Littérature scientifique sur le sujet « Acid α-glucosidase »

ABSTRACT Aspergillus nidulans possessed an α-glucosidase with strong transglycosylation activity. The enzyme, designated α-glucosidase B (AgdB), was purified and characterized. AgdB was a heterodimeric protein comprising 74- and 55-kDa subunits and catalyzed hydrolysis of maltose along with formation of isomaltose and panose. Approximately 50% of maltose was converted to isomaltose, panose, and other minor transglycosylation products by AgdB, even at low maltose concentrations. The agdB gene was cloned and sequenced. The gene comprised 3,055 bp, interrupted by three short introns, and encoded a polypeptide of 955 amino acids. The deduced amino acid sequence contained the chemically determined N-terminal and internal amino acid sequences of the 74- and 55-kDa subunits. This implies that AgdB is synthesized as a single polypeptide precursor. AgdB showed low but overall sequence homology to α-glucosidases of glycosyl hydrolase family 31. However, AgdB was phylogenetically distinct from any other α-glucosidases. We propose here that AgdB is a novel α-glucosidase with unusually strong transglycosylation activity.

Nuxia oppositifolia is traditionally used in diabetes treatment in many Arabian countries; however, scientific evidence is lacking. Hence, the present study explored the antidiabetic and antioxidant activities of the plant extracts and their purified compounds. The methanolic crude extract of N. oppositifolia was partitioned using a two-solvent system. The n-hexane fraction was purified by silica gel column chromatography to yield several compounds including katononic acid and 3-oxolupenal. Antidiabetic activities were assessed by α-amylase and α-glucosidase enzyme inhibition. Antioxidant capacities were examined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) scavenging assays. Further, the interaction between enzymes (α-amylase and α-glucosidase) and ligands (3-oxolupenal and katononic acid) was followed by fluorescence quenching and molecular docking studies. 3-oxolupenal and katononic acid showed IC50 values of 46.2 μg/mL (101.6 µM) and 52.4 μg/mL (119.3 µM), respectively against the amylase inhibition. 3-oxolupenal (62.3 µg/mL or 141.9 μM) exhibited more potent inhibition against α-glucosidases compared to katononic acid (88.6 µg/mL or 194.8 μM). In terms of antioxidant activity, the relatively polar crude extract and n-butanol fraction showed the greatest DPPH and ABTS scavenging activity. However, the antioxidant activities of the purified compounds were in the low to moderate range. Molecular docking studies confirmed that 3-oxolupenal and katononic acid interacted strongly with the active site residues of both α-amylase and α-glucosidase. Fluorescence quenching results also suggest that 3-oxolupenal and katononic acid have a good affinity towards both α-amylase and α-glucosidase enzymes. This study provides preliminary data for the plant’s use in the treatment of type 2 diabetes mellitus.

Fruit of salak (Salaaca zalacca) is traditionally used and commercialized as an antidiabetic agent. However, scientific evidence to prove this folk claim is quite lacking. Therefore, this research was aimed to evaluate the α-glucosidase inhibition activity of S. zalacca fruit and identify the bioactive compounds. The fruits were extracted by different ratios of ethanol and water (0, 20, 40, 60, 80, 100%, v/v) to get E0 (100% water), E20 (20% ethanol), E40 (40% ethanol), E60 (60% ethanol), E80 (80% ethanol), and E100 (100% ethanol) extracts. The extracts obtained were subjected to the α-glucosidase inhibitory assay. Gas chromatography-mass spectrometry- (GC-MS-) based metabolomics approach was used in profiling the bioactive metabolites present in the extracts. Orthogonal partial least square (OPLS) was used to correlate GC-MS data and α-glucosidase assay results to identify the possible chemical markers. All active compounds identified were subjected to molecular docking. The extracts from the S. zalacca fruit showed potent inhibition activity against α-glucosidase. The IC50 values from the α-glucosidase inhibitory assay ranged between 16 and 275 µg/ml. Overall, E60 displayed significantly higher α-glucosidase inhibition activity, while E0 showed the lowest α-glucosidase inhibition activity. Major compounds detected in S. zalacca fruits were sugars, fatty acids, and sterols, including myo-inositol, palmitic acid, stearic acid, and β-sitosterol. Moreover, the results obtained from molecular docking indicated that palmitic acid and β-sitosterol were close to the active side of the enzyme. Some of the residues that interacted include HID295, ASN259, LEU313, LYS125, PHE159, VAL216, PHE178, TYR72, TYR158, HIE315, ARG315, and PHE303. The bioassay result strongly suggests that E60 extract from S. zalacca fruits has potential α-glucosidase inhibitory activity. The hydrophobic compounds, including palmitic acid and β-sitosterol, were found to induce the α-glucosidase inhibition activity.

This paper reviews biological activity of some cinnamic acid derivative compounds which are isolated from natural materials and synthesized from the chemical compounds as an agent of α-glucosidase inhibitors for the antidiabetic drug. Aegeline, anhydroaegeline and aeglinoside B are natural products isolated compounds that have potential as an α-glucosidase inhibitor. Meanwhile, α-glucosidase inhibitor class of derivatives of cinnamic acid synthesized compounds are p-methoxy cinnamic acid and p-methoxyethyl cinnamate. Chemically, cinnamic acid has three main functional groups: first is the substitution of the phenyl group, second is the additive reaction into the α-β unsaturated, and third is the chemical reaction with carboxylic acid functional groups. The synthesis and modification of the structure of cinnamic acid are very influential in inhibitory activity against α-glucosidase.

Deoxynojirimycin (DNJ) is the archetypal iminosugar, in which the configuration of the hydroxyl groups in the piperidine ring truly mimic those of d-glucopyranose; DNJ and derivatives have beneficial effects as therapeutic agents, such as anti-diabetic and antiviral agents, and pharmacological chaperones for genetic disorders, because they have been shown to inhibit α-glucosidases from various sources. However, attempts to design a better molecule based solely on structural similarity cannot produce selectivity between α-glucosidases that are localized in multiple organs and tissues, because the differences of each sugar-recognition site are very subtle. In this study, we provide the first example of a design strategy for selective lysosomal acid α-glucosidase (GAA) inhibitors focusing on the alkyl chain storage site. Our design of α-1-C-heptyl-1,4-dideoxy-1,4-imino-l-arabinitol (LAB) produced a potent inhibitor of the GAA, with an IC50 value of 0.44 µM. It displayed a remarkable selectivity toward GAA (selectivity index value of 168.2). A molecular dynamic simulation study revealed that the ligand-binding conformation stability gradually improved with increasing length of the α-1-C-alkyl chain. It is noteworthy that α-1-C-heptyl-LAB formed clearly different interactions from DNJ and had favored hydrophobic interactions with Trp481, Phe525, and Met519 at the alkyl chain storage pocket of GAA. Moreover, a molecular docking study revealed that endoplasmic reticulum (ER) α-glucosidase II does not have enough space to accommodate these alkyl chains. Therefore, the design strategy focusing on the shape and acceptability of long alkyl chain at each α-glucosidase may lead to the creation of more selective and practically useful inhibitors.

We examined the relation between nutrient-stimulated insulin secretion and the islet lysosome acid glucan-1,4-α-glucosidase system in rats undergoing total parenteral nutrition (TPN). During TPN treatment, serum glucose was normal, but free fatty acids, triglycerides, and cholesterol were elevated. Islets from TPN-infused rats showed increased basal insulin release, a normal insulin response to cholinergic stimulation but a greatly impaired response when stimulated by glucose or α-ketoisocaproic acid. This impairment of glucose-stimulated insulin release was only slightly ameliorated by the carnitine palmitoyltransferase 1 inhibitor etomoxir. However, in parallel with the impaired insulin response to glucose, islets from TPN-infused animals displayed reduced activities of islet lysosomal enzymes including the acid glucan-1,4-α-glucosidase, a putative key enzyme in nutrient-stimulated insulin release. By comparison, the same lysosomal enzymes were increased in liver tissue. Furthermore, in intact control islets, the pseudotetrasaccharide acarbose, a selective inhibitor of acid α-glucosidehydrolases, dose dependently suppressed islet acid glucan-1,4-α-glucosidase and acid α-glucosidase activities in parallel with an inhibitory action on glucose-stimulated insulin secretion. By contrast, when incubated with intact TPN islets, acarbose had no effect on either enzyme activity or glucose-induced insulin release. Moreover, when acarbose was added directly to TPN islet homogenates, the dose-response effect on the catalytic activity of the acid α-glucosidehydrolases was shifted to the right compared with control homogenates. We suggest that a general dysfunction of the islet lysosomal/vacuolar system and reduced catalytic activities of acid glucan-1,4-α-glucosidase and acid α-glucosidase may be important defects behind the impairment of the transduction mechanisms for nutrient-stimulated insulin release in islets from TPN-infused rats.

Inhibiting the intestinal α-glucosidase can effectively control postprandial hyperglycemia for type 2 diabetes mellitus (T2DM) treatment. In the present study, we reported the binding interaction of betulinic acid (BA), a pentacyclic triterpene widely distributed in nature, on α-glucosidase and its alleviation on postprandial hyperglycemia. BA was verified to exhibit a strong inhibitory effect against α-glucosidase with an IC50 value of 16.83 ± 1.16 μM. More importantly, it showed a synergistically inhibitory effect with acarbose. The underlying inhibitory mechanism was investigated by kinetics analysis, surface plasmon resonance (SPR) detection, molecular docking, molecular dynamics (MD) simulation and binding free energy calculation. BA showed a non-competitive inhibition on α-glucosidase. SPR revealed that it had a strong and fast affinity to α-glucosidase with an equilibrium dissociation constant (KD) value of 5.529 × 10−5 M and a slow dissociation. Molecular docking and MD simulation revealed that BA bound to the active site of α-glucosidase mainly due to the van der Waals force and hydrogen bond, and then changed the micro-environment and secondary structure of α-glucosidase. Free energy decomposition indicated amino acid residues such as PHE155, PHE175, HIE277, PHE298, GLU302, TRY311 and ASP347 of α-glucosidase at the binding pocket had strong interactions with BA, while LYS153, ARG210, ARG310, ARG354 and ARG437 showed a negative contribution to binding affinity between BA and α-glucosidase. Significantly, oral administration of BA alleviated the postprandial blood glucose fluctuations in mice. This work may provide new insights into the utilization of BA as a functional food and natural medicine for the control of postprandial hyperglycemia.

An important signal involved in glucose-stimulated insulin secretion is transduced through the action of a lysosomal acid, glucan 1,4-α-glucosidase. We investigated the Ca2+ dependency of this enzyme activity in relation to insulin release. In isolated islets, increased levels of extracellular Ca2+induced a large increase in acid glucan 1,4-α-glucosidase activity accompanied by a similar increase in insulin release at both substimulatory and stimulatory concentrations of glucose. At low glucose the Ca2+ “inflow” blocker nifedipine unexpectedly stimulated enzyme activity without affecting insulin release. However, nifedipine suppressed45Ca2+outflow from perifused islets at low glucose and at Ca2+ deficiency when intracellular Ca2+ was mobilized by carbachol. This nifedepine-induced retention of Ca2+ was reflected in increased acid glucan 1,4-α-glucosidase activity. Adding different physiological Ca2+ concentrations or nifedipine to islet homogenates did not increase enzyme activity. Neither selective glucan 1,4-α-glucosidase inhibition nor the ensuing suppression of glucose-induced insulin release was overcome by a maximal Ca2+ concentration. Hence, Ca2+-induced changes in acid glucan 1,4-α-glucosidase activity were intimately coupled to similar changes in Ca2+-glucose-induced insulin release. Ca2+ did not affect the enzyme itself but presumably activated either glucan 1,4-α-glucosidase-containing organelles or closely interconnected messengers.

α-glucosidase is a major enzyme that is involved in starch digestion and type 2 diabetes mellitus. In this study, the inhibition of hypericin by α-glucosidase and its mechanism were firstly investigated using enzyme kinetics analysis, real-time interaction analysis between hypericin and α-glucosidase by surface plasmon resonance (SPR), and molecular docking simulation. The results showed that hypericin was a high potential reversible and competitive α-glucosidase inhibitor, with a maximum half inhibitory concentration (IC50) of 4.66 ± 0.27 mg/L. The binding affinities of hypericin with α-glucosidase were assessed using an SPR detection system, which indicated that these were strong and fast, with balances dissociation constant (KD) values of 6.56 × 10−5 M and exhibited a slow dissociation reaction. Analysis by molecular docking further revealed that hydrophobic forces are generated by interactions between hypericin and amino acid residues Arg-315 and Tyr-316. In addition, hydrogen bonding occurred between hypericin and α-glucosidase amino acid residues Lys-156, Ser-157, Gly-160, Ser-240, His-280, Asp-242, and Asp-307. The structure and micro-environment of α-glucosidase enzymes were altered, which led to a decrease in α-glucosidase activity. This research identified that hypericin, an anthracene ketone compound, could be a novel α-glucosidase inhibitor and further applied to the development of potential anti-diabetic drugs.

Il glucosio in eccesso viene immagazzinato come glicogeno nel muscolo scheletrico e nel fegato come substrato energetico facilmente disponibile attraverso la via glicolitica. Il malfunzionamento degli enzimi glicolitici provoca disturbi da accumulo di glicogeno come la malattia di Pompe (PD) o glicogenosi di tipo II. PD è una malattia metabolica autosomica recessiva con un'incidenza stimata di 1 su 40000 nati vivi. La malattia di Pompe è causata da difetti a carico dell'enzima lisosomiale acid α-glucosidasi (GAA) o maltasi acida, necessario per la degradazione del glicogeno. Lo spettro di gravità della malattia comprende diversi fenotipi clinici. Essi vanno dalla forma "classica" più grave, caratterizzata da insorgenza durante la prima infanzia, cardiomiopatia grave, decorso progressivo rapido ed esito fatale prima dei due anni, fino ad una forma infantile "intermedia" esprimendo un fenotipo più mite e forme giovanili e adulte caratterizzate dal coinvolgimento prevalente del muscolo scheletrico. La quasi totale carenza dell'enzima GAA causa la forma infantile grave della malattia, mentre la carenza parziale è responsabile delle forme intermedie e lievi. La terapia sostitutiva enzimatica (ERT), in cui l’enzima GAA viene fornito tramite infusione endovenosa è l'unica terapia disponibile dal 2006. Nonostante l'ERT abbia rappresentato una pietra miliare nel trattamento dei pazienti con malattia di Pompe, e abbia dimostrato di essere efficace nella forma infantile grave, non tutti i casi ad esordio tardivo rispondono ugualmente bene a questo trattamento. Pertanto, la correzione del fenotipo muscolare nei casi ad esordio tardivo è ancora ostica, mettendo in luce la necessità di trovare terapie più efficaci. Le difficoltà nel ripristino della funzione muscolare da parte della GAA esogena sono state attribuite ad una concomitante alterazione dell’autofagia. Il processo autofagico è un meccanismo molecolare chiave nel mantenimento dell’omeostasi cellulare, e assicura il corretto turnover delle macromolecole nella cellula. Tuttavia, non è chiaro quali siano le modificazioni dell'autofagia nella malattia di Pompe, poiché non è ancora noto se sia presente un'accelerazione o una riduzione eccessiva di questo processo. In particolare, la recente scoperta di un processo autofagico difettoso nella malattia di Pompe, ha stimolato sia una rivalutazione dei meccanismi patogeni della patologia, sia lo studio di nuovi approcci terapeutici, compresa la ricerca di terapie alternative mirate sia all'accumulo di glicogeno che all'autofagia. Tra le numerose molecole interessanti per il loro effetto di interferire con l'accumulo di glicogeno, abbiamo selezionato l'Acido-3-Bromopiruvico (3-BrPA), un inibitore dell'esochinasi (HK), il quale riveste un ruolo molto importante, essendo un enzima glicolitico. Studi in vitro e in vivo hanno riportato che il 3-BrPA è un efficace farmaco antitumorale, in particolare in quei tipi di tumori in cui le cellule, per crescere e proliferare, dipendono preferibilmente dalla glicolisi per produrre adenosina trifosfato (ATP). La proprietà anticancro di questo particolare composto è dovuta alla sua capacità di inibire la glicolisi. Essa abolisce la produzione di ATP da parte della cellula, impedendo di conseguenza la trasformazione da parte dell’HK del glucosio in glucosio-6-fosfato, e innescando successivamente la modulazione del processo autofagico. Tra le 4 diverse isoforme di esochinasi presenti nei mammiferi (HKI, HKII, HKIII e HKIV), si è visto che l’isoforma HKII è espressa a livello relativamente alto solo nel muscolo scheletrico, nel tessuto adiposo e nel cuore. Lo scopo di questo progetto è quello di testare l’azione del 3-BrPA, valutandone gli effetti sia sul sistema muscolare sia a livello subcellulare, e per fare questo, è stato generato un modello malattia in zebrafish.
Excess glucose is stored as glycogen in skeletal muscle and liver as an energy substrate readily available through the glycolytic pathway. Perturbation of glycolytic enzymes results in glycogen storage disorders such as Pompe disease (PD) or glycogenosis type II. PD is an autosomal recessive metabolic disease with an estimated incidence of 1:40000 live births. PD is due to a defect of the lysosomal enzyme acid α-glucosidase (GAA), or acid maltase, necessary for glycogen degradation. The spectrum of disease severity encompasses a broad continuum of clinical phenotypes ranging from the most severe “classic” form, characterized by early childhood onset, severe cardiomyopathy, rapidly progressive course and fatal outcome before two years of age, to an “intermediate” infantile form expressing a milder phenotype, and to juvenile and adult forms characterized by prevalent involvement of skeletal muscle. The almost total deficiency of the GAA enzyme results in the severe infantile form, while partial deficiency is responsible for the intermediate and mild forms. Enzyme replacement therapy (ERT), where GAA is provided via intravenous infusion is the only therapy available since 2006. While ERT represented a major milestone in the treatment of patients with Pompe disease and it has been shown to be efficacious in infantile severe PD, not all late onset cases respond equally well to this treatment. Therefore, the correction of the skeletal muscle phenotype in late onset cases is still challenging, revealing a need for more effective therapies. GAA difficulties in restoring muscle function have been ascribed to a concomitant altered autophagy, a key molecular mechanism that maintains cellular homeostasis and ensures correct macromolecule turnover in the cell. However, it remains unclear how autophagy is disrupted in PD, since it is yet unknown if an excessive acceleration or reduction of this process is present. Notably, this recent defective autophagy finding in PD has stimulated both a reassessment of the pathogenic mechanisms as well as the investigation of new therapeutic approaches, including search for adjunctive and alternative therapies addressing both glycogen accumulation and autophagy. Among the small molecules to be explored for interfering with glycogen accumulation we have selected the Acid-3-Bromopyruvic (3-BrPA), an inhibitor of hexokinase (HK), which is a key glycolytic enzyme. In vitro and in vivo studies have reported this molecule to be an efficacious anti-tumor drug, in those tumor phenotypes in which cancer cells preferentially depend on glycolysis to produce adenosine triphosphate (ATP) for growth and proliferation. The anti-cancer property of this particular compound is due to its ability to inhibit glycolysis, by abolishing cell ATP production and consequently impeding the transformation by hexokinase of glucose into glucose-6- phosphate, and to trigger modulation of the autophagic process. Among the different hexokinase isoforms HKI, HKII, HKIII, and HKIV found in mammals, HKII is expressed at relatively high level only in skeletal muscle, adipose tissue, and heart. The aim of this project was to use this molecule, as an inhibitor of the key glycolytic enzyme hexokinase-II, to modulate glycogen incorporation into cells. We used zebrafish as in vivo model, in order to evaluate the effect of this specific molecule on the muscular system at subcellular detail. The demonstration of its role as HKII inhibitor and as an autophagy modulator, has created the basis for developing a new strategy to improve muscle function in PD patients.

碩士
實踐大學
食品營養與保健生技學系碩士班
103
Soy isoflavones comprises of glycosidic isoflavones and isoflavone aglucones. The glycosidic isoflavones are formed by β-linkage of aglucone with any glycosides. Previous studies have shown that lactic acid bacteria with a cell surface enzyme β- glucosidase may be able to hydrolyze the β glycosidic bond, including isoflavone glycosides, and produces glucose and the aglucones. Daidzein has been proved as an α- glucosidase inhibitor, may reduce the absorption of glucose. However, the inhibition mechanism is not clear. Furthermore, no evidence has shown the effectiveness of the use of lactic acid and soy isoflavone composition on α- glucosidase inhibition. Therefore, this study is to study: (1) α- glucosidase enzyme kinetics by Michaelis-Menten equation, Lineweaver-Burk plot to obtaine α- glucosidase Vmax and Km, (2) the inhibiton mechanism ofα- glucosidase by glucosidic isoflavone, daidzin and genstin, and aglucone, daidzein, genstein, respectively, (3) the effect of the fermentation broth of a lactic acid bacteria and soy isoflavone composition on α- glucosidase enzyme inhibition. The results show that: (1) the mechanism of α- glucosidase enzyme inhibition by isoflavone is uncompetitive inhibition, (2) α- glucosidase inhibition rate of aglcone genistein, daidzein is significantly greater than that of glucosidic isoflavone genistin, daidzin, (3) the fermentation broth of Lactobacillus casei A39 and soy isoflavone composition, which containing a higher genistein, daidzein concentration, shows a significant inhibition of α- glucosidase activity than that of unfermented group. Taken together, this study demonstrated that β-glucosidase of lactic acid cell surface can hydrolyze isoflavone glycoside and produces aglucones, daidzein and genistein, which may be able to effectively inhibit α- glucosidase activity, and belongs to an uncompetitive inhibition mechanism; furthermore, lactic acid bacteria and soy isoflavones together, may be used as a hypoglycemic or obesity prevention food composition.

Diabetes is a worldwide health issue that has been expanding mainly in developed countries. It is characterized by abnormal levels of blood sugar due to several factors. The most common are resistance to insulin and the production of defective insulin which exerts little or no effect. Its most common symptoms include tissue damage to several systems due to elevated levels of blood sugar. One of the key enzymes in hydrocarbon metabolism is α-glucosidase (EC 3.2.1.20). It catalyzes the breakdown of complex carbohydrates into their respective monomers (glucose) which allows them to be absorbed. In this work, caffeoyl quinic acids and their metabolites were analyzed as potential inhibitors for α-glucosidase. The search for the best inhibitor was conducted using molecular docking. The affinity of each compound was compared to the inhibitor present in the crystal structure of the protein. As no inhibitor with a similar affinity was´found, a new approach was used, in situ drug design. It was not possible to achieve an inhibitor capable of competing with the one present in the crystal structure of the enzyme, which is also its current commercial inhibitor. It is possible to draw some conclusions as to which functional groups interact best with certain residues of the active site. This work was divided into three main sections. The first section, Diabetes, serves as an introduction to what is Diabetes, its symptoms and/or side effects and how caffeoyl quinic acids could be used as a treatment. The second section, Caffeoylquinic acids and their metabolites as inhibitors for Alfa-glucosidase, corresponds to the search through molecular docking of caffeoyl quinic acids as inhibitors for α-glucosidase and what was possible to draw from this search. The last section, In situ design of an inhibitor for α-glucosidase (EC 3.2.1.20), corresponds to the in situ drug design study and what it achieved. The representation of each of the molecules used as a ligand can be found in the Annexes.
Universidade da Madeira

Introduction: Pompe disease (PD) affects lysosomal digestion due to absence or low action of the enzyme acid α-glucosidase (GAA), with accumulation of glycogen, causing overflow of enzymes and autophagy, which affects striated muscle. PD is divided into infantile, juvenile, and adult clinical forms, with severity determined by amount of residual GAA activity. Case: P1) 45-year-old man admitted with acute respiratory failure (RF), starts mechanical ventilation. History of weakness, dyspnea, dysphagia. He had decreased proximal muscle strength at lower limbs (LL). Sequencing of GAA gene: autosomal recessive deficiency of two variants. Apnea-hypopnea-index (AHI):10.5. GAA enzyme replacement therapy (ERT) was requested. Judicially denied by disease progression. P2) 40-year-old man presented with loss of muscle strength at LL for 15 years, associated with snoring, daytime somnolence. Brother with similar complaints. He had proximal muscle weakness at LL. Positive genetic panel for PD. AHI:23.5. Judicially released ERT treatment and reported improvement. Discussion: Adult form of PD manifests itself with mild phenotype, with presence of residual GAA activity, which causes different clinical expressions. Main manifestations are symmetric proximal muscle weakness in LL and Gowers’ sign. Frequent death cause in late form is RF, which occurs early, unlike other neuromuscular diseases. In Brazil, PD is underdiagnosed, with approximately 2500 cases. Treatment is performed with Myozyme®, an ERT, not available in SUS, which makes treatment difficult. Conclusion: PD is a serious condition, with high underdiagnosis because of its similarity to other myopathies, which allows disease progression. Furthermore, the variability of GAA mutations allows for distinct phenotypes