CNS manifestations of Fabry's disease

doi:10.1016/S1474-4422(06)70548-8

The Lancet Neurology

Volume 5, Issue 9, September 2006, Pages 791-795

https://doi.org/10.1016/S1474-4422(06)70548-8 Get rights and content

Summary

Background

Fabry's disease is a rare hereditary lysosomal storage disease with multiorgan involvement. Deficiency of α-galactosidase A activity leads to accumulation of neutral glycosphingolipids, especially in vascular endothelial and smooth-muscle cells. Along with progressive renal and cardiac dysfunction, stroke is a major and often life-threatening burden of the disease. Cerebral vasculopathy, confirmed by neuropathological, neuroradiological, and functional studies, occurs commonly and leads to ischaemic cerebrovascular events at an early age.

Recent developments

Fabry's disease is an X-linked disease and women have been regarded as only mildly affected carriers. However, research has shown a high prevalence of ischaemic stroke and transient ischaemic attacks, along with imaging evidence of CNS involvement, in female patients with the disease, which suggests that at least in a subgroup of clinically affected women the severity of CNS disease is comparable to that in men. Another study has shown a high prevalence of the disease in young patients of both sexes with cryptogenic stroke, emphasising the need for more clinical attention to be paid to this under-diagnosed disease.

Where next?

These new findings should be replicated in larger samples. Brain structural changes and CNS involvement in the disease need to be monitored carefully in follow-up studies to broaden our knowledge of the course of neurobiological changes and to identify potential effects of enzyme-replacement therapy, which is already showing some benefit in cardiac and renal dysfunction in the disease. Finally, a diagnosis of Fabry's disease should always be considered in young patients who have had a stroke.

Introduction

Fabry's disease is a rare inherited multisystem lysosomal storage disorder. Several mutations have been described that lead to deficient activity of the enzyme α-galactosidase A¹ and progressive accumulation of neutral glycosphingolipids, mainly globotriaosylceramide (Gb₃), in various organ systems. Lipid deposits occur preferentially in vascular endothelial and smooth-muscle cells, resulting in vascular dysfunction, tissue ischaemia, and vessel occlusion, although the exact pathogenetic mechanism linking lipid accumulation to ischaemic tissue damage is unclear. The clinical hallmarks of the disease include neuropathic pain, cutaneous angiokeratomas, corneal dystrophy (cornea verticillata), hypohidrosis, gastrointestinal disturbances, renal dysfunction, cardiac disease (especially left ventricular hypertrophy), and CNS involvement with premature stroke,² especially in the vertebrobasilar circulation (figure).3, 4 A patient with progressive brainstem features, initially misdiagnosed as being caused by multiple sclerosis, was the focus of a recent Lancet Neurology Grand Round.⁵ Peripheral and central neurological complications of Fabry's disease are listed in the panel.

In this review, we summarise current research on the clinical manifestations of CNS involvement and on structural brain changes in both men and women with the disease.

Section snippets

CNS involvement

The extent of CNS disease is illustrated by data from the Fabry outcome survey (FOS), a comprehensive registry of patients with the disease supported by Shire Human Genetic Therapies. The overall prevalence of ischaemic stroke or transient ischaemic attack for patients in FOS was 13%.⁶ These events tended to occur at an early age; thus, for men in the 25–44 years age-group the observed number of ischaemic strokes in FOS was about 12 times greater than that expected in a comparable general

Cerebrovascular events in women

Fabry's disease is an X-linked disorder. In heterozygous women, α-galactosidase A activity in blood can lie within the reference range, in accordance with the Lyon hypothesis of random X chromosome inactivation.⁷ Female patients were therefore regarded merely as carriers, with mild features of the disease at worst. But research has now shown a high frequency of ischaemic cerebrovascular events in women with the disease. Thus, in the FOS the prevalence of ischaemic stroke or transient ischaemic

Structural brain imaging

The table summarises brain-imaging studies in Fabry's disease.3, 4, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 Examples of abnormalities on MRI are shown in the figure. The most prominent structural imaging findings in the disease are severe progressive white-matter lesions (WMLs), which occur from an early age. In a longitudinal MRI study of 50 patients with the disease, who had a mean age of 33 years, 52% had WMLs. The lesions were present in all patients older than 55 years.⁹ A report

Fabry's disease and stroke in young patients

A study of 721 patients with cryptogenic stroke, aged 18–55 years, showed a high prevalence of Fabry's disease in this group: 5% (21/432) of men and 3% (7/289) of women.³³ Combining results for both sexes showed that 4% of young patients with stroke of previously unknown cause had Fabry's disease, corresponding to about 1·2% of the general population of young stroke patients. By way of comparison with other rare causes of stroke in young people, the frequency of vasculitis is variably quoted as

Quantitative assessment of structural changes

Quantification of structural cerebrovascular involvement simply by applying visual rating scales to WMLs is constrained by limited accuracy.³⁸ Moreover, WMLs are thought to represent non-specific endpoints of chronic cerebral perfusion alterations, with the same appearances being caused by combinations of several pathological processes, including disturbances in the walls of small blood vessels, small infarcts in the white matter, breakdown of the blood–brain barrier, glial activation, and

Stroke pathogenesis

The mechanisms linking glycolipid accumulation to ischaemic tissue damage in Fabry's disease are poorly understood. Some strokes are probably a consequence of cardiogenic embolism since Fabry's disease predisposes to cardiomyopathy, valvular heart disease, ischaemic heart disease, and arrhythmias. Hypertension, secondary to renal failure, could also be a contributory factor. There is clear evidence, however, of vascular disease in situ in the brain in Fabry's disease. Both large and small

Enzyme replacement therapy

Enzyme replacement therapy has proved an effective treatment option for progressive impairment of renal and cardiac function and for quality of life in Fabry's disease, albeit largely in uncontrolled studies.⁴⁴ Regarding the peripheral nervous system, significant improvements in C, A(δ), and A(β) nerve fibre and intradermal vibration receptor function have been reported.⁴⁵ For the CNS, a tendency to normalisation of cerebral-vessel compliance and regional cerebral hyperperfusion has been shown

Conclusion

There is important new evidence of substantial CNS involvement in men and women with Fabry's disease, both clinically and on imaging. Furthermore, the disease should be considered as a relatively common cause of cryptogenic stroke in young patients. Although not formally studied, there is no reason to suppose that the burden of disability arising from strokes in Fabry's disease differs from that of cerebrovascular disease in the general population. These new clinical and structural data need to

Search strategy and selection criteria

References for this review were identified by searches of PubMed from 1990 until May, 2006, with the terms “Fabry disease”, “cerebrovascular”, “stroke”, “CNS”, “MRI”, and “white matter lesion”. Articles were also identified through searches of the authors' own files. No language restrictions were applied.

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Cited by (163)

Prevalence of Fabry disease and GLA variants in young patients with acute stroke: The challenge to widen the screening. The Fabry-Stroke Italian Registry
2024, Journal of the Neurological Sciences
Fabry disease (FD) is a treatable X-linked lysosomal storage disorder caused by GLA gene variants leading to alpha-galactosidase A deficiency. FD is a rare cause of stroke, and it is still controversial whether in stroke patients FD should be searched from the beginning or at the end of the diagnostic workup (in cryptogenic strokes).
Fabry-Stroke Italian Registry is a prospective, multicentric screening involving 33 stroke units. FD was sought by measuring α-galactosidase A activity (males) and by genetic tests (males with reduced enzyme activity and females) in patients aged 18–60 years hospitalized for TIA, ischemic stroke, or intracerebral hemorrhage. We diagnosed FD in patients with 1) already known pathogenic GLA variants; 2) novel GLA variants if additional clinical, laboratory, or family-derived criteria were present.
Out of 1906 patients, we found a GLA variant in 15 (0.79%; 95%CI 0.44–1.29) with a certain FD diagnosis in 3 (0.16%; 95%CI 0.03–0.46) patients, none of whom had hemorrhage. We identified 1 novel pathogenic GLA variant. Ischemic stroke etiologies in carriers of GLA variants were: cardioaortic embolism (33%), small artery occlusion (27%), other causes (20%), and undetermined (20%). Mild severity, recurrence, previous TIA, acroparesthesias, hearing loss, and small artery occlusion were predictors of GLA variant.
In this large multicenter cohort the frequency of FD and GLA variants was consistent with previous reports. Limiting the screening for GLA variants to patients with cryptogenic stroke may miss up to 80% of diagnoses. Some easily recognizable clinical features could help select patients for FD screening.
Prevalence of GLA gene mutations and polymorphisms in patients with multiple sclerosis: A cross-sectional study
2020, Journal of the Neurological Sciences
Fabry Disease (FD) has been frequently proposed as possible underestimated differential diagnosis of Multiple Sclerosis (MS), but no study has been performed to test prevalence of GLA gene mutations in a population fulfilling diagnostic criteria of MS. Aim of this study is to determine the prevalence of GLA gene mutations in a large and representative population diagnosed with MS, simultaneously providing a critical revision of current literature reports of coexistence or misdiagnosis between these two conditions.
In this mono-centric cross-sectional study, 927 patients fulfilling McDonald diagnostic criteria and encompassing all MS phenotypes were enrolled. Patients underwent evaluation of α-GalA activity and genotyping. Both genetic variants annotated as pathogenic and GVUS were considered. Estimated alleles frequencies were then compared to the ones reported in the gnomAD database.
GLA gene variants were found in seven individuals. Five patients carried variants previously described having controversial impact on FD phenotype, and the analysis of exome database revealed that they are not rare among healthy individuals. One patient showed a new variant never described before, and another one carried a late-onset FD cardiac variant.
The overall prevalence of GLA gene variants in MS patients is comparable to the one estimated in healthy population. This result is further supported by critical revision of current literature evidences of misdiagnosis between MS and FD, arguing in favour of independence between these disorders.
Fabry disease: α-galactosidase A deficiency
2020, Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease: Volume 1
Fabry disease, an X-linked lysosomal storage disease, results from mutations in the α-galactosidase A gene (GLA) that encodes no or markedly deficient α-galactosidase A (α-Gal A) enzyme activity. The enzymatic defect causes the progressive accumulation of globotriaosylceramide (GL-3 or Gb3), its deacylated derivative, globotriaosylsphingosine (Lyso-Gb3), and related glycosphingolipids in the plasma and tissue lysosomes throughout the body. There are two major phenotypic subtypes: Type 1 “classic” and Type 2 “later-onset” previously known as the renal and cardiac variants. Type 1 classically affected males have no or <3% of normal α-Gal A activity and prominent microvascular GL-3 accumulation. Onset in Type 1 males occurs in childhood/adolescence characterized by severe acroparesthesias, episodic pain crises, gastrointestinal manifestations, angiokeratoma, hypohidrosis, and corneal/lenticular opacities. With advancing age the progressive GL-3 accumulation in the microvasculature, renal podocytes, and cardiomyocytes leads to premature demise from renal, cardiac, and/or cerebrovascular disease. Type 2 later-onset males have residual α-Gal A activity and no vascular endothelial involvement; they develop cardiac and renal disease in maturity. Type 1 or 2 heterozygous females may be asymptomatic or as severely affected as their male relatives. Diagnosis of Type 1 or 2 affected males by α-Gal A enzyme assay is reliable, whereas the identification of heterozygous females requires GLA gene mutation analyses. Treatment by enzyme replacement with recombinant human α-Gal A has been shown to be safe and effective in clinical trials and subsequent studies. Experience has shown that dosage and early treatment are required for optimal outcomes. Recently, oral pharmacologic chaperone therapy has become available for adult patients with “amenable” GLA mutations. Currently, substrate reduction therapy and gene therapy trials are underway.
Multiple sclerosis and fabry Disease, two sides of the coin? The case of an Italian family
2018, Multiple Sclerosis and Related Disorders
Citation Excerpt :
Renal failure, cardiomyopathy, peripheral and Central Nervous System (CNS) alterations are the main causes of morbi-mortality. CNS involvement includes acute cerebrovascular events, white matter lesions (WML), peripheral neuropathy, vertebra-basilar abnormalities and cochleo-vestibular dysfunction (Fellgiebel et al., 2006). In adulthood, heterogeneity and complexity of FD presentation might pose difficulties in clinical identification, evaluation and treatment.
Multiple Sclerosis (MS) is considered among possible differential diagnosis of Fabry Disease (FD), especially in early stages when findings are suggestive but not diagnostic for MS. We report the case of a family in which FD and MS coexist, offering an overview on clues for differential diagnosis and speculating on shared etiopathogenic mechanisms for these conditions.
Taking as starting point the diagnosis of FD in a dialysis patient during a screening programme, we retrospectively rebuilt his family history and revised clinical and imaging examinations of his five siblings, two of which with previous diagnosis of MS.
After genetic testing, two subjects were found positive to a new α-galactosidase A mutation, probably causative for FD classical variant. The two subjects meeting diagnostic criteria for MS were found negative to any GLA gene mutation, therefore initial diagnosis was confirmed. The remaining two siblings resulted unaffected, with neither clinical nor instrumental evidence of FD and MS.
Differential diagnosis between FD and MS may be challenging, especially in early clinical stages when only extensive clinical evaluation and correct MRI interpretation may reduce the risk of misdiagnosis. Moreover this report allows speculating on potential etiological and pathogenic mechanisms, common both to FD and MS.
Clinical and neuroimaging review of monogenic cerebral small vessel disease from the prenatal to adolescent developmental stage
2024, Japanese Journal of Radiology
Basilar artery diameter as neuroimaging biomarker in Chinese Fabry disease patients
2023, Orphanet Journal of Rare Diseases

View all citing articles on Scopus

View full text

Rapid ReviewCNS manifestations of Fabry's disease

Summary

Background

Recent developments

Where next?

Introduction

Section snippets

CNS involvement

Cerebrovascular events in women

Structural brain imaging

Fabry's disease and stroke in young patients

Quantitative assessment of structural changes

Stroke pathogenesis

Enzyme replacement therapy

Conclusion

Search strategy and selection criteria

J Mol Biol

Lancet Neurol

Brain Res Bull

Medicine (Baltimore)

J Pediatr

Lancet

Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry outcome survey

Eur J Clin Invest

Cerebrovascular complications of Fabry's disease

Ann Neurol

Magnetic resonance imaging changes in Fabry disease

Acta Paediatr Suppl

Natural history of the cerebrovascular complications of Fabry disease

Acta Paediatr Suppl

Gene action in the X-chromosome of the mouse (Mus musculus L)

Nature

The neurological complications of Anderson-Fabry disease (alpha-galactosidase A deficiency): investigation of symptomatic and presymptomatic patients

Q J Med

Quantitative analysis of cerebral vasculopathy in patients with Fabry disease

Neurology

Diffuse central neuronal involvement in Fabry disease: a proton MRS imaging study

Neurology

Elevated CNS average diffusion constant in Fabry disease

Acta Paediatr Suppl

T1 hyperintensity in the pulvinar: key imaging feature for diagnosis of Fabry disease

AJNR Am J Neuroradiol

Increased signal intensity in the pulvinar on T1-weighted images: a pathognomonic MR imaging sign of Fabry disease

AJNR Am J Neuroradiol

CNS involvement in Fabry disease: clinical and imaging studies before and after 12 months of enzyme replacement therapy

J Inherit Metab Dis

White matter lesion severity in male and female patients with Fabry disease

Neurology

Pattern of microstructural brain tissue alterations in Fabry disease: a diffusion-tensor imaging study

J Neurol

Magnetic resonance image findings in 5 young patients with Fabry disease

Neurologist

Diffuse structural and metabolic brain changes in Fabry disease

J Neurol

Reduced cerebral blood flow velocity and impaired cerebral autoregulation in patients with Fabry disease

J Neurol

Rapid Review
CNS manifestations of Fabry's disease