Christiane Auray-Blais

• LL.M. PH.D.
• Professor-Researcher Biochemist at Université de Sherbrooke

Introduction Mucopolysaccharidosis type II (Hunter syndrome) is an X-linked recessive disorder caused by iduronate-2-sulfatase deficiency, affecting mainly male patients. The lack of its enzyme activity causes the accumulation of the glycosaminoglycans heparan sulfate and dermatan sulfate in all body tissues and leads to a secondary accumulation of...

Background Fabry disease is an X‐linked lysosomal storage disorder due to a deficiency of α‐galactosidase A (α‐gal A) activity. Our goal was to correct the enzyme deficiency in Fabry patients by transferring the cDNA for α‐gal A into their CD34+ hematopoietic stem/progenitor cells (HSPCs). Overexpression of α‐gal A leads to secretion of the hydrola...

Background: Early detection of sphingolipidoses is crucial to prevent irreversible complications and improve patient outcomes. The use of urine samples dried on filter paper (DUS) is a non-invasive strategy that simplifies the collection, storage, and shipping of samples compared to using liquid urine specimens. Objectives: (1) Develop and validate...

Purpose This prospective, longitudinal study was designed to determine the natural history of Fabry disease (FD) in early pediatric patients across the disease spectrum. Methods In this observational study of children under 5 years of age with variants in the GLA gene, prospective phenotypic and urinary biomarker data were collected annually over...

Aim: In 2016, a team of Canadian researchers initiated the world’s first gene therapy clinical trial for Fabry disease. The study, aiming to determine the safety and toxicity of lentivirus α-galactosidase A transduced autologous CD34+ cells in adult males with Fabry disease (n = 5), was conducted at three Canadian centers. The objective of the pres...

Hyperlysinemia is a rare autosomal recessive deficiency of 2‐aminoadipic semialdehyde synthase (AASS) affecting the initial step in lysine degradation. It is thought to be a benign biochemical abnormality, but reports on cases remain scarce. The description of additional cases, in particular, those identified without ascertainment bias, may help co...

Background: A biomarker profile was evaluated longitudinally in patients with Fabry disease switched from enzyme replacement therapy (ERT) to migalastat. Methods: Sixteen Gb 3 isoforms and eight lyso-Gb 3 analogues were analyzed in plasma and urine by LC–MS/MS at baseline and at three different time points in naive participants and participants swi...

Objective To present phenotypic characteristics and biomarkers of a family with the rare mutation Thr410Ala of the α-galactosidase A gene (T410A/ GLA ) causing Fabry disease (FD). Methods and results In a woman in her 60s with hypertrophic cardiomyopathy, T410A/ GLA was found in screening for variants in 59 cardiomyopathy-related genes. Her son in...

Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency of the enzyme beta-glucocerebrosidase. This leads to the accumulation of glycolipids in macrophages and ultimately results in tissue damage. Recent metabolomic studies highlighted several potential biomarkers in plasma specimens. In hopes of better understanding the distrib...

The safety and efficacy of lentivirus-mediated gene therapy was recently demonstrated in five male patients with Fabry disease-a rare X-linked lysosomal storage disorder caused by GLA gene mutations that result in multiple end-organ complications. To evaluate the risks of clonal dominance and leukemogenesis, which have been reported in multiple gen...

Background: Vitamin B-12 deficiency can result in irreversible neurological damages. It is most prevalent among older adults (∼5-15%), mainly due to impaired absorption. Vitamin B-12 bioavailability varies between food sources, so their importance in preventing deficiency may also vary. Objective: Using the NuAge Database and Biobank, we examine...

Gaucher disease is a rare inherited disorder caused by a deficiency of the lysosomal acid beta-glucocerebrosidase enzyme. Metabolomic studies by our group targeted several new potential urinary biomarkers. Apart from lyso-Gb1, these studies highlighted lyso-Gb1 analogs −28, −26, −12 (A/B), +2, +14, +16 (A/B), +30, and +32 Da, and polycyclic lyso-Gb...

Aim: Methylmalonic acid (MMA) analysis in urine represents a noninvasive approach to screening for vitamin B 12 deficiency in older adults. A method allowing the analysis of MMA/creatinine in fasting urine collected on filter paper was developed/validated. Method: Dry urine specimens were eluted using a solution containing internal standards, filtr...

Aim: Gaucher disease (GD) is caused by a deficiency of the lysosomal enzyme acid β-glucocerebrosidase. Recent metabolomic studies highlighted several new metabolites increased in the plasma of GD patients. We aimed to develop and validate a UPLC-MS/MS method allowing a relative quantitation of lyso-Gb1 and lyso-Gb1 analogs -28, -12, -2, +14, +16 an...

Background: Sphingolipidoses are caused by a defective sphingolipid catabolism, leading to an accumulation of several glycolipid species in tissues and resulting in neurotoxicity and severe systemic manifestations. Methods & results: Urine samples from controls and patients were purified by solid-phase extraction prior to the analysis by ultra-high...

The cytosolic-oriented glucosylceramide (GlcCer) synthase is enigmatic, requiring nascent GlcCer translocation to the luminal Golgi membrane to access glycosphingolipid (GSL) anabolic glycosyltransferases. The mechanism by which GlcCer is flipped remains unclear. To investigate the role of GlcCer binding partners in this process, we previously made...

The Quebec Neonatal Urine Screening Program was initiated in 1971 with overall screening inception of newborns in 1973. Forty-seven years later, over 3.5 million babies have been screened for up to 25 inborn errors of metabolism divided into two groups: (1) urea cycle disorders and organic acidurias; and (2) disorders of amino acid metabolism and t...

Enzyme and chaperone therapies are used to treat Fabry disease. Such treatments are expensive and require intrusive biweekly infusions; they are also not particularly efficacious. In this pilot, single-arm study (NCT02800070), five adult males with Type 1 (classical) phenotype Fabry disease were infused with autologous lentivirus-transduced, CD34+-...

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Gaucher disease (GD) is a rare autosomal recessive multisystemic lysosomal storage disorder presenting a marked phenotypic and genotypic variability. GD is caused by a deficiency in the glucocerebrosidase enzyme. The diagnosis of GD remains challenging because of the large clinical spectrum associated with the disease. Moreover, GD biomarkers are o...

Introduction: Recent studies showed the usefulness of globotriaosylsphingosine (lyso-Gb3) and related analogues, deacylated forms of globotriaosylceramide (Gb3), for high-risk screening, treatment monitoring and follow-up for patients with Fabry disease. Methods: We evaluated Gb3, lyso-Gb3 and analogues using tandem mass spectrometry in 57 women...

Enzyme replacement therapy (ERT) has been shown to stabilize certain aspects of Fabry disease (FD). However, in some patients on ERT, high antibody titres have been documented, with limited clinical improvement in systemic manifestations and often with significant adverse drug reactions. We present two related adolescent males with a 4.5 kb GLA del...

Purpose: To assess the utility of globotriaosylsphingosine (lyso-Gb3) for clinical monitoring of treatment response in patients with Fabry disease receiving migalastat. Methods: A post hoc analysis evaluated data from 97 treatment-naive and enzyme replacement therapy (ERT)-experienced patients with migalastat-amenable GLA variants from FACETS (N...

Fabry disease is caused by deficient activity of α-galactosidase A—an enzyme that hydrolyses the terminal α-galactosyl moieties from glycolipids and glycoproteins­—and subsequent accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3) and galabiosylceramide. However, there is no known link between...

Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding the α-galactosidase A enzyme. This enzyme cleaves the last sugar unit of glycosphingolipids, including globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), and galabiosylceramide (Ga2). Enzyme impairment leads to substrate accumulation...

Aim: Vitamin B12 deficiency is characterized metabolically by increased serum and urine methylmalonic acid (MMA). Urinary MMA/creatinine ratio is suggested for screening for metabolic vitamin B12 deficiency in older populations. Results: A UPLC-MS/MS method for the analysis of urinary MMA and creatinine was developed/validated. A good separation of...

Mucopolysaccharidoses (MPSs) are lysosomal storage disorders caused by deficiencies of enzymes involved in the catabolism of glycosaminoglycans (GAGs). Various treatments such as enzyme replacement therapy and/or hematopoietic stem cell transplant are available for MPSs. Early initiation of treatment improves the outcome and delays the onset of sym...

Background: Fabry disease is an X-linked lysosomal storage disorder with a highly heterogeneous clinical presentation. This complex disease is caused by a deficient activity of the enzyme α-galactosidase A, which is involved in the catabolism of glycosphingolipids. The prevalence of Fabry disease is underestimated, due to the presence of atypical...

Background: Fabry disease (FD) is a genetic disorder caused by defective α-galactosidase-A enzyme due to mutations in the GLA gene. A reliable diagnosis in classical FD males can be made by measuring the enzyme activity while diagnosing classical FD females and non-classical FD patients requires mutation analysis. Plasma globotriaosylsphingosine (...

Background Patients with Fabry disease (FD) and amenable mutations can be treated with the chaperone migalastat to restore endogenous α-galactosidase A (AGAL) activity. However, certain amenable mutations do not respond biochemically in vivo as expected. Here, we aimed to establish a patient-specific and mutation-specific cell model to evaluate the...

Aim: Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by a deficiency of the iduronate-2-sulfatase enzyme leading to the accumulation of heparan sulfate (HS) and dermatan sulfate (DS) in organs and biological fluids. enzyme-replacement therapy is available for affected patients. Results/methodology: A 6-min UPLC-MS/MS m...

Fabry disease (FD) is a rare X-linked genetic disorder caused by mutations in the GLA gene encoding the lysosomal enzyme, α-galactosidase A (α-gal A). The mutations lead to lack of or faulty enzyme causing accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids including globotriaosylsphingosine (lyso-Gb3). Treatment options for...

Background: Podocytes are highly differentiated visceral cells, and several related specific proteins, such as podocalyxin and podocin are potential tools for the evaluation of podocyturia. However, precise quantitation of podocyturia-related proteins is complex and often unreliable. Method: A reversed-phase ultra-performance liquid chromatograp...

Background The clinical significance of combined malonic and methylmalonic aciduria due to ACSF3 deficiency (CMAMMA) is controversial. In most publications, affected patients were identified during the investigation of various complaints. Methods Using a cross‐sectional multicenter retrospective natural history study, we describe the course of all...

Fabry disease is due to a deficiency in alpha-galactosidase A (a-gal A) activity. Enzyme therapy is used to treat Fabry disease although the cost is high and biweekly infusions are required long-term. We have shown that when a-gal A is overexpressed in cells, a portion of the hydrolase is secreted and can be taken up and used functionally by unmodi...

Fabry disease is a multisystemic, X-linked lysosomal storage disorder caused by a deficit of the enzyme alpha-galactosidase A which leads to the accumulation of glycosphingolipids in tissues and biological fluids. The clinical presentation is heterogeneous with many atypical variants, leading to an underestimated prevalence. Enzyme replacement ther...

Knockout mouse model of Fabry disease (Ohshima, 1997) is widely used, and has been proven an invaluable tool to investigate disease pathogenesis and therapies. However, the importance of genetic background of this mouse line has been underestimated, and in many publications WT control mice were chosen incorrectly. Our aim was to examine the effects...

Philosophers engaged in the field of applied ethics are often challenged to re-visit certain philosophical debates in order to clarify the background concepts involved in a given undertaking at stake. This is particularly evident in the field of Health Technological Assessment (HTA) where the integration of ethics has been a debate for many years....

Background Because systemic inflammation and endothelial dysfunction lead to heart failure with preserved ejection fraction, we characterized plasma levels of inflammatory and cardiac remodeling biomarkers in patients with Fabry disease (FD). Methods and Results Plasma biomarkers were studied in multicenter cohorts of patients with FD (n=68) and h...

Lysosomal storage disorders (LSDs) are characterized by the accumulation of metabolites, mainly due to enzyme deficiencies. There is a wide range of clinical manifestations in affected patients due to a marked variability in the genotype and phenotype. It is thus important to find reliable biomarkers for early detection (high-risk/mass screening),...

Aim: Since 2014, enzyme replacement therapy (ERT) has been available for treatment of Morquio A syndrome. During clinical trials, urinary keratan sulfate (KS) has been a useful biomarker and showed a marked decrease in patients on ERT, demonstrating therapy efficacy. Unfortunately, quantitative urinary KS testing is not widely available in biochem...

Background: The clinical significance of combined malonic and methylmalonic aciduria due to ACSF3 deficiency (CMAMMA) is controversial. In most publications, affected patients were identified during the investigation of various complaints. Methods: Using a cross-sectional multicenter retrospective natural history study, we describe the course of...

Tandem mass spectrometry (MS/MS) is a highly sensitive and specific technique. Thanks to the development of triple quadrupole analyzers, it is becoming more widely used in laboratories working in the field of inborn errors of metabolism. We review here the state of the art of this technique applied to the diagnosis of lysosomal storage disorders (L...

Fabry disease is an X-linked lysosomal storage disorder with marked variability in the phenotype and genotype. Glycosphingolipids such as globotriaosylceramide (Gb3) isoforms/analogs, globotriaosylsphingosine (lyso-Gb3) and analogs, and galabiosylceramide (Ga2) isoforms/analogs may accumulate in biological fluids and different organs. The aims of t...

Fabry disease (FD) is a multi-systemic X-linked lysosomal disorder caused by the deficient activity of α-galactosidase-A enzyme, which leads to accumulation of glycosphingolipids in various body tissues. The N215S mutation is a known variant of FD, with a late onset cardiac phenotype. Consensus guidelines acknowledged the use of globotriaosylsphing...

The aberrant accumulation of alpha-synuclein (α-syn) is believed to contribute to the onset and pathogenesis of Parkinson's disease (PD). The autophagy-lysosome pathway (ALP) is responsible for the high capacity clearance of α-syn. ALP dysfunction is documented in PD and pre-clinical evidence suggests that inhibiting the ALP promotes the pathologic...

Fabry disease is an X-linked lysosomal storage disorder caused by alpha-galactosidase A (α-GAL A) deficiency. This enzyme contributes to the cellular recycling of glycosphingolipids such as galabiosylceramide (Ga2), globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) by hydrolysing the terminal alpha-galactosyl moiety. Urine and pla...

Fabry disease is a rare Lysosomal Storage Disorder (LSD). We designed multiple recombinant lentivirus vectors (LVs) and tested their ability to engineer expression of human α-galactosidase A (α-gal A) in transduced Fabry patient CD34⁺ hematopoietic cells. We further investigated the safety and efficacy of a clinically-directed vector, LV/AGA, in bo...

Glutaric aciduria type 3 (GA3) is associated with decreased conversion of free glutaric acid to glutaryl-coA, reflecting deficiency of succinate-hydroxymethylglutarate coA-transferase, caused by variants in the SUGCT (C7orf10) gene. GA3 remains less well known, characterised and understood than glutaric aciduria types 1 and 2. It is generally consi...

Background: Fabry disease is a lysosomal storage disorder with an incidence of 1:1600 for the late-onset IVS4+919G>A cardiac variant mutation in Taiwan. Signs and symptoms of this cardiac variant include left ventricular hypertrophy, mitral insufficiency and/or arrhythmias. The search for biomarkers that might predict the clinical outcomes and gui...

Background Late-onset Pompe disease (LOPD) is a rare treatable lysosomal storage disorder characterized by progressive lysosomal glycogen accumulation and muscle weakness, with often a limb-girdle pattern. Despite published guidelines, testing for LOPD is often overlooked or delayed in adults, owing to its low frequency compared to other muscle dis...

Aim Fabry disease is caused by α-galactosidase A deficiency leading to accumulation of globotriaosylceramide (Gb3) in tissues. Clinical manifestations do not appear to correlate with total Gb3 levels. Studies examining tissue distribution of specific acyl chain species of Gb3 and upstream glycosphingolipids are lacking. Material & methods/Results...

Fabry disease is a multisystemic, X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency and resulting in the accumulation of glycosphingolipids in different tissues and biological fluids. Glycosphingolipid biomarkers, such as globotriaosylceramide (Gb3) isoforms, globotriaosylsphingosine (l...

Aim: Fabry disease is a lysosomal storage disorder leading to glycosphingolipid accumulation in different organs, tissues and biological fluids. The development of a Fabry disease gene therapy trial is underway in Canada. A tool to determine the distribution of Gb3 biomarkers in tissues of Fabry mice might be applicable to monitor the effect of ge...

Fabry disease is an X-linked lysosomal storage disorder caused by the absence or reduction of the enzyme α-galactosidase A activity. Currently, globotriaosylsphingosine (lyso-Gb3 ) and globotriaosylceramide (Gb3 ) are used as biomarkers to diagnose and monitor Fabry patients. However, recent metabolomic studies have shown that several glycosphingol...

Fabry disease is an X-linked lysosomal storage disorder, caused by a deficit in α-galactosidase A enzyme activity, leading to the storage of sphingolipids such as globotriaosylsphingosine (lyso-Gb3 ), globotriaosylceramide (Gb3 ), and galabiosylceramide (Ga2 ) in organs, tissues and biological fluids. A recent metabolomic study performed in plasma...

Mucopolysaccharidoses (MPSs) are a group of disorders resulting from primary defects in lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). Depending on the specific enzyme defect, the catabolism of one or more GAGs is blocked leading to accumulation in tissues and biological fluids. GAG measurements are important for high-r...

Background: Despite recommendations to use inhaled corticosteroids as treatment to control asthma during pregnancy, it is unknown whether inhaled fluticasone propionate (FP) reaches the fetus. Results & methodology: We collected maternal blood on the morning following delivery. FP was detected by ultra-performance LC-MS/MS (UPLC-MS/MS) in 9/17 ast...

Background: Glycosaminoglycan analysis for the diagnosis of Morquio patients has been daunting due to lack of sensitivity/specificity of the dimethylmethylene blue-based spectrophotometry methodology, routinely used by several clinical laboratories. MS methods have been devised for quantification of keratan sulfate for Morquio patients, but some u...

Previous studies demonstrated that Parkinson disease (PD) is associated with a decreased activity of the glucocerebrosidase (GCase) enzyme in brain tissues. The objective of this study was to determine if GCase deficiency is associated with the accumulation of its glucosylceramide (GluCer) substrate in PD brain tissues. A UPLC-MS/MS method was deve...

Background: Fabry disease is a lysosomal storage disorder leading to the accumulation of glycosphingolipids in biological fluids and tissues. Globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) are currently used for Fabry screening and diagnosis. However, these biomarkers are not always increased in Fabry patients with residual en...

Recent data have shown that lyso-Gb3, the deacylated derivative of globotriaosylceramide (Gb3), is possibly involved in the pathogenesis of Fabry disease (FD) and might be a clinically useful biomarker of its metabolic load. To test this hypothesis, we assayed Gb3 and lyso-Gb3 and related analogs in plasma and/or urine samples of 12 clinically well...