Characteristics of Cerebral Microbleeds in Patients with Fabry Disease

doi:10.1016/j.jstrokecerebrovasdis.2016.02.019

Journal of Stroke and Cerebrovascular Diseases

Volume 25, Issue 6, June 2016, Pages 1320-1325

https://doi.org/10.1016/j.jstrokecerebrovasdis.2016.02.019 Get rights and content

Background and Purpose

Fabry disease (FD) is an X-linked lysosomal storage disorder frequently associated with the central nervous system manifestations. Although white matter hyperintensity (WMH) on MRI has been previously reported, little is known about cerebral microbleeds (CMBs) in patients with FD. Our aim is to investigate the clinical characteristics of CMBs in patients with FD.

Methods

All patients with FD were diagnosed by enzyme activity and/or gene analysis at Jikei University Hospital. We retrospectively enrolled consecutive patients with FD who underwent MRI study, including fluid-attenuated inversion recovery and susceptibility-weighted imaging, between July 2008 and September 2013. After categorizing the patients into CMB-positive and CMB-negative groups, we compared the clinical characteristics between the 2 groups.

Results

We enrolled 54 patients (males, 24; median age 39 years, interquartile range; 29-50 years). The CMB-positive group included 16 (30%) patients. The number of males was significantly higher in the CMB-positive group than in the CMB-negative group (75% versus 32%, P = .003). The prevalence rates of chronic kidney disease (CKD) (estimated glomerular filtration rate < 60 mL/min/1.73 m²) and WMH were higher in the CMB-positive group than in the CMB-negative group (CKD: 44% versus 13%, P = .013; WMH: 88% versus 58%, P = .035). No significant differences in the number of vascular risk factors were observed between the 2 groups.

Conclusions

The distinct characteristics of FD patients with CMBs were male sex, presence of CKD, and WMH. These factors may play an important role in the mechanism of hemorrhagic stroke in FD.

Introduction

Fabry disease (FD) is an X-linked recessive lysosomal storage disorder that is caused by deficiency in the activity of alpha-galactosidase A. Systemic glycosphingolipid deposits occur with a predilection for vascular endothelial and smooth muscle cells, myocardium, renal epithelium, cornea, and the central nervous system, causing renal and cardiac failure, painful acroparesthesias, angiokeratomas, hypohydrosis, corneal opacity (verticillata), and stroke.1, 2 Stroke is a common manifestation of FD and has been identified in approximately 25% of patients.3, 4, 5, 6 FD also has been recognized as rare but one of the causes of juvenile stroke. A previous large cohort study indicated that FD occurs in .5% of juvenile stroke patients.7, 8, 9, 10 Therefore, brain magnetic resonance imaging (MRI) studies in patients with FD would allow a better understanding of the natural course and may lead to earlier treatment.

The most prominent structural imaging findings of brain MRI in FD are white matter hyperintensity (WMH) on T2-weighted imaging, dilatation of large vessels (dolichoectasia) on magnetic resonance angiography, and the pulvinar sign as seen on T1-weighted imaging.¹¹ In contrast, little is known about cerebral microbleeds (CMBs) in patients with FD. Our aim is to investigate the clinical characteristics of CMBs in patients with FD.

Section snippets

Patients

All patients with FD are diagnosed by an alpha-galactosidase assay and/or gene analysis in the Department of Pediatrics at Jikei University Hospital, Japan. We retrospectively enrolled consecutive patients with FD who underwent an MRI study, including fluid-attenuated inversion recovery (FLAIR) and susceptibility-weighted imaging (SWI) between July 2008 and September 2013. After categorizing the patients into the CMB-positive group or the CMB-negative group, we compared the clinical

Results

We enrolled a total of 54 patients (males, 24; females, 30; median age, 39 years [interquartile range 29-50 years]) in the present study. Table 1 shows the baseline clinical characteristics of the patients after they were divided into the CMB-positive and CMB-negative groups.

CMBs were found in 16 (30%) of the 54 study patients. There was no significant difference in age between the 2 groups. There were significantly more males in the CMB-positive group than in the CMB-negative group (75% versus

Discussion

One of the most important results of the present study is that 30% of the FD patients had CMB lesions. Second, CMBs in FD patients tends to occur at young ages. Third, the present study showed that sex differences (male), CKD, and WMH in FD patients were associated with the frequency of CMB positivity. To the best of our knowledge, this is the first large cohort study to clarify the clinical characteristics of CMBs in FD patients.

There have been a few previous reports concerning CMBs in FD

Conclusion

The present study found a linear association between the development of CMBs in FD and the factors of male sex, CKD, and WMH. This finding suggests that these 3 factors may induce a shared pathogenesis of vasculopathy. We also emphasized that CMBs in FD tend to occur at young ages. The presence of CMBs is recognized as a risk factor for subsequent hemorrhagic stroke with or without the use of antiplatelet therapy.³⁸ Hence, the results of the present study play a role in uncovering the

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Cited by (25)

An expert consensus on the recommendations for the use of biomarkers in Fabry disease
2023, Molecular Genetics and Metabolism
Fabry disease is an X-linked lysosomal storage disorder caused by the accumulation of glycosphingolipids in various tissues and body fluids, leading to progressive organ damage and life-threatening complications. Phenotypic classification is based on disease progression and severity and can be used to predict outcomes. Patients with a classic Fabry phenotype have little to no residual α-Gal A activity and have widespread organ involvement, whereas patients with a later-onset phenotype have residual α-Gal A activity and disease progression can be limited to a single organ, often the heart. Diagnosis and monitoring of patients with Fabry disease should therefore be individualized, and biomarkers are available to support with this. Disease-specific biomarkers are useful in the diagnosis of Fabry disease; non-disease-specific biomarkers may be useful to assess organ damage. For most biomarkers it can be challenging to prove they translate to differences in the risk of clinical events associated with Fabry disease. Therefore, careful monitoring of treatment outcomes and collection of prospective data in patients are needed. As we deepen our understanding of Fabry disease, it is important to regularly re-evaluate and appraise published evidence relating to biomarkers. In this article, we present the results of a literature review of evidence published between February 2017 and July 2020 on the impact of disease-specific treatment on biomarkers and provide an expert consensus on clinical recommendations for the use of those biomarkers.
Cardiac involvement in Fabry disease - A non-invasive assessment and the role of specific therapies
2022, Molecular Genetics and Metabolism
Citation Excerpt :
In childhood and adolescence, systematic symptoms, such as acroparesthesias, hypo/anhidrosis and angiokearatoma, are typical findings of Fabry disease [3,4]. In adults, major organ damage, including that to the heart, kidney and central nervous system, is induced, which influences the morbidity and mortality of Fabry disease [5–7]. Cardiac involvement has been managed properly in Fabry disease patients, as 1) not only male hemizygous patients but also most female heterozygous patients develop cardiac manifestations, such as left ventricular hypertrophy [4]; and 2) the most frequent cause of death in Fabry disease is cardiovascular complications [5,8].
Fabry disease is an X-linked inherited metabolic disorder due to the pathogenic mutation of the GLA gene, which codes lysosomal enzyme alpha-galactosidase A. The resultant accumulation of glycosphingolipids causes various systemic symptoms in childhood and adolescence, and major organ damage in adulthood. Cardiac involvement is important as the most frequent cause of death in Fabry disease patients. Progressive left ventricular hypertrophy with varying degrees of contractile dysfunction as well as conduction abnormalities and arrhythmias are typical cardiac features, and these findings can be evaluated in detail via non-invasive modalities, such as an electrocardiogram, echocardiography and cardiac magnetic resonance. In addition, specific therapies of enzyme replacement therapy and pharmacological chaperone therapy are available, and their beneficial effects on cardiac involvement have been reported. This minireview highlights recent evidence concerning non-invasive modalities for assessing cardiac involvement in Fabry disease and the effects of enzyme replacement therapy and pharmacological chaperone therapy on the findings of those modalities.
Clinical findings of gadolinium-enhanced cardiac magnetic resonance in Fabry patients
2020, Journal of Cardiology
Citation Excerpt :
The target organs are widely distributed, and typical features, such as acroparesthesias, hypohidrosis, angiokeratoma, and corneal opacity, can develop as early as childhood or adolescence [1]. The systematic appearance of multi-organ involvement is evident in adulthood, and serious complications of the kidney (progressive renal failure), heart (left ventricular hypertrophy [LVH] and heart failure), and central nervous system (transient ischemic attack and stroke) can determine the prognosis of Fabry disease [4–6]. Heart complications are particularly important because more than half of deaths in Fabry patients are attributed to cardiovascular disorders [7,8].
Fabry disease is one of the causes of left ventricular hypertrophy (LVH) and can be treated with enzyme replacement therapy or pharmacological chaperone therapy. Late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR) can identify myocardial fibrosis and be used for the stratification in LVH. However, the details of the prevalence and characteristics of LGE in Japanese Fabry patients have not been reported.
We evaluated myocardial involvement in 26 Fabry patients (10 males, 16 females) using gadolinium-enhanced CMR. LGE areas were analyzed using the previously reported scoring method. Echocardiography was also performed to evaluate the left ventricular function and left ventricular mass.
LGE on CMR images was positive in 5 out of 26 patients, and all patients with LGE-positive findings suffered from LVH (2 out of 5 male patients and 3 out of 4 female patients with LVH on echocardiography). LGE was specifically localized at the mid-wall in the infero-lateral area of the left ventricle. LGE-positive patients seemed to be older, and tended to have a larger left ventricular mass index and higher B-type natriuretic peptide level than LGE-negative patients.
These results revealed that specific localization of LGE was present in Fabry patients.
Development and clinical consequences of white matter lesions in Fabry disease: a systematic review
2018, Molecular Genetics and Metabolism
Citation Excerpt :
After screening for title and abstract 170 articles and 17 abstracts were assessed for eligibility. A total of 46 articles [1,3–5,12–53] and eight abstracts were included in the qualitative synthesis [54–61], see Supplementary Table A for an overview table of all articles. Different field strengths and MRI sequences were used in the assessment of WMLs.
Fabry disease (FD) is a rare lysosomal storage disorder that might result in, amongst other complications, early stroke and white matter lesions (WMLs). More insight in WMLs in FD could clarify the role of WMLs in the disease presentation and prognosis in FD. In this systematic review we assessed the prevalence, severity, location and course of WMLs in FD. We also systematically reviewed the evidence on the relation between WMLs, disease characteristics and clinical parameters.
We searched Pubmed, EMBASE and CINAHL (inception to Feb 2018) and identified articles reporting on FD and WMLs assessed with MRI. Prevalence and severity were assessed for all patients combined and divided by sex.
Out of 904 studies a total of 46 studies were included in the analyses. WMLs were present in 46% of patients with FD (581 out of 1276 patients, corrected mean age: 38.8 years, range 11.8–79.3) and increased with age. A total of 16.4% of patients (31 out of 189 patients, corrected mean age: 41.1 years, range 35.8–43.3 years) showed substantial confluent WMLs. Men and women showed comparable prevalence and severity of WMLs. However, men were significantly younger at time of WML assessment. Patients with classical FD had a higher chance on WMLs compared to non-classical patients.
Progression of WMLs was seen in 24.6% of patients (49 out of 199 patients) during 38.1 months follow-up. Progression was seen in both men and women, with and without enzyme replacement therapy, but at an earlier age in men. Stroke seemed to be related to WMLs, but cerebrovascular risk factors, cardiac and renal (dys)function did not. Pathology in the brain in FD seemed to extend beyond the WMLs into the normal appearing white matter.
A significant group of FD patients has substantial WMLs and male patients develop WMLs earlier compared to female patients. WMLs could be used in clinical trials to evaluate possible treatment effects on the brain. Future studies should focus on longitudinal follow-up using modern imaging techniques, focusing on the clinical consequences of WMLs. In addition, ischemic and non-ischemic pathways resulting in WML development should be studied.
The beneficial effects of long-term enzyme replacement therapy on cardiac involvement in Japanese Fabry patients
2018, Molecular Genetics and Metabolism
Citation Excerpt :
The most frequent clinical event was end-stage renal disease (ESRD), which required chronic dialysis, ESRD events only occurred in male patients [4]. One male patient suffered from an evident stroke; however, subclinical cerebrovascular complications may have occurred in a significant number of Fabry patients [12]. Only one female patient died due to uncontrolled refractory CHF under treatment while receiving various medications for heart failure.
Fabry disease is a hereditary disorder that occurs due to the reduction or absence of alpha-galactosidase A activity, which leads to cardiac involvement including left ventricular hypertrophy (LVH). Enzyme replacement therapy (ERT) provides better patient outcomes by preventing serious complications. However, there have been very few studies on the long-term effects of ERT on the cardiac manifestations in Japanese Fabry patients. We retrospectively analyzed the data from the medical records of 42 Fabry patients (male, n = 17; female, n = 25) who were followed at Jikei University Hospital, and in whom the long-term effects of ERT could be evaluated (median follow-up period: male, 11 years; female, 8 years). The slope of the left ventricular mass (LVM) increase was 3.02 ± 3.41 g/m²/year in males and 1.69 ± 2.73 g/m²/year in females. In a subgroup analysis, the slopes of males with and without LVH did not differ to a statistically significant extent; however, the slope in female patients without LVH was significantly smaller than that of female patients with LVH. We then compared our data to the natural historical data that have previously been reported. In comparison to the previously reported data, we found a significant reduction in the LVM changes (g/height^2.7/year) of patients who received long-term ERT (male, 4.07 ± 1.03 to 1.25 ± 1.39; female, 2.31 ± 0.81 to 0.78 ± 1.23). Long-term ERT effectively prevents LVH in Fabry patients. This effect was also observed in the patients with LVH prior to the initiation of ERT.
Brain MRI correlations with disease burden and biomarkers in Fabry disease
2023, Journal of Neurology

View all citing articles on Scopus

: Y.K. received research funding from Genzyme Corporation; T.O. received research funding from Genzyme Corporation, Dainippon Sumitomo Pharma, and Shire Corporation; Y.E. received research funding from Genzyme Corporation; H.I. received research funding from Genzyme Corporation and Dainippon Sumitomo Pharma; Y.I. received research funding from Genzyme Corporation.

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Characteristics of Cerebral Microbleeds in Patients with Fabry Disease

Background and Purpose

Methods

Results

Conclusions

Introduction

Section snippets

Patients

Results

Discussion

Conclusion

Lancet

Lancet Neurol

J Neurol Sci

Lancet Neurol

Mol Genet Metab

Lancet Neurol

Genet Med

Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy

Ann Intern Med

Stroke in Fabry disease frequently occurs before diagnosis and in the absence of other clinical events: natural history data from the Fabry Registry

Stroke

Natural history of the cerebrovascular complications of Fabry disease

Acta Paediatr Suppl

Neurological features of Fabry disease: clinical, pathophysiological aspects and therapy

Acta Neurol Scand

Stroke and Fabry disease

J Neurol

Zurich Fabry study—prevalence of Fabry disease in young patients with first cryptogenic ischaemic stroke or TIA

Eur J Neurol

Fabry disease in unselected patients with TIA or stroke: population-based study

Eur J Neurol

Acute cerebrovascular disease in the young: the Stroke in Young Fabry Patients study

Stroke

Cerebrovascular involvement in Fabry disease: current status of knowledge

Stroke

MR signal abnormalities at 1.5 T in Alzheimer's dementia and normal aging

AJR Am J Roentgenol

The Microbleed Anatomical Rating Scale (MARS): reliability of a tool to map brain microbleeds

Neurology

Vertebrobasilar dolicoectasia in Fabry disease: the earliest marker of neurovascular involvement?

J Inborn Errors Metab Screen