BACKGROUND: There is limited information on the α-galactosidase A (α-Gal-A) in vivo response in Fabry patients receiving migalastat. In this single centre study, we evaluated changes from baseline in α-Gal A activity, lyso-Gb3 and other assessments in patients on migalastat.
RESULTS: 79 patients were recruited (48 M:31F; median duration receiving migalastat 3.8 years [range = 0.4-14.9 years]). N215S was the commonest genotype in males (67 %) and females (29 %). Leukocyte α-Gal-A showed a positive change from baseline in males (n = 4; median = 20.05); females (n = 8; median = 26). Of these, 3 males and 1 female had N215S (median = 16.7), while 7 females and 1 male had other genotypes (median = 26). No significant changes observed in plasma α-Gal-A. Cross-sectional analysis of post-baseline data confirmed leukocyte α-Gal-A enhancement in males (n = 47; median = 20); females (n = 30; median = 72); N215S (n = 41; median = 29) and other genotypes (n = 36; median = 36.5). Plasma and dried blood spot (DBS) lyso-Gb3 correlated at baseline and post-baseline (r = 0.77 and r = 0.96; p=<0.0001).
CONCLUSIONS: In the 12 patients with paired data, there was a median enzyme enhancement of 17.4 (relative change = 2.54) and 33 (relative change = 0.87) in males and in females, respectively. The cross-sectional post-baseline data in 47 patients corroborated leukocyte α-Gal-A enhancement on migalastat. Plasma and DBS lyso-Gb3 correlated well supporting DBS utility for disease monitoring.

Fabry disease (FD) manifests decreased α-galactosidase A (α-Gal A) activity and multiorgan damage. There are some undiagnosed cases of the condition among patients on dialysis. The prevalence of FD may also vary with the region. Among 227 male patients undergoing maintenance hemodialysis in Awaji Island, a remote island in Japan, 201 (88.5%) were included in this study. Patients with α-Gal A activity <5.0 pmol/h/disk proceeded to secondary screening. Patients with positive secondary screening underwent further genetic analysis. The number of patients with a family history of cardiac, cerebrovascular, and kidney diseases was 31 (15.4%), 23 (11.4%), and 31 (15.4%) patients, respectively. Although three patients (1.5%) had low α-Gal A activity, none of them was positive in the secondary screening. We could not identify any male hemodialysis patient with FD in Awaji Island, even though some patients had a family history of kidney and cardiovascular diseases.

Fabry disease (FD), which is a lysosomal storage disease resulting from a deficiency of α-galactosidase A, leads to the accumulation of globotriaosylceramide in various tissues and multiorgan impairment. Early diagnosis is important to improve long-term prognosis. Early clinical manifestations of FD include neuropathic pain, vascular skin lesions, and sweating abnormalities. Hypohidorosis is one of the clinical findings in the early stage of FD. However, there have been no studies on prospective screening of FD in patients with definitive diagnosis of hypohidrosis. We examined α-galactosidase A activity in white blood cells in 17 (one female and 16 male) patients with generalized hypohidorosis. Among 17 patients, one male patient (approximately 5.8%) had significantly reduced α-galactosidase A activity. He presented with a history of hypohidrosis with heat intolerance and neuropathic tingling pain in a warm environment from 6 years ago. He had a few angiokeratoma on the trunk and extremities. Ultrastructural examination of skin biopsy from the angiokeratoma revealed lamellar inclusions in endothelial cells. Kidney biopsy revealed swollen podocytes and Gb3 deposition in the glomerulus, and urinalysis revealed mulberry bodies. He was finally diagnosed with FD and started on enzyme replacement therapy with agalsidase alpha in the early stage. In addition, his family screening led to find the patients of four additional FD. Screening for FD in patients with hypohidrosis may lead to efficient early detection of FD.

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.

Fabry disease (FD) is an X-linked recessive lysosomal storage disease caused by a mutation of the galactosidase alpha (GLA) gene, leading to deficiency of α-galactosidase A (alpha-Gal A). This deficiency results in a progressive, multiorgan accumulation of glycolipids, most notably globotriaosylceramide (Gb3), leading to multiorgan failure and subsequently premature death. Gb3 accumulation in the podocytes, epithelial, and mesangial cells of the glomeruli results in progressive renal disease and eventually renal failure and hemodialysis (HD). There are two types of FD: early-onset classical type 1 and late-onset type 2. Although nearly a thousand mutations of the GLA gene have been identified, the majority of them are of unknown significance. Herein we report the case of a 25-year-old Caucasian male with no significant medical history who presented with peripheral neuropathy and end-stage renal failure, requiring HD. He was diagnosed with FD based on the electron microscopy findings of renal biopsy and severely reduced alpha-Gal A activity (<0.4 nmol/mL/hour). A novel mutation of c.281G>T; p.Cys94Phe was identified. On discharge from our facility, he was referred to a renal transplant center and genetic counseling.

Fabry disease is a rare X-linked inherited disorder caused by deficiency of α-Galactosidase A. Hundreds of mutations and non-coding haplotypes in the GLA gene have been described; however, many are variants of unknown significance, prompting doubts about the diagnosis and treatment. The α-Galactosidase A enzymatic activity in dried blood spot (DBS) samples are widely used for screening purposes; however, even when values below the normal are found, new tests are required to confirm the diagnosis. Here we describe an analysis of GLA variants and their correlation with DBS α-Galactosidase A enzymatic activity in a large Brazilian population with Fabry disease symptoms.
We analyzed GLA variants by DNA sequencing of 803 male patients with suspected Fabry disease or belonging to high-risk populations; in 179 individuals, 58 different exonic variants were detected. From these, 50 are variants described as pathogenic and eight described as variants of unknown significance. The other individuals presented complex non-coding haplotypes or had no variants. Interestingly, the enzymatic activity in DBS was different among pathogenic variants and the other genotypes, including variants of unknown significance; the first presented mean of 12% of residual activity, while the others presented levels above 70% of the activity found in healthy controls.
The activity of α-Galactosidase A in DBS was markedly reduced in males with known pathogenic variants when compared with subjects presenting variants of unknown significance, non-coding haplotypes, or without variants, indicating a possible non-pathogenic potential of these latter genotypes. These findings bring a better understanding about the biochemical results of α-Galactosidase A in DBS samples, as well as the possible non-pathogenic potential of non-coding haplotypes and variants of unknown significance in GLA gene. These results certainly will help clinicians to decide about the treatment of patients carrying variants in the gene causing this rare but life-threatening disease.

We report a case of kidney transplantation from mother to son, both of whom were likely to have had an unrecognized renal variant phenotype of Fabry disease. The patient was a 54-year-old man, with an unknown primary cause of end stage renal disease. He had no notable past medical history, other than end stage renal disease. He underwent living-related kidney transplantation from his mother at age 40 years. Foam cells in the glomeruli were identified on histology assessment of a 0-hour allograft biopsy, with zebra bodies identified in the glomerular visceral epithelial cells by electron microscopy. These findings were indicative of Fabry disease in the donated kidney. As a definitive diagnosis of Fabry\'s disease could not be confirmed, enzyme replacement therapy was not initiated. Thirteen years after kidney transplantation, the patient underwent left nephrectomy for a left renal tumour, with pathological findings of clear cell carcinoma, foam cells and zebra bodies in the native kidney. Detailed examinations identified low α-galactosidase A activity and mutation of the α-Gal A gene, confirming a diagnosis of a renal variant phenotype of Fabry disease. Histology of several allograft biopsies performed over the 14 years from the time of kidney transplantation revealed only moderate interstitial fibrosis and tubular atrophy, with no evidence of disease progression on electron microscopy, despite the presence of zebra bodies in the glomerular visceral epithelial cells.