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Anteroposterior view of postembolization right internal carotid artery angiography demonstrating complete occlusion of aneurysm preserving a posterior communicating artery.
Source publication
We report an unusual case of cerebral aneurysmal subarachnoid hemorrage (SAH) with Fabry's disease. A 42-year-old woman presented with aneurysmal SAH originated from a saccular aneurysm of the right posterior communicating artery. The patient was treated by an endovascular coil embolization of aneurysm. Postoperatively the patient recovered favorab...
Citations
... However, in contrast to many other lysosomal storage diseases, most patients remain clinically asymptomatic or mildly symptomatic during the first years of life, with first symptoms typically arising in childhood or adolescence [11]. Several intracranial vascular and parenchymal abnormalities occur, including basilar artery dolichoectasia, intracerebral hemorrhages, subarachnoid hemorrhage, microbleeds, and cerebral venous thrombosis [15][16][17][18][19][20][21]. ...
Purpose of Review
Since brain pericytes guarantee appropriate development and maintenance of the cerebrovascular system, we reviewed their role in neurometabolic diseases (NMDs), a subclass of inborn errors of metabolism that selectively cause neurological sequels and widespread cerebrovascular alterations.
Recent Findings
Main findings about pericyte involvement in NMDs arise from glutaric acidemia type I (GA-I) models. In this regard, we found that (i) a single intracisternal injection of the main accumulated metabolite (glutaric acid, GA) in rat neonates disturbed the neurovascular unit (NVU) as evidenced by blood-brain barrier hyperpermeability, and altered immunoreactivity of pericyte and astrocyte markers surrounding brain microvessels; (ii) GA-elicited capillary constriction near pericyte somata likely inducing reduced brain blood flow as reported in GA-I patients; (iii) GA-elicited pericyte contraction probably results from a defective interplay among NVU components and could be relevant in case of metabolic decompensation or energetic deficiency.
Summary
Although pericyte pathological features have been studied in few NMDs, their involvement in NMD pathophysiology is largely unknown. Thus, further studies are needed to identify their roles and therapeutic potentiality.
... Brain tissue embedded in paraffin from a limited number of regions was obtained from a second cognitively unimpaired 50-year-old white male FD patient from the NIH University of Maryland Neurobiobank. This individual came to autopsy following a subarachnoid hemorrhage resulting from a ruptured basilar artery aneurysm (68,80). No data about a-Gal A levels were available, and it was not reported to what extent he might have received ERT, hematopoietic stem cell transplantation therapy, or therapy with pharmacological chaperones (44,81). ...
Although Gaucher disease can be accompanied by Lewy pathology (LP) and extrapyramidal symptoms, it is unknown if LP exists in Fabry disease (FD), another progressive multisystem lysosomal storage disorder. We aimed to elucidate the distribution patterns of FD-related inclusions and LP in the brain of a 58-year-old cog-nitively unimpaired male FD patient suffering from predominant hypokinesia. Immunohistochemistry (CD77, a-synuclein, collagen IV) and neuropathological staging were performed on 100-mm sections. Tissue from the enteric or peripheral nervous system was unavailable. As controls, a second cognitively unimpaired 50-year-old male FD patient without LP or motor symptoms and 3 age-matched individuals were examined. Inclusion body pathology was semiquantitatively evaluated. Although Lewy neurites/ bodies were not present in the 50-year-old individual or in controls , severe neuronal loss in the substantia nigra pars compacta and LP corresponding to neuropathological stage 4 of Parkinson disease was seen in the 58-year-old FD patient. Major cerebrovas-cular lesions and/or additional pathologies were absent in this individual. We conclude that Lewy body disease with parkinson-ism can occur within the context of FD. Further studies determining the frequencies of both inclusion pathologies in large autopsy-controlled FD cohorts could help clarify the implications of both lesions for disease pathogenesis, potential spreading mechanisms, and therapeutic interventions.
... Brain tissue embedded in paraffin from a limited number of regions was obtained from a second cognitively unimpaired 50-year-old white male FD patient from the NIH University of Maryland Neurobiobank. This individual came to autopsy following a subarachnoid hemorrhage resulting from a ruptured basilar artery aneurysm (68,80). No data about a-Gal A levels were available, and it was not reported to what extent he might have received ERT, hematopoietic stem cell transplantation therapy, or therapy with pharmacological chaperones (44,81). ...
... Brain tissue embedded in paraffin from a limited number of regions was obtained from a second cognitively unimpaired 50-year-old white male FD patient from the NIH University of Maryland Neurobiobank. This individual came to autopsy following a subarachnoid hemorrhage resulting from a ruptured basilar artery aneurysm (68,80). No data about a-Gal A levels were available, and it was not reported to what extent he might have received ERT, hematopoietic stem cell transplantation therapy, or therapy with pharmacological chaperones (44,81). ...
Although Gaucher disease can be accompanied by Lewy pathology (LP) and extrapyramidal symptoms, it is unknown if LP exists in Fabry disease (FD), another progressive multisystem lysosomal storage disorder. We aimed to elucidate the distribution patterns of FD-related inclusions and LP in the brain of a 58-year-old cognitively unimpaired male FD patient suffering from predominant hypokinesia. Immunohistochemistry (CD77, α-synuclein, collagen IV) and neuropathological staging were performed on 100-µm sections. Tissue from the enteric or peripheral nervous system was unavailable. As controls, a second cognitively unimpaired 50-year-old male FD patient without LP or motor symptoms and 3 age-matched individuals were examined. Inclusion body pathology was semiquantitatively evaluated. Although Lewy neurites/bodies were not present in the 50-year-old individual or in controls, severe neuronal loss in the substantia nigra pars compacta and LP corresponding to neuropathological stage 4 of Parkinson disease was seen in the 58-year-old FD patient. Major cerebrovascular lesions and/or additional pathologies were absent in this individual. We conclude that Lewy body disease with parkinsonism can occur within the context of FD. Further studies determining the frequencies of both inclusion pathologies in large autopsy-controlled FD cohorts could help clarify the implications of both lesions for disease pathogenesis, potential spreading mechanisms, and therapeutic interventions.
Fabry disease is a genetic disease caused by enzyme α-galactosidase A deficiency, encoded by GLA gene, which is located in the X-chromosome. The impairment of the α-galactosidase A activity leads to cellular accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in many organs. Fabry disease is a lysosomal disease, and primarily affects kidney, heart, gastrointestinal tract, and nervous system. Both the central nervous system (CNS) and the peripheral nervous system (PNS) can be affected. This chapter highlights the clinical features involving the PNS (including the autonomic system) and CNS. The involvement of the cerebral circulation is a major feature of Fabry disease, with ischemic stroke and cerebral small vessel disease as the most relevant findings. This chapter comprehensively focuses on the epidemiology, clinical features, neuroimaging, and pathogenesis of stroke and cerebrovascular disease in Fabry disease. The chapter also discusses the current knowledge regarding diagnosis, treatment, and monitoring of patients with Fabry disease.
Background and purpose:
Cerebral small vessel disease is a common manifestation among patients with Fabry disease (FD). As a biomarker of cerebral small vessel disease, the prevalence of impaired cerebral autoregulation as assessed by transcranial Doppler (TCD) ultrasonography was evaluated in FD patients and healthy controls.
Methods:
TCD was performed to assess pulsatility index (PI) and vasomotor reactivity expressed by breath-holding index (BHI) for the middle cerebral arteries of included FD patients and healthy controls. Prevalence of increased PI (>1.2) and decreased BHI (<0.69) and ultrasound indices of cerebral autoregulation were compared in FD patients and controls. The potential association of ultrasound indices of impaired cerebral autoregulation with white matter lesions and leukoencephalopathy on brain MRI in FD patients was also evaluated.
Results:
Demographics and vascular risk factors were similar in 23 FD patients (43% women, mean age: 51 ± 13 years) and 46 healthy controls (43% women, mean age: 51 ± 13 years). The prevalence of increased PI (39%; 95% confidence interval [CI]: 20%-61%), decreased BHI (39%; 95% CI: 20%-61%), and the combination of increased PI and/or decreased BHI (61%; 95% CI: 39%-80%) was significantly (p < .001) higher in FD patients compared to healthy controls (2% [95% CI: 0.1%-12%], 2% [95% CI: 0.1%-12%], and 4% [95% CI: 0.1%-15%], respectively). However, indices of abnormal cerebral autoregulation were not associated independently with white matter hyperintensities and presented a low-to-moderate predictive ability for the discrimination of FD patients with and without white matter hyperintensities.
Conclusions:
Impaired cerebral autoregulation as assessed by TCD appears to be highly more prevalent among FD patients compared to healthy controls.
Fabry disease (FD, OMIM 301500) is a progressive inborn error of metabolism with important roles being played by cellular dysfunction and microvascular pathology induced by lysosomal glycosphingolipid deposition. Absent or deficient activity of lysosomal exoglycohydrolase alpha galactosidase A (a-Gal A) results in progressive accumulation of globotriaosylceramide (Gb3 or GL3; also known as ceramidetrihexoside or CTH) and related glycosphingolipids (galabiosylceramide) within lysosomes which are ubiquitous subcellular organelles, in a variety of cell types, including capillary endothelial and vascular smooth muscle cells (SMCs), renal (podocytes, tubular cells, glomerular endothelial, mesangial and interstitial cells), cardiac (cardiomyocytes and fibroblasts) and nerve cells (neurons, Schwann cells, etc.). The primary disease process starts in infancy, or even as early as in the fetal stage of development. However, in contrast to many other lysosomal storage diseases, most patients remain clinically asymptomatic or mildly symptomatic during the first years of life. First symptoms typically arise in childhood or adolescence and include, among others, neuropathic pain, angiokeratoma and cornea verticillata. Serious complications developing in adulthood include progressive renal insufficiency, cardiac complications (arrhythmia, hypertrophic cardiomyopathy) and/or cerebrovascular complications (e.g. early stroke).
The neurocutaneous disorders (NCDs) embrace an extensive group of developmental disorders associated with involvement of the skin, central nervous system (CNS), and/or the peripheral nervous system (PNS). The neurocutaneous manifestations relate to the common ectodermal origin of these organs. This review intended for the practicing clinical neurologist focuses on selected aspects of the NCDs primarily those associated with cerebrovascular disease. Our emphasis is primarily on those NCDs with genetic heterogeneity and their neurological manifestations.
Fabry disease (FD) is a rare and highly debilitating lysosomal storage disorder that results from a total lack of, or deficiency in, the enzyme α-galactosidase A (α-Gal A) because of mutations in the GLA gene.1 FD is inherited as an X-linked trait; many of the male patients develop a classic severe phenotype with early onset of symptoms, whereas heterozygous females exhibit phenotypes ranging from asymptomatic to major involvement of vital organs.2 Most families inherit private mutations; to date, >600 mutations have been identified and are listed in the online FD database (Fabry-database.org).3 The deficiency in α-Gal A causes the accumulation of globotriaosylceramide (GL-3; also abbreviated Gb3) in various cellular compartments, particularly lysosomes, causing structural damage and cellular dysfunction, as well as triggering secondary, tissue-level responses, such as inflammation, ischemia, hypertrophy, and the development of fibrosis resulting in progressive organ dysfunction.4 Deacylated globotriaosylceramide (lyso- globotriaosylceramide [lyso-GL-3]) has also been shown to be present in increased concentrations in the plasma of patients with FD. It has been suggested that lyso-GL-3 promotes GL-3 accumulation, induces proliferation of smooth muscle cells in vitro, and may have deleterious effects on the intima and media of small arterioles.5 Many cell types are involved in FD pathology, including vascular cells (endothelial and smooth muscle cells), cardiac cells (cardiomyocytes and valvular cells), a variety of renal cells (tubular and glomerular cells, and podocytes), and nerve cells.2
The underlying pathophysiological mechanisms of FD are complex and incompletely understood.6 Early pathophysiological changes are thought to predominantly involve the microvasculature.7 As age increases, arterial remodeling and intima-media thickening in medium-to-large caliber vessels occur.2 The first clinical symptoms of FD occur in childhood (eg, neuropathic pain, hypohidrosis, and gastrointestinal problems)8 and are primarily because of autonomic neuropathy.9 As the disease …
