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Radiological Evidence of Early Cerebral Microvascular Disease in Young Children with Fabry Disease
RADIOLOGICAL EVIDENCE OF EARLY CEREBRAL MICROVASCULAR DISEASE IN YOUNG CHILDREN WITH FABRY DISEASE MARIO A. CABRERA-SALAZAR, MD, ERIN O’ROURKE, MS, CGC, GUSTAVO CHARRIA-ORTIZ, MD, AND JOHN A. BARRANGER, MD, PHD
We report on 2 children with Fabry disease who had radiologic evidence of microvascular central nervous system involvement despite the clinical absence of renal, cardiac, or cerebral manifestations. This suggests that treatment with enzyme replacement therapy may be necessary early in the disease to avoid irreversible complications. (J Pediatr 2005;147:102-5)
abry disease is a rare X-linked recessive disease caused by deficient activity of the lysosomal hydrolase a-galactosidase A (a-Gal A), which leads to accumulation of a-galactosyl-terminal lipids, particularly globotriaosylceramide in lysosomes, resulting in severe renal, cardiac, and cerebrovascular involvement.1 Males with the classical phenotype, who have virtually no detectable a-Gal A activity, develop end-stage renal disease at a mean age of 39 years2 and have a median lifespan of approximately 50 years.2,3 Carrier women can also have a wide range of disease manifestations ranging from no symptoms to symptoms as severe as those of classically affected males.4,5 Diagnosis of Fabry disease is often delayed, especially in the absence of a family history, because early symptoms can be subtle or nonspecific.6 Until enzyme replacement therapy (ERT) became available in 2001, treatment for Fabry disease consisted of symptombased treatment that did not address the underlying cause of the disease. With the availability of this disease-specific therapy, prompt diagnosis has assumed new importance so that treatment can begin before irreversible organ damage occurs, although the ability of ERT to treat parenchymal central nervous system (CNS) damage remains controversial. Cerebrovascular manifestations in patients with the classical form of the disease include early stroke, transient ischemic attacks, white matter lesions, hemiparesis, vertigo or dizziness, and complications of vascular disease (such as diplopia, dysarthria, nystagmus, tinnitus, hemiataxia, memory loss, and hearing loss).7,8 A longitudinal study of cerebrovascular involvement in 50 patients who had a total of 129 magnetic resonance imaging (MRI) scans demonstrated increasing cerebral vasculopathy with age.9 The effects of progressive vasculopathy is seen in pediatric patients with Fabry disease, leading to transient ischemic attacks in patients as young as 12 years.10 Progressive neuroradiologic findings in Fabry disease include dolichoectasia (vascular elongation with fusiform dilation) and extensive periventricular white matter signal hyperintensity associated with deep small vessel infarcts or lacunae in the basal ganglia. Classical periventricular white matter lesions can be found on T2 weighted images or fluid attenuated inversion recovery (FLAIR).11,12 Dolichoectasia is a common finding in the posterior circulation of these individuals, especially in the vertebrobasilar system.7 None of From the Department of Human these findings is specific for Fabry disease. However, 2 recent reports describe pulvinar Genetics, University of Pittsburgh, hyperintensity as a pathognomonic MRI sign of Fabry disease in some adults, with Pittsburgh PA and the Department of Neurology, University of Miami, increasing frequency with age.11,12 These hyperintense images, attributed to tissue Miami, FL. mineralization (calcification), can also be seen in computed tomography scans of the Dr. Barranger is a consultant to the 12 corresponding areas. Genzyme Corporation. Here we describe brain MRI abnormalities found in two boys with Fabry disease who Submitted for publication Apr 30, 2004; last revision received Feb 14, had no clinical evidence of cerebral involvement. The findings are similar to those seen in 2005; accepted Mar 5, 2005. microvascular disease caused by chronic hypertension or atherosclerosis in adults, although Reprint requests: John A. Barranger, the specific changes in the posterior circulation seen in adults with Fabry disease were not MD, PhD, University of Pittsburgh, Department of Human Gentics, E1650 observed.
F
CNS ERT FLAIR
102
Central nervous system Enzyme replacement therapy Fluid attenuated inversion recovery
a-Gal A MRI
a Galactosidase A Magnetic resonance imaging
Biomedical Science Tower, Pittsburgh, PA 15261. E-mail: john.barranger@ mail.hgen.pitt.edu. 0022-3476/$ - see front matter Copyright ª 2005 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2005.03.004
Figure 2. T2 image of patient 1. Areas of microvascular involvement are indicated by arrows. Note periventricular disposition and increased signal present in white matter.
Figure 1. T2-weighted MRI axial section of patient 1. Arrows indicate sites of increased signal in periventricular white matter similar to those observed in adult vascular disease.
Fabry disease, and sequence analysis revealed an R227Q mutation in the a-Gal A gene. Baseline audiologic examination, electrocardiography, and echocardiography results were unremarkable. The ophthalmologic examination showed whorled corneal opacities in both eyes. Creatinine clearance was 147 mL/min (2.45 mL/s), and no proteinuria was found. The patient currently receives gabapentin 400 mg/day for pain management and agalsidase beta infusions (Fabrazyme, Genzyme Corporation, Cambridge, Mass) (1.0 mg/kg) every 2 weeks. In axial T2 images there is minimally increased signal in both the basal ganglia and the subcortical white matter of both hemispheres (Figure 1). These areas are punctuate in shape and similar to the ones observed in adult microvascular disease. Minimal prominence of the cerebral sulci is also observed but without clear evidence of atrophy. A similarly increased signal in the periventricular white matter is also observed in the axial FLAIR sequence (Figure 2). No hyperintensities were observed in the pulvinar of this patient, as should be expected for patients in this age group.
PATIENT 2 PATIENT 1 An 11-year-old white male who had complaints of acroparesthesias in the hands and feet beginning at age 7, anhidrosis, and frequent loose bowel movements was tested for Fabry disease after diagnosis in his maternal grandfather. Decreased activity of a Gal A confirmed the suspicion of Radiological Evidence Of Early Cerebral Microvascular Disease In Young Children With Fabry Disease
An 8-year-old, white, symptom-free male was tested for Fabry disease after the diagnosis of his maternal grandfather. Decreased activity of a Gal A confirmed the suspicion of Fabry disease, and sequence analysis revealed a 196-basepair deletion in the gene for a-Gal A. Cardiac and renal evaluations in this patient are unremarkable, and creatinine clearance was estimated at 140.3 mL/min (2.34 mL/s). 103
disease (a symptomatic 11-year-old and a symptom-free 8year-old) who, in spite of having no clinical evidence of CNS, renal or cardiac involvement, showed early microvascular cerebral involvement demonstrated by MRI. These observations underscore the progressive nature of this disease and that it progresses silently well before clinical symptoms of organ damage are evident. These MRI findings, together with the reported occurrence of transient ischemic attacks in a 12-yearold patient with Fabry disease,10 suggest that the accumulation of substrates in the blood vessels of the CNS can produce serious consequences even at an early age. A report by Giacommini et al15 addresses the case of a previously symptom-free 19-year-old woman who presented with neurologic deficits secondary to basal ganglia and pontine infarction. The diagnosis of Fabry disease was made after cardiac, arterial and hematologic investigations did not identify the cause of the stroke, and the diagnosis was suggested only after a histologic evaluation. A similar argument may be applied to other organs. It is possible that delaying treatment may compromise the overall effectiveness of enzyme replacement therapy. Although it has been shown that intravenous enzymes cannot cross the blood brain barrier,16 the parenchymal consequences derived from vascular disease and endothelial deposition may be preventable with early intervention. Taking these facts into account, we suggest the use of MRI for baseline and follow-up of pediatric patients with Fabry disease to identify potential abnormalities that could benefit from enzyme replacement therapy.
REFERENCES
Figure 3. T1 image of patient 2. Microvascular involvement is also seen in periventricular white matter; however, it is observed to lesser degree than in patient 1.
T1 sagittal cuts of the brain show minimal prominence of the Virchow-Robin spaces (Figure 3). On the axial T2 sequences, multiple punctate areas in the subcortical white matter of both hemispheres showed a minimal increase in the signal, similar to the changes observed in patient 1, although they seem to be less prominent.
DISCUSSION Although the pathologic condition of Fabry disease begins at birth or before birth,13 laboratory evaluations of children with this condition usually reveal no apparent abnormalities, and symptoms often do not manifest until 10 years of age or later.14 Here we report on 2 children with Fabry 104
Cabrera-Salazar et al
1. Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency: Fabry disease. In: Scriver C, Beaudet A, Sly W, Valle D, Childs B, Kinzler K, et al, eds. Metabolic and Molecular Bases of Inherited Disease. New York: McGraw Hill; 2001. p. 3733-74. 2. Branton MH, Schiffmann R, Sabnis SG, Murray GJ, Quirk JM, Altarescu G, et al. Natural history of Fabry renal disease: influence of a´-galactosidase A activity and genetic mutations on clinical course. Medicine (Baltimore) 2002;81:122-38. 3. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet 2001;38:750-60. 4. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet 2001;38:769-75. 5. Van Loo A, Vanholder R, Madsen K, Praet M, Kint J, De Paepe A, et al. Novel frameshift mutation in a heterozygous woman with Fabry disease and end-stage renal failure. Am J Nephrol 1996;16:352-7. 6. Desnick RJ, Brady R, Barranger J, Collins AJ, Germain DP, Goldman M, et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 2003;138:338-46. 7. Mitsias P, Levine SR. Cerebrovascular complications of Fabry’s disease. Ann Neurol 1996;40:8-17. 8. Grewal RP. Stroke in Fabry’s disease. J Neurol 1994;241:153-6. 9. Crutchfield KE, Patronas NJ, Dambrosia JM, Frei KP, Banerjee TK, Barton NW, et al. Quantitative analysis of cerebral vasculopathy in patients with Fabry disease. Neurology 1998;50:1746-9. 10. Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, Kampmann C, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest 2004;34: 236-42.
The Journal of Pediatrics July 2005
11. Takanashi J, Barkovich AJ, Dillon WP, Sherr EH, Hart KA, Packman S. T1 hyperintensity in the pulvinar: key imaging feature for diagnosis of Fabry disease. AJNR Am J Neuroradiol 2003;24:916-21. 12. Moore DF, Ye F, Schiffmann R, Butman JA. Increased signal intensity in the pulvinar on T1-weighted images: a pathognomonic MR imaging sign of Fabry disease. AJNR Am J Neuroradiol 2003;24:1096-101. 13. Popli S, Leehey DJ, Molnar ZV, Nawab ZM, Ing TS. Demonstration of Fabry’s disease deposits in placenta. Am J Obstet Gynecol 1990;162:464-5.
Radiological Evidence Of Early Cerebral Microvascular Disease In Young Children With Fabry Disease
14. Ries M, Ramaswami U, Parini R, Lindblad B, Whybra C, Willers I, et al. The early clinical phenotype of Fabry disease: a study on 35 European children and adolescents. Eur J Pediatr 2003;162:767-72. 15. Giacomini PS, Shannon PT, Clarke JT, Jaigobin C. Fabry’s disease presenting as stroke in a young female. Can J Neurol Sci 2004;31:112-4. 16. Johnson WG, Desnick RJ, Long DM, Sharp HL, Krivit W, Brady B, Brady RO. Intravenous injection of purified hexosaminidase A into a patient with Tay-Sachs disease. Birth Defects Orig Artic Ser 1973;9:120-4.
105
We report on 2 children with Fabry disease who had radiologic evidence of microvascular central nervous system involvement despite the clinical absence of renal, cardiac, or cerebral manifestations. This suggests that treatment with enzyme replacement therapy may be necessary early in the disease to avoid irreversible complications. (J Pediatr 2005;147:102-5)
abry disease is a rare X-linked recessive disease caused by deficient activity of the lysosomal hydrolase a-galactosidase A (a-Gal A), which leads to accumulation of a-galactosyl-terminal lipids, particularly globotriaosylceramide in lysosomes, resulting in severe renal, cardiac, and cerebrovascular involvement.1 Males with the classical phenotype, who have virtually no detectable a-Gal A activity, develop end-stage renal disease at a mean age of 39 years2 and have a median lifespan of approximately 50 years.2,3 Carrier women can also have a wide range of disease manifestations ranging from no symptoms to symptoms as severe as those of classically affected males.4,5 Diagnosis of Fabry disease is often delayed, especially in the absence of a family history, because early symptoms can be subtle or nonspecific.6 Until enzyme replacement therapy (ERT) became available in 2001, treatment for Fabry disease consisted of symptombased treatment that did not address the underlying cause of the disease. With the availability of this disease-specific therapy, prompt diagnosis has assumed new importance so that treatment can begin before irreversible organ damage occurs, although the ability of ERT to treat parenchymal central nervous system (CNS) damage remains controversial. Cerebrovascular manifestations in patients with the classical form of the disease include early stroke, transient ischemic attacks, white matter lesions, hemiparesis, vertigo or dizziness, and complications of vascular disease (such as diplopia, dysarthria, nystagmus, tinnitus, hemiataxia, memory loss, and hearing loss).7,8 A longitudinal study of cerebrovascular involvement in 50 patients who had a total of 129 magnetic resonance imaging (MRI) scans demonstrated increasing cerebral vasculopathy with age.9 The effects of progressive vasculopathy is seen in pediatric patients with Fabry disease, leading to transient ischemic attacks in patients as young as 12 years.10 Progressive neuroradiologic findings in Fabry disease include dolichoectasia (vascular elongation with fusiform dilation) and extensive periventricular white matter signal hyperintensity associated with deep small vessel infarcts or lacunae in the basal ganglia. Classical periventricular white matter lesions can be found on T2 weighted images or fluid attenuated inversion recovery (FLAIR).11,12 Dolichoectasia is a common finding in the posterior circulation of these individuals, especially in the vertebrobasilar system.7 None of From the Department of Human these findings is specific for Fabry disease. However, 2 recent reports describe pulvinar Genetics, University of Pittsburgh, hyperintensity as a pathognomonic MRI sign of Fabry disease in some adults, with Pittsburgh PA and the Department of Neurology, University of Miami, increasing frequency with age.11,12 These hyperintense images, attributed to tissue Miami, FL. mineralization (calcification), can also be seen in computed tomography scans of the Dr. Barranger is a consultant to the 12 corresponding areas. Genzyme Corporation. Here we describe brain MRI abnormalities found in two boys with Fabry disease who Submitted for publication Apr 30, 2004; last revision received Feb 14, had no clinical evidence of cerebral involvement. The findings are similar to those seen in 2005; accepted Mar 5, 2005. microvascular disease caused by chronic hypertension or atherosclerosis in adults, although Reprint requests: John A. Barranger, the specific changes in the posterior circulation seen in adults with Fabry disease were not MD, PhD, University of Pittsburgh, Department of Human Gentics, E1650 observed.
F
CNS ERT FLAIR
102
Central nervous system Enzyme replacement therapy Fluid attenuated inversion recovery
a-Gal A MRI
a Galactosidase A Magnetic resonance imaging
Biomedical Science Tower, Pittsburgh, PA 15261. E-mail: john.barranger@ mail.hgen.pitt.edu. 0022-3476/$ - see front matter Copyright ª 2005 Elsevier Inc. All rights reserved. 10.1016/j.jpeds.2005.03.004
Figure 2. T2 image of patient 1. Areas of microvascular involvement are indicated by arrows. Note periventricular disposition and increased signal present in white matter.
Figure 1. T2-weighted MRI axial section of patient 1. Arrows indicate sites of increased signal in periventricular white matter similar to those observed in adult vascular disease.
Fabry disease, and sequence analysis revealed an R227Q mutation in the a-Gal A gene. Baseline audiologic examination, electrocardiography, and echocardiography results were unremarkable. The ophthalmologic examination showed whorled corneal opacities in both eyes. Creatinine clearance was 147 mL/min (2.45 mL/s), and no proteinuria was found. The patient currently receives gabapentin 400 mg/day for pain management and agalsidase beta infusions (Fabrazyme, Genzyme Corporation, Cambridge, Mass) (1.0 mg/kg) every 2 weeks. In axial T2 images there is minimally increased signal in both the basal ganglia and the subcortical white matter of both hemispheres (Figure 1). These areas are punctuate in shape and similar to the ones observed in adult microvascular disease. Minimal prominence of the cerebral sulci is also observed but without clear evidence of atrophy. A similarly increased signal in the periventricular white matter is also observed in the axial FLAIR sequence (Figure 2). No hyperintensities were observed in the pulvinar of this patient, as should be expected for patients in this age group.
PATIENT 2 PATIENT 1 An 11-year-old white male who had complaints of acroparesthesias in the hands and feet beginning at age 7, anhidrosis, and frequent loose bowel movements was tested for Fabry disease after diagnosis in his maternal grandfather. Decreased activity of a Gal A confirmed the suspicion of Radiological Evidence Of Early Cerebral Microvascular Disease In Young Children With Fabry Disease
An 8-year-old, white, symptom-free male was tested for Fabry disease after the diagnosis of his maternal grandfather. Decreased activity of a Gal A confirmed the suspicion of Fabry disease, and sequence analysis revealed a 196-basepair deletion in the gene for a-Gal A. Cardiac and renal evaluations in this patient are unremarkable, and creatinine clearance was estimated at 140.3 mL/min (2.34 mL/s). 103
disease (a symptomatic 11-year-old and a symptom-free 8year-old) who, in spite of having no clinical evidence of CNS, renal or cardiac involvement, showed early microvascular cerebral involvement demonstrated by MRI. These observations underscore the progressive nature of this disease and that it progresses silently well before clinical symptoms of organ damage are evident. These MRI findings, together with the reported occurrence of transient ischemic attacks in a 12-yearold patient with Fabry disease,10 suggest that the accumulation of substrates in the blood vessels of the CNS can produce serious consequences even at an early age. A report by Giacommini et al15 addresses the case of a previously symptom-free 19-year-old woman who presented with neurologic deficits secondary to basal ganglia and pontine infarction. The diagnosis of Fabry disease was made after cardiac, arterial and hematologic investigations did not identify the cause of the stroke, and the diagnosis was suggested only after a histologic evaluation. A similar argument may be applied to other organs. It is possible that delaying treatment may compromise the overall effectiveness of enzyme replacement therapy. Although it has been shown that intravenous enzymes cannot cross the blood brain barrier,16 the parenchymal consequences derived from vascular disease and endothelial deposition may be preventable with early intervention. Taking these facts into account, we suggest the use of MRI for baseline and follow-up of pediatric patients with Fabry disease to identify potential abnormalities that could benefit from enzyme replacement therapy.
REFERENCES
Figure 3. T1 image of patient 2. Microvascular involvement is also seen in periventricular white matter; however, it is observed to lesser degree than in patient 1.
T1 sagittal cuts of the brain show minimal prominence of the Virchow-Robin spaces (Figure 3). On the axial T2 sequences, multiple punctate areas in the subcortical white matter of both hemispheres showed a minimal increase in the signal, similar to the changes observed in patient 1, although they seem to be less prominent.
DISCUSSION Although the pathologic condition of Fabry disease begins at birth or before birth,13 laboratory evaluations of children with this condition usually reveal no apparent abnormalities, and symptoms often do not manifest until 10 years of age or later.14 Here we report on 2 children with Fabry 104
Cabrera-Salazar et al
1. Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency: Fabry disease. In: Scriver C, Beaudet A, Sly W, Valle D, Childs B, Kinzler K, et al, eds. Metabolic and Molecular Bases of Inherited Disease. New York: McGraw Hill; 2001. p. 3733-74. 2. Branton MH, Schiffmann R, Sabnis SG, Murray GJ, Quirk JM, Altarescu G, et al. Natural history of Fabry renal disease: influence of a´-galactosidase A activity and genetic mutations on clinical course. Medicine (Baltimore) 2002;81:122-38. 3. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet 2001;38:750-60. 4. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet 2001;38:769-75. 5. Van Loo A, Vanholder R, Madsen K, Praet M, Kint J, De Paepe A, et al. Novel frameshift mutation in a heterozygous woman with Fabry disease and end-stage renal failure. Am J Nephrol 1996;16:352-7. 6. Desnick RJ, Brady R, Barranger J, Collins AJ, Germain DP, Goldman M, et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 2003;138:338-46. 7. Mitsias P, Levine SR. Cerebrovascular complications of Fabry’s disease. Ann Neurol 1996;40:8-17. 8. Grewal RP. Stroke in Fabry’s disease. J Neurol 1994;241:153-6. 9. Crutchfield KE, Patronas NJ, Dambrosia JM, Frei KP, Banerjee TK, Barton NW, et al. Quantitative analysis of cerebral vasculopathy in patients with Fabry disease. Neurology 1998;50:1746-9. 10. Mehta A, Ricci R, Widmer U, Dehout F, Garcia de Lorenzo A, Kampmann C, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest 2004;34: 236-42.
The Journal of Pediatrics July 2005
11. Takanashi J, Barkovich AJ, Dillon WP, Sherr EH, Hart KA, Packman S. T1 hyperintensity in the pulvinar: key imaging feature for diagnosis of Fabry disease. AJNR Am J Neuroradiol 2003;24:916-21. 12. Moore DF, Ye F, Schiffmann R, Butman JA. Increased signal intensity in the pulvinar on T1-weighted images: a pathognomonic MR imaging sign of Fabry disease. AJNR Am J Neuroradiol 2003;24:1096-101. 13. Popli S, Leehey DJ, Molnar ZV, Nawab ZM, Ing TS. Demonstration of Fabry’s disease deposits in placenta. Am J Obstet Gynecol 1990;162:464-5.
Radiological Evidence Of Early Cerebral Microvascular Disease In Young Children With Fabry Disease
14. Ries M, Ramaswami U, Parini R, Lindblad B, Whybra C, Willers I, et al. The early clinical phenotype of Fabry disease: a study on 35 European children and adolescents. Eur J Pediatr 2003;162:767-72. 15. Giacomini PS, Shannon PT, Clarke JT, Jaigobin C. Fabry’s disease presenting as stroke in a young female. Can J Neurol Sci 2004;31:112-4. 16. Johnson WG, Desnick RJ, Long DM, Sharp HL, Krivit W, Brady B, Brady RO. Intravenous injection of purified hexosaminidase A into a patient with Tay-Sachs disease. Birth Defects Orig Artic Ser 1973;9:120-4.
105