Characteristics of Cerebral Microbleeds in Patients with Fabry Disease
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
References (38)
- et al.
Fabry's disease
Lancet
(2008) - et al.
CNS manifestations of Fabry's disease
Lancet Neurol
(2006) - et al.
Brain MRI findings in patients with Fabry disease
J Neurol Sci
(2011) - et al.
Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis
Lancet Neurol
(2010) - et al.
Vasculopathy in patients with Fabry disease: current controversies and research directions
Mol Genet Metab
(2010) - et al.
Cerebral microbleeds: a guide to detection and interpretation
Lancet Neurol
(2009) - et al.
Effects of enzyme replacement therapy in Fabry disease—a comprehensive review of the medical literature
Genet Med
(2010) - et al.
Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy
Ann Intern Med
(2003) - et al.
Stroke in Fabry disease frequently occurs before diagnosis and in the absence of other clinical events: natural history data from the Fabry Registry
Stroke
(2009) - et al.
Natural history of the cerebrovascular complications of Fabry disease
Acta Paediatr Suppl
(2005)
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
Cited by (25)
An expert consensus on the recommendations for the use of biomarkers in Fabry disease
2023, Molecular Genetics and MetabolismCardiac involvement in Fabry disease - A non-invasive assessment and the role of specific therapies
2022, Molecular Genetics and MetabolismCitation 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].
Clinical findings of gadolinium-enhanced cardiac magnetic resonance in Fabry patients
2020, Journal of CardiologyCitation 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].
Development and clinical consequences of white matter lesions in Fabry disease: a systematic review
2018, Molecular Genetics and MetabolismCitation 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.
The beneficial effects of long-term enzyme replacement therapy on cardiac involvement in Japanese Fabry patients
2018, Molecular Genetics and MetabolismCitation 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.
Brain MRI correlations with disease burden and biomarkers in Fabry disease
2023, Journal of Neurology
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.