The New Pharmacological Chaperones PBXs Increase α-Galactosidase A Activity in Fabry Disease Cellular Models.

Fabry disease is an X-linked multisystemic disorder caused by the impairment of lysosomal α-Galactosidase A, which leads to the progressive accumulation of glycosphingolipids and to defective lysosomal metabolism. Currently, Fabry disease is treated by enzyme replacement therapy or the orally administrated pharmacological chaperone Migalastat. Both therapeutic strategies present limitations, since enzyme replacement therapy has shown low half-life and bioavailability, while Migalastat is only approved for patients with specific mutations. The aim of this work was to assess the efficacy of PBX galactose analogues to stabilize α-Galactosidase A and therefore evaluate their potential use in Fabry patients with mutations that are not amenable to the treatment with Migalastat. We demonstrated that PBX compounds are safe and effective concerning stabilization of α-Galactosidase A in relevant cellular models of the disease, as assessed by enzymatic activity measurements, molecular modelling, and cell viability assays. This experimental evidence suggests that PBX compounds are promising candidates for the treatment of Fabry disease caused by mutations which affect the folding of α-Galactosidase A, even for GLA variants that are not amenable to the treatment with Migalastat.

Perfil de pacientes con enfermedades minoritarias en Galicia. Perspectiva desde la medicina interna / Clinical profile of patients with rare diseases. An approach from Internal Medicine

Objetivos: Las enfermedades minoritarias constituyen un grupo heterogéneo de patologías de baja prevalencia, con un origen genético en la mayoría de los casos y frecuentemente asociadas a un retraso en su diagnóstico y notable morbi-mortalidad. Conocer las características clínicas y el grado de complejidad asistencial de los pacientes con enfermedades minoritarias que acuden a las consultas de medicina interna en Galicia podría facilitar una atención más eficaz y eficiente. Material y métodos: Estudio epidemiológico, transversal y multicéntrico en pacientes con enfermedad de baja prevalencia ≥ 18 años atendidos en las consultas y unidades específicas de medicina interna en Galicia hasta el 31 de Diciembre de 2020. Se obtuvieron de cada centro el número de pacientes atendidos según la patología, la media en años desde la aparición de los síntomas, número de comorbilidades, número de visitas anuales al centro y a otros especialistas, número de tratamientos (incluidos aquellos de alto impacto económico), grado de deterioro cognitivo y estimación del nivel de dependencia. Resultados: Se analizaron los indicadores de seis centros correspondientes a seis áreas sanitarias de Galicia, representando a un total de 324 pacientes, con una edad media de 41,3 ±15,8 años. Los tres principales grupos de patologías atendidas fueron por este orden las enfermedades genéticas raras, los errores innatos del metabolismo y las enfermedades neurológicas raras. El retraso medio en el diagnóstico fue de 4,8 ±7,9 años y un 34,17% de los pacientes tardaron 5 o más años en tener una confirmación diagnóstica. Este grupo de mayor retraso diagnóstico presenta menor puntuación en la escala de dependencia de Barthel y 1,75 veces mayor utilización de recursos sanitarios (consultas a medicina interna y otras especialidades). El 11,75% de los pacientes presentan un nivel de dependencia severa o total y el 9,9%, un bajo coeficiente intelectual. Conclusiones: ... (AU)

Objectives: Rare diseases (RD) constitute a heterogeneous group of low prevalence conditions, with genetic origin in most cases and frequently associated with a delay in their diagnosis and notable morbidity and mortality. Knowing the clinical profile and the complexity degree of patientswith RD who attend internal medicine units in Galicia could facilitate more effective and efficient care settings. Methods: Epidemiological, cross-sectional and multicenter study in patients with low prevalence diseases ≥ 18 years attending the outpatients departments and specific units of internal medicine in Galicia up to December 31, 2020. Data were collected on the number of patients treatedregarding their condition at each center, the average age at disease onset, number of comorbidities, number of annual visits to the center and other specialists, number of treatments (including those with a high economicimpact), degree of cognitive impairment and assessment of the degree of autonomy. Results: We analyzed data from six participating centers (from six healthareas of Galicia), representing a total of 324 patients, with a mean age of 41.3 ±15.8 years. The three main groups of pathologies treated were, in this order, rare genetic diseases, innate errors of metabolism and rareneurological diseases. The mean delay in diagnosis was 4.8 ±7.9 years and 34.17% of patients took 5 or more years to have a diagnostic confirmation. This group with the longest diagnostic delay has a lower scoreon the Barthel dependency scale and 1.75 times greater use of health resources (consultations with internal medicine and other specialties). 11.75% of the patients present a level of severe or total dependence and 9.9%, a low IQ. Conclusions: Despite their low average age, patients with minority diseases treated in internal medicine services present a high complexity of care derived from the number of comorbidities, visits to consultations, the need for hospital admissions and polypharmacy... (AU)

Enfermedad de Rendu Osler Weber: presentación de un caso / Rendu Osler Weber Disease: a case report

La Telangiectasia Hemorrágica Hereditaria o Enfermedad de Rendu-OslerWeber, es una entidad infradiagnosticada y el retraso diagnóstico es frecuente, lo que va a dificultar el screening y tratamiento preventivo de los pacientes y de sus familiares afectos. Presentamos el caso de una paciente que debutó con una complicación grave de la enfermedad, a pesar de lo cual el diagnóstico de la enfermedad no se realizó hasta pasados 10 años. (AU)

Hereditary heamorrhagic telangiectasia or Rendu Osler disease is an underdiagnosed condition with long diagnostic delay time which will make difficult the screening and early treatment of patients and affected family members. We report a case of a patient diagnosed 10 years lapsing from initial onset of severe complications of the disease (AU)

Esclerosis Tuberosa: presentación de un caso clínico / Tuberous Sclerosis: a case report

La Esclerosis Tuberosa (ET) ó Complejo Esclerosis Tuberosa es un trastorno genético autosómico dominante que afecta a niños y adultos. Se debe a la ausencia parcial o total de la expresión de los genes TSC1 (hamartina) o TSC2 (tuberina), lo que genera disfunción orgánica por crecimiento de hamartomas en sistema nervioso central, riñón, corazón, pulmón y piel. Un seguimiento protocolizado nos ayuda a confirmar el diagnóstico así como a identificar precozmente complicaciones clínicamente significativas. Nos permite además identificar portadores de mutaciones entre los familiares y realizar eficazmente labores de consejo genético. (AU)

Tuberous Sclerosis (TS) or Tuberous Sclerosis Complex is an autosomal dominant genetic disorder that affects children and adults. It is due to the partial or total absence of the expression of the TSC1 (hamartin) or TSC2 (tuberin) genes, which generates organic dysfunction due to the growth of hamartomas in the central nervous system, kidney, heart, lung and skin. A protocolized follow-up helps us to confirm the diagnosis as well as to promptly detect clinically significant complications. It also allows us to identify carriers of mutations among relatives and effectively carry out genetic counseling tasks (AU)