RESUMEN
Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine-generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced or absent sulfatase activities and, as a result, clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are limited and mostly palliative. We performed a screen of FDA-approved drugs using immortalized MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of primary MSD fibroblasts with tazarotene and bexarotene, two retinoids, led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose- and time-dependent manner, reduced glycosaminoglycan content decreased and lysosomal position and size normalized. Treatment of MSD patient derived induced pluripotent stem cells (iPSC) differentiated into neuronal progenitor cells (NPC) resulted in a positive treatment response. Tazarotene and bexarotene act to ultimately increase the stability of FGE variants. The results lay the basis for future research on the development of a first therapeutic option for MSD patients.
Asunto(s)
Enfermedad por Deficiencia de Múltiples Sulfatasas , Humanos , Enfermedad por Deficiencia de Múltiples Sulfatasas/diagnóstico , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Enfermedad por Deficiencia de Múltiples Sulfatasas/patología , Bexaroteno , Evaluación Preclínica de Medicamentos , Sulfatasas/genética , Oxidorreductasas actuantes sobre Donantes de Grupos SulfuroRESUMEN
Sufficient folate supplementation is essential for a multitude of biological processes and diverse organ systems. At least five distinct inherited disorders of folate transport and metabolism are presently known, all of which cause systemic folate deficiency. We identified an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 (FOLR1) gene coding for folate receptor alpha (FRalpha). Three patients carrying FOLR1 mutations developed progressive movement disturbance, psychomotor decline, and epilepsy and showed severely reduced folate concentrations in the cerebrospinal fluid (CSF). Brain magnetic resonance imaging (MRI) demonstrated profound hypomyelination, and MR-based in vivo metabolite analysis indicated a combined depletion of white-matter choline and inositol. Retroviral transfection of patient cells with either FRalpha or FRbeta could rescue folate binding. Furthermore, CSF folate concentrations, as well as glial choline and inositol depletion, were restored by folinic acid therapy and preceded clinical improvements. Our studies not only characterize a previously unknown and treatable disorder of early childhood, but also provide new insights into the folate metabolic pathways involved in postnatal myelination and brain development.
Asunto(s)
Encéfalo/metabolismo , Encéfalo/patología , Proteínas Portadoras/genética , Ácido Fólico/metabolismo , Vaina de Mielina/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/terapia , Receptores de Superficie Celular/genética , Secuencia de Aminoácidos , Transporte Biológico , Mapeo Encefálico , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Preescolar , Análisis Mutacional de ADN , Femenino , Receptor 1 de Folato , Receptores de Folato Anclados a GPI , Perfilación de la Expresión Génica , Humanos , Lactante , Masculino , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Modelos Biológicos , Datos de Secuencia Molecular , Proteínas Mutantes/metabolismo , Mutación/genética , Especificidad de Órganos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de Superficie Celular/química , Receptores de Superficie Celular/metabolismoRESUMEN
BACKGROUND/AIM: Neural tube defects (NTDs) are the most common birth defects, resulting in severe mortality and morbidity. In 1995, the supplementation of folic acid periconceptionally was officially recommended in Germany. The impact of the recommendations on the rate of NTDs was assessed. METHODS: An active surveillance system was established in the northern Rhine area. From 1996, all departments of obstetrics were asked to report cases of NTDs in all abortions, live births and stillbirths. Compliance with the recommendations was evaluated in a sample of mothers who delivered at the Department of Obstetrics of Düsseldorf University in 2001. RESULTS: From 1996-2003, 520 NTDs were reported. Compared to the rate of NTDs in 1996 (10.5/10,000), the average incidence in the years 1997 to 2003 dropped (6.8/10,000). The intake of folic acid, as recommended, was low among the general population (21.1%). CONCLUSION: Active surveillance data on the rate of NTDs are compatible with the maximum decrease of about 20% to be expected from data on the implementation of the recommendations. A much greater decrease in NTDs should be the challenge for the future.