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Assessing small fiber neuropathy and subtle cardiac involvement in Fabry disease

Abstract

Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by reduced or absent activity of the enzyme α-galactosidase A. Due to systemic accumulation of glycolipids, FD phenotype is diverse, and diagnosis may be challenging. Clinical manifestations include small fiber neuropathy, renal dysfunction, cardiac involvement, cerebrovascular disease, among others. In the present study, we describe biopsy proven small fiber neuropathy and subclinical cardiac involvement in two cousins diagnosed with FD secondary to a recently described pathogenic variant, highlighting the importance of diagnostic tools to document organ damage and allow early treatment.

Keywords
Fabry disease; small fiber neuropathy; cardiomyopathy

Introduction

Fabry disease (FD) was originally described as “angiokeratoma corporis diffusum” by the dermatologists Johannes Fabry and William Anderson, in 1898 [11. Anderson W. A case of “angeio-keratoma”. British J Dermatol. 1898;10(4):113-117. doi:10.1111/j.1365-2133.1898.tb16317.x.
https://doi.org/10.1111/j.1365-2133.1898...
-22. Fabry J. Ein Beitrag zur Kenntniss der Purpura haemorrhagica nodularis (Purpura papulosa haemorrhagica Hebrae). Arch für Dermat. 1898;(43):187-200. doi:10.1007/BF01986897.
https://doi.org/10.1007/BF01986897...
], being currently recognized as the most frequent systemic lysosomal storage disorder [33. Platt FM, d'Azzo A, Davidson BL, Neufeld EF, Tifft CJ. Lysosomal storage diseases. Nat Rev Dis Primers. 2018;4(1):27. doi:10.1038/s41572-018-0025-4.
https://doi.org/10.1038/s41572-018-0025-...
]. Markedly reduced or absent activity of the enzyme α-galactosidase A (α-Gal A) results in progressive accumulation of glycolipids, primarily globotriaosylceramide (Gb3) and its deacylated form, globotriaosylsphingosine (lyso-Gb3), within lysosomes in a variety of cell types, including vascular endothelial cells, cardiomyocytes, renal, arterial smooth muscle cells and nerve cells [44. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. doi:10.1186/1750-1172-5-30.
https://doi.org/10.1186/1750-1172-5-30...
-55. Desnick RJI, Yiannis A, Christine M, et al. Alfa-galactosidase a deficiency: Fabry Disease. The online metabolic and molecular bases of inherited disease. McGraw-Hill Education; 2019.]. The X-linked nature of the disease was first recognized in 1965, and α-Gal A is a homodimeric glycoprotein encoded by the GLA gene located on the long arm of the X chromosome [66. Opitz JM, Stiles FC, Wise D, et al. The genetics of angiokeratoma corporis diffusum (fabry's disease) and its linkage relations with the Xg Locus. Am J Hum Genet. 1965;17(4):325-342. -77. Ortiz A, Germain DP, Desnick RJ, et al. Fabry disease revisited: management and treatment recommendations for adult patients. Mol Genet Metab. 2018;123(4):416-427. doi:10.1016/j.ymgme.2018.02.014.
https://doi.org/10.1016/j.ymgme.2018.02....
]. By this pattern of inheritance men are characteristically affected, and prediction of disease course in female patients is challenging, since this depends on the occurrence of random inactivation of the X chromosome [88. Echevarria L, Benistan K, Toussaint A, et al. X-chromosome inactivation in female patients with Fabry disease. Clin Genet. 2016;89(1):44-54. doi:10.1111/cge.12613.
https://doi.org/10.1111/cge.12613...
]. The phenotype of male patients with FD was initially described as the classic form, manifested with a severe and early onset resulting from the absence or significant reduction (< 1% of mean normal) of α-Gal A enzyme activity. Nonetheless, a proportion of patients will manifest with late onset disease, with varying residual levels of enzyme activity and clinical manifestations [44. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. doi:10.1186/1750-1172-5-30.
https://doi.org/10.1186/1750-1172-5-30...
,77. Ortiz A, Germain DP, Desnick RJ, et al. Fabry disease revisited: management and treatment recommendations for adult patients. Mol Genet Metab. 2018;123(4):416-427. doi:10.1016/j.ymgme.2018.02.014.
https://doi.org/10.1016/j.ymgme.2018.02....
].

In classic FD, neuropathic pain and pain attacks are often the presenting symptoms, typically emerging during childhood, and are usually described as burning or shooting pains or painful pins and needles in hands and/or feet [99. Biegstraaten M, Hollak CE, Bakkers M, Faber CG, Aerts JM, van Schaik IN. Small fiber neuropathy in Fabry disease. Mol Genet Metab. 2012;106(2):135-41. doi:10.1016/j.ymgme.2012.03.010.
https://doi.org/10.1016/j.ymgme.2012.03....
-1010. Mehta A, Ricci R, Widmer U, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest. 2004;34(3):236-242. doi:10.1111/j.1365-2362.2004.01309.x.
https://doi.org/10.1111/j.1365-2362.2004...
]. Cardiac damage usually starts early, progresses sub-clinically and classically manifests as left ventricular hypertrophy (LVH) mimicking hypertrophic cardiomyopathy (HCM). Cardiac involvement is the main cause of impaired quality of life and death in those patients, wherein adequate evaluation with cardiac imaging is essential for diagnosis and staging of FD [1111. Pieroni M, Moon JC, Arbustini E, et al. Cardiac involvement in fabry disease: JACC review topic of the week. J Am Coll Cardiol. 2021;77(7):922-936. doi:10.1016/j.jacc.2020.12.024.
https://doi.org/10.1016/j.jacc.2020.12.0...
-1212. Linhart A, Germain DP, Olivotto I, et al. An expert consensus document on the management of cardiovascular manifestations of Fabry disease. Eur J Heart Fail. 2020;22(7):1076-1096. doi:10.1002/ejhf.1960.
https://doi.org/10.1002/ejhf.1960...
].

In the present study, we describe subclinical cardiac involvement and small fiber neuropathy in two cousins diagnosed with FD secondary to a recently described likely pathogenic variant [13]. Family history is resumed in Figure 1.

Figure 1.
Family pedigree.

Case 1

A 34-year-old man reported that at the age of 11 he started burning sensation in hands and feet during physical activity, improving with rest and when he placed his hands under ice water. These symptoms have improved in frequency and intensity, and he only keeps burning sensation in hands when exposed to heat. Since childhood he has intestinal constipation, evacuating only twice a week, and also postprandial vomiting after a fatty meal. Neurological examination revealed painful hypoesthesia in the feet. Nerve conduction studies were normal. Family history was positive for Fabry disease. Since genetic testing of family members was not available, GLA gene was sequenced and identified a variant of unknown significance (PM2, PP3) NM_000169.2: c.454T>G, p.Tyr152Asp (GRCh37). Further studies were performed; MLPA of GLA gene didn’t reveal any copy number variants, GLA enzyme activity was 0,10 µmol/L/h (normal ≥ 15,3 µmol/L/h) and the serum level of Lyso-Gb-3 was elevated at 41,3 ng/ml (normal ≤ 1,8 ng/ml).

Information from other family members [1313. Dias FV, Lima HMC, Esteves JFC, et al. Insuficiência renal crônica na doença de Fabry - relato de caso. Braz J Surg Clin Res - BJSCR. 2017;18(3):68-70.], enzyme activity and serum level of Lyso-Gb3 in this patient and his cousin where helpful to stablish PP1 as a further criteria and reclassify this variant as likely pathogenic [1414. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi:10.1038/gim.2015.30.
https://doi.org/10.1038/gim.2015.30...
]. Also, a different variant in the same codon has been reported as pathogenic and related to classic FD by Duro et al. [1515. Duro G, Zizzo C, Cammarata G, et al. Mutations in the GLA Gene and LysoGb3: is it really Anderson-Fabry disease? Int J Mol Sci. 2018;19(12):3726. doi:10.3390/ijms19123726.
https://doi.org/10.3390/ijms19123726...
] (PM5).

Considering the current diagnostic impression of small fiber neuropathy, a skin biopsy was performed and showed a significant reduction of intraepidermal nerve fiber density (IENFD) in the samples from the distal leg, with an average density of approximately 1,2 IENFD/mm in the evaluated cuts (Figure 2). The observed densities are below the expected values for the patient's age and sex, thus confirming the diagnosis of small fiber neuropathy. A cardiological investigation was also carried out with 12-lead ECG showing sinus rhythm with short PR interval and 24-hour Holter with periods of junctional rhythm. Transthoracic echocardiography (2D-echo) showed mild left ventricular dilatation without increased thickness, but with increased ventricular mass index (LVMI=121.9 g/m2), compatible with eccentric hypertrophy. Traditional measurements of diastolic function showed no abnormalities except for a slight increase in left atrial volume. In speckel-tracking echo evaluation, global longitudinal strain (GLS) was also borderline (-16.9%), and it was reduced, mainly in basal segments with a relative apical sparing pattern, confirming apparent initial cardiac involvement. Cardiac magnetic resonance (CMR) was further performed and demonstrated normal function with boundary thickness of septum and posterior wall of left ventricle. There was a reduction in myocardial native-T1 time, calculated between 759ms and 869ms (normal >900ms) and no alteration in extracellular volume (ECV). In addition, it was described late gadolinium enhancement (LGE) with inferolateral basal uptake, mid-myocardium distribution pattern and total fibrosis estimated in 2% (Figure 2). Audiometry was within normal range. Ophthalmologic evaluation revealed cornea verticillata (Figure 2) and increased vascular tortuosity.

Figure 2.
A and B: Skin biopsy showing a significant reduction of intraepidermal nerve fiber density in the samples from the distal leg, in comparison with proximal leg. C: Cardiac magnetic resonance imaging showing late gadolinium enhancement with inferolateral basal uptake. D: Cornea verticillata.

Case 2

A 30-year-old man reported that at the age of 13 he started burning sensation in hands and feet and lipothymia triggered by excessive heat. Such symptoms improved when he lay on the cold floor for 15-30 minutes. He mentions that there was complete improvement of this condition before the age of 25, remaining asymptomatic until the present moment. Neurological examination was normal. Genetic testing identified, as expected, the familial variant on GLA gene. The GLA enzyme activity was < 0,8 µmol/L/h (normal ≥ 15,3 µmol/L/h) and the serum level of Lyso-Gb3 was elevated at 45,8 ng/ml (normal ≤ 1,8 ng/ml). Cardiac assessment with 12 -lead ECG and 24-hour Holter were unremarkable. 2D-echo showed mild increased left ventricular inferolateral wall thickness. The longitudinal strain was reduced in lateral wall, but GLS still preserved. CMR has also demonstrated slight thickness of septum and posterior wall of left ventricle and reduction in myocardial native-T1 time. ECV was preserved and subtle LGE was present in inferolateral basal segment, showing underlying fibrosis with mid-myocardium distribution.

Discussion

In FD, as a consequence of an abnormal function of the lysosomal enzyme α-Gal A, Gb3 starts to accumulate within several tissues including blood vessels, kidneys, nervous system and heart, accounting for the corresponding clinical manifestations [1616. Liguori R, Incensi A, de Pasqua S, et al. Skin globotriaosylceramide 3 deposits are specific to Fabry disease with classical mutations and associated with small fibre neuropathy. PLoS One. 2017;12(7):e0180581. doi:10.1371/journal.pone.0180581.
https://doi.org/10.1371/journal.pone.018...
]. Considering the peripheral nervous system, early neural damage involves small nerve fibers of the peripheral somatic and autonomic systems [1616. Liguori R, Incensi A, de Pasqua S, et al. Skin globotriaosylceramide 3 deposits are specific to Fabry disease with classical mutations and associated with small fibre neuropathy. PLoS One. 2017;12(7):e0180581. doi:10.1371/journal.pone.0180581.
https://doi.org/10.1371/journal.pone.018...
-1717. Cable WJ, Kolodny EH, Adams RD. Fabry disease: impaired autonomic function. Neurology. 1982;32(5):498-502. doi:10.1212/wnl.32.5.498.
https://doi.org/10.1212/wnl.32.5.498...
]. Neuropathological studies reveal loss of cell bodies in the dorsal root ganglia together with a pronounced reduction of small, thinly myelinated (Aδ) and unmyelinated (C) nerve fibers in sural nerve biopsy specimens [1818. Gemignani F, Marbini A, Bragaglia MM, Govoni E. Pathological study of the sural nerve in Fabry's disease. Eur Neurol. 1984;23(3):173-181. doi:10.1159/000115700.
https://doi.org/10.1159/000115700...
-1919. Onishi A, Dyck PJ. Loss of small peripheral sensory neurons in Fabry disease. Histologic and morphometric evaluation of cutaneous nerves, spinal ganglia, and posterior columns. Arch Neurol. 1974;31(2):120-127. doi:10.1001/archneur.1974.00490380068009.
https://doi.org/10.1001/archneur.1974.00...
]. The preferential involvement of these nerve fibers characterizes the common finding of small fiber neuropathy (SFN), with onset of related symptoms generally occurring at an earlier age in boys than in girls [2020. Hopkin RJ, Bissler J, Banikazemi M, et al. Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry. Pediatr Res. Nov 2008;64(5):550-555. doi:10.1203/PDR.0b013e318183f132.
https://doi.org/10.1203/PDR.0b013e318183...
]. Neuropathic pain is a frequent feature of SFN, described in 60-80% of classically affected boys and girls, and can manifest as episodic crises (known as “Fabry crises”) of burning pain in hands and feet, usually precipitated by fever, exercise, fatigue, stress, and rapid changes in temperature, and chronic pain with burning and/or tingling sensations [2121. Hilz MJ, Stemper B, Kolodny EH. Lower limb cold exposure induces pain and prolonged small fiber dysfunction in Fabry patients. Pain. 2000;84(2-3):361-365. doi:10.1016/s0304-3959(99)00236-5.
https://doi.org/10.1016/s0304-3959(99)00...
-2222. Hoffmann B, Beck M, Sunder-Plassmann G, et al. Nature and prevalence of pain in Fabry disease and its response to enzyme replacement therapy--a retrospective analysis from the Fabry Outcome Survey. Clin J Pain. 2007;23(6):535-542. doi:10.1097/AJP.0b013e318074c986.
https://doi.org/10.1097/AJP.0b013e318074...
]. In both cases described in the present study, patients manifested with typical “Fabry crises” during childhood/adolescence, in which the painful symptoms were precipitated by specific triggers. As pain may become less prominent in adulthood, it is important to search for a previous history of acroparesthesia in infancy/adolescence during the first examination of a newly diagnosed adult patient, as well as suspect of FD in an adult patient with previous neuropathic symptoms in infancy [2323. Naleschinski D, Arning K, Baron R. Fabry disease--pain doctors have to find the missing ones. Pain. 2009;145(1-2):10-11. doi:10.1016/j.pain.2009.07.025.
https://doi.org/10.1016/j.pain.2009.07.0...
]. Autonomic dysfunction also composes SFN, often starts in childhood and usually remain present during adulthood. It frequently manifests with gastrointestinal involvement, as abdominal pain (often after eating), diarrhea, nausea, and vomiting, possible related to the deposition of Gb3 in the autonomic ganglia of the bowel and mesenteric blood vessels [2424. Hoffmann B, Schwarz M, Mehta A, Keshav S; Investigators FOSE. Gastrointestinal symptoms in 342 patients with Fabry disease: prevalence and response to enzyme replacement therapy. Clin Gastroenterol Hepatol. 2007;5(12):1447-1453. doi:10.1016/j.cgh.2007.08.012.
https://doi.org/10.1016/j.cgh.2007.08.01...
-2525. Eng CM, Germain DP, Banikazemi M, et al. Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet Med. 2006;8(9):539-548. doi:10.1097/01.gim.0000237866.70357.c6.
https://doi.org/10.1097/01.gim.000023786...
]. In addition, sweating disorders (anhidrosis or hypohidrosis) are also common and can cause heat and exercise intolerance [2525. Eng CM, Germain DP, Banikazemi M, et al. Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet Med. 2006;8(9):539-548. doi:10.1097/01.gim.0000237866.70357.c6.
https://doi.org/10.1097/01.gim.000023786...
-2626. Shelley ED, Shelley WB, Kurczynski TW. Painful fingers, heat intolerance, and telangiectases of the ear: easily ignored childhood signs of Fabry disease. Pediatr Dermatol. 1995;12(3):215-219. doi:10.1111/j.1525-1470.1995.tb00161.x.
https://doi.org/10.1111/j.1525-1470.1995...
]. Despite more extensive knowledge about the phenotype of SFN in FD, the exact underlying pathophysiological mechanism remains unknown, and it is uncertain whether the neuropathy arises from deposits of lipids in ganglia leading to dying-back neuropathy, or from direct damage to small nerve fiber axons [99. Biegstraaten M, Hollak CE, Bakkers M, Faber CG, Aerts JM, van Schaik IN. Small fiber neuropathy in Fabry disease. Mol Genet Metab. 2012;106(2):135-41. doi:10.1016/j.ymgme.2012.03.010.
https://doi.org/10.1016/j.ymgme.2012.03....
]. Moreover, diagnosing SFN remains challenging as a golden standard is not yet available [2727. Raasing LRM, Vogels OJM, Veltkamp M, van Swol CFP, Grutters JC. Current view of diagnosing small fiber neuropathy. J Neuromuscul Dis. 2021;8(2):185-207. doi:10.3233/JND-200490.
https://doi.org/10.3233/JND-200490...
]. Skin biopsy with linear quantification of intraepidermal nerve fibers density (IENFD) is a reliable and efficient technique to confirm the clinical diagnosis of SFN and should be based on the comparison with normative reference values adjusted by age and possibly gender [2828. Lauria G, Hsieh ST, Johansson O, et al. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. Eur J Neurol. 2010;17(7):903-912. doi:10.1111/j.1468-1331.2010.03023.x.
https://doi.org/10.1111/j.1468-1331.2010...
]. In previous studies, reduced IENFD were described in 19 out of 20 male patients [2929. Scott LJ, Griffin JW, Luciano C, et al. Quantitative analysis of epidermal innervation in Fabry disease. Neurology. 1999;52(6):1249-1254. doi:10.1212/wnl.52.6.1249.
https://doi.org/10.1212/wnl.52.6.1249...
] and in 27-53% of female patients with FD [3030. Liguori R, Di Stasi V, Bugiardini E, et al. Small fiber neuropathy in female patients with Fabry disease. Muscle Nerve. 2010;41(3):409-412. doi:10.1002/mus.21606.
https://doi.org/10.1002/mus.21606...
]. Further studies showed that 100% of male and 57% of female patients had an abnormal IENFD [99. Biegstraaten M, Hollak CE, Bakkers M, Faber CG, Aerts JM, van Schaik IN. Small fiber neuropathy in Fabry disease. Mol Genet Metab. 2012;106(2):135-41. doi:10.1016/j.ymgme.2012.03.010.
https://doi.org/10.1016/j.ymgme.2012.03....
], together indicating that almost all male and about half to three quarters of female Fabry patients have diagnostic features compatible with SFN. In both cases reported in the present study, symptoms suggestive of SFN were present early, being later confirmed by normal nerve conduction studies and reduced IENFD in the patient who underwent skin biopsy. The diagnostic documentation of SFN allows the establishment of specific organ damage by FD and the indication of early specific treatment.

Although the classically described cardiac involvement is LVH, more common after 40 years of age, cardiac disease is progressive, affects both genders, but in men it occurs earlier than in women [1212. Linhart A, Germain DP, Olivotto I, et al. An expert consensus document on the management of cardiovascular manifestations of Fabry disease. Eur J Heart Fail. 2020;22(7):1076-1096. doi:10.1002/ejhf.1960.
https://doi.org/10.1002/ejhf.1960...
,3131. Kampmann C, Linhart A, Baehner F, et al. Onset and progression of the Anderson-Fabry disease related cardiomyopathy. Int J Cardiol. 2008;130(3):367-373. doi:10.1016/j.ijcard.2008.03.007.
https://doi.org/10.1016/j.ijcard.2008.03...
]. With the introduction of new technologies and their use in clinical practice, it is reasonable that we can detect intermediate phenotypes between patients without evidence of heart disease and those with classic signs [3232. Augusto JB, Johner N, Shah D, et al. The myocardial phenotype of Fabry disease pre-hypertrophy and pre-detectable storage. Eur Heart J Cardiovasc Imaging. 2021;22(7):790-799. doi:10.1093/ehjci/jeaa101.
https://doi.org/10.1093/ehjci/jeaa101...
]. Assessment of GLS and T1 mapping /CMR were pivotal at presented cases. GLS (obtained by speckel-tracking echo or CMR) has been shown to add diagnostic value in heart disease associated with FD [3232. Augusto JB, Johner N, Shah D, et al. The myocardial phenotype of Fabry disease pre-hypertrophy and pre-detectable storage. Eur Heart J Cardiovasc Imaging. 2021;22(7):790-799. doi:10.1093/ehjci/jeaa101.
https://doi.org/10.1093/ehjci/jeaa101...
-3333. Rob D, Marek J, Dostalova G, Linhart A. Heart failure in Fabry disease revisited: application of current heart failure guidelines and recommendations. ESC Heart Fail. 2022;9(6):4043-4052. doi:10.1002/ehf2.14091.
https://doi.org/10.1002/ehf2.14091...
]. Although nonspecific, reduced GLS can present including reduced longitudinal strain in the basal inferolateral segment, and it has been described as useful to detect subclinical cardiomyopathy [3434. Yim J, Yau O, Yeung DF, Tsang TSM. Fabry cardiomyopathy: current practice and future directions. Cells. 2021;10(6):1532. doi:10.3390/cells10061532.
https://doi.org/10.3390/cells10061532...
]. A reduced regional longitudinal strain involving basal segments with a relative apical sparing was recently described in patients with FD [3535. Réant P, Testet E, Reynaud A, et al. Characterization of Fabry disease cardiac involvement according to longitudinal strain, cardiometabolic exercise test, and T1 mapping. Int J Cardiovasc Imaging. 2020;36(7):1333-1342. doi:10.1007/s10554-020-01823-7.
https://doi.org/10.1007/s10554-020-01823...
]. CMR can be useful, in addition to 2D-echo, in the detection of LVH, specially from apical segments and to assess papillary muscle hypertrophy, described as an early marker [1212. Linhart A, Germain DP, Olivotto I, et al. An expert consensus document on the management of cardiovascular manifestations of Fabry disease. Eur J Heart Fail. 2020;22(7):1076-1096. doi:10.1002/ejhf.1960.
https://doi.org/10.1002/ejhf.1960...
]. Beyond that, myocardial native T1 mapping is usually altered. It represents a quantitative myocardial signal which is reduced by the sphingolipid storage tissue, representing an initial phase of cardiac involvement and risk factor for disease worsening [3636. Pica S, Sado DM, Maestrini V, et al. Reproducibility of native myocardial T1 mapping in the assessment of Fabry disease and its role in early detection of cardiac involvement by cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2014;16:99. doi:10.1186/s12968-014-0099-4.
https://doi.org/10.1186/s12968-014-0099-...
,3737. Camporeale A, Pieroni M, Pieruzzi F, et al. Predictors of clinical evolution in Prehypertrophic Fabry disease. Circ Cardiovasc Imaging. 2019;12(4):e008424. doi:10.1161/CIRCIMAGING.118.008424.
https://doi.org/10.1161/CIRCIMAGING.118....
]. On the opposite, the ECV is classically normal and can be useful as differential diagnosis from other infiltrations myocardium conditions where the ECV is increased [3838. Haaf P, Garg P, Messroghli DR, Broadbent DA, Greenwood JP, Plein S. Cardiac T1 Mapping and Extracellular Volume (ECV) in clinical practice: a comprehensive review. J Cardiovasc Magn Reson. 2016;18(1):89. doi:10.1186/s12968-016-0308-4.
https://doi.org/10.1186/s12968-016-0308-...
]. Here, we described reduced regional longitudinal strain and a native myocardial T1 decreased in patients with FD even before evident and classical LVH. The use of these diagnostic tools is actually recommended [3939. Germain DP, Altarescu G, Barriales-Villa R, et al. An expert consensus on practical clinical recommendations and guidance for patients with classic Fabry disease. Mol Genet Metab. 2022;137(1-2):49-61. doi:10.1016/j.ymgme.2022.07.010.
https://doi.org/10.1016/j.ymgme.2022.07....
]. In both cases, tenuous fibrosis was detected through the subtle LGE with a mid-myocardial non-ischemic pattern [4040. Moon JC, Sheppard M, Reed E, Lee P, Elliott PM, Pennell DJ. The histological basis of late gadolinium enhancement cardiovascular magnetic resonance in a patient with Anderson-Fabry disease. J Cardiovasc Magn Reson. 2006;8(3):479-482. doi:10.1080/10976640600605002.
https://doi.org/10.1080/1097664060060500...
], reaffirming cardiac FD.

Diagnosis of FD is always challenging. The stand-alone identification of a GLA variant is not sufficient for diagnosis of this condition. In men with clinical symptoms, the first diagnostic testing should be enzyme activity, unless the familial variant has been identified and has a well stablished classification of pathogenic/likely pathogenic [4141. Stiles AR, Zhang H, Dai J, et al. A comprehensive testing algorithm for the diagnosis of Fabry disease in males and females. Mol Genet Metab. 2020;130(3):209-214. doi:10.1016/j.ymgme.2020.04.006.
https://doi.org/10.1016/j.ymgme.2020.04....
-4242. Silva CAB, Andrade LGM, Vaisbich MH, Barreto FC. Brazilian consensus recommendations for the diagnosis, screening, and treatment of individuals with Fabry disease: Committee for Rare Diseases - Brazilian Society of Nephrology/2021. J Bras Nefrol. 2022;44(2):249-267. doi:10.1590/2175-8239-JBN-2021-0208.
https://doi.org/10.1590/2175-8239-JBN-20...
]. The variant identified in this family has been previously reported by Dias et al [1313. Dias FV, Lima HMC, Esteves JFC, et al. Insuficiência renal crônica na doença de Fabry - relato de caso. Braz J Surg Clin Res - BJSCR. 2017;18(3):68-70.]. However, the authors didn’t report which criteria were used to classify this variant nor enzyme activity levels. The case reported by Dias et al is the uncle of the patients reported here. Additionally, in this study we provide detailed evidence that this variant is associated with <5% enzyme activity, accumulation of Lyso-Gb3 and organ damage consistent with classical FD.

Conclusion

In the present study we describe male patients from the same family, both with neuropathic and autonomic symptoms that started in childhood, molecular testing and laboratory findings consistent with FD. Non-invasive tests were conclusive in the unequivocal diagnosis of SFN with proven histological evidence in one of them. Despite the absence of cardiac symptoms, it was possible to diagnose early-stage cardiac FD assessed by techniques available but not widely used in daily clinical practice. We hope that reports like this can be useful to encourage screening and follow-up routines in FD patients, enabling early diagnosis and adequate treatment. Up to the moment this variant has not been included in specialized Fabry disease databases (International Fabry disease Genotype-Phenotype database and the Japanese Fabry Database). Therefore, the evidence provided in this study may help to improve the variant classification and refine genotype-phenotype correlations in FD.

Acknowledgments

We would like to thank the patients who participated in the present study, as well as all patients with Fabry Disease regularly followed by our team.

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  • Funding

    This research has not received any specific grants from any funding agency in the public, commercial, or not-for-profit sectors.

Publication Dates

  • Publication in this collection
    30 June 2023
  • Date of issue
    2023

History

  • Received
    31 Jan 2023
  • Accepted
    02 June 2023
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