Next Article in Journal
FOXE1-Dependent Regulation of Macrophage Chemotaxis by Thyroid Cells In Vitro and In Vivo
Next Article in Special Issue
Molecular Research in Medical Genetics
Previous Article in Journal
Effects of Brain Size on Adult Neurogenesis in Shrews
Previous Article in Special Issue
TGF-β Signaling: From Tissue Fibrosis to Tumor Microenvironment
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

X Chromosome Inactivation in Carriers of Fabry Disease: Review and Meta-Analysis

by
Emanuela Viggiano
1,* and
Luisa Politano
2,*
1
Department of Prevention, UOC Hygiene Service and Public Health, ASL Roma 2, 00142 Rome, Italy
2
Cardiomyology and Medical Genetics, Department of Experimental Medicine, Luigi Vanvitelli University, 80138 Naples, Italy
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(14), 7663; https://doi.org/10.3390/ijms22147663
Submission received: 23 May 2021 / Revised: 13 July 2021 / Accepted: 14 July 2021 / Published: 17 July 2021
(This article belongs to the Special Issue Molecular Research in Medical Genetics)

Abstract

:
Anderson-Fabry disease is an X-linked inborn error of glycosphingolipid catabolism caused by a deficiency of α-galactosidase A. The incidence ranges between 1: 40,000 and 1:117,000 of live male births. In Italy, an estimate of incidence is available only for the north-western Italy, where it is of approximately 1:4000. Clinical symptoms include angiokeratomas, corneal dystrophy, and neurological, cardiac and kidney involvement. The prevalence of symptomatic female carriers is about 70%, and in some cases, they can exhibit a severe phenotype. Previous studies suggest a correlation between skewed X chromosome inactivation and symptoms in carriers of X-linked disease, including Fabry disease. In this review, we briefly summarize the disease, focusing on the clinical symptoms of carriers and analysis of the studies so far published in regards to X chromosome inactivation pattern, and manifesting Fabry carriers. Out of 151 records identified, only five reported the correlation between the analysis of XCI in leukocytes and the related phenotype in Fabry carriers, in particular evaluating the Mainz Severity Score Index or cardiac involvement. The meta-analysis did not show any correlation between MSSI or cardiac involvement and skewed XCI, likely because the analysis of XCI in leukocytes is not useful for predicting the phenotype in Fabry carriers.

1. Anderson-Fabry Disease

Anderson-Fabry disease (OMIM #301500) is a progressive X-linked inborn error of glycosphingolipid catabolism caused by a deficiency of α-galactosidase A (α-gal), belonging to the family of lysosomal exoglycosidases. The incidence ranges between 1:40,000 and 1:117,000 [1,2] live male births. In Italy, an estimate of incidence is available only for north-western Italy, where it is approximately 1:4000 [3]. The GLA gene is located on Xq22.1 and consists of 7 exons, encoding the α-gal protein. It is a polypeptide of 429 amino acids, while the mature protein is a glycoprotein of about 100 kDa, with a homodimer structure [4]. So far, more than 900 variants have been reported in the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/gene.php?gene=GLA, accessed on 16 July 2021), about 69% of which are missense mutations, 17% deletions, 5% splicing and 5% insertions or duplications. The pathogenetic mechanisms of Fabry disease are not completely clear. The enzyme deficiency determines a progressive accumulation of glycolipids, in particular globotriaosylceramide (Gb3) in the lysosomes and cytosol of cells in several tissues, predominantly in cardiovascular, peripheral and central nervous systems, and kidney [5,6,7]. The onset of symptoms and the phenotype depend on the residual enzyme activity; in particular, a level less than 1% of normal activity leads to the classical form, and levels between 1 to 30% to atypical forms [8,9,10,11].

1.1. Inheritance

Fabry’s disease is inherited in an X-linked manner. The heterozygous mothers have a 50% chance of passing the defective gene to all offspring at each conception. The sons who inherit the defective gene will have Fabry’s disease; the daughters, once thought to be asymptomatic carriers, may instead develop disease manifestations from mild to severe [12]. Though a positive family history is a strong indicator of Fabry’s disease, de novo mutations have been documented, and so the absence of a family history does not rule it out.

1.2. Pathophysiology

The functional defect of α-gal leads to a progressive accumulation of Gb3 in all body cells containing lysosomes, including vascular endothelium and smooth muscle cells, cardiomyocytes in the left ventricle and atrium, valvular fibroblasts, endothelial cells and vascular smooth muscle cells [13]. However, Gb3 storage cannot alone explain the absence of complications in newborns [14], the absence of correlation between the severity of clinical symptoms and the level of Gb3 in plasma or urine [15,16], symptoms in female carriers despite the presence of residual α-gal enzyme and the intra-familial phenotypic variability despite the same genetic mutation [17,18]. Moreover, the contribution of the stored material to the increase in cardiac mass was limited to about 1–2% [7]. For those reasons, some researchers argue that the increased levels of Gb3 can trigger other pathogenetic mechanisms. First, an increased level of globotriaosylsphingosine (Lyso-Gb3) is observed in the plasma of Fabry patients, including female carriers [19]. Lyso-Gb3 is involved in the vasculopathy, as it induces the proliferation of smooth muscle cells that is associated with hypertrophy and myocardial arterial walls and fibrosis, in vitro [20,21,22]. The storage of Gb3 induces an excessive production of reactive oxygen, thereby increasing oxidative stress [23]. In particular, the increase in radical oxygen production and the decrease of anti-oxidants, such as glutathione and superoxide, cause an impairment of the myofilaments, altering contractility and distensibility, and favoring apoptosis at the cardiac level [24,25]. Gb3 also up-regulates the expression of adherence molecules in vascular endothelium [26]. Other data indicate that Gb3 may cause the release of pro-inflammatory cytokines, especially in dendritic cells and monocytes [27], since inflammatory mediators (such as TNF-α, IL 1β, IL-6) are increased in the plasma of patients with Fabry [27,28]. Moreover, GB3 would activate the innate response, through binding the TLR4 receptor on immune cells, which increases the release of inflammatory mediators from peripheral blood mononuclear cells [28]. The role of inflammation is also supported by the endomyocardial biopsy that shows an increase in inflammatory macrophages in the tissue [29,30]. The inflammatory response can also be triggered by the vascular alteration. In fact, vascular remodeling could reduce the arterial compliance, determining upregulation of the renin-angiotensin system and the increase of angiotensin 1 and 2 in endothelial cells [31,32], which trigger the inflammation [31,33]. The consequence of inflammation is the release of pro-thrombotic factors in the vessels, increasing the risk of ischemia by increasing the extracellular matrix deposition and fibrosis [31,34].
These data suggest that the Gb3 storage may act by triggering a cascade of pathophysiological processes leading to structural cellular changes, tissue defects, and—over time—to organ failure.

1.3. Clinical Presentation

The classical form of Fabry disease develops in childhood or adolescence, usually with endothelial dysfunction leading to angiokeratomas, and corneal dystrophy, that represent the physical stigmata of the disease [35]. The progression of the disease involves the peripheral and autonomic nervous systems leading to paraesthesia, neuropathic pain; in particular “Fabry crises” are described as pain in the extremities which radiates proximally. Other symptoms depend by the involvement of gastrointestinal systems, in particular abdominal pain, diarrhea or constipation, especially in female carriers [36], and hypohidrosis; less frequently hyperhidrosis. Moreover, patients can present cerebrovascular involvement, in particular transient ischemic attacks (TIA) and stroke.
Finally, kidneys and heart are affected, and, when untreated, patients can die from heart and/or kidney failure in the fourth or fifth decade of life [5]. The renal involvement in Fabry’s has been known since the original reports by Anderson and Fabry in the late nineteenth century. It is likely to start at an early age, around the age of 22, and to be more severe in patients with α-gal enzyme less than 1% than in those with detectable enzyme levels, in whom renal involvement begins late in life. Urinary concentration defects, polyuria, proteinuria, and chronic renal insufficiency are known as clinical renal manifestations of Fabry’s disease. Concentration defects are the earliest functional manifestation. Proteinuria may begin in the teens, becoming more common in the second–third decade. Twenty-five percent of patients may progress to chronic renal insufficiency [37].
Facial dysmorphisms are reported in male Fabry patients, characterized by peri-orbital fullness, prominent supra-orbital ridges, large bitemporal width, ptosis, broad nasal base, bulbous nasal tip, full lips and coarse features [38,39]. The identification of deposits of Gb3 at the reproductive tract level has suggested an impairment of male gonadal function in Fabry disease. Papaxanthos–Roche et al. have recently shown that patients with FD might have a detrimental effect on semen characteristics, but the reproductive function is only slightly diminished [40]. The impact of Fabry Disease on reproductive fitness was studied by Laney et al. on a large, multi-centered population (n = 376) of individuals, both males and females with FD. They conclude that in this large multicenter sample, patients with FD did not exhibit reduced reproductive fitness [41]. However, previous studies [42] have reported azoospermia as a possible complication of Fabry disease. A routine sperm analysis in the follow-up of young patients with Fabry disease was recommended as far as sperm cryopreservation.
The later-onset atypical forms are usually more benign, because they involve a more restricted number of organs, usually limited to the kidneys, heart or nervous system [1].

Cardiac Manifestations

Cardiac involvement in Fabry disease is frequent in male and in heterozygote females [43,44]. The progression of cardiomyopathy is determined by the involvement of cardiac muscle, and the conduction and vascular systems.
In particular, at the cardiac muscle level, patients with Fabry usually show concentric and non-obstructive left ventricular hypertrophy (LVH). Sometimes the cardiomyopathy in Fabry patients mimics the hypertrophic cardiomyopathy due to sarcomeric genes mutations, particularly when isolated. MYH7 gene-encoding β-cardiac myosin heavy chain (MHC) and MYBPC3, which encodes myosin binding protein C, account for more than 50% of HCM patients with pathogenic variants [45,46,47]. Other sarcomere protein genes causing HCM include cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), α-tropomyosin (TPM1), myosin regulatory light chain 2 (MYL2), myosin essential light chain (MYL3), and actin (ACTC1) [48,49]. However, the global ejection fraction is preserved [50]. Other typical findings in Fabry cardiomyopathy are prominent papillary muscles [43,44] and a preserved global ejection fraction combined with early stages of diastolic dysfunction [51,52]. The onset of cardiomyopathy usually occurs in males aged >30 years and in females aged >40 years. Valvular fibrosis leading to valvular abnormalities frequently occurs; however, the involvement is generally mild and clinically insignificant. Conduction system abnormalities like short PR interval, atrium-ventricular blocks, supraventricular and ventricular arrhythmias are also reported [53]. Myocardial ischemia, frequently observed, has in most instances a functional origin due to endothelial dysfunction of coronary arteries and to the increased oxygen demand of hypertrophic myocardium [51].
The end-stage Fabry cardiomyopathy is characterized by intramural replacement fibrosis limited to the basal postero-lateral wall of the left ventricle [43]
The most common diagnostic tools to assess cardiac functions in Fabry’s are electrocardiogram and Holter monitoring for conduction abnormalities, echocardiography and magnetic resonance imaging (MRI) for the myocardial mass assessment. Echocardiography, which is widely available and easily applicable, shows the early stages of the disease, the typical images of prominent papillary muscles as well as of a thickened interventricular septum and hypertrophy of the left ventricle lateral wall [54]. Echocardiography is also the method of choice to monitor treatment effects. However, the non-invasive gold-standard to detect myocardial fibrosis is late gadolinium-enhanced MRI [55].

1.4. Genotype-Phenotype Correlation

As in other inherited metabolic diseases, the phenotype usually depends on the residual enzyme activity, which in turn depends on the type of mutation [56]. In general, mutations, that cause less than 1% of enzyme activity, lead to the classical form, while those causing between 1–30% of normal activity, lead to atypical forms [8,9,10,11].
In the Fabry Outcome Survey (FOS), which included 545 patients belonging to 157 families from nine European countries, a highly significant positive correlation was found between the age at entry into FOS and the FOS Severity Index as well as between the age at entry into FOS and the number of affected organs (p < 0.001) in males with GLA missense mutations, irrespective of whether the change in the amino acid side chain predicted in the α-gal protein was classified as a conservative or non-conservative change [57].
However, the analysis of genotype–phenotype correlations in Fabry disease is complicated by a number of factors, such as the high proportion of private mutations, the large intra and inter-familial phenotypic heterogeneity associated with the same mutation, and disease-related complications observed with high prevalence in the general population [58,59,60,61,62,63].

1.5. Treatment

Comprehensive and timely treatment of adult patients with Fabry disease are directed toward prevention of further progression to irreversible tissue damage and organ failure. Care should include enzyme replacement therapy (ERT) and adjunctive therapies to treat symptoms that arise due to tissue injury and prevent non-specific progression of the disease [64].
Currently, two different forms of ERT are available; agalsidase-alfa (Replagal, Takeda), produced in human fibroblasts and registered at a dose of 0.2 mg/kg biweekly, and agalsidase-beta (Fabrazyme, Sanofi Genzyme), produced in Chinese hamster ovary cells and registered at a dose of 1.0 mg/kg biweekly. Long-term clinical studies have shown a small but significant effect of ERT on cardiovascular and renal complication rate, with some superiority of the higher dosed agalsidase-beta compared to agalsidase-alfa [64,65]. Especially loss of renal function, occurring in the vast majority of male patients with classic Fabry, is attenuated by ERT [66]. These clinical benefits were mainly observed in patients who started ERT before the presence of irreversible organ damage [67,68]. For patients with missense mutations that result in a mutant protein with normal α-gal catalytic activity and reduced protein stability, the use of a pharmacological chaperone is indicated, given its ability to bind and stabilize protein specifically [69]. In particular, the pharmacological chaperone 1-deoxy-galactonojirimycin (DGJ, Amigal or Migalastat) Migalastat (commercial name Galafold™) is currently the only oral treatment for Fabry disease approved by the US Food Drug Administration (FDA) and European Medicines Agency (EMA). Migalastat is able to stabilize α-gal, prolonging the half-life of α-gal in vivo, both in mouse models and in humans and leads to an improved clearance of Gb3 [70,71,72,73], but it also inhibits α-gal. For this reason, the therapy is intermittent, and consists in two phases: in the first phase Migalastat is administered, inhibiting and stabilizing α-gal, while in a second phase α-gal is activated in absence of the drug [71], A useful database with predictive tool for mutations, Fabry_CEP, can be used to evaluate the responsiveness of GLA mutations to Migalastat [74]. Migalastat can be used in synergy with ERT, either co-administrating both drugs intravenously or one orally (Migalastat) and the other intravenously (recombinant enzyme) [75,76].
Treatments currently under evaluation in preclinical trials are second generation ERTs (Pegunigalsidase-alfa, Moss-aGal), substrate reduction therapies (Venglustat and Lucerastat), mRNA and gene-based therapy [77]. The follow-up assessments to evaluate treatment responses should ideally be supervised by a physician experienced in the management of patients with Fabry disease, with input from sub-specialists who also have Fabry disease experience as part of a multidisciplinary clinical team that includes neurologists, nephrologists, cardiologists, clinical geneticists, genetic counsellors and psychologists [78]

2. Female Carriers of Fabry Disease

Given the X-linked pattern of inheritance, clinical manifestations of Fabry disease in heterozygous females, as obligate carriers, have long been considered rare or mild. However, the prevalence of symptomatic female carriers is estimated about 70% [79,80], with phenotypes ranging from very mild to severe cases [81,82,83]. Moreover, data in literature indicate that females are affected much more commonly than previously believed [84].
Fabry carriers usually show late onset of symptoms, slower progression of the disease and longer life expectancy, estimated to be around 70 years, compared to 50–55 for male patients [85,86]. Neuropathic pain is reported in about 10% of carriers, usually intermittently [87] and often misdiagnosed as polyarthritis or polyarteritis nodosa; cornea verticillata is present in about 72% of girls, while hearing impairment is reported in about 33% of cases [88,89]. Other reported symptoms in about 33% of cases are renal involvement and proteinuria [90,91], requiring dialysis or kidney transplantation in 10% of cases [92]. According to the Fabry Outcome Survey (FOS) [93], 65% of affected females develop cardiac involvement, including cardiac ischemia of microvascular origin, hypertrophic cardiomyopathy and arrhythmias (atrio-ventricular block, tachyarrhythmias and ST-segment/T-wave abnormalities) that may require pacemaker implantation [94,95,96]. Cardiac involvement correlates with age; in particular, Kampmann et al. [97] reported the presence of cardiomyopathy in about 56% of heterozygous females aged <38 years, in 86% of those aged >38 years and in 100% carriers aged >45 years.
A systematic review of risk factors in Fabry heart disease that included 13 studies for a total of 4185 patients—with a follow-up period of 1.2–10 years—revealed 8.3% of deaths of these, while 75% had cardiovascular causes and 62% were attributable to sudden cardiac death (SCD), a leading cause of cardiovascular mortality in Fabry disease [98]. The mean prevalence of ventricular tachycardia was 15.3%, while age, male gender, LVH, late gadolinium enhancement (LGE) on MRI and Non-Sustained Ventricular Tachycardia (NSVT) were associated with SCD [98].
Niemann et al. [99] demonstrated a clear difference in Fabry cardiomyopathy between males and females, when assessed with cardiac MRI and LGE. Unlike in male patients, loss of myocardial function and the development of fibrosis were not necessarily related to myocardial hypertrophy in female carriers.
Finally, Wilcox et al., analysing the data from the Fabry Registry, a global clinical effort to collect longitudinal data on Fabry disease, reported that of the 1077 females enrolled, 69.4% had symptoms and signs of Fabry disease. The median age at onset of symptoms in females was 13 years, and although about 84% had a positive family history, the diagnosis was delayed up to a mean age of about 30 years. Twenty percent experienced major cerebrovascular, cardiac or renal events at a mean age of 46 years. Among adult females (n = 638) in whom glomerular filtration rate (eGFR) was estimated, 62.5% had an eGFR < 90 mL/min/1.73 m2 and 19.0% had eGFR <60 mL/min/1.73 m2. Proteinuria at 300 mg/day was present in 39.0% and > 1 g/day in 22.2%. The Quality of life (QoL), as measured by the SF-36((R)) survey, was impaired at an older age compared with males, but both genders experience significantly reduced QoL from the third decade of life onward. The authors concluded that Fabry’s carriers have a significant risk for major organ involvement and decreased QoL, and therefore, they should be carefully monitored for a precise estimation of signs and symptoms, as well as adequate therapy [12].

3. Skewed X-Chromosome Inactivation

Clinical symptoms in carriers of X-linked diseases depend on the levels of the main protein in the affected tissues. Several mechanisms have been hypothesized such as gene mutation on both alleles [100], loss of one X chromosome as in Turner’s Syndrome [101,102], uniparental disomy [103] or skewed X chromosome inactivation (XCI), with preferential inactivation of the X chromosome carrying the normal allele [92,104,105,106,107,108,109,110].
XCI is an epigenetic mechanism that equalizes the dosage of X-linked genes between sexes through the inactivation of one X chromosome in females. At the end of the process, the females are a mosaic of two cell types expressing either the maternal or paternal X chromosome. Random XCI indicates that about 50% of the cells presents the inactivation of the maternal or paternal X chromosome, while skewed XCI indicates an inactivation of the maternal or paternal X chromosome higher than 50%, usually a ratio of 75:25 or 80:20 between the two chromosomes. The term “extremely skewed XCI” indicates the preferential inactivation of one X chromosome in more than 90% of cells [111] (Figure 1).
Skewed XCI could depend by several factors, such as genetic mechanisms, as the mutations in the X-inactive specific transcript (XIST) gene, involved in familiar cases of skewed XCI [112,113]. Another factor is the plasticity, as cells with high turnover, such as hematopoietic cells, show a higher skewed XCI than cells with lower mitotic activity [114,115]. Skewed XCI in many older females may be related to selection, indeed, a growth or survival advantage conferred by one of the parental X chromosomes [116].

3.1. Skewed XCI in the Normal (Healthy) Asymptomatic Females

Previous studies reported a normal distribution of the XCI pattern in the general female population and an extremely skewed XCI in about 5% [116,117,118]. Moreover, XCI correlates with age and type of tissue [119,120]. In particular, the prevalence of skewed XCI is about 16–37% in females over 60 years of age and 49% in centenarians, while it is 14% in females aged ≤ 25 years, and 4.9–14.2% in newborns [118,121,122]. The prevalence of an extremely skewed XCI is about 16–27% in females aged ≥ 60 years and 18% in the centenarians [115,121,122], while it is 7% in females aged ≤ 25 years, and 0.7–2.7% in newborns [118,122,123]. However, a higher percentage of a skewing (about 27%) and an extreme skewing (about 5%) was reported in mothers compared to their newborns, suggesting that hematopoietic cells are affected by age [118]. Considering the type of tissue, a good correlation was reported between blood and epithelial tissue of the same individual [114,115,118,119], as well as between thyroid and muscle, or leucocytes and muscle [108], suggesting that tissues deriving from the same embryogenic layer have the same XCI pattern [105].

3.2. Skewed XCI in Carriers of Inherited X-Linked Disorders

Previous studies have shown the correlation between skewed XCI and phenotype in carriers of X-linked diseases, such as Duchenne and Becker muscular dystrophies [104,106,107,108], EDMD1 or myotubular myopathy [124], haemophilia B [125,126], dyskeratosis congenita [127], retinitis pigmentosa [128], Lesch-Nyhan disease, haemophilia A [110,125], Rett-syndrome and others. In fact, skewed XCI, resulted in a higher percentage of mutant cells than normal cells and could lead to clinical symptoms in X-linked disease (Figure 2).
However, despite a large number of studies, the correlation is still debated. It is possible to argue that contradictory results depend on several factors, such as (i) analysis of non-homogeneous groups of carriers and absence of control groups [129,130]; (ii) age of patients, with the analysis of only young patients, who can develop clinical symptoms later in life [131]; (iii) lack of identification of the allele carrying the mutant gene [129,132]; (iv) use of different cut-off for skewed XCI [104,105,108,129,131,132,133]; (v) non-X-linked alleles that can modify the phenotype [134]. Finally, the type of tissue analyzed is of extreme importance, as XCI performed in leukocytes could not reflect the XCI pattern of other cells, which have a different embryogenic origin. [135,136]. The XCI pattern seems not to be inherited, excluding the familiar cases due to XIST mutation, because the mother-daughters did not show the same pattern, as demonstrated in the carriers of dystrophinopathies [106,108], and no concordance is found in the monozygotic female twins [137].

4. Meta-Analysis

To assess the possible role of skewed XCI in the clinical manifestations of Fabry carriers, all the studies to date published that examined the XCI in Fabry carriers were considered for the meta-analysis, using the words “Fabry inactivation”, database search engines, PubMed http://www.pubmed.com (accessed on 2 January 2021), Scopus http://www.scopus.com/ (accessed on 2 January 2021) and Cocraine reviews https://www.cochranelibrary.com (accessed on 2 January 2021). We considered as criteria of inclusion research work in English, in which the analysis of XCI was performed in the leukocyte, and the Mainz Severity Score Index (MSSI) and/or cardiac involvement was reported.
Out of 151 identified records, only 8 articles were eligible for the analysis (Figure 3). Of them, only 3 studies reported the MSSI score, and 4 the cardiac involvement and the analysis of XCI pattern (Table 1).
Dobrovolny et al. [138] analyzed the pattern of XCI in 38 female carriers, of which only 11 (28.9%) exhibited skewed XCI considering the cut-off of 75:25. Moreover, 24 females showed a MMSI < 20 (63.1%), and 14 female MSSI > 20 (36.8%), but of these only 4 (28.6%) were skewed. There was a correlation between age onset and skewed XCI. No data on cardiomyopathy in female with random XCI were reported, so it was not included in the meta-analysis on the correlation between cardiac involvement and skewed XCI.
Maier et al. [139] analyzed the XCI pattern in 28 symptomatic carriers, considering a different cut-off, in particular the ratio between the two X chromosome 65:35 as moderate skewing, and a ratio of greater than 80:20 as extremely skewed. Thirteen (46%) females showed random XCI, ten (36%) moderate skewing, and five (18%) highly skewed XCI. They also analyzed 56 healthy females, reporting respectively random XCI in 29 (52%), moderate skewing in 16 female (29%), and highly skewed patterns of XCI in 11 subjects (20%) without any significant difference.
If we consider the ratio of 75:25, taking the data by the table reported in this study, out of 28 symptomatic carriers, ten female (35.7%) presented skewed XCI, of which 5 (50%) presented a MSSI > 20. While 13 female (46.4%) with random XCI showed a MSSI > 20. Out of 16 females with skewed XCI, 6 (37.5%) showed cardiovascular involvement. The authors conclude that skewed XCI is not correlated with phenotype.
Echevarria et al. [140] presented the data on a cohort of 56 female carriers, of which 52 were informative for XCI analysis. Ten female (19.2%) showed a preferential inactivation of the X chromosome carrying the normal allele, of them 7presented a MSSI > 20. Out of 10 skewed females, 7 (70%) showed increase LVM. The authors also analyzed different types of tissue (blood, skin, buccal smears, urine), demonstrated no correlation between XCI pattern in the blood and the others tissue. Moreover, they showed a correlation between age and severity of phenotype, and between skewed XCI and age onset.
Morrone et al. [141] and Rossanti et al. [142] analyzed a limited number of carriers (9 and 4 subjects, respectively). They did not presented data on MSSI in Fabry carriers, while the cardiomyopathy was reported in 5/13 carriers, but only 1 showed a skewed XCI pattern in the leukocytes.
The Fabry carriers from these studies were divided into two groups: symptomatic and asymptomatic, based on the Mainz Severity Score Index (MSSI) and/or the presence of cardiac involvement. Considering the severity of symptoms according to the MSSI score, symptomatic carriers were further subdivided in two subgroups, mild (MSSI < 20) vs. moderate-severe (MSSI > 20).
The meta-analysis was performed with the Pro-Meta 3. The statistical heterogeneity among the studies was assessed with the I-squared test (I2), where I2 value ≥ 75% represents a large heterogeneity between studies.
In this model, only one study included in the analysis showed a statistically significant association between skewed XCI and disease severity. The weight given for Dobrovolny et al., Echeivarra et al., Maier et al. was 34.3, 33.7 and 31.9%, respectively. The results of the meta-analysis are shown in the forest plot (Figure 4).
No preferential inactivation of the X chromosome carrying the normal allele was confirmed in mild compared to moderate-severe symptomatic carriers [OR 0.78 (95% CI 0.18–3.46), p = 0.74].
When looking at skewed XCI and cardiac involvement, none of the studies included in the analysis showed a statistically significant association between skewed XCI and phenotype. The weight given for Echeivarra et al., Maier et al., Morrone et al., and Rossanti et al. was 40.59, 44.63, 5.97 and 8.82%, respectively. The results of the meta-analysis are shown in the forest plot (Figure 5). Also in this case, no preferential inactivation of the X chromosome carrying the normal allele was confirmed in symptomatic compared to asymptomatic carriers [OR 0.6 (95% CI 0.221–1.7), p = 0.332].

5. Discussion

Fabry disease involves several tissues, leading to a complex phenotype including skin lesions, cardiac, renal and nervous system complications. The key of pathogenesis is the accumulation of Gb3 determined by the absent or decreased levels of α-gal in different types of cells, in particular in lysosomes but also in the cytosol. The excessive store of Gb3 increases the level of Lyso-Gb3, and triggers the inflammatory cascade, that in turn causes ischemia, fibrosis and apoptosis.
As in other X-linked disorders, the presence of cell mosaicism is considered an advantage for female carriers, because random XCI usually results in the presence of wild-type alleles in at least 50% of the cells, allowing female carriers not to show clinical symptoms. Furthermore, the interaction between the cells expressing the wild-type or mutant X chromosome determines a metabolic cooperation which leads to the correction, at least in part, of the defect in the mutant cells [143,144]. This appears to occur in X-linked lysosomal disorders, such as Hunter and Fabry diseases, in which the normal enzyme is transferred to a mutant cell by mannose-6-phosphate–mediated endocytosis [116]. Like the carriers of muscular dystrophies (MD), such as Duchenne/Becker (DMD/BMD) or Emery-Dreifuss (EDMD), Fabry female carriers can also exhibit clinical symptoms, and in particular cardiac involvement, either as cardiomyopathy or conduction system defects. The preferential inactivation of the X chromosome carrying the normal allele has suggested to explain the onset of symptoms in female carriers.
In fact, a significant correlation was found between cardiomyopathy and skewed XCI assessed in leukocytes in BMD/DMD carriers, suggesting that the analysis of XCI in this tissue can be useful to predict the phenotype [107]. This correlation has also been explored in recent studies on carriers of Fabry disease. Echevarria et al. [140], analyzing the human androgen receptor gene in females with Fabry disease, showed a positive correlation between a skewed XCI and disease severity. Dobrovolny et al. [138] found a statistically significant difference between the severity score values of heterozygotes with random and non-random X-chromosome inactivation, suggesting that X-inactivation is a major factor determining the severity of clinical involvement in Fabry heterozygotes, and that its status could serve as an important indicator for an early, presymptomatic treatment of heterozygotes. Conversely, other studies [139,142] reported that X inactivation patterns in symptomatic females, heterozygous for Fabry disease, did not differ from those of female controls of the same age.
The present meta-analysis failed to observe any correlation between clinical symptoms, including cardiac involvement and skewed XCI.
This apparent discrepancy can be linked to several factors: first, it cannot be excluded those carriers with skewed XCI (≥75:25) and no symptoms at the time of evaluation, will develop them later with age. In fact, the number of symptomatic females analysed in the study of Dobrovolny et al. [138] or Maier et al. [139] are younger than 40 y. Second, the type of cardiac involvement, cardiomyopathy or conduction system defects, was not specified; third, it cannot ruled out that the XCI pattern analyzed in leukocytes is not always useful to predict carrier phenotypes or disease progression. XCI is usually assessed in leukocytes from peripheral blood because it is the most common source of DNA supply, but, as suggested for EDMD1 carriers [145], the discordance between cardiac phenotype (conduction system defects) and degree of the XCI can be explained as likely depending by the different embryological origin of the tissues analyzed (constituents of the conduction cardiac tissue and blood).
The same explanation (hypothesis) could apply to Fabry disease, where the pathogenesis of cardiac involvement can be related both to the involvement of cardio-myocytes leading to cardiomyopathy, and to the involvement of conduction system leading to arrhythmias [146]. The different embryological origin of the tissues analyzed could also explain the absence of correlation observed between skewed XCI and the MSSI score. MSSI is in fact focused on different target organs, such as the neurological system, heart and kidney, which all have an embryological origin different from blood.
In conclusion, we hypothesize that the analysis of XCI in leukocytes is not always useful for predicting the phenotype in Fabry carriers, and suggest extending to other tissues the study of XCI to better evaluate the correlation between skewed XCI and the severity of symptoms.

Author Contributions

E.V. conceived the work, wrote and supervised the manuscript; L.P. participated in the writing, and critically revised the manuscript. Both authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not Applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Desnick, R.J.; Brady, R.; Barranger, J.; Collins, A.J.; Germain, D.P.; Goldman, M.; Grabowski, G.; Packman, S.; Wilcox, W.R. Fabry disease, an under-recognized multisystemic disorder: Expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann. Intern. Med. 2003, 138, 338–346. [Google Scholar] [CrossRef] [Green Version]
  2. Gibas, A.L.; Klatt, R.; Johnson, J.; Clarke, J.T.R.; Katz, J. Disease rarity, carrier status, and gender: A triple disadvantage for women with fabry disease. J. Genet. Couns. 2008, 17, 528–537. [Google Scholar] [CrossRef] [Green Version]
  3. Spada, M.; Pagliardini, S.; Yasuda, M.; Tukel, T.; Thiagarajan, G.; Sakuraba, H.; Ponzone, A.; Desnick, R.J. High Incidence of Later-Onset Fabry Disease Revealed by Newborn Screening. Am. J. Hum. Genet. 2006, 79, 31–40. [Google Scholar] [CrossRef] [Green Version]
  4. Garman, S.C.; Garboczi, D.N. The molecular defect leading to fabry disease: Structure of human α-galactosidase. J. Mol. Biol. 2004, 337, 319–335. [Google Scholar] [CrossRef]
  5. Scriver, C.R.; Beaudet, A.L.; Sly, W.S.; Valle, D.; Childs, B.; Kinzler, K.W.; Vogelstein, B. The Metabolic and Molecular Bases of Inherited Disease, 8th ed.; McGraw-Hill: New York, NY, USA, 2001. [Google Scholar]
  6. Schiffmann, R.; Kopp, J.B.; Iii, H.A.A.; Sabnis, S.; Moore, D.F.; Weibel, T.; Balow, J.E.; Brady, R.O. Enzyme replacement therapy in fabry disease. JAMA 2001, 285, 2743–2749. [Google Scholar] [CrossRef] [PubMed]
  7. Hsu, M.-J.; Chang, F.-P.; Lu, Y.-H.; Hung, S.-C.; Wang, Y.-C.; Yang, A.-H.; Lee, H.-J.; Sung, S.-H.; Wang, Y.-F.; Yu, W.-C.; et al. Identification of lysosomal and extralysosomal globotriaosylceramide (Gb3) accumulations before the occurrence of typical pathological changes in the endomyocardial biopsies of Fabry disease patients. Genet. Med. 2018, 21, 224–232. [Google Scholar] [CrossRef] [PubMed]
  8. Von Scheidt, W.; Eng, C.M.; Fitzmaurice, T.F.; Erdmann, E.; Hübner, G.; Olsen, E.G.; Christomanou, H.; Kandolf, R.; Bishop, D.F.; Desnick, R.J. An Atypical Variant of Fabry’s Disease with Manifestations Confined to the Myocardium. N. Engl. J. Med. 1991, 324, 395–399. [Google Scholar] [CrossRef] [PubMed]
  9. Nakao, S.; Kodama, C.; Takenaka, T.; Tanaka, A.; Yasumoto, Y.; Yoshida, A.; Kanzaki, T.; Enriquez, A.L.; Eng, C.M.; Tanaka, H.; et al. Fabry disease: Detection of undiagnosed hemodialysis patients and identification of a “renal variant” phenotype. Kidney Int. 2003, 64, 801–807. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  10. Yoshitama, T.; Nakao, S.; Takenaka, T.; Teraguchi, H.; Sasaki, T.; Kodama, C.; Tanaka, A.; Kisanuki, A.; Tei, C. Molecular genetic, biochemical, and clinical studies in three families with cardiac Fabry’s disease. Am. J. Cardiol. 2001, 87, 71–75. [Google Scholar] [CrossRef]
  11. Nakao, S.; Takenaka, T.; Maeda, M.; Kodama, C.; Tanaka, A.; Tahara, M.; Yoshida, A.; Kuriyama, M.; Hayashibe, H.; Sakuraba, H.; et al. An Atypical Variant of Fabry’s Disease in Men with Left Ventricular Hypertrophy. N. Engl. J. Med. 1995, 333, 288–293. [Google Scholar] [CrossRef]
  12. Wilcox, W.R.; Oliveira, J.P.; Hopkin, R.; Ortiz, A.; Banikazemi, M.; Feldt-Rasmussen, U.; Sims, K.; Waldek, S.; Pastores, G.M.; Lee, P.; et al. Females with Fabry disease frequently have major organ involvement: Lessons from the Fabry Registry. Mol. Genet. Metab. 2008, 93, 112–128. [Google Scholar] [CrossRef]
  13. Hůlková, H.; Ledvinová, J.; Poupĕtová, H.; Bultas, J.; Zeman, J.; Elleder, M. Postmortem diagnosis of Fabry disease in a female heterozygote leading to the detection of undiagnosed manifest disease in the family. Cas. Lek. Ceskych 1999, 138, 660–664. [Google Scholar]
  14. Laney, D.A.; Peck, D.S.; Atherton, A.M.; Manwaring, L.; Christensen, K.M.; Shankar, S.P.; Grange, D.K.; Wilcox, W.R.; Hopkin, R.J. Fabry disease in infancy and early childhood: A systematic literature review. Genet. Med. 2015, 17, 323–330. [Google Scholar] [CrossRef] [Green Version]
  15. Moura, A.P.; Hammerschmidt, T.G.; Deon, M.; Giugliani, R.; Vargas, C.R. Investigation of correlation of urinary globotriaosylceramide (Gb3) levels with markers of renal function in patients with Fabry disease. Clin. Chim. Acta 2018, 478, 62–67. [Google Scholar] [CrossRef]
  16. Vedder, A.C.; Linthorst, G.E.; Van Breemen, M.J.; Groener, J.E.M.; Bemelman, F.J.; Strijland, A.; Mannens, M.M.A.M.; Aerts, J.; Hollak, C.E.M. The Dutch Fabry cohort: Diversity of clinical manifestations and Gb3 levels. J. Inherit. Metab. Dis. 2007, 30, 68–78. [Google Scholar] [CrossRef] [PubMed]
  17. Laney, D.A. Interfamily variability in patients with classical Fabry disease. Mol. Genet. Metab. 2019, 126, S90–S91. [Google Scholar] [CrossRef]
  18. Tuttolomondo, A.; Simonetta, I.; Duro, G.; Pecoraro, R.; Miceli, S.; Colomba, P.; Zizzo, C.; Nucera, A.; Daidone, M.; Di Chiara, T.; et al. Inter-familial and intra-familial phenotypic variability in three Sicilian families with Anderson-Fabry disease. Oncotarget 2017, 8, 61415–61424. [Google Scholar] [CrossRef] [Green Version]
  19. Effraimidis, G.; Feldt-Rasmussen, U.; Rasmussen, Å.K.; Lavoie, P.; Abaoui, M.; Boutin, M.; Auray-Blais, C. Globotriaosylsphingosine (lyso-Gb3) and analogues in plasma and urine of patients with Fabry disease and correlations with long-term treatment and genotypes in a nationwide female Danish cohort. J. Med. Genet. 2020. [Google Scholar] [CrossRef] [PubMed]
  20. Aerts, J.M.; Groener, J.E.; Kuiper, S.; Donker-Koopman, W.E.; Strijland, A.; Ottenhoff, R.; van Roomen, C.; Mirzaian, M.; Wijburg, F.A.; Linthorst, G.E.; et al. Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc. Natl. Acad. Sci. USA 2008, 105, 2812–2817. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  21. Rombach, S.; Dekker, N.; Bouwman, M.; Linthorst, G.; Zwinderman, A.; Wijburg, F.; Kuiper, S.; Weerman, M.V.B.; Groener, J.; Poorthuis, B.; et al. Plasma globotriaosylsphingosine: Diagnostic value and relation to clinical manifestations of Fabry disease. Biochim. Biophys. Acta Mol. Basis Dis. 2010, 1802, 741–748. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Togawa, T.; Kodama, T.; Suzuki, T.; Sugawara, K.; Tsukimura, T.; Ohashi, T.; Ishige, N.; Suzuki, K.; Kitagawa, T.; Sakuraba, H. Plasma globotriaosylsphingosine as a biomarker of Fabry disease. Mol. Genet. Metab. 2010, 100, 257–261. [Google Scholar] [CrossRef]
  23. Seydelmann, N.; Wanner, C.; Störk, S.; Ertl, G.; Weidemann, F. Fabry disease and the heart. Best Pract. Res. Clin. Endocrinol. Metab. 2015, 29, 195–204. [Google Scholar] [CrossRef] [Green Version]
  24. Shu, L.; Vivekanandan-Giri, A.; Pennathur, S.; Smid, B.E.; Aerts, J.; Hollak, C.E.; Shayman, J.A. Establishing 3-nitrotyrosine as a biomarker for the vasculopathy of Fabry disease. Kidney Int. 2014, 86, 58–66. [Google Scholar] [CrossRef] [Green Version]
  25. Biancini, G.B.; Vanzin, C.S.; Rodrigues, D.B.; Deon, M.; Ribas, G.S.; Barschak, A.; Manfredini, V.; Netto, C.B.; Jardim, L.B.; Giugliani, R.; et al. Globotriaosylceramide is correlated with oxidative stress and inflammation in Fabry patients treated with enzyme replacement therapy. Biochim. Biophys. Acta Mol. Basis Dis. 2012, 1822, 226–232. [Google Scholar] [CrossRef] [Green Version]
  26. Shen, J.-S.; Meng, X.-L.; Moore, D.F.; Quirk, J.M.; Shayman, J.A.; Schiffmann, R.; Kaneski, C.R. Globotriaosylceramide induces oxidative stress and up-regulates cell adhesion molecule expression in Fabry disease endothelial cells. Mol. Genet. Metab. 2008, 95, 163–168. [Google Scholar] [CrossRef] [Green Version]
  27. De Francesco, P.N.; Mucci, J.M.; Ceci, R.; Fossati, C.A.; Rozenfeld, P.A. Fabry disease peripheral blood immune cells release inflammatory cytokines: Role of globotriaosylceramide. Mol. Genet. Metab. 2013, 109, 93–99. [Google Scholar] [CrossRef]
  28. Mauhin, W.; Lidove, O.; Masat, E.; Mingozzi, F.; Mariampillai, K.; Ziza, J.-M.; Benveniste, O. Innate and Adaptive Immune Response in Fabry Disease. JIMD Rep. 2015, 22, 1–10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Beer, G.; Reinecke, P.; Gabbert, H.E.; Hort, W.; Kuhn, H. Fabry disease in patients with hypertrophic cardiomyopathy (HCM). Z. Kardiol. 2002, 91, 992–1002. [Google Scholar] [CrossRef] [PubMed]
  30. Hayashi, Y.; Hanawa, H.; Jiao, S.; Hasegawa, G.; Ohno, Y.; Yoshida, K.; Suzuki, T.; Kashimura, T.; Obata, H.; Tanaka, K.; et al. Elevated endomyocardial biopsy macrophage-related markers in intractable myocardial diseases. Inflammation 2015, 38, 2288–2299. [Google Scholar] [CrossRef] [PubMed]
  31. Rombach, S.; Twickler, T.; Aerts, J.; Linthorst, G.; Wijburg, F.; Hollak, C. Vasculopathy in patients with Fabry disease: Current controversies and research directions. Mol. Genet. Metab. 2010, 99, 99–108. [Google Scholar] [CrossRef]
  32. Del Pinto, R.; Ferri, C. The role of immunity in fabry disease and hypertension: A Review of a novel common pathway. High Blood Press. Cardiovasc. Prev. 2020, 27, 539–546. [Google Scholar] [CrossRef] [PubMed]
  33. Rombach, S.M.; van den Bogaard, B.; De Groot, E.; Groener, J.E.; Poorthuis, B.J.; Linthorst, G.E.; van den Born, B.-J.H.; Hollak, C.E.; Aerts, J.M. Vascular aspects of fabry disease in relation to clinical manifestations and elevations in plasma globotriaosylsphingosine. Hypertension 2012, 60, 998–1005. [Google Scholar] [CrossRef] [Green Version]
  34. Weidemann, F.; Sanchez-Niño, M.D.; Politei, J.; Oliveira, J.-P.; Wanner, C.; Warnock, D.G.; Ortiz, A. Fibrosis: A key feature of Fabry disease with potential therapeutic implications. Orphanet J. Rare Dis. 2013, 8, 116. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Brady, R.O. Clinical Features of and Recent Advances in Therapy for Fabry Disease. JAMA 2000, 284, 2771–2775. [Google Scholar] [CrossRef] [PubMed]
  36. Zar-Kessler, C.; Karaa, A.; Sims, K.B.; Clarke, V.; Kuo, B. Understanding the gastrointestinal manifestations of Fabry disease: Promoting prompt diagnosis. Ther. Adv. Gastroenterol. 2016, 9, 626–634. [Google Scholar] [CrossRef] [Green Version]
  37. Grünfeld, J.-P.; Lidove, O.; Joly, D.; Barbey, F. Renal disease in Fabry patients. J. Inherit. Metab. Dis. 2001, 24, 71–74. [Google Scholar] [CrossRef]
  38. Ries, M.; Moore, D.F.; Robinson, C.J.; Tifft, C.J.; Rosenbaum, K.N.; Brady, R.O.; Schiffmann, R.; Krasnewich, D. Quantitative dysmorphology assessment in Fabry disease. Genet. Med. 2006, 8, 96–101. [Google Scholar] [CrossRef] [Green Version]
  39. Cox-Brinkman, J.; Vedder, A.C.; Hollak, C.E.M.; Richfield, L.; Mehta, A.; Orteu, K.; Wijburg, F.A.; Hammond, P. Three-dimensional face shape in Fabry disease. Eur. J. Hum. Genet. 2007, 15, 535–542. [Google Scholar] [CrossRef]
  40. Papaxanthos-Roche, A.; Maillard, A.; Chansel-Debordeaux, L.; Albert, M.; Patrat, C.; Lidove, O.; Germain, D.P.; Perez, P.; Lacombe, D. Semen and male genital tract characteristics of patients with Fabry disease: The Fertifabry multicentre observational study. Basic Clin. Androl. 2019, 29, 7. [Google Scholar] [CrossRef]
  41. Laney, D.A.; Clarke, V.; Foley, A.; Hall, E.W.; Gillespie, S.E.; Holida, M.; Simmons, M.; Wadley, A.; Baumgartner, M.; Patterson, M.; et al. The impact of Fabry disease on reproductive fitness. JIMD Rep. 2017, 37, 85–97. [Google Scholar] [CrossRef] [Green Version]
  42. Papaxanthos-Roche, A.; Deminiere, C.; Bauduer, F.; Hocké, C.; Mayer, G.; Lacombe, D. Azoospermia as a new feature of Fabry disease. Fertil. Steril. 2007, 88, 212.e15–212.e18. [Google Scholar] [CrossRef] [PubMed]
  43. Weidemann, F.; Strotmann, J.M.; Niemann, M.; Herrmann, S.; Wilke, M.; Beer, M.; Voelker, W.; Ertl, G.; Emmert, A.; Wanner, C.; et al. Heart valve involvement in fabry cardiomyopathy. Ultrasound Med. Biol. 2009, 35, 730–735. [Google Scholar] [CrossRef] [PubMed]
  44. Weidemann, F.; Wanner, C.; Breunig, F. Nomen est omen. Fabry disease. Eur. Heart J. Cardiovasc. Imaging 2008, 9, 831–832. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Teekakirikul, P.; Kelly, M.A.; Rehm, H.L.; Lakdawala, N.K.; Funke, B.H. Inherited Cardiomyopathies. J. Mol. Diagn. 2013, 15, 158–170. [Google Scholar] [CrossRef] [Green Version]
  46. Wolf, C.M. Hypertrophic cardiomyopathy: Genetics and clinical perspectives. Cardiovasc. Diagn. Ther. 2019, 9, S388–S415. [Google Scholar] [CrossRef]
  47. Ho, C.Y.; Charron, P.; Richard, P.; Girolami, F.; Van Spaendonck-Zwarts, K.Y.; Pinto, Y. Genetic advances in sarcomeric cardiomyopathies: State of the art. Cardiovasc. Res. 2015, 105, 397–408. [Google Scholar] [CrossRef] [Green Version]
  48. Walsh, R.; Exome Aggregation Consortium; Thomson, K.L.; Ware, J.S.; Funke, B.H.; Woodley, J.; McGuire, K.J.; Mazzarotto, F.; Blair, E.; Seller, A.; et al. Reassessment of Mendelian gene pathogenicity using 7855 cardiomyopathy cases and 60,706 reference samples. Genet. Med. 2017, 19, 192–203. [Google Scholar] [CrossRef] [Green Version]
  49. Alfares, A.A.; Kelly, M.A.; McDermott, G.; Funke, B.H.; Lebo, M.S.; Baxter, S.B.; Shen, J.; McLaughlin, H.M.; Clark, E.H.; Babb, L.J.; et al. Results of clinical genetic testing of 2912 probands with hypertrophic cardiomyopathy: Expanded panels offer limited additional sensitivity. Genet. Med. 2015, 17, 880–888. [Google Scholar] [CrossRef] [Green Version]
  50. Gersh, B.J.; Maron, B.J.; Bonow, R.O.; Dearani, J.A.; Fifer, M.A.; Link, M.S.; Naidu, S.S.; Nishimura, R.A.; Ommen, S.R.; Rakowski, H.; et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy. J. Thorac. Cardiovasc. Surg. 2011, 142, e153–e203. [Google Scholar] [CrossRef] [Green Version]
  51. Linhart, A.; Lubanda, J.-C.; Palecek, T.; Bultas, J.; Karetová, D.; Ledvinová, J.; Elleder, M.; Aschermann, M. Cardiac manifestations in Fabry disease. J. Inherit. Metab. Dis. 2001, 24, 75–83. [Google Scholar] [CrossRef]
  52. Pieroni, M.; Chimenti, C.; Ricci, R.; Sale, P.; Russo, M.A.; Frustaci, A. Early detection of Fabry cardiomyopathy by tissue doppler imaging. Circulation 2003, 107, 1978–1984. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Shah, J.S.; Hughes, D.; Sachdev, B.; Tome, M.; Ward, D.; Lee, P.; Mehta, A.B.; Elliott, P.M. Prevalence and clinical significance of cardiac arrhythmia in anderson-fabry disease. Am. J. Cardiol. 2005, 96, 842–846. [Google Scholar] [CrossRef] [PubMed]
  54. Krämer, J.; Niemann, M.; Liu, D.; Hu, K.; Machann, W.; Beer, M.; Wanner, C.; Ertl, G.; Weidemann, F. Two-dimensional speckle tracking as a non-invasive tool for identification of myocardial fibrosis in Fabry disease. Eur. Heart J. 2013, 34, 1587–1596. [Google Scholar] [CrossRef] [Green Version]
  55. Moon, J.; Sachdev, B.; Elkington, A.G.; McKenna, W.J.; Mehta, A.; Pennell, D.; Leed, P.J.; Elliott, P. Gadolinium enhanced cardiovascular magnetic resonance in Anderson-Fabry disease Evidence for a disease specific abnormality of the myocardial interstitium. Eur. Heart J. 2003, 24, 2151–2155. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Viggiano, E.; Marabotti, A.; Politano, L.; Burlina, A. Galactose-1-phosphate uridyltransferase deficiency: A literature review of the putative mechanisms of short and long-term complications and allelic variants. Clin. Genet. 2017, 93, 206–215. [Google Scholar] [CrossRef] [PubMed]
  57. Schaefer, E.; Mehta, A.; Gal, A. Genotype and phenotype in Fabry disease: Analysis of the Fabry Outcome Survey. Acta Paediatr. 2007, 94, 87–92. [Google Scholar] [CrossRef] [PubMed]
  58. Ries, M.; Gal, A. Genotype–phenotype correlation in Fabry disease. In Fabry Disease: Perspectives from 5 Years of FOS; Mehta, A., Beck, M., Sunder-Plassmann, G., Eds.; Oxford PharmaGenesis: Oxford, UK, 2006; ISBN 978-1-903539-03-3. [Google Scholar]
  59. Pan, X.; Ouyang, Y.; Wang, Z.; Ren, H.; Shen, P.; Wang, W.; Xu, Y.; Ni, L.; Yu, X.; Chen, X.; et al. Genotype: A Crucial but Not Unique Factor Affecting the Clinical Phenotypes in Fabry Disease. PLoS ONE 2016, 11, e0161330. [Google Scholar] [CrossRef] [Green Version]
  60. Koca, S.; Tümer, L.; Okur, I.; Erten, Y.; Bakkaloğlu, S.; Biberoğlu, G.; Kasapkara, Ç.; Küçükçongar, A.; Dalgıç, B.; Oktar, S.Ö.; et al. High incidence of co-existing factors significantly modifying the phenotype in patients with Fabry disease. Gene 2019, 687, 280–288. [Google Scholar] [CrossRef]
  61. Mignani, R.; Moschella, M.; Cenacchi, G.; Donati, I.; Flachi, M.; Grimaldi, D.; Cerretani, D.; De Giovanni, P.; Montevecchi, M.; Rigotti, A.; et al. Different renal phenotypes in related adult males with Fabry disease with the same classic genotype. Mol. Genet. Genom. Med. 2017, 5, 438–442. [Google Scholar] [CrossRef]
  62. Lukas, J.; Giese, A.; Markoff, A.; Grittner, U.; Kolodny, E.; Mascher, H.; Lackner, K.J.; Meyer, W.; Wree, P.; Saviouk, V.; et al. Functional characterisation of alpha-galactosidase a mutations as a basis for a new classification system in Fabry disease. PLoS Genet. 2013, 9, e1003632. [Google Scholar] [CrossRef] [Green Version]
  63. Smid, B.E.; Van Der Tol, L.; Biegstraaten, M.; Linthorst, G.E.; Hollak, C.E.M.; Poorthuis, B.J.H.M. Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease. J. Med. Genet. 2015, 52, 262–268. [Google Scholar] [CrossRef]
  64. El Dib, R.; Gomaa, H.; Carvalho, R.P.; Camargo, S.E.A.; Bazan, R.; Barretti, P.; Barreto, F.C. Enzyme replacement therapy for Anderson-Fabry disease. Cochrane Database Syst. Rev. 2016, 7, CD006663. [Google Scholar] [CrossRef] [PubMed]
  65. Arends, M.; Biegstraaten, M.; Wanner, C.; Sirrs, S.; Mehta, A.; Elliott, P.; Oder, D.; Watkinson, O.T.; Bichet, D.G.; Khan, A.; et al. Agalsidase alfa versus agalsidase beta for the treatment of Fabry disease: An international cohort study. J. Med. Genet. 2018, 55, 351–358. [Google Scholar] [CrossRef] [Green Version]
  66. Arends, M.; Biegstraaten, M.; Hughes, D.; Mehta, A.; Elliott, P.; Oder, D.; Watkinson, O.T.; Vaz, F.; Van Kuilenburg, A.B.P.; Wanner, C.; et al. Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: Analysis of prognostic factors. PLoS ONE 2017, 12, e0182379. [Google Scholar] [CrossRef]
  67. Weidemann, F.; Niemann, M.; Breunig, F.; Herrmann, S.; Beer, M.; Störk, S.; Voelker, W.; Ertl, G.; Wanner, C.; Strotmann, J. Long-Term Effects of Enzyme Replacement Therapy on Fabry Cardiomyopathy. Circulation 2009, 119, 524–529. [Google Scholar] [CrossRef] [Green Version]
  68. Arends, M.; Wijburg, F.A.; Wanner, C.; Vaz, F.M.; van Kuilenburg, A.B.; Hughes, D.A.; Biegstraaten, M.; Mehta, A.; Hollak, C.E.; Langeveld, M. Favourable effect of early versus late start of enzyme replacement therapy on plasma globotriaosylsphingosine levels in men with classical Fabry disease. Mol. Genet. Metab. 2017, 121, 157–161. [Google Scholar] [CrossRef] [PubMed]
  69. Citro, V.; Cammisa, M.; Liguori, L.; Cimmaruta, C.; Lukas, J.; Cubellis, M.V.; Andreotti, G. The large phenotypic spectrum of fabry disease requires graduated diagnosis and personalized therapy: A Meta-analysis can help to differentiate missense mutations. Int. J. Mol. Sci. 2016, 17, 2010. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  70. Germain, D.; Hughes, D.; Nicholls, K.; Bichet, D.-G.; Giugliani, R.; Wilcox, W.R.; Feliciani, C.; Shankar, S.P.; Ezgu, F.; Amartino, H.; et al. Treatment of Fabry’s Disease with the Pharmacologic Chaperone Migalastat. N. Engl. J. Med. 2016, 375, 545–555. [Google Scholar] [CrossRef] [PubMed]
  71. Liguori, L.; Monticelli, M.; Allocca, M.; Mele, B.H.; Lukas, J.; Cubellis, M.V.; Andreotti, G. Pharmacological chaperones: A Therapeutic approach for diseases caused by destabilizing missense mutations. Int. J. Mol. Sci. 2020, 21, 489. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  72. Simonetta, I.; Tuttolomondo, A.; Daidone, M.; Miceli, S.; Pinto, A. Treatment of Anderson-FabryDisease. Curr. Pharm. Des. 2020, 26, 5089–5099. [Google Scholar] [CrossRef] [PubMed]
  73. Felis, A.; Whitlow, M.; Kraus, A.; Warnock, D.G.; Wallace, E. Current and investigational therapeutics for fabry disease. Kidney Int. Rep. 2020, 5, 407–413. [Google Scholar] [CrossRef] [PubMed]
  74. Cammisa, M.; Correra, A.; Andreotti, G.; Cubellis, M.V. Fabry_CEP: A tool to identify Fabry mutations responsive to pharmacological chaperones. Orphanet J. Rare Dis. 2013, 8, 111. [Google Scholar] [CrossRef] [Green Version]
  75. Porto, C.; Pisani, A.; Rosa, M.; Acampora, E.; Avolio, V.; Tuzzi, M.R.; Visciano, B.; Gagliardo, C.; Materazzi, S.; la Marca, G.; et al. Synergy between the pharmacological chaperone 1-deoxygalactonojirimycin and the human recombinant alpha-galactosidase A in cultured fibroblasts from patients with Fabry disease. J. Inherit. Metab. Dis. 2011, 35, 513–520. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Hughes, D.A.; Nicholls, K.; Shankar, S.P.; Sunder-Plassmann, G.; Koeller, D.; Nedd, K.; Vockley, G.; Hamazaki, T.; Lachmann, R.; Ohashi, T.; et al. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study. J. Med. Genet. 2017, 54, 288–296. [Google Scholar] [CrossRef] [PubMed]
  77. Van Der Veen, S.J.; Hollak, C.E.M.; Van Kuilenburg, A.B.P.; Langeveld, M. Developments in the treatment of Fabry disease. J. Inherit. Metab. Dis. 2020, 43, 908–921. [Google Scholar] [CrossRef] [Green Version]
  78. Ortiz, A.; Germain, D.P.; Desnick, R.J.; Politei, J.; Mauer, M.; Burlina, A.; Eng, C.; Hopkin, R.J.; Laney, D.; Linhart, A.; et al. Fabry disease revisited: Management and treatment recommendations for adult patients. Mol. Genet. Metab. 2018, 123, 416–427. [Google Scholar] [CrossRef]
  79. Pinto, L.L.C.; Vieira, T.A.; Giugliani, R.; Schwartz, I.V. Expression of the disease on female carriers of X-linked lysosomal disorders: A brief review. Orphanet J. Rare Dis. 2010, 5, 14. [Google Scholar] [CrossRef] [Green Version]
  80. Deegan, P.B.; Bähner, F.; Barba, M.; Hughes, D.A.; Beck, M. Fabry disease in females: Clinical characteristics and effects of enzyme replacement therapy. In Fabry Disease: Perspectives from 5 Years of FOS; Mehta, A., Beck, M., Sunder-Plassmann, G., Eds.; Oxford PharmaGenesis: Oxford, UK, 2006; ISBN 978-1-903539-03-3. [Google Scholar]
  81. Doi, Y.; Toda, G.; Yano, K. Sisters with atypical Fabry’s disease with complete atrioventricular block. Heart 2003, 89, e2. [Google Scholar] [CrossRef] [PubMed]
  82. Baehner, F.; Kampmann, C.; Whybra, C.; Miebach, E.; Wiethoff, C.M.; Beck, M. Enzyme replacement therapy in heterozygous females with Fabry disease: Results of a phase IIIB study. J. Inherit. Metab. Dis. 2003, 26, 617–627. [Google Scholar] [CrossRef]
  83. Ro, L.S.; Chen, S.T.; Tang, L.M.; Hsu, W.C.; Chang, H.S.; Huang, C.C. Current Perception Threshold Testing in Fabry’s Disease. Muscle Nerve 1999, 22, 1531–1537. [Google Scholar] [CrossRef]
  84. Whybra, C.; Kampmann, C.; Willers, I.; Davies, J.; Winchester, B.; Kriegsmann, J.; Brühl, K.; Gal, A.; Bunge, S.; Beck, M. Anderson-Fabry disease: Clinical manifestations of disease in female heterozygotes. J. Inherit. Metab. Dis. 2001, 24, 715–724. [Google Scholar] [CrossRef]
  85. Germain, D.; Benistan, K.; Angelova, L. X-linked inheritance and its implication in the diagnosis and management of female patients in Fabry disease. Revue Méd. Interne 2010, 31, S209–S213. [Google Scholar] [CrossRef]
  86. MacDermot, K.D.; Holmes, A.; Miners, A.H. Anderson-Fabry disease: Clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J. Med. Genet. 2001, 38, 769–775. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Chowdhury, M.M.; Holt, P.J. Pain in Anderson-Fabry’s disease. Lancet 2001, 357, 887. [Google Scholar] [CrossRef]
  88. Ramaswami, U.; Parini, R.; Pintos-Morell, G. Natural history and effects of enzyme replacement therapy in children and ad-olescents with Fabry disease. In Fabry Disease: Perspectives from 5 Years of FOS; Mehta, A., Beck, M., Sunder-Plassmann, G., Eds.; Oxford PharmaGenesis: Oxford, UK, 2006; ISBN 978-1-903539-03-3. [Google Scholar]
  89. Pintos-Morell, G.; Beck, M. Fabry disease in children and the effects of enzyme replacement treatment. Eur. J. Nucl. Med. Mol. Imaging 2009, 168, 1355–1363. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  90. Fukushima, M.; Tsuchiyama, Y.; Nakato, T.; Yokoi, T.; Ikeda, H.; Yoshida, S.; Kusumoto, T.; Itoh, K.; Sakuraba, H. A female heterozygous patient with fabry’s disease with renal accumulation of trihexosylceramide detected with a monoclonal antibody. Am. J. Kidney Dis. 1995, 26, 952–955. [Google Scholar] [CrossRef]
  91. Yuen, N.W.-F.; Lam, C.-W.; Chow, T.-C.; Chiu, M.-C. A Characteristic dissection microscopy appearance of a renal biopsy of a fabry heterozygote. Nephron 1997, 77, 354–356. [Google Scholar] [CrossRef]
  92. Migeon, B.R. X Inactivation, Female Mosaicism, and Sex Differences in Renal Diseases. J. Am. Soc. Nephrol. 2008, 19, 2052–2059. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Mehta, A.; Beck, M.; Sunder-Plassmann, G. Fabry Disease: Perspectives from 5 Years of FOS; Oxford PharmaGenesis: Oxford, UK, 2006; ISBN 978-1-903539-03-3. [Google Scholar]
  94. Murata, R.; Takatsu, H.; Noda, T.; Nishigaki, K.; Tsuchiya, K.; Takemura, G.; Kanoh, M.; Kunishima, A.; Sano, K.; Minatoguchi, S.; et al. Fifteen-year follow-up of a heterozygous fabry’s disease patient associated with pre-excitation syndrome. Intern. Med. 1999, 38, 476–481. [Google Scholar] [CrossRef] [Green Version]
  95. Koitabashi, N.; Utsugi, T.; Seki, R.; Okamoto, E.; Sando, Y.; Kaneko, Y.; Nagai, R. Biopsy-proven cardiomyopathy in heterozygous fabry’s disease. Jpn. Circ. J. 1999, 63, 572–575. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Wang, R.; Lelis, A.; Mirocha, J.; Wilcox, W.R. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet. Med. 2007, 9, 34–45. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  97. Kampmann, C.; Baehner, F.; Whybra, C.; Martin, C.; Wiethoff, C.M.; Ries, M.; Gal, A.; Beck, M. Cardiac manifestations of Anderson–Fabry disease in heterozygous females. J. Am. Coll. Cardiol. 2002, 40, 1668–1674. [Google Scholar] [CrossRef] [Green Version]
  98. Baig, S.; Edward, N.C.; Kotecha, D.; Liu, B.; Nordin, S.; Kozor, R.; Moon, J.C.; Geberhiwot, T.; Steeds, R.P. Ventricular arrhythmia and sudden cardiac death in Fabry disease: A systematic review of risk factors in clinical practice. Europace 2017, 20, f153–f161. [Google Scholar] [CrossRef]
  99. Niemann, M.; Herrmann, S.; Hu, K.; Breunig, F.; Strotmann, J.; Beer, M.; Machann, W.; Voelker, W.; Ertl, G.; Wanner, C.; et al. Differences in fabry cardiomyopathy between female and male patients: Consequences for diagnostic assessment. JACC Cardiovasc. Imaging 2011, 4, 592–601. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  100. Fujii, K.; Minami, N.; Hayashi, Y.; Nishino, I.; Nonaka, I.; Tanabe, Y.; Takanashi, J.-I.; Kohno, Y. Homozygous female Becker muscular dystrophy. Am. J. Med. Genet. Part A 2009, 149A, 1052–1055. [Google Scholar] [CrossRef]
  101. Baiget, M.; Tizzano, E.; Volpini, V.; Del Rio, E.; Perez-Vidal, T.; Gallano, P. DMD carrier detection in a female with mosaic Turner’s syndrome. J. Med. Genet. 1991, 28, 209–210. [Google Scholar] [CrossRef] [Green Version]
  102. Satre, V.; Monnier, N.; Devillard, F.; Amblard, F.; Lunardi, P.J. Prenatal diagnosis of DMD in a female foetus affected by Turner syndrome. Prenat. Diagn. 2004, 24, 913–917. [Google Scholar] [CrossRef]
  103. Quan, F.; Janas, J.; Toth-Fejel, S.; Johnson, D.B.; Wolford, J.K.; Popovich, B.W. Uniparental disomy of the entire X chromosome in a female with Duchenne muscular dystrophy. Am. J. Hum. Genet. 1997, 60, 160–165. [Google Scholar] [PubMed]
  104. Soltanzadeh, P.; Friez, M.J.; Dunn, D.; von Niederhausern, A.; Gurvich, O.L.; Swoboda, K.; Sampson, J.B.; Pestronk, A.; Connolly, A.; Florence, J.M.; et al. Clinical and genetic characterization of manifesting carriers of DMD mutations. Neuromuscul. Disord. 2010, 20, 499–504. [Google Scholar] [CrossRef] [Green Version]
  105. Azofeifa, J.; Voit, T.; Cremer, M. X-chromosome methylation in manifesting and healthy carriers of dystrophinopathies: Concordance of activation ratios among first degree female relatives and skewed inactivation as cause of the affected phenotypes. Hum. Gen. 1995, 96, 167–176. [Google Scholar] [CrossRef]
  106. Viggiano, E.; Picillo, E.; Ergoli, M.; Cirillo, A.; Del Gaudio, S.; Politano, L. Skewed X-chromosome inactivation plays a crucial role in the onset of symptoms in carriers of Becker muscular dystrophy. J. Gene Med. 2017, 19, e2952. [Google Scholar] [CrossRef]
  107. Viggiano, E.; Ergoli, M.; Picillo, E.; Politano, L. Determining the role of skewed X-chromosome inactivation in developing muscle symptoms in carriers of Duchenne muscular dystrophy. Hum. Gen. 2016, 135, 685–698. [Google Scholar] [CrossRef]
  108. Viggiano, E.; Picillo, E.; Cirillo, A.; Politano, L. Comparison of X-chromosome inactivation in Duchenne muscle/myocardium-manifesting carriers, non-manifesting carriers and related daughters. Clin. Genet. 2012, 84, 265–270. [Google Scholar] [CrossRef]
  109. Cho, S.Y.; Lam, C.-W.; Tong, S.-F.; Siu, W.-K. X-linked glycogen storage disease IXa manifested in a female carrier due to skewed X chromosome inactivation. Clin. Chim. Acta 2013, 426, 75–78. [Google Scholar] [CrossRef] [PubMed]
  110. Garagiola, I.; Mortarino, M.; Siboni, S.M.; Boscarino, M.; Mancuso, M.E.; Biganzoli, M.; Santagostino, E.; Peyvandi, F. X Chromosome inactivation: A modifier of factor VIII and IX plasma levels and bleeding phenotype in Haemophilia carriers. Eur. J. Hum. Genet. 2021, 29, 241–249. [Google Scholar] [CrossRef] [PubMed]
  111. Ørstavik, K.H. X chromosome inactivation in clinical practice. Hum. Gen. 2009, 126, 363–373. [Google Scholar] [CrossRef] [PubMed]
  112. Pugacheva, E.M.; Tiwari, V.K.; Abdullaev, Z.; Vostrov, A.A.; Flanagan, P.T.; Quitschke, W.W.; Loukinov, D.I.; Ohlsson, R.; Lobanenkov, V.V. Familial cases of point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation. Hum. Mol. Genet. 2005, 14, 953–965. [Google Scholar] [CrossRef] [Green Version]
  113. Plenge, R.M.; Hendrich, B.D.; Schwartz, C.; Arena, J.F.; Naumova, A.; Sapienza, C.; Winter, R.M.; Willard, H.F. A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation. Nat. Genet. 1997, 17, 353–356. [Google Scholar] [CrossRef] [PubMed]
  114. Knudsen, G.; Pedersen, J.; Klingenberg, O.; Lygren, I.; Ørstavik, K. Increased skewing of X chromosome inactivation with age in both blood and buccal cells. Cytogenet. Genome Res. 2007, 116, 24–28. [Google Scholar] [CrossRef] [PubMed]
  115. Sharp, A.; Robinson, D.; Jacobs, P. Age- and tissue-specific variation of X chromosome inactivation ratios in normal women. Qual. Life Res. 2000, 107, 343–349. [Google Scholar] [CrossRef]
  116. Migeon, B.R. The Role of X inactivation and cellular mosaicism in women’s health and sex-specific diseases. JAMA 2006, 295, 1428–1433. [Google Scholar] [CrossRef] [PubMed]
  117. Amos-Landgraf, J.; Cottle, A.; Plenge, R.M.; Friez, M.; Schwartz, C.E.; Longshore, J.; Willard, H.F. X Chromosome–Inactivation Patterns of 1005 Phenotypically Unaffected Females. Am. J. Hum. Genet. 2006, 79, 493–499. [Google Scholar] [CrossRef] [Green Version]
  118. Bolduc, V.; Chagnon, P.; Provost, S.; Dube, M.-P.; Belisle, C.; Gingras, M.; Mollica, L.; Busque, L. No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans. J. Clin. Investig. 2008, 118, 333–341. [Google Scholar] [CrossRef] [Green Version]
  119. Gale, R.E.; Fielding, A.K.; Harrison, C.N.; Linch, D.C. Acquired skewing of X-chromosome inactivation patterns in myeloid cells of the elderly suggests stochastic clonal loss with age. Br. J. Haematol. 1997, 98, 512–519. [Google Scholar] [CrossRef] [Green Version]
  120. Fey, M.F.; Liechti-Gallati, S.; von Rohr, A.; Borisch, B.; Theilkäs, L.; Schneider, V.; Oestreicher, M.; Nagel, S.; Ziemiecki, A.; Tobler, A. Clonality and x-inactivation patterns in hematopoietic cell populations detected by the highly informative m27 beta dna probe. Blood 1994, 83, 931–938. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  121. Christensen, K.; Kristiansen, M.; Hagen-Larsen, H.; Skytthe, A.; Bathum, L.; Jeune, B.; Andersen-Ranberg, K.; Vaupel, J.W.; Orstavik, K.H. X-Linked genetic factors regulate hematopoietic stem-cell kinetics in females. Blood 2000, 95, 2449–2451. [Google Scholar] [CrossRef] [PubMed]
  122. Busque, L.; Mio, R.; Mattioli, J.; Brais, E.; Blais, N.; Lalonde, Y.; Maragh, M.; Gilliland, D.G. Nonrandom X-inactivation patterns in normal females: Lyonization ratios vary with age. Blood 1996, 88, 59–65. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Lanasa, M.C.; Hogge, W.; Kubik, C.J.; Ness, R.B.; Harger, J.; Nagel, T.; Prosen, T.; Markovic, N.; Hoffman, E. A novel X chromosome–linked genetic cause of recurrent spontaneous abortion. Am. J. Obstet. Gynecol. 2001, 185, 563–568. [Google Scholar] [CrossRef]
  124. Kristiansen, M.; Knudsen, G.; Tanner, S.; McEntagart, M.; Jungbluth, H.; Muntoni, F.; Sewry, C.; Gallati, S.; Ørstavik, K.; Wallgren-Pettersson, C. X-inactivation patterns in carriers of X-linked myotubular myopathy. Neuromuscul. Disord. 2003, 13, 468–471. [Google Scholar] [CrossRef]
  125. Espinós, C.; Lorenzo, J.I.; Casaña, P.; Martínez, F.; Aznar, J.A. Haemophilia B in a female caused by skewed inactivation of the normal X-chromosome. Haematologica 2000, 85, 1092–1095. [Google Scholar]
  126. Okumura, K.; Fujimori, Y.; Takagi, A.; Murate, T.; Ozeki, M.; Yamamoto, K.; Katsumi, A.; Matsushita, T.; Naoe, T.; Kojima, T. Skewed X chromosome inactivation in fraternal female twins results in moderately severe and mild haemophilia B. Haemophilia 2008, 14, 1088–1093. [Google Scholar] [CrossRef] [PubMed]
  127. Devriendt, K.; Matthijs, G.; Legius, E.; Schollen, E.; Blockmans, D.; Van Geet, C.; Degreef, H.; Cassiman, J.J.; Fryns, J.P. Skewed X-chromosome inactivation in female carriers of dyskeratosis congenita. Am. J. Hum. Genet. 1997, 60, 581–587. [Google Scholar] [PubMed]
  128. Fahim, A.T.; Sullivan, L.S.; Bowne, S.J.; Jones, K.D.; Wheaton, D.K.; Khan, N.W.; Heckenlively, J.R.; Jayasundera, K.; Branham, K.H.; Andrews, C.; et al. X-Chromosome inactivation is a biomarker of clinical severity in female carriers of rpgr-associated x-linked retinitis pigmentosa. Ophthalmol. Retin. 2020, 4, 510–520. [Google Scholar] [CrossRef] [PubMed]
  129. Bushby, K.; Goodship, J.; Nicholson, L.; Johnson, M.; Haggerty, I.; Gardner-Medwin, D. Variability in clinical, genetic and protein abnormalities in manifesting carriers of Duchenne and Becker muscular dystrophy. Neuromuscul. Disord. 1993, 3, 57–64. [Google Scholar] [CrossRef]
  130. Sumita, D.R.; Vainzof, M.; Campiotto, S.; Cerqueira, A.M.; Cánovas, M.; Otto, P.A.; Passos-Bueno, M.R.; Zatz, M. Absence of Correlation between Skewed X Inactivation in Blood and Serum Creatine-Kinase Levels in Duchenne/Becker Female Carriers. Am. J. Med. Genet. 1998, 80, 356–361. [Google Scholar] [CrossRef]
  131. Seemann, N.; Selby, K.; McAdam, L.; Biggar, D.; Kolski, H.; Goobie, S.; Yoon, G.; Campbell, C. Symptomatic dystrophinopathies in female children. Neuromuscul. Disord. 2011, 21, 172–177. [Google Scholar] [CrossRef]
  132. Matthews, P.M.; Benjamin, D.; Van Bakel, I.; Squier, M.; Nicholson, L.; Sewry, C.; Barnes, P.; Hopkin, J.; Brown, R.; Hilton-Jones, D.; et al. Muscle X-inactivation patterns and dystrophin expression in Duchenne muscular dystrophy carriers. Neuromuscul. Disord. 1995, 5, 209–220. [Google Scholar] [CrossRef]
  133. Pegoraro, E.; Schimke, R.N.; Arahata, K.; Hayashi, Y.; Stern, H.; Marks, H.; Glasberg, M.R.; Carroll, J.E.; Taber, J.W.; Wessel, H.B.; et al. Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females. Am. J. Hum. Genet. 1994, 54, 989–1003. [Google Scholar]
  134. Pegoraro, E.; Schimke, R.N.; Garcia, C.; Stern, H.; Cadaldini, M.; Angelini, C.; Barbosa, E.; Carroll, J.; Marks, W.A.; Neville, H.E.; et al. Genetic and biochemical normalization in female carriers of Duchenne muscular dystrophy: Evidence for failure of dystrophin production in dystrophin-competent myonuclei. Neurology 1995, 45, 677–690. [Google Scholar] [CrossRef] [PubMed]
  135. Azofeifa, J.; Cremer, M.; Waldherr, R. X-chromosome methylation ratios as indicators of chromosomal activity: Evidence of intraindividual divergencies among tissues of different embryonal origin. Hum. Gen. 1996, 97, 330–333. [Google Scholar] [CrossRef] [PubMed]
  136. Fialkow, P.J. Primordial cell pool size and lineage relationships of five human cell types. Ann. Hum. Genet. 1973, 37, 39–48. [Google Scholar] [CrossRef]
  137. Lupski, J.R.; Garcia, C.A.; Zoghbi, H.Y.; Hoffman, E.; Fenwick, R.G. Discordance of muscular dystrophy in monozygotic female twins: Evidence supporting asymmetric splitting of the inner cell mass in a manifesting carrier of Duchenne dystrophy. Am. J. Med. Genet. 1991, 40, 354–364. [Google Scholar] [CrossRef]
  138. Dobrovolny, R.; Dvořáková, L.; Ledvinová, J.; Magage, S.; Bultas, J.; Lubanda, J.-C.; Elleder, M.; Karetová, D.; Pavlikova, M.; Hřebíček, M. Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the α-galactosidase A gene in the Czech and Slovak population. J. Mol. Med. 2005, 83, 647–654. [Google Scholar] [CrossRef]
  139. Maier, E.; Osterrieder, S.; Whybra, C.; Ries, M.; Gal, A.; Beck, M.; Roscher, A.; Muntau, A. Disease manifestations and X inactivation in heterozygous females with Fabry disease. Acta Paediatr. 2006, 95, 30–38. [Google Scholar] [CrossRef]
  140. Echevarria, L.; Benistan, K.; Toussaint, A.; Dubourg, O.; Hagege, A.; Eladari, D.; Jabbour, F.; Beldjord, C.; De Mazancourt, P.; Germain, D. X-chromosome inactivation in female patients with Fabry disease. Clin. Genet. 2016, 89, 44–54. [Google Scholar] [CrossRef]
  141. Morrone, A.; Cavicchi, C.; Bardelli, T.; Antuzzi, D.; Parini, R.; Di Rocco, M.; Feriozzi, S.; Gabrielli, O.; Barone, R.; Pistone, G.; et al. Fabry disease: Molecular studies in Italian patients and X inactivation analysis in manifesting carriers. J. Med. Genet. 2003, 40, 103e. [Google Scholar] [CrossRef] [Green Version]
  142. Rossanti, R.; Nozu, K.; Fukunaga, A.; Nagano, C.; Horinouchi, T.; Yamamura, T.; Sakakibara, N.; Minamikawa, S.; Ishiko, S.; Aoto, Y.; et al. X-chromosome inactivation patterns in females with Fabry disease examined by both ultra-deep RNA sequencing and methylation-dependent assay. Clin. Exp. Nephrol. 2021, 1–7. [Google Scholar] [CrossRef]
  143. Cox, R.P.; Krauss, M.R.; Balis, M.E.; Dancis, J. Evidence for transfer of enzyme product as the basis of metabolic cooperation between tissue culture fibroblasts of lesch-nyhan disease and normal cells. Proc. Natl. Acad. Sci. USA 1970, 67, 1573–1579. [Google Scholar] [CrossRef] [Green Version]
  144. Fratantoni, J.C.; Hall, C.W.; Neufeld, E.F. Hurler and Hunter Syndromes: Mutual correction of the defect in cultured fibroblasts. Science 1968, 162, 570–572. [Google Scholar] [CrossRef]
  145. Viggiano, E.; Madej-Pilarczyk, A.; Carboni, N.; Picillo, E.; Ergoli, M.; Del Gaudio, S.; Marchel, M.; Nigro, G.; Palladino, A.; Politano, L.; et al. X-Linked emery–dreifuss muscular dystrophy: Study of x-chromosome inactivation and its relation with clinical phenotypes in female carriers. Genes 2019, 10, 919. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  146. Frustaci, A. Pathology and Function of Conduction Tissue in Fabry Disease Cardiomyopathy. Circ Arrhythm Electrophysiol. 2015, 8, 799–805. [Google Scholar] [CrossRef] [PubMed] [Green Version]
Figure 1. Pattern of XCI in healthy females. Each tissue of females is a mosaic of cells, including cells (white circle) in which the paternal X chromosome is activated (Xpa) and the maternal X chromosome is inactivated (Xmi) and cells (grey circle) in which the maternal X chromosome is activated (Xma) and the paternal X chromosome is inactivated (Xpi).
Figure 1. Pattern of XCI in healthy females. Each tissue of females is a mosaic of cells, including cells (white circle) in which the paternal X chromosome is activated (Xpa) and the maternal X chromosome is inactivated (Xmi) and cells (grey circle) in which the maternal X chromosome is activated (Xma) and the paternal X chromosome is inactivated (Xpi).
Ijms 22 07663 g001
Figure 2. Example of cellular mosaicism in a female carrier of X-linked disease. The figure represents an example of (a) a random XCI pattern with the same percentage of cells expressing the paternal (white) mutated X chromosome (Xp•) and the maternal (grey) X chromosome (Xm) (on the left); (b) a skewed XCI pattern with a higher percentage of cells expressing the maternal X chromosome that determines the absence of symptoms or a skewed XCI pattern with a higher percentage of cells expressing the Xp• that determines the presence of symptoms (in the center); (c) an extremely skewed XCI with a higher percentage of cells expressing the maternal X chromosome that determines the absence of symptoms or an extremely skewed XCI pattern with a higher percentage of cells expressing the Xp• that determines the presence of symptoms (on the right). a = activated; i = inactivated.
Figure 2. Example of cellular mosaicism in a female carrier of X-linked disease. The figure represents an example of (a) a random XCI pattern with the same percentage of cells expressing the paternal (white) mutated X chromosome (Xp•) and the maternal (grey) X chromosome (Xm) (on the left); (b) a skewed XCI pattern with a higher percentage of cells expressing the maternal X chromosome that determines the absence of symptoms or a skewed XCI pattern with a higher percentage of cells expressing the Xp• that determines the presence of symptoms (in the center); (c) an extremely skewed XCI with a higher percentage of cells expressing the maternal X chromosome that determines the absence of symptoms or an extremely skewed XCI pattern with a higher percentage of cells expressing the Xp• that determines the presence of symptoms (on the right). a = activated; i = inactivated.
Ijms 22 07663 g002
Figure 3. Flow chart.
Figure 3. Flow chart.
Ijms 22 07663 g003
Figure 4. Forest plots for skewed versus random XCI in mild and moderate-severe symptomatic Fabry carriers. Heterogeneity I2 = 65.43%, p = 0.055.
Figure 4. Forest plots for skewed versus random XCI in mild and moderate-severe symptomatic Fabry carriers. Heterogeneity I2 = 65.43%, p = 0.055.
Ijms 22 07663 g004
Figure 5. Forest plots for skewed versus random XCI in symptomatic Fabry carriers at cardiac level. Heterogeneity I2 = 0.0%, p = 0.609.
Figure 5. Forest plots for skewed versus random XCI in symptomatic Fabry carriers at cardiac level. Heterogeneity I2 = 0.0%, p = 0.609.
Ijms 22 07663 g005
Table 1. Results of studies on the XCI in Fabry carriers.
Table 1. Results of studies on the XCI in Fabry carriers.
ArticlesAge Skewed XCI
Tissue AnalyzedMild MSSI Score (Total Subjects)Moderate-Severe
MSSI Score (Total Subjects)
Cardiac Involvement (Total Subjects)No Cardiac Involvement (Total Subjects)
Dobrovolny et al., 2005Young/AdultL, U, SE7 (24)4 (14)n.d.n.d.
Maier et al., 2006Young/AdultL5 (10)5 (18)6 (16)4 (12)
Echeivarra et al., 2015Young/AdultL, U, SE, skin3 (35)7 (21)7 (41)3 (8)
Morrone et. al., 2003Young/AdultLn.d.n.d.2 (0)2 (4)
Rossanti et al., 2021AdultL, n.d.n.d.0 (5)1 (2)
n.d. = not determined; L = peripheral blood leukocytes; SE = salivary epithelia; U = urinary sediment cells; skewed XCI is referred to preferential inactivation of wild X chromosome with a ratio of 75:25.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Viggiano, E.; Politano, L. X Chromosome Inactivation in Carriers of Fabry Disease: Review and Meta-Analysis. Int. J. Mol. Sci. 2021, 22, 7663. https://doi.org/10.3390/ijms22147663

AMA Style

Viggiano E, Politano L. X Chromosome Inactivation in Carriers of Fabry Disease: Review and Meta-Analysis. International Journal of Molecular Sciences. 2021; 22(14):7663. https://doi.org/10.3390/ijms22147663

Chicago/Turabian Style

Viggiano, Emanuela, and Luisa Politano. 2021. "X Chromosome Inactivation in Carriers of Fabry Disease: Review and Meta-Analysis" International Journal of Molecular Sciences 22, no. 14: 7663. https://doi.org/10.3390/ijms22147663

APA Style

Viggiano, E., & Politano, L. (2021). X Chromosome Inactivation in Carriers of Fabry Disease: Review and Meta-Analysis. International Journal of Molecular Sciences, 22(14), 7663. https://doi.org/10.3390/ijms22147663

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop