evaluated the phenotypic and genotypic features of 14 patients with McArdle disease attending the West of Scotland adult muscle clinic. Although all patients experienced exercise-induced cramps, exercise intolerance and hyperCKaemia, only 71% (n = 10) experienced the second wind phenomenon, rhabdomyolysis and/or myoglobinuria. We observed a high rate of fixed muscle weakness (50%; n = 7), coronary artery disease (36%; n = 5), and psychological comorbidity (50%; n = 7). Although 79% had symptom onset in the first decade of life, the mean age at presentation and at genetic diagnosis was 43.8 years and 47.7 years, respectively. 93% had at least one copy of the common PYGM pathogenic variant, c.148C > T, p.(Arg50*), with 50% (n = 7) of the cohort being homozygous. Our cohort highlights the phenotypic variability seen in McArdle disease and underscores the potential for late-onset presentations. It emphasises the need for improved awareness and recognition of this condition amongst neurologists, rheumatologists and general physicians. A history of exercise intolerance and second wind phenomenon may not always be volunteered by the patient, underscoring the need to ask specific questions in clinic to extrapolate the relevant symptoms in this patient cohort.

McArdle disease and pregnancy: A case report and scoping review of pregnancy outcomes.

McArdle disease is an autosomal recessive disorder affecting skeletal muscle glycogen metabolism. Limited data are available regarding pregnancy outcomes with this genetic condition. We present a recent case of a woman with McArdle disease, along with a scoping review of all published literature regarding pregnancy and delivery outcomes for women with McArdle disease. A total of 35 cases are summarised. Overall, pregnancy does not worsen or increase the risk for disease flare. Women can successfully deliver vaginally, with consideration of an assisted second stage recommended to reduce the risk of postpartum rhabdomyolysis.

Successful pregnancy in a woman with glycogen storage disease type 6

Glycogen storage disease type VI is caused by biallelic variants in the PYGL gene that result in hepatic glycogen phosphorylase deficiency. The disorder is clinically characterized by hepatomegaly and recurrent ketotic hypoglycemia from infancy. Although most patients reach adulthood without major complications, no pregnancies in women with GSD VI have been reported so far. We report on a successful pregnancy in a GSD VI patient that resulted in a healthy offspring and describe the pre- and perinatal management.

Muscle Glycogen Phosphorylase and Its Functional Partners in Health and Disease.

Glycogen phosphorylase (PG) is a key enzyme taking part in the first step of glycogenolysis. Muscle glycogen phosphorylase (PYGM) differs from other PG isoforms in expression pattern and biochemical properties. The main role of PYGM is providing sufficient energy for muscle contraction. However, it is expressed in tissues other than muscle, such as the brain, lymphoid tissues, and blood. PYGM is important not only in glycogen metabolism, but also in such diverse processes as the insulin and glucagon signaling pathway, insulin resistance, necroptosis, immune response, and phototransduction. PYGM is implicated in several pathological states, such as muscle glycogen phosphorylase deficiency (McArdle disease), schizophrenia, and cancer. Here we attempt to analyze the available data regarding the protein partners of PYGM to shed light on its possible interactions and functions. We also underline the potential for zebrafish to become a convenient and applicable model to study PYGM functions, especially because of its unique features that can complement data obtained from other approaches.

Magnetization Transfer Ratio in Lower Limbs of Late Onset Pompe Patients Correlates With Intramuscular Fat Fraction and Muscle Function Tests.

Objectives: Magnetization transfer (MT) imaging exploits the interaction between bulk water protons and protons contained in macromolecules to induce signal changes through a special radiofrequency pulse. MT detects muscle damage in patients with neuromuscular conditions, such as limb-girdle muscular dystrophies or Charcot-Marie-Tooth disease, which are characterized by progressive fiber loss and replacement by fatty tissue. In Pompe disease, in which there is, in addition, an accumulation of glycogen inside the muscle fibers, MT has not been tested yet. Our aim is to estimate MT ratio (MTR) in the skeletal muscle of these patients and correlate it with intramuscular fat fraction (FF) and results of muscle function tests.Methods: We obtained two-point axial Dixon and Dixon-MT sequences of the right thigh on a 1.5 Teslas MRI scanner in 60 individuals, including 29 late onset Pompe disease patients, 2 patients with McArdle disease, and 29 age and sex matched healthy controls. FF and MTR were estimated. Muscle function using several muscle function tests, including quantification of muscle strength, timed test quality of life scales, conventional spirometry obtaining forced vital capacity while sitting and in the supine position, were assessed in all patients.Results: MTR was significantly lower in Pompe patients compared with controls (45.5 ± 8.5 vs. 51.7 ± 2.3, Student T-test, p < 0.05). There was a negative correlation between the MTR and FF muscles studied (correlation coefficient: −0.65, Spearman test: p < 0.05). MTR correlated with most of the muscle function test results. We analyzed if there was any difference in MTR values between Pompe patients and healthy controls in those muscles that did not have an increase in fat, a measure that could be related to the presence of glycogen in skeletal muscles, but we did not identify significant differences except in the adductor magnus muscle (48.4 ± 3.6 in Pompe vs. 51 ± 1.3 in healthy controls, Student T-test = 0.023).Conclusions: MTR is a sensitive tool to identify muscle loss in patients with Pompe disease and shows a good correlation with muscle function tests. Therefore, the MT technique can be useful in monitoring muscle degeneration in Pompe disease in clinical trials or natural history studies.

Retinopathy in McArdle Disease

Retinopathy in McArdle Disease

When POTS is the tip of the iceberg: Rare cases of dysautonomia as a possible manifestation of another disorder.

Postural tachycardia syndrome (POTS) is a heterogenous disorder of the autonomic nervous system that is commonly associated with small fiber neuropathy, Ehlers-Danlos Syndrome and autoimmune disorders, but association with rare conditions may also occur. Reported here are clinical features, diagnostic tests and treatment outcomes of 6 unique patients who presented with POTS and were subsequently diagnosed with Fabry disease, McArdle disease, Complex V mitochondrial disease, carcinoid tumor, Hodgkin's lymphoma and chemotherapy-induced neuropathy. All patients (age range 15-57 years, 3 females, 3 males) presented with orthostatic intolerance of at least 6 months duration, and all patients had co-morbid small fiber neuropathy. Five patients presented with symptoms of POTS months to years before the underlying or associated medical condition was discovered, and three out of six patients experienced either complete resolution or significant improvement of POTS after treatment of the underlying or associated medical condition. In rare cases, POTS can present as a possible manifestation of genetic, neoplastic or neurotoxic disorders. Unusual clinical features that fall outside of the typical spectrum of dysautonomia can point toward the presence of another disorder and help guide further diagnostic investigation.

Unilateral pattern of macular dystrophy and associated systemic pathology

Retinal pattern dystrophies are a heterogeneous group of generally bilateral and symmetrical maculopathies that, curiously, can be associated with different systemic diseases. This article describes a patient with unilateral pattern dystrophies, as well as associated McArdle disease and idiopathic pulmonary fibrosis.

Generation of the iPSC line IISHDOi007-A from peripheral blood mononuclear cells from a patient with McArdle disease harbouring the mutation c.2392T>C; p.Trp798Arg.

Peripheral blood mononuclear cells (PBMCs) from a McArdle patient carrying a homozygous mutation in the PYGM gene: c.2392T>C; p.Trp798Arg were used for the generation of the human iPSC line, IISHDOi007-A. For the delivery of the reprogramming factors Oct3/4, Sox2, Klf4, and c-Myc, a non-integrative methodology that implies the use of Sendai virus has been applied.