AbstractObjectivesGaucher disease (GD) is the most common inherited lysosomal storage disease, caused by mutations in acid β-glucosidase (GBA) gene. This study aimed to identify mutations in Andalusia patients with GD and their genotype-phenotype correlation.MethodsDescriptive observational study. University Hospital Virgen del Rocio patients diagnosed from GD from 1999 to 2019 were included. Demographic and clinical data, β-glucocerebrosidase activity, variants pathogenic in GBA gene and biomarkers for monitoring treatment were collected from digital medical record.ResultsTwenty-six patients with aged between 1 day and 52 years were studied. A total of six mutations described as pathogenic and one mutation not described above [c.937T>C (p.Tyr313His)] were identified in the GBA gene, four patients were homozygotes and 22 compound heterozygotes. Twenty-four patients were diagnosed in non-neuropathic form (type 1) and two cases presented neurological involvement (type 2 or 3). The most common variant was c.1226A>G (p.Asn409Ser), which was detected in 24 patients, followed by c.1448T>C (p.Leu483Pro) variant, identified in 13 patients. The c.1448T>C (p.Leu483Pro) mutation has been presented in the most severe phenotypes with neurological involvement associated with type 2 and 3 GD, while c.1226A>G (p.Asn409Ser) mutation has not been associated with neurological alterations. Splenomegaly and bone disease were the most frequent clinical manifestations, and thrombocytopenia was the most common hematological disorder.ConclusionsThe c.1226A>G (p.Asn409Ser) and c.1448T>C (p.Leu483Pro) mutations were the most common. The c.937T>C (p.Tyr313His) was identified as a novel mutation. The c.1448T>C (p.Leu483Pro) mutation was associated with neurological alterations and c.1226A>G (p.Asn409Ser) mutation has not been associated it.

The purpose of this study was to examine the applicability of the use of samples in dried blood spot (DBS) for the definitive diagnosis of Fabry disease (FD) in males and females and to compare the diagnostic role of α-galactosidase A activity (α-Gal A), levels of lyso-Gb3 and sequencing of the GLA gene in screening patients with suspected FD. Measurement of α-Gal A activity in suspected FD patients in DBS was made followed by lyso-Gb3 determination and GLA gene sequencing. Of the 2381 subjects analyzed, FD was confirmed in 24 patients. Thirteen different variants were considered like pathogenic, five of which had not been previously described (c.143A > G; c.455A > C; c.487G > T; c.554delA; c.1045_1046insA). None of the patients with normal enzyme activity had FD confirmation. The DBS measurement of α-Gal A was more sensitive than lyso-Gb3 levels in both men and women. Definitive diagnosis of FD from a single DBS is possible, allowing samples to be easily sent from anywhere to the reference laboratory.dried blood spot, Fabry disease, GLA gene, lyso-Gb3, α-galactosidase a activity | INTRODUCTIONFabry disease (FD) is a rare X-linked recessive inherited disorder (OMIM 301500) caused by pathogenic variants in the GLA gene that produce α-galactosidase A (α-Gal A) deficiency. This results in an accumulation of globotriaosylceramide (Gb3) and its deacylated derivative lyso-Gb3 inside of lysosomes, leading to multisystemic disease. 1,2 FD exhibits a wide spectrum of clinical manifestations, from the classic early onset form to the milder later-onset phenotype. Male patients with the classic form develop acroparesthesias, neuropathic pain, corneal opacity (cornea verticillata), angiokeratomas and/or hypohydrosis in childhood or adolescence. Progressive damage to organs occurs with age, and patients may suffer cardiac, renal, and cerebrovascular complications. On the other hand, male patients with the later-onset form develop organic damage during adulthood, mainly chronic kidney disease, hypertrophic cardiomyopathy, and stroke at young age.Females with FD present a heterogeneous expression of disease, from asymptomatic to severe, depending on random X-chromosomal inactivation. [3][4][5] The determination of α-Gal A activity is usually the first step in the laboratory diagnosis. 6,7 However, it is known that in heterozygous females the enzyme activity could be within the normal range. 2,8 A promising biomarker to improve the diagnosis of FD is lyso-Gb3.There is marked elevation of lyso-Gb3 in dried blood spot (DBS) in patients with classic phenotype and its determination has been shown to be a useful tool in screening patients with suspected FD. 9-11 However, the genetic study of the GLA gene continues to be the gold standard for diagnosis, especially in the case of women. 10 Until now, more

Background Pompe disease (PD) is an autosomal recessive metabolic disorder caused by pathogenic variants in the acid α-glucosidase gene (GAA) that produces defects in the lysosomal acid α-1,4-glucosidase. We aimed to identify genetic variations and clinical features in Spanish subjects to establish genotype–phenotype correlation. Methods A total of 2637 samples of patients who showed symptoms or susceptible signs of PD were enrolled in this observational study. Enzymatic activity was detected by fluorometric techniques and the genetic study was carried out using Next-Generation Sequencing. Results Fourteen different variants from 17 diagnosed patients were identified, seven males and nine females with LOPD (mean age 36.07, SD 20.57, range 7–64) and a 2-day-old boy with IOPD, four genetic variants had not been described in the literature previously, including a homozygous variant. In all of them α-glucosidase activity was decreased. Muscle weakness, respiratory distress, exercise intolerance, hypotonia, dysphagia and myalgia were commonly observed in patients. Conclusions This study report four new genetic variants that contribute to the pathogenic variants spectrum of the GAA gene. We confirm that patients in Spain have a characteristic profile of a European population, with c.-32-13T>G being the most prevalent variant. Furthermore, it was confirmed that the c.236_246delCCACACAGTGC pathogenic variant in homozygosity is associated with early disease and a worse prognosis.