Recommendations for the diagnosis and management of Fabry disease in pediatric patients: a document from the Rare Diseases Committee of the Brazilian Society of Nephrology (Comdora-SBN)

Vaisbich, Maria Helena; Andrade, Luís Gustavo Modelli de; Silva, Cassiano Augusto Braga; Barreto, Fellype de Carvalho

doi:10.1590/2175-8239-JBN-2021-0216

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Brazilian Journal of Nephrology

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Brazilian Society of Nephrology • Braz. J. Nephrol. 44 (2) • Apr-Jun 2022 • https://doi.org/10.1590/2175-8239-JBN-2021-0216 copy

Recommendations for the diagnosis and management of Fabry disease in pediatric patients: a document from the Rare Diseases Committee of the Brazilian Society of Nephrology (Comdora-SBN)

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Fabry disease (FD) is a genetic disease, with X-chromosome linked inheritance, due to variants in the GLA gene that encodes the α-galactosidase A (α-GAL) enzyme. The purpose of the present study was to create a consensus aiming to standardize the recommendations regarding the renal involvement of FD with guidelines on the diagnosis, screening, and treatment of pediatric patients. This consensus is an initiative of the Rare Diseases Committee (Comdora) of the Brazilian Society of Nephrology (SBN). Randomized controlled clinical studies and studies with real-life data added to the authors' experience were considered for this review. The result of this consensus was to help manage patient and physician expectations regarding treatment outcomes. Thus, this consensus document recommends the investigation of the pediatric family members of an index case, as well as cases with suggestive clinical signs. From the diagnosis, assess all possible FD impairments and grade through scales. From an extensive review of the literature including pediatric protocols and particularly evaluating pediatric cases from general studies, it can be concluded that the benefits of early treatment are great, especially in terms of neuropathic pain and renal impairment parameters and outweigh the possible adverse effects that were mainly manifested by infusion reactions.

Keywords:
Fabry Disease; Consensus; Rare Diseases

Signs / symptoms	Frequency % total; ♂%;♀%	Median Onset: years (a); Earliest age reported (+)	Main differential diagnosis
Pain (dysesthesia); burning spells in hands and feet⁹9 Biegstraaten M, Arngrímsson R, Barbey F, Boks L, Cecchi F, Deegan PB, et al. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document. Orphanet J Rare Dis. 2015 Mar;10:36.	50-72% ♂59-67%; ♀40-65%	♂ 7-10 y; ♀ 8-15 y + early: 2-4 y	Growing pain Rheumatologic diseases (fibromyalgia and others).¹⁰10 Wijburg FA, Bénichou B, Bichet DG, Clarke LA, Dostalova G, Fainboim A, et al. Characterization of early disease status in treatment-naive male paediatric patients with Fabry disease enrolled in a randomized clinical trial. PLoS One. 2015 May;10(5):e0124987.
Hypohidrosis or anhidrosis	25-59% ♂ 28-93% ♀17-25%	♂ 8-10 y; ♀ 4 y + early: 2,5 y	Causes of dysautonomia; usually with other manifestations.
Cornea verticillata	50-71,5% ♂ 36-73%; ♀65-70%	♂12 y; ♀ 9 y + early: newborn	Use of hydroxychloroquine or amiodarone.¹¹11 Mauer M, Glynn E, Svarstad E, Tøndel C, Gubler MC, West M, et al. Mosaicism of podocyte involvement is related to podocyte injury in females with Fabry disease. PLoS One. 2014 Nov;9(11):e112188.
Gastrointestinal symptoms	18-50% ♂ 23-40%; ♀ 11-20%	♂5 y; ♀ 9,5 y + early: 1 y 4 y	Irritable bowel syndrome, food intolerances¹²12 Whybra C, Kampmann C, Krummenauer F, Ries M, Mengel E, Miebach E, et al. The Mainz Severity Score Index: a new instrument for quantifying the Anderson-Fabry disease phenotype, and the response of patients to enzyme replacement therapy. Clin Genet. 2004 Apr;65(4):299-307.
Intolerance to exercise/heat/cold	17-39% ♂ 17-39%; ♀ 17-38%	♂5-7y; ♀ 8-16 y + early: 3,5 y	Disorders of muscle channels of Ca⁺⁺ and K⁺.¹³13 Hughes DA, Ramaswami U, Romero MÁB, Deegan P, FOS Investigators. Age adjusting severity scores for Anderson-Fabry disease. Mol Genet Metab. 2010 Oct/Nov;101(2-3):219-27.
Angiokeratomas	14-40% ♂ 20-57%; ♀ 8-38%	♂7-9 y; ♀9,5-14 y	Some deposit diseases. In FD, it usually occurs, but not only, in the region of the swimming trunks, posterior face of the buttocks and thighs and, periumbilical.¹⁴14 Ramaswami U, Stull DE, Parini R, Pintos-Morell G, Whybra C, Kalkum G, et al. Measuring patient experiences in Fabry disease: validation of the Fabry-specific Pediatric Health and Pain Questionnaire (FPHPQ). Health Qual Life Outcomes. 2012 Sep;10:116.
Hearing loss	19-22% ♂19%; ♀24%	♂2,7 y; ♀ 14,4 y + early: 4 y	Other disorders with sensorineural deafness that have other manifestations.¹⁵15 Giannini EH, Mehta AB, Hilz MJ, Beck M, Bichet DG, Brady RO, et al. A validated disease severity scoring system for Fabry disease. Mol Genet Metab. 2010 Mar;99(3):283-90.
Kidney changes - Hyperfiltration - Microalbuminuria - Proteinuria	- ??? - 13-16%⁴4 Nakao S, Kodama C, Takenaka T, Tanaka A, Yasumoto Y, Yoshida A, et al. Fabry disease: detection of undiagnosed hemodialysis patients and identification of a “renal variant” phenotype. Kidney Int. 2003;64(3):801-7.,⁵5 Fervenza FC, Torra R, Warnock DG. Safety and efficacy of enzyme replacement therapy in the nephropathy of Fabry disease. Biologics. 2008 Dec;2(4):823-43. - 14-20%⁴4 Nakao S, Kodama C, Takenaka T, Tanaka A, Yasumoto Y, Yoshida A, et al. Fabry disease: detection of undiagnosed hemodialysis patients and identification of a “renal variant” phenotype. Kidney Int. 2003;64(3):801-7.,⁵5 Fervenza FC, Torra R, Warnock DG. Safety and efficacy of enzyme replacement therapy in the nephropathy of Fabry disease. Biologics. 2008 Dec;2(4):823-43.	- ??? -♂ 16 y; ♀ 16 y -♂ 14 y; ♀ 14 y	Causes of proteinuria without SN¹⁶16 Lehman PJ, Carl RL. Growing pains. Sports Health. 2017;9(2):132-8.. HF+ is an impactful data for the diagnosis of FD. Do not hesitate to have a kidney biopsy.
Heart alterations - conduction - Valve disfunction - Arrhythmias - LVH	- 8%; ♂8-10%; ♀4-7%⁶6 Sociedade Brasileira de Nefrologia (SBN). Comitê de Doenças Raras (COMDORA). Consenso Brasileiro de doença de Fabry - Recomendações de diagnóstico, triagem e tratamento. São Paulo: SBN; 2021. - 15-18%; ♂6-23%; ♀ 14-24%⁶6 Sociedade Brasileira de Nefrologia (SBN). Comitê de Doenças Raras (COMDORA). Consenso Brasileiro de doença de Fabry - Recomendações de diagnóstico, triagem e tratamento. São Paulo: SBN; 2021. - 1-5%; ♂3-7%; ♀ 0-2,5%⁶6 Sociedade Brasileira de Nefrologia (SBN). Comitê de Doenças Raras (COMDORA). Consenso Brasileiro de doença de Fabry - Recomendações de diagnóstico, triagem e tratamento. São Paulo: SBN; 2021. - 3/22 (13,6%) children with DF⁶6 Sociedade Brasileira de Nefrologia (SBN). Comitê de Doenças Raras (COMDORA). Consenso Brasileiro de doença de Fabry - Recomendações de diagnóstico, triagem e tratamento. São Paulo: SBN; 2021.	- ♂ 10 y;♀ 17 y - ♂ 8,6 y;♀ 14 y - ♂ 9,3 y - ???	Other causes of these alterations¹⁶16 Lehman PJ, Carl RL. Growing pains. Sports Health. 2017;9(2):132-8.. Positive family history is an important data for the diagnosis
CNS involvement - Rare in pediatrics; usually in Young adults.¹⁷17 Üçeyler N, Ganendiran S, Kramer D, Sommer C. Characterization of pain in Fabry disease. Clin J Pain. 2014 Oct;30(10):915-20.	MRI in FD in pediatrics (mean age, 14 years) versus controls:17 Asymptomatic white matter lesion: 16% versus 6.5% 91% of patients already had neuropathic pain, cornea verticillata and/or abdominal pain. No cases with CKD, heart disease or high blood pressure. Positive family history is an important data for the diagnosis.

Author	Year	Patients	Findings
Elleder M et al.²¹21 Elleder M, Poupĕtová H, Kozich V. Fetal pathology in Fabry’s disease and mucopolysaccharidosis type I. Cesk Patol. 1998 Jan;34(1):7-12.	1998	fetus	GL3 inclusions, mainly in fetal podocytes.
Tøndel et al.²²22 Tøndel C, Bostad L, Hirth A, Svarstad E. Renal biopsy findings in children and adolescents with Fabry disease and minimal albuminuria. Am J Kidney Dis. 2008 May;51(5):767-76.	2008	9 children (7 to 18 years) with normal GFR and minimal or no proteinuria	GL3 inclusions in podocytes and distal tubules accompanied by fusion of the pedicels processes in all cases, arteriolopathy in almost 50% of patients and focal segmental glomerulosclerosis (FSGS) in adolescents.
Ramaswami U et al.²³23 Ramaswami U, Najafian B, Schieppati A, Mauer M, Bichet DG. Assessment of renal pathology and dysfunction in children with Fabry disease. Clin J Am Soc Nephrol. 2010 Feb;5(2):365-70.	2010	children	Renal histological changes before microalbuminuria/proteinuria.
Najafian et al.²⁴24 Najafian B, Mauer M, Hopkin RJ, Svarstad E. Renal complications of Fabry disease in children. Pediatr Nephrol. 2013 May;28(5):679-87.	2013	children	An increase in podocyte GL3 correlates with foot processes fusion and albuminuria.
Branton et al.²⁵25 Branton MH, Schiffmann R, Sabnis SG, Murray GJ, Quirk JM, Altarescu G, et al. Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course. Medicine (Baltimore). 2002 Mar;81(2):122-38.	2002	Not reported	There was a faster decrease in GFR in patients with higher initial proteinuria, corroborating the understanding that proteinuria is a late indicator of FD nephropathy.
Riccio E et al.²⁶26 Riccio E, Sabbatini M, Bruzzese D, Petruzzelli LA, Pellegrino A, Spinelli L, et al. Glomerular hyperfiltration: an early marker of nephropathy in Fabry disease. Nephron. 2019;141(1):10-7.	2019	children	Initial kidney lesions in younger patients are earlier translated into glomerular hyperfiltration and are often detected before the onset of microalbuminuria, usually associated with mild or no extrarenal symptoms. There was negative correlation between GFR and age, GFR and levels of proteinuria and GFR and cardiovascular manifestations.
Trimarchi H et al.²⁷27 Trimarchi H, Canzonieri R, Muryan A, Schiel A, Araoz A, Forrester M, et al. Copious podocyturia without proteinuria and with normal renal function in a young adult with Fabry disease. Case Rep Nephrol. 2015;2015:257628.	2015	patients	Podocyturia in FD patients precedes microalbuminuria.
Politei et al.²⁸28 Politei J, Alberton V, Amoreo O, Antongiovanni N, Arán MN, Barán M, et al. Clinical parameters, LysoGb3, podocyturia, and kidney biopsy in children with Fabry disease: is a correlation possible? Pediatr Nephrol. 2018 Nov;33(11):2095-101.	2018	children (4 to 9 years)	They found increased plasma lyso-GL3 and podocyturia in all of them, but still with normal estimated GFR (eGFR) and only half of them had microalbuminuria. The kidney histology of these patients revealed glomerular, interstitial and vascular changes.

Men		Women
Having the genetic variant		Having the genetic variant
+		+
α-GAL deficiency ≤ 5%		Not necessary to measure α-GAL
+
A or B or C or D #
A (clinical) Having 1 or more factors: neuropathic pain, cornea verticillata or angiokeratoma	B (biochemical) Elevated plasma or urinary GL3 or lyso-GL3 (> 1.8ng/ml)	C (familiar) Family member with a definitive diagnosis of FD carrying the same variant	D (histological) Histological changes suggestive of lysosomal deposits in target organs (kidneys, skin, heart)

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[1] Correspondence to: Maria Helena Vaisbich. E-mail: mhvaisbich@gmail.com

EVALUATION INTERVAL
Baseline (upon diagnosis/ERT onset)	All the cases
sequential OBS.: In symptomatic cases and under ERT, the intervals should be reduced according to the needs.	Boys, at least annually (asymptomatic). Girls, at least every 2 years (asymptomatic).
OVERAL CLINICAL ASSESSMENT OF THE PATIENT
General physical examination data, examples.	Adequate assessment of anthropometric data. Adequate measurement of blood pressure in the office or ABPM in selected cases.
GENERAL CLINICAL EVALUATION OF FD - PREFERENTIALLY USE SCALES
General scales, examples	Pain Scales: Brief Pain Inventory (BPI) Scale for GI Symptoms: Gastrointestinal Symptom Rating Scaled
Specific scales for Fabry disease, examples	MSSI, DS3, Fabry Stabilization index - FASTEx
GENERAL LABORATORIAL ASESSMENT
FD-related laboratory tests	At least annual serum Lyso-GL3 (DBS)
Monitoring the general situation of the patient according to needs, examples.	Lipid profile, uric acid and blood glucose assessment.
SPECIFIC LABORATORIAL ASESSMENT
Kidney function assessment	Albuminuria, tubular dysfunction, eGFR (Schwartz, Modified Schwartz, CKD-EPI), measured GFR (24-hour urine creatinine clearance, radioisotopic methods in selected cases)
Heart assessment	EKG, Doppler echocardiogram (preferably with strain), cardiac MRI - not routine in Pediatrics; perform exceptionally in selected cases.