Dolor muscular en una mujer de 46 años

A 46-year-old woman presented with weakness, muscular pain and persistent elevations of creatinine kinase. The analysis (including hormones, autoimmunity and serology), magnetic resonance and an electromyogram did not provide a conclusive diagnosis. However, after performing a muscle biopsy, we diagnosed a glycogen storage disease type V (McArdle disease). Glycogenosis occurs in a group of metabolic and genetic diseases characterized by a disorder in the catabolism of glycogen. The McArdle disease is defined by an absence of glycogen phosphorylase, an enzyme that catalyzes the conversion of glycogen to glucose-1-phosphate in muscle tissue.Se presenta el caso de una paciente que consulta por debilidad y dolor muscular de años de evolución junto con elevación persistente de la creatinina cinasa. Los análisis realizados (que incluyeron hormonas, autoinmunidad y serologías), la resonancia magnética y el electromiograma no mostraron resultados concluyentes. Tras la práctica de una biopsia muscular se diagnostica de glucogenosis tipo V (enfermedad de McArdle). Las glucogenosis son un conjunto de enfermedades metabólicas de base genética caracterizadas por un trastorno en el catabolismo del glucógeno. La enfermedad de McArdle se define por la ausencia de la miofosforilasa, una enzima que cataliza la transformación de glucógeno en glucosa-1-fosfato en las fibras musculares esqueléticas, representando una forma de miopatía pura

Miocardiopatía dilatada y distrofia muscular de cinturas leve causada por la variante genética p.Gly424Ser en fukutina

Scientific lette

Therapeutic Approaches in Lysosomal Storage Diseases

Lysosomal Storage Diseases are multisystemic disorders determined by genetic variants, which affect the proteins involved in lysosomal function and cellular metabolism. Different therapeutic approaches, which are based on the physiologic mechanisms that regulate lysosomal function, have been proposed for these diseases. Currently, enzyme replacement therapy, gene therapy, or small molecules have been approved or are under clinical development to treat lysosomal storage disorders. The present article reviews the main therapeutic strategies that have been proposed so far, highlighting possible limitations and future perspectives

Systemic treatment of Fabry disease using a novel AAV9 vector expressing α-galactosidase A

Fabry disease is a rare X-linked disorder affecting α-galactosidase A, a rate-limiting enzyme in lysosomal catabolism of glycosphingolipids. Current treatments present important limitations, such as low half-life and limited distribution, which gene therapy can overcome. The aim of this work was to test a novel adeno-associated viral vector, serotype 9 (AAV9), ubiquitously expressing human α-galactosidase A to treat Fabry disease (scAAV9-PGK-GLA). The vector was preliminary tested in newborns of a Fabry disease mouse model. 5 months after treatment, α-galactosidase A activity was detectable in the analyzed tissues, including the central nervous system. Moreover, we tested the vector in adult animals of both sexes at two doses and disease stages (presymptomatic and symptomatic) by single intravenous injection. We found that the exogenous α-galactosidase A was active in peripheral tissues as well as the central nervous system and prevented glycosphingolipid accumulation in treated animals up to 5 months following injection. Antibodies against α-galactosidase A were produced in 9 out of 32 treated animals, although enzyme activity in tissues was not significantly affected. These results demonstrate that scAAV9-PGK-GLA can drive widespread and sustained expression of α-galactosidase A, cross the blood brain barrier after systemic delivery, and reduce pathological signs of the Fabry disease mouse modelAssociation Vaincre Les Maladies Lysosomales | Ref. AO2017-3Ministerio de Ciencia e Innovación | Ref. PI11/00842Instituto de Salud Carlos III | Ref. PI19/01886Ministerio de Ciencia e Innovación | Ref. PEJ2018-005289-

Systemic Treatment of Fabry Disease Using a Novel AAV9 Vector Expressing α-Galactosidase A

International audienceFabry disease is a rare X-linked disorder affectinga-galactosi-dase A, a rate-limiting enzyme in lysosomal catabolism of gly-cosphingolipids. Current treatments present important limita-tions, such as low half-life and limited distribution, which genetherapy can overcome. The aim of this work was to test a noveladeno-associated viral vector, serotype 9 (AAV9), ubiquitouslyexpressing humana-galactosidase A to treat Fabry disease(scAAV9-PGK-GLA). The vector was preliminary tested innewborns of a Fabry disease mouse model. 5 months after treat-ment,a-galactosidase A activity was detectable in the analyzedtissues, including the central nervous system. Moreover, wetested the vector in adult animals of both sexes at two dosesand disease stages (presymptomatic and symptomatic) by sin-gle intravenous injection. We found that the exogenousa-galactosidase A was active in peripheral tissues as well asthe central nervous system and prevented glycosphingolipidaccumulation in treated animals up to 5 months following in-jection. Antibodies againsta-galactosidase A were produced in9 out of 32 treated animals, although enzyme activity in tissueswas not significantly affected. These results demonstrate thatscAAV9-PGK-GLA can drive widespread and sustained expres-sion ofa-galactosidase A, cross the blood brain barrier aftersystemic delivery, and reduce pathological signs of the Fabrydisease mouse model