Po1.145 AAN book 2008 first author L Marchesoni. Argentina.
Fabry's disease is an x linked recessive lysosomal storage disease due to deficient alpha galactosidase A. Untreated males usually die by the end of the sixth decade. The initial presentation is usually acroparesthesias, not relieved by rubbing, but prevented with acetophenacetin and ingestion of large amounts of liquids. Subsequently, abdominal pain, angiokeratomas and anhidrosis occur. Most are diagnosed after 15 years or more. Misdiagnoses included cryptogenic/psychogenic pain, RF, flatfoot, gout, food intoxication, cholecystitis, "glandular block", petechiae, vascular fragility, and others. Angiokeratomas are seen first around the umbilicus, and on the extensor surfaces of the elbows and knees, and in body creases including the hips and the genital areas. Opthalmic signs include whirl like feathery opacities, dust like haziness on cornea, dilated and tortuous corneal vessels, and corneal dystrophy on slit lamp that does not affect vision(cornea vittilicata). The opthalmic abnormality is present in nearly 90 % including female carriers who can thus be diagnosed by slit lamp exam.
Features can include tinnitus and deafness, although that is not in many textbooks (Lou Caplan); also vertigo. Other features are heat intolerance, inability to sweat, with the skin turning beet red on heat exposure. Other factors are postprandial abdominal cramping, and diverticula that can rupture. Left ventricular hypertrophy is seen as is small fiber neuropathy with decreased TEMPERATURE sensation. A recent case was reported of a patient presenting with a mimic of TGA (The Neurologist 2012; 18:413-4).
Strokes occur in posterior circulation , large and small arteries.
Pathologically, thickened walls in smaller arterioles is noted and in the brain, a double refractile material is seen. Cardiac and renal disease predominate, and many strokes are subclinical. Treatment must begin very early. Misdiagnosis of MS is common especially with brainstem strokes. CRAO, optic atrophy, loss of nasal field, third nerve palsy, lateral medullary syndrome, TMB are all reported, as are various lacunar syndromes. Cardiac evaluation shows hypertrophic cardiomyopathy and MVP in more than half. Renal failure is due to the deposition of lipid in glomeruli and tubules. Proteinuria is a feature. Lymphedema is seen . Basilar artery is described as pathologically enlarged and at times dolichoectatic.
The gene for alpha galactosidase a is Xq22.1, and different mutations are known. Female heterozygotes still have early stroke and can have heart and kidney disease and elevated ceramide trihexoside in urine. Treatment is biochemical Fabrazyme made by Genzyme (see pubmed how to do). CBZ, PTN, ASA ticlid, Vit E can be used for various symptoms/problems.
Additional material:
Testai FD, Gorelick PB. Inherited metabolic disorders and stroke part I: Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes. Arch Neurol; 2010: 67: 19-24.
More than 400 mutations of the alpha gal gene are identified, most being missense or nonsense substitutions. Absent family history does not rule out the diagnosis. The incidence is 1: 117,000 births and 1: 40,000 men. However, in cryptogenic stroke in the young, FD is responsible for 1.2 % (of age less than 55). Inn the database, women have more strokes than men, 2:1 with mean age 43 for women, and 28 for men. Basilar artery diameter is said to be a sensitive measure of FD (Neurology 2009).
Due to skewed organ specific X chromosome inactivation (nonrandom lionization), women may have atypical organ specific presentation, leading to challenges in diagnosis. These may include cardiac, renal and cerebrovascular manifestations. Diagnosis is made by alpha gal activity in leukocytes or plasma, but in women, gene sequencing and linkage studies may be needed, due to heterozygosity.
Acroparesthesias are associated with accumulation glycosphingolipids in DRG and Nerve conductions and EMG's are negative.
Measurement of leukocyte GAL activity is 100 percent sensitive in males but only five percent in women
MRI shows T2 hyperintense signal in frontal and parietal white matter and T1 hyperintensity in pulvinar as well as dolichoectasia. Treatment decreased LV mass and pain but unknown if it helps stroke.
Fabry's disease is an x linked recessive lysosomal storage disease due to deficient alpha galactosidase A. Untreated males usually die by the end of the sixth decade. The initial presentation is usually acroparesthesias, not relieved by rubbing, but prevented with acetophenacetin and ingestion of large amounts of liquids. Subsequently, abdominal pain, angiokeratomas and anhidrosis occur. Most are diagnosed after 15 years or more. Misdiagnoses included cryptogenic/psychogenic pain, RF, flatfoot, gout, food intoxication, cholecystitis, "glandular block", petechiae, vascular fragility, and others. Angiokeratomas are seen first around the umbilicus, and on the extensor surfaces of the elbows and knees, and in body creases including the hips and the genital areas. Opthalmic signs include whirl like feathery opacities, dust like haziness on cornea, dilated and tortuous corneal vessels, and corneal dystrophy on slit lamp that does not affect vision(cornea vittilicata). The opthalmic abnormality is present in nearly 90 % including female carriers who can thus be diagnosed by slit lamp exam.
Features can include tinnitus and deafness, although that is not in many textbooks (Lou Caplan); also vertigo. Other features are heat intolerance, inability to sweat, with the skin turning beet red on heat exposure. Other factors are postprandial abdominal cramping, and diverticula that can rupture. Left ventricular hypertrophy is seen as is small fiber neuropathy with decreased TEMPERATURE sensation. A recent case was reported of a patient presenting with a mimic of TGA (The Neurologist 2012; 18:413-4).
Strokes occur in posterior circulation , large and small arteries.
Pathologically, thickened walls in smaller arterioles is noted and in the brain, a double refractile material is seen. Cardiac and renal disease predominate, and many strokes are subclinical. Treatment must begin very early. Misdiagnosis of MS is common especially with brainstem strokes. CRAO, optic atrophy, loss of nasal field, third nerve palsy, lateral medullary syndrome, TMB are all reported, as are various lacunar syndromes. Cardiac evaluation shows hypertrophic cardiomyopathy and MVP in more than half. Renal failure is due to the deposition of lipid in glomeruli and tubules. Proteinuria is a feature. Lymphedema is seen . Basilar artery is described as pathologically enlarged and at times dolichoectatic.
The gene for alpha galactosidase a is Xq22.1, and different mutations are known. Female heterozygotes still have early stroke and can have heart and kidney disease and elevated ceramide trihexoside in urine. Treatment is biochemical Fabrazyme made by Genzyme (see pubmed how to do). CBZ, PTN, ASA ticlid, Vit E can be used for various symptoms/problems.
Additional material:
Testai FD, Gorelick PB. Inherited metabolic disorders and stroke part I: Fabry disease and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes. Arch Neurol; 2010: 67: 19-24.
More than 400 mutations of the alpha gal gene are identified, most being missense or nonsense substitutions. Absent family history does not rule out the diagnosis. The incidence is 1: 117,000 births and 1: 40,000 men. However, in cryptogenic stroke in the young, FD is responsible for 1.2 % (of age less than 55). Inn the database, women have more strokes than men, 2:1 with mean age 43 for women, and 28 for men. Basilar artery diameter is said to be a sensitive measure of FD (Neurology 2009).
Due to skewed organ specific X chromosome inactivation (nonrandom lionization), women may have atypical organ specific presentation, leading to challenges in diagnosis. These may include cardiac, renal and cerebrovascular manifestations. Diagnosis is made by alpha gal activity in leukocytes or plasma, but in women, gene sequencing and linkage studies may be needed, due to heterozygosity.
Acroparesthesias are associated with accumulation glycosphingolipids in DRG and Nerve conductions and EMG's are negative.
Measurement of leukocyte GAL activity is 100 percent sensitive in males but only five percent in women
MRI shows T2 hyperintense signal in frontal and parietal white matter and T1 hyperintensity in pulvinar as well as dolichoectasia. Treatment decreased LV mass and pain but unknown if it helps stroke.
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