Frequency of Fabry disease in a juvenile idiopathic arthritis cohort

Abstract Background Fabry disease (FD) is a rare, X-linked, multisystemic lysosomal storage disorder (LSD) that results from a deficiency in the hydrolase alpha-galactosidase A (⍺-GalA). During childhood, classic FD symptomatology is rare. The majority of children may show non-specific symptoms, including in the musculoskeletal system. The prevalence of FD among juvenile idiopathic arthritis (JIA) patients is unknown. Objective This study aimed to identify the frequency of FD in a JIA cohort, characterizing early clinical symptoms, enzyme titers, and GLA genotyping. Methods Children with JIA followed in a tertiary Children Hospital cohort were selected. Clinical, laboratory and familiar information were recorded. Molecular genetic testing to detect GLA gene mutations was performed in girls and enzymatic analysis in boys. Results In 89 patients (56.2% female, age at disease onset: 8.93 ± 4.35 years), one male (1.12%) patient presented pathogenic mutation in GLA gene, c.1244 T > C p.L415P, one female patient had a variant of uncertain significance c.38C > T (p.Ala13Val). Three additional (3.4%) patients had the enzymatic activity of alpha-galactosidase slightly decreased. We observed the presence of intronic variants in 44.44% of patients in our cohort: c.1000-22C > T; c.370-81_-77del; c.640-16A > G; c.10C > T; c.548-125C > G and c.-12G > A. These variants and their combination were associated with clinical symptoms in our cohort. Conclusions The incidence of FD in our cohort was 1.12%. Intronic variants were associated with symptoms previously described in the literature. Screening for FD in JIA may be a reasonable strategy for those with an atypical pattern of pain.

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Frequency of Fabry disease in a Juvenile Idiopathic Arthritis Cohort

10.21203/rs.3.rs-60936/v3 ◽

2021 ◽

Author(s):

Luciana Paim-Marques ◽

Amanda Virginia Cavalcante ◽

Islane Verçosa ◽

Paula Carneiro ◽

Marcia Souto-Maior ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Fabry Disease ◽

Clinical Laboratory ◽

Clinical Symptoms ◽

Molecular Genetic ◽

Disease Onset ◽

Lysosomal Storage ◽

Variant Of Uncertain Significance ◽

Alpha Galactosidase ◽

Intronic Variants

Abstract Background: Fabry disease (FD) is a rare, X-linked, multisystemic lysosomal storage disorder (LSD) that results from a deficiency in the hydrolase alpha-galactosidase A (⍺-GalA). During childhood, classic FD symptomatology is rare. The majority of children may show non-specific symptoms, including in the musculoskeletal system. The prevalence of FD among juvenile idiopathic arthritis (JIA) patients is unknown.Objective: This study aimed to identify the frequency of FD in a JIA cohort, characterizing early clinical symptoms, enzyme titers, and GLA genotyping.Methods: Children with JIA followed in a tertiary Children Hospital cohort were selected. Clinical, laboratory and familiar information were recorded. Molecular genetic testing to detect GLA gene mutations was performed in girls and enzymatic analysis in boys.Results: In 89 patients (56.2% female, age at disease onset: 8.93 ± 4.35 years), one male (1.12%) patient presented pathogenic mutation in GLA gene, c.1244T>C p.L415P, one female patient had a variant of uncertain significance c.38C>T (p.Ala13Val). Three additional (3.4%) patients had the enzymatic activity of alpha-galactosidase slightly decreased. We observed the presence of intronic variants in 44.44% of patients in our cohort: c.1000-22C> T; c.370-81_-77del; c.640-16A> G; c.10C>T; c.548-125C> G and c.-12G> A. These variants and their combination were associated with clinical symptoms in our cohort.Conclusions: The incidence of FD in our cohort was 1.12%. Intronic variants were associated with symptoms previously described in the literature. Screening for FD in JIA may be a reasonable strategy for those with an atypical pattern of pain.

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Frequency of Fabry Disease in a Juvenile Idiopathic Arthritis Cohort

10.21203/rs.3.rs-60936/v1 ◽

2020 ◽

Author(s):

Luciana Paim-Marques ◽

Amanda Virginia Cavalcante ◽

Islane Verçosa ◽

Paula Carneiro ◽

Marcia Souto-Maior ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Fabry Disease ◽

Clinical Symptoms ◽

Molecular Genetic ◽

Disease Onset ◽

Pathogenic Mutation ◽

Lysosomal Storage ◽

Variant Of Uncertain Significance ◽

Alpha Galactosidase ◽

Intronic Variants

Abstract Background: Fabry disease (FD) is a rare, X-linked, multisystemic lysosomal storage disorder (LSD) that results from a deficiency in the hydrolase alpha-galactosidase A (⍺-GalA). In childhood, classic FD symptomatology is rare. Majority of children present with mild non-specific symptoms, including the musculoskeletal system. The prevalence of FD among juvenile idiopathic arthritis (JIA) patients is unknown. Objective: The aim was to identify the frequency of FD in a JIA cohort, characterizing early clinical symptoms, enzyme titers and GLA genotyping. Methods: Children with JIA followed in tertiary Children Hospital cohort were selected. Clinical, laboratorial, and familiar information was recorded. Molecular genetic testing to detect GLA gene mutations was performed in the girls and enzymatic analysis in the boys. Results: In 89 patients (56.2% female, age at disease onset: 8.93 ± 4.35 years), one male (1.12%) patient presented pathogenic mutation in GLA gene, c.1244T>C p.L415P, one female patient had a variant of uncertain significance c.38C>T (p.Ala13Val). The enzymatic activity of alpha galactosidase was slightly decreased in 3 additional (3.4%) patients. We observed the presence of intronic variants in 44.44% of our cohort: c.1000-22C> T; c.370-81_-77del; c.640-16A> G; c.10C>T; c.548-125C> G and c.-12G> A. These variants and their combination were associated with clinical symptoms in our cohort. Conclusions: The incidence of FD in our cohort was 1.12%. Intronic variants were associated with symptomatology described in the literature. Screening for FD in JIA may be a reasonable strategy for those with atypical pattern pain.

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Frequency of Fabry disease in a Juvenile Idiopathic Arthritis Cohort

10.21203/rs.3.rs-60936/v2 ◽

2020 ◽

Author(s):

Luciana Paim-Marques ◽

Amanda Virginia Cavalcante ◽

Islane Verçosa ◽

Paula Carneiro ◽

Marcia Souto-Maior ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Fabry Disease ◽

Clinical Symptoms ◽

Molecular Genetic ◽

Disease Onset ◽

Pathogenic Mutation ◽

Lysosomal Storage ◽

Variant Of Uncertain Significance ◽

Alpha Galactosidase ◽

Intronic Variants

Abstract Background: Fabry disease (FD) is a rare, X-linked, multisystemic lysosomal storage disorder (LSD) that results from a deficiency in the hydrolase alpha-galactosidase A (⍺-GalA). During childhood, classic FD symptomatology is rare. The majority of children may show non-specific symptoms, including in the musculoskeletal system. The prevalence of FD among juvenile idiopathic arthritis (JIA) patients is unknown. Objective: The aim of this study was to identify the frequency of FD in a JIA cohort, characterizing early clinical symptoms, enzyme titers and GLA genotyping. Methods: Children with JIA followed in a tertiary Children Hospital cohort were selected. Clinical, laboratorial, and familiar information were recorded. Molecular genetic testing to detect GLA gene mutations was performed in girls and enzymatic analysis in boys. Results: In 89 patients (56.2% female, age at disease onset: 8.93 ± 4.35 years), one male (1.12%) patient presented pathogenic mutation in GLA gene, c.1244T>C p.L415P, one female patient had a variant of uncertain significance c.38C>T (p.Ala13Val). The enzymatic activity of alpha galactosidase was slightly decreased in 3 additional (3.4%) patients. We observed the presence of intronic variants in 44.44% patients in our cohort: c.1000-22C> T; c.370-81_-77del; c.640-16A> G; c.10C>T; c.548-125C> G and c.-12G> A. These variants and their combination were associated with clinical symptoms in our cohort.Conclusions: The incidence of FD in our cohort was 1.12%. Intronic variants were associated with symptoms previously described in literature. Screening for FD in JIA may be a reasonable strategy for those with atypical pattern of pain.

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The Cardiovascular Phenotype in Fabry Disease: New Findings in the Research Field

International Journal of Molecular Sciences ◽

10.3390/ijms22031331 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1331

Author(s):

Daniela Sorriento ◽

Guido Iaccarino

Keyword(s):

Fabry Disease ◽

Molecular Mechanisms ◽

Cell Damage ◽

Research Field ◽

Cardiac Cell ◽

Lysosomal Storage ◽

Clinical Level ◽

New Findings ◽

Alpha Gene ◽

Alpha Galactosidase

Fabry disease (FD) is a lysosomal storage disorder, depending on defects in alpha-galactosidase A (GAL) activity. At the clinical level, FD shows a high phenotype variability. Among them, cardiovascular dysfunction is often recurrent or, in some cases, is the sole symptom (cardiac variant) representing the leading cause of death in Fabry patients. The existing therapies, besides specific symptomatic treatments, are mainly based on the restoration of GAL activity. Indeed, mutations of the galactosidase alpha gene (GLA) cause a reduction or lack of GAL activity leading to globotriaosylceramide (Gb3) accumulation in several organs. However, several other mechanisms are involved in FD’s development and progression that could become useful targets for therapeutics. This review discusses FD’s cardiovascular phenotype and the last findings on molecular mechanisms that accelerate cardiac cell damage.

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Fabry disease

10.1093/med/9780199592548.003.0336 ◽

2015 ◽

Author(s):

Stephen Waldek

Keyword(s):

Fabry Disease ◽

Ventricular Hypertrophy ◽

Severe Disease ◽

Sensorineural Deafness ◽

Left Ventricular ◽

Lysosomal Storage ◽

Long Time ◽

Alpha Galactosidase ◽

Multiorgan Disease ◽

Echocardiographic Evidence

Fabry disease is a rare X-linked lysosomal storage disorder in which deficiency of alpha-galactosidase A leads to accumulation of substrate, mostly globotriaosylceramide, which causes a progressive, multiorgan disease affecting predominantly the kidneys, skin, heart, gut, and nervous system. Painful peripheral (‘acral’) neuropathy is characteristic. The disease is commonly diagnosed in children and young men often after some years of usually neuropathic symptoms, with exacerbations (Fabry crises), that commonly elude diagnosis for a long time. These usually occur years in advance of overt involvement of other organs. Diagnosis may also be suspected from renal biopsy, echocardiographic evidence of cardiomyopathy commonly beginning as left ventricular hypertrophy, or characteristic angiokeratomas typically in ‘bathing trunk’ distribution on skin. Renal manifestations are of proteinuria leading to progressive chronic kidney disease associated with deposits in podocytes. Diarrhoea is common. Disordered sweating is typical. Corneal lesions are also typical and there may be tortuosity of retinal vessels. Strokes are increased in frequency, and sensorineural deafness may occur. Women have fewer and later overt manifestations but some develop severe disease.

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First two years of reimbursed enzyme replacement therapy in the treatment of Fabry disease in Poland

F1000Research ◽

10.12688/f1000research.55313.1 ◽

2021 ◽

Vol 10 ◽

pp. 841

Author(s):

Michał Nowicki ◽

Monika Komar ◽

Mariusz Kusztal ◽

Katarzyna Mizia-Stec ◽

Tomasz Liberek ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Replacement Therapy ◽

Clinical Symptoms ◽

Final Diagnosis ◽

The Body ◽

Lysosomal Storage ◽

Enzyme Replacement ◽

Number Of Patients ◽

Mean Time

Fabry disease (FD) is an ultra-rare genetic lysosomal storage disease caused by pathologic gene variants resulting in insufficient expression of α-galactosidase A. This enzyme deficiency leads to accumulation of globotriaosylceramide and globotriaosylsphingosine in plasma and in different cells throughout the body, causing major cardiovascular, renal, and nervous system complications. Until 2018, reimbursed enzyme replacement therapy (ERT) for FD was available in all European Union countries except Poland. We present the preliminary results of the first two years of reimbursed ERT in Poland. We obtained data from the seven largest academic centers in Katowice, Kraków, Wrocław, Poznań, Gdańsk, Warszawa, and Łódź. The questionnaire included the following data: number of patients treated, number of patients qualified for ERT, and patient characteristics. All centers returned completed questionnaires that included data for a total of 71 patients (28 men and 43 women) as of June 2021. Thirty-five patients with the diagnosis of FD confirmed by genetic testing (22 men and 13 women) had already qualified for reimbursed ERT. Mean (SD) age at the commencement of the ERT program was 39.6 (15.5) years (range 18-79 years). Mean time from the first clinical symptoms reported by the patients to the FD diagnosis was 21.1 (8.9) years, and the mean time from the final diagnosis of FD to the beginning of ERT was 4.7 (4.6) years. FD is still underdiagnosed in Poland. To identify undiagnosed FD patients and to ensure that patients in Poland benefit fully from ERT, implementation of an effective nationwide screening strategy and close cooperation with a network of rare disease centers is advised.

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Nationwide screening for Fabry disease in unselected stroke patients

PLoS ONE ◽

10.1371/journal.pone.0260601 ◽

2021 ◽

Vol 16 (12) ◽

pp. e0260601

Author(s):

Aleš Tomek ◽

Reková Petra ◽

Jaroslava Paulasová Schwabová ◽

Anna Olšerová ◽

Miroslav Škorňa ◽

...

Keyword(s):

Fabry Disease ◽

Dried Blood Spots ◽

Lysosomal Storage ◽

Limited Data ◽

Stroke Patients ◽

Stroke Event ◽

Index Stroke ◽

Alpha Galactosidase ◽

Stroke Type ◽

Ischemic Attack

Background and aims Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by disease-associated variants in the alpha-galactosidase A gene (GLA). FD is a known cause of stroke in younger patients. There are limited data on prevalence of FD and stroke risk in unselected stroke patients. Methods A prospective nationwide study including 35 (78%) of all 45 stroke centers and all consecutive stroke patients admitted during three months. Clinical data were collected in the RES-Q database. FD was diagnosed using dried blood spots in a stepwise manner: in males—enzymatic activity, globotriaosylsphingosine (lyso-Gb3) quantification, if positive followed by GLA gene sequencing; and in females GLA sequencing followed by lyso-Gb3. Results 986 consecutive patients (54% men, mean age 70 years) were included. Observed stroke type was ischemic 79%, transient ischemic attack (TIA) 14%, intracerebral hemorrhage (ICH) 7%, subarachnoid hemorrhage 1% and cerebral venous thrombosis 0.1%. Two (0.2%, 95% CI 0.02–0.7) patients had a pathogenic variant associated with the classical FD phenotype (c.1235_1236delCT and p.G325S). Another fourteen (1.4%, 95% CI 0.08–2.4) patients had a variant of GLA gene considered benign (9 with p.D313Y, one p.A143T, one p.R118C, one p.V199A, one p.R30K and one p.R38G). The index stroke in two carriers of disease-associated variant was ischemic lacunar. In 14 carriers of GLA gene variants 11 strokes were ischemic, two TIA, and one ICH. Patients with positive as compared to negative GLA gene screening were younger (mean 60±SD, min, max, vs 70±SD, min, max, P = 0.02), otherwise there were no differences in other baseline variables. Conclusions The prevalence of FD in unselected adult patients with acute stroke is 0.2%. Both patients who had a pathogenic GLA gene variant were younger than 50 years. Our results support FD screening in patients that had a stroke event before 50 years of age.

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Screening for Fabry Disease in Young Strokes in the Australian Stroke Clinical Registry (AuSCR)

Frontiers in Neurology ◽

10.3389/fneur.2020.596420 ◽

2020 ◽

Vol 11 ◽

Author(s):

Alejandra Malavera ◽

Dominique A. Cadilhac ◽

Vincent Thijs ◽

Joyce Y. Lim ◽

Brenda Grabsch ◽

...

Keyword(s):

Fabry Disease ◽

Future Research ◽

Unknown Etiology ◽

Lysosomal Storage ◽

Clinical Registry ◽

Stroke Registry ◽

Case Identification ◽

South Wales ◽

Alpha Galactosidase ◽

Gla Gene

Introduction: Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by a deficiency or absence of alpha-galactosidase A (α-GAL A) enzyme, where stroke can be a serious complication. The aim of this study is to determine the feasibility of centralized screening for FD, among young stroke adults registered in the national Australian Stroke Clinical Registry (AuSCR).Methods: The study was conducted in young (age 18 – 55 years) survivors of acute stroke of unknown etiology registered in AuSCR at hospitals in Queensland, Tasmania, New South Wales, and Victoria during 2014 – 2015; and who, at the 3-month outcome assessment, agreed to be re-contacted for future research. Descriptive analyses of case identification from responses and specific enzyme and DNA sequencing analyses were conducted for α-galactosidase A (α-GLA) from dried blood spot (DBS) testing.Results: Of 326 AuSCR-identified patients invited to participate, 58 (18%) provided consent but six were subsequently unable to provide a blood sample and two later withdrew consent to use their data. Among the remaining 50 participants (median age 53 years [48 – 56 years]; 47% female), 67% had experienced an acute ischemic stroke. All males (n = 27) had an initial screen for α-GLA enzyme activity of whom seven with low enzyme levels had normal secondary α-GLA gene analysis. All females (n = 23) had genetic analysis, with one shown to have a pathogenic c.352C>T p.(Arg118Cys) missense mutation of the α-GLA gene for FD.Conclusions: These findings provide logistical data for embedding a process of automated central stroke registry screening for an additional case-finding tool in FD.

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Previously Unidentified Gene Variation Associated with Fabry Disease: The Impact on One Family

Case Reports in Nephrology ◽

10.1155/2020/8899703 ◽

2020 ◽

Vol 2020 ◽

pp. 1-3

Author(s):

Amaresh R. Vanga ◽

Samantha A. Schrier Vergano ◽

Jolanta Kowalewska ◽

Thomas R. McCune

Keyword(s):

Fabry Disease ◽

Genetic Disorder ◽

Missense Variant ◽

Lysosomal Storage ◽

Normal Range ◽

Genetic Studies ◽

Gene Variation ◽

Zebra Bodies ◽

Alpha Galactosidase ◽

The Impact

Fabry disease is an X-linked lysosomal storage genetic disorder associated with over 1000 mutations in the alpha-galactosidase-A gene region. We report here a 69-year-old male who underwent a kidney biopsy to evaluate progressive renal failure. He was found to have zebra bodies in visceral epithelial cells on biopsy, with electron microscopy showing inclusions within the cytoplasm of multiple podocytes consistent with Fabry disease. An alpha-galactosidase level was found to be 21 nm/hr/mg (normal range 50–150 nm/hr/mg). Genetic studies revealed a missense variant in the GLA gene with alanine replaced by cysteine at position 682 (c.682 A > C, p.N228H) that had not been previously associated with Fabry disease. The same variant was detected in two additional family members. The pathologic findings, clinical features, and low alpha-galactosidase level suggest that the c.682 A > C variant is associated with Fabry disease.

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Accuracy of Wallace Criteria for Clinical Remission in Juvenile Idiopathic Arthritis: a Cohort Study of 761 Consecutive Cases

The Journal of Rheumatology ◽

10.3899/jrheum.080434 ◽

2009 ◽

Vol 36 (7) ◽

pp. 1532-1535 ◽

Cited By ~ 22

Author(s):

ALFREDOMARIA LURATI ◽

ALESSANDRA SALMASO ◽

VALERIA GERLONI ◽

MAURIZIO GATTINARA ◽

FLAVIO FANTINI

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Clinical Laboratory ◽

Survival Function ◽

Disease Onset ◽

Remission Status ◽

Kaplan Meier ◽

Significant Difference ◽

Laboratory Variables ◽

The Mean ◽

Seronegative Polyarthritis

Objective.To evaluate disease course and clinical usefulness in some categories of juvenile idiopathic arthritis (JIA) by applying newly developed Wallace definitions of remission off drugs.Methods.In a retrospective study, charts of patients with chronic form of primary (idiopathic) arthritis followed from our center since 1970 were reviewed and clinical/laboratory variables were collected for further analysis.Results.The cohort included 761 eligible patients [516 (67.8%) female, 245 (32.2%) male] with JIA. Mean disease onset age (± standard deviation) was 6.25 ± 4.4 years (range 0.5–15.9). Disease mean duration to last visit was 10.02 ± 4.31 years. Followup mean period was 7.6 ± 6.4 years (range 1.5–35 yrs). A total of 247 (32.46%) patients achieved remission according to criteria [persistent oligoarthritis 153 (42.9%); extended oligoarthritis 15 (13.1%); seronegative polyarthritis 21 (22.4%); systemic arthritis 33 (33.7%); enthesitis related arthritis (ERA) plus juvenile psoriatic arthritis (JPsA) 25 (33.4%)]. No patients with seropositive polyarthritis achieved remission status (p < 0.001). In remitted patients the mean survival function (± standard error of the mean) before relapse calculated by Kaplan-Meier was of 20.9 (± 1.3) months overall: 21.7 (± 0.46) in persistent oligoarthritis, 25.0 (± 6.6) in extended oligoarthritis, 26.7 (± 13.2) in seronegative polyarthritis, and 17.6 (± 2.44) in ERA+JPsA (p > 0.1).Conclusion.In our cohort about one-third of cases obtained a remission episode in 4 decades of observation, with a significant difference between oligoarthritis and other categories (p < 0.001) using the Kaplan-Meier method; the remission status duration before a relapse has been about 20 months, without a significant difference between JIA categories.

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