Anderson-Fabry's disease: Neuropathological and neurochemical investigation

Tagliavini, Fabrizio; Pietrini, Vladimiro; Gemignani, F; Lechi, A; Pallini, Andrea; Federico, Antonio

doi:10.1007/bf00690579

Cited by 32 publications

(16 citation statements)

References 30 publications

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“…Nevertheless in a recent clinical, neuropathological and neurochemical study [48] of a case of Anderson-Fabry's disease the neuropathological examination is dominated by severe alterations in the cerebral vessels due to glycolipid deposits on the walls, with reduction or occlusion of the lumen. This is correlated with secondary ischaemic foci scattered throughout the cortex as well as through the white matter.…”

Section: Cns Involvementmentioning

confidence: 99%

Anderson-Fabry Disease: A Multiorgan Disease

Tuttolomondo¹,

Pecoraro²,

Simonetta³

et al. 2013

CPD

111

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Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency of the enzyme -galactosidase A. FD causes glycolipids, such as globotriaosylceramide (Gb3), to accumulate in the vascular endothelium of several organs (Fig. 2), including the skin, kidneys, nervous system, and heart, thereby triggering inflammation and fibrosis. These processes generally result in organ dysfunction, which is usually the first clinical evidence of FD. Patients with classic FD have various symptoms, eg, acroparesthesias, hypohidrosis, angiokeratomas, corneal opacities, cerebrovascular lesions, cardiac disorders, andrenal dysfunction.However, evolving knowledge about the natural course of disease suggests that it is more appropriate to describe FD as a disease with a wide spectrum of heterogeneously progressive clinical phenotypes. Indeed, most female heterozygotes develop symptoms due to yet undetermined mechanisms and a high percentage of females develops vital organ involvement including the kidneys, heart and/or brain about a decade later than males. Renal failure is a serious complication of this disease. Fabry nephropathy lesions are present and progress in childhood while the disease commonly remains silent by routine clinical measures. Early and timely diagnosis of Fabry nephropathy is crucial since late initiation of enzyme replacement therapy may not halt progressive renal dysfunction. This may be challenging due to difficulties in diagnosis of Fabry disease in children and absence of a sensitive non-invasive biomarker of early Fabry nephropathy. Accurate measurement of glomerular filtration rate and regular assessment for proteinuria and microalbuminuria are useful, though not sensitive enough to detect early lesions in the kidney. The principal clinical manifestations in Fabry disease consist of artery associated complications (such as cerebral disease and nephropathy), but the pathophysiology of this specific vasculopathy is unclear. Several studies indicate that the specific vascular lesions that are present in Fabry disease occur as a result of vascular dysfunction with major components being endothelial dysfunction, alterations in cerebral perfusion and a pro-thrombotic phenotype. Fabry cardiac involvement has several clinical manifestations (Table 10): concentric left ventricular hypertrophy without left ventricular dilation and severe loss of left ventricular systolic function, mitral and aortic valvulopathy, disorders of the atrioventricular conduction or repolarization, and compromised diastolic function. The neurological manifestations of Fabry disease include both peripheral nervous system and CNS involvement, with globotriaosylceramide accumulation found in Schwann cells and dorsal root ganglia together with deposits in CNS neurones. The main involvement of the CNS is attributable to cerebrovasculopathy, with an increased incidence of stroke. The abnormal neuronal accumulation of glycosphingolipid appears to have little clinical effect on the natural history of Fabry disease, wi...

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Section: Cns Involvementmentioning

confidence: 99%

Anderson-Fabry Disease: A Multiorgan Disease

Tuttolomondo¹,

Pecoraro²,

Simonetta³

et al. 2013

CPD

111

View full text Add to dashboard Cite

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“…In a number of patients [14,17,18,26, 271, the medium-and small-sized arteries were markedly thickened and their lumina were narrowed, and the large intracranial arteries, especially those of the posterior circulation, were dolichoectatic [ l l , 15 dolichoectasia may cause reduction of blood flow and, more important, stretching, distortion, and obstruction of the already stenotic basilar tributaries, thus resulting in brainstem or cerebellar ischemia [43]. Complete or partial thrombosis resulting in unilateral restricted pontine infarct in the territory of a penetrating artery (presumably related to distortion and obstruction of paramedian or circumferential basilar artery branches, or reduced flow from atherosclerosis) have occurred.…”

Section: Ischemic Cerebrovascular Diseasementioning

confidence: 99%

Cerebrovascular complications of Fabry's disease

Mitsias

Levine

1996

Annals of Neurology

270

101

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Fabry's disease (FD) is a rare, sex-linked disorder resulting from alpha-galactosidase deficiency. Cerebrovascular complications have been reported in the literature but have not been systematically analyzed. We report 2 patients and review 51 previously reported cases (descriptive meta-analysis) to clarify the clinical, radiologic, and pathologic features. The average age at onset of cerebrovascular symptoms was 33.8 years for hemizygous individuals (n = 43) and 40.3 years of heterozygotes (n = 10). The most frequent symptoms and signs were as follows (in descending order of frequency): hemiparesis, vertigo/dizziness, diplopia, dysarthria, nystagmus, nausea/vomiting, head pain, hemiataxia, and ataxia of gait, in the hemizygote group; and memory loss, dizziness, ataxia, hemiparesis, loss of consciousness and hemisensory symptoms, in the heterozygote group. The vertebrobasilar circulation was symptomatic in 67% of the hemizygotes and 60% of the heterozygotes. Intracerebral hemorrhage was found in 4 patients (3 hemizygotes and 1 heterozygote). Elongated, ectatic, tortuous vertebral and basilar arteries were the most common angiographic and pathologic features. For the hemizygotes, the recurrence rate for cerebrovascular disease was 76% and the death rate was 55%; 86% of the heterozygotes had recurrent cerebrovascular event(s) and 40% died. The cerebrovascular manifestations of FD, in both hemizygotes and heterozygotes, are predominantly due to dilative arteriopathy of the vertebrobasilar circulation, frequently recur, and portend a poor prognosis.

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“…Prominent alterations in cerebral blood vessels, including stenosis of small vessels and enlargement of large vessels may occur either primary to glycosphingolipid accumulation or secondary to unresolved downstream signaling mechanisms and contribute to an increased risk and incidence for stroke in Fabry patients, in particular those that involve the vertebrobasilar system [6, 7]. White matter lesions are also common neuropathological findings, in addition to neuronal swelling, axonal degeneration and accumulation of ceroid lipofuscin [8–10]. …”

Section: Introductionmentioning

confidence: 99%

Autophagy-lysosome pathway associated neuropathology and axonal degeneration in the brains of alpha-galactosidase A-deficient mice

Nelson

Tse

O’Quinn

et al. 2014

acta neuropathol commun

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BackgroundMutations in the gene for alpha-galactosidase A result in Fabry disease, a rare, X-linked lysosomal storage disorder characterized by a loss of alpha-galactosidase A enzymatic activity. The resultant accumulation of glycosphingolipids throughout the body leads to widespread vasculopathy with particular detriment to the kidneys, heart and nervous system. Disruption in the autophagy-lysosome pathway has been documented previously in Fabry disease but its relative contribution to nervous system pathology in Fabry disease is unknown. Using an experimental mouse model of Fabry disease, alpha-galactosidase A deficiency, we examined brain pathology in 20-24 month old mice with particular emphasis on the autophagy-lysosome pathway.ResultsAlpha-galactosidase A-deficient mouse brains exhibited enhanced punctate perinuclear immunoreactivity for the autophagy marker microtubule-associated protein light-chain 3 (LC3) in the parenchyma of several brain regions, as well as enhanced parenchymal and vascular immunoreactivity for lysosome-associated membrane protein-1 (LAMP-1). Ultrastructural analysis revealed endothelial cell inclusions with electron densities and a pronounced accumulation of electron-dense lipopigment. The pons of alpha-galactosidase A-deficient mice in particular exhibited a striking neuropathological phenotype, including the presence of large, swollen axonal spheroids indicating axonal degeneration, in addition to large interstitial aggregates positive for phosphorylated alpha-synuclein that co-localized with the axonal spheroids. Double-label immunofluorescence revealed co-localization of phosphorylated alpha-synuclein aggregates with ubiquitin and LC3.ConclusionTogether these findings indicate widespread neuropathology and focused axonal neurodegeneration in alpha-galactosidase A-deficient mouse brain in association with disruption of the autophagy-lysosome pathway, and provide the basis for future mechanistic assessment of the contribution of the autophagy-lysosome pathway to this histologic phenotype.Electronic supplementary materialThe online version of this article (doi:10.1186/2051-5960-2-20) contains supplementary material, which is available to authorized users.

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Anderson-Fabry's disease: Neuropathological and neurochemical investigation

Cited by 32 publications

References 30 publications

Anderson-Fabry Disease: A Multiorgan Disease

Anderson-Fabry Disease: A Multiorgan Disease

Cerebrovascular complications of Fabry's disease

Autophagy-lysosome pathway associated neuropathology and axonal degeneration in the brains of alpha-galactosidase A-deficient mice

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