S E C T I O N
6 Disorders of Lipid Metabolism
78 FABRY DISEASE 272.7
(Angiokeratoma Corporis Diffusum
Universale, Anderson–Fabry Disease,
Glycolipid Lipidosis)
Koji Hirano, MD, PhD
Aichi, Japan
ETIOLOGY/INCIDENCE
Fabry disease is an X-linked inborn error of glycosphingolipid metabolism caused by a deficiency of the lysosomal hydrolase α-galactosidase A (α-Gal A). Typically, in affected males who have little if any residual α-Gal A activity, the first clinical manifestations occur in childhood when episodes of severe pain in the extremities (i.e. acroparesthesias), hypohidrosis, corneal and lenticular changes, and characteristic skin lesions (i.e. angiokeratomas) are noted. With advancing age, progressive kidney, cardiovascular, and cerebrovascular disease develop and are the major causes of mortality.
The complete clinical manifestations of Fabry disease occur only in males (hemizygotes); in heterozygous female carriers, Fabry disease is usually limited to the eyes, and life expectancy is near normal because renal and cerebrovascular involvement is uncommon.
COURSE/PROGNOSIS
Systemic
Fabry disease is not a symptomatic disease of early childhood but may be diagnosed before 10 years of age. Children may complain of:
●Pain in the extremities;
●Anhidrosis;
●Which can give rise to fevers.
With progression, there are complaints of:
●Easy fatigability, due to glycosphingolipids accumulating in skeletal muscle;
●Psychologic disturbances, due to decreased blood flow from thrombus formation in the brain;
●Multiple wine-red angiokeratomas involve the trunk, fingers, penis, lips and tongue; these lesions may be distributed in the swim-trunk region in hemizygous adults;
●Female carriers (heterozygotes) are involved to a lesser extent and usually develop symptoms at a later age; in hemizygous males, death usually occurs before the fourth or fifth decade due to renal or cardiac failure or cerebrovascular disease.
DIAGNOSIS
Clinical signs and symptoms
Ocular
Ocular findings in Fabry disease are often subtle but can result in compromised vision in several ways; the abnormal accumulation of intracytoplasmic lipid occurs throughout endothelial, perithelial, and smooth muscle cells of the eye. The epithelium of the conjunctiva, cornea, and lens can be affected, as well as the vasculature of the retina. Characteristic ocular symptoms include:
●Cornea verticillata: fine, whorl-like superficial corneal opacities that affect both males and females; on slit-lamp examination, golden-brown pigmentation is visible in the corneal epithelium.
Once thought to be a separate entity and termed the familial corneal dystrophy of Fleischer–Gruber, this vortex pattern is known to be a sign of Fabry disease and resembles the corneal changes found after the chronic ingestion of chloroquine, amiodarone, and other agents that cause a drug-induced lipidosis.
●Dilated, sausage-shaped conjunctival blood vessels (telangiectasia).
●Two specific types of cataracts occur in patients with Fabry disease.
●Granular anterior subcapsular deposits.
●An unusual spoke-like posterior subcapsular opacity that is best seen through retroillumination (termed Fabry cataract).
●Internuclear ophthalmoplegia can affect the extraocular muscles.
●Edema in the area of the optic disk, periorbitally, or both is possible.
●Tortuous retinal vessels common.
●Decreased visual acuity results primarily from occlusive retinal vascular disease or complications of hypertensive retinopathy.
●Profound vision loss from central retinal artery occlusion is sometimes the initial presenting symptom.
Laboratory findings
Affected males have the following:
●A reduced a-galactosidase A level in plasma, serum, leukocytes, tears, and skin fibroblasts;
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Metabolism6 SECTIONLipid of Disorders •
●Elevated trihexosyl ceramide level in urine, plasma and skin fibroblasts;
●Abnormal intracytoplasmic and intracellular lipid deposits.
Ultrastructural examination of these inclusions in epithelial cells of the cornea, conjunctiva, and lens reveals that they consist of a single membrane surrounding concentrically arranged membranous lamellae; however; the myelin-like structures are not pathognomonic of Fabry disease.
The histopathologic basis for the whorl-like corneal pattern has been the subject of debate; increasing evidence indicates that the pattern is due to a combination of:
●Lysosomal granules in the epithelium (which have been detected even in fetal eyes);
●Duplication of the basal lamina of the corneal epithelium.
TREATMENT
Systemic
The intravenous administration of purified placental a-galac- tosidase has been investigated but offers little promise. Phlebotomy does not alter plasma or urinary levels of ceramide trihexoside, and plasmapheresis is ineffective in treating the acroparesthesia of Fabry disease.
Treatment of the pain associated with the disease is symptomatic and has been used with varying levels of success.
●Diphenylhydantoin 20 mg/24 hour; or
●Carbamazepine 200 mg/hour.
Surgical
No satisfactory treatment is available. Renal transplantation has been performed for amelioration of chronic uremia, and cardiac transplantation has been performed for the cardiovascular aspects of the disease; however, recurrence of the storage disease is common in the allografts.
The disproportionately high incidence of sepsis in some patients may be due to the deficient immunologic function of lipid-laden leukocytes.
Hemodialysis remains an alternative mode of therapy for uremia but does not alter the accompanying cerebrovascular or cardiovascular impairment and simply postpones renal failure.
Recently, attention has been given to modeling the disease in animals to permit exploration of various therapies; gene manipulation (especially at the carboxyl terminus) has begun to show some promise for the future.
COMMENTS
The diagnosis of Fabry disease is easily missed, especially in female carriers. The ophthalmologist is in an excellent position to make the diagnosis because the ocular changes (corneal verticillata and spoke-like cataracts) are among the earliest and most consistent signs. Corneal changes occur in about 90% of affected male patients and may be the only ocular sign in female carriers. The posterior spoke-like cataracts may be pathognomonic of Fabry disease, and the whorl-like corneal opacities are highly indicative of the disease, especially if there has been no previous history of consumption of drugs such as chloroquine.
REFERENCES
Cantor WJ, Daly P, Iwanochko M, et al: Cardiac transplantation for Fabry disease. Can J Cardiol 14:81–84, 1998.
Dantas MA, Fonseca RA, Kaga T, et al: Retinal and choroidal vascular changes in heterozygous Fabry disease. Retina 21:87–90, 2001.
Hirano K, Murata K, Miyagawa A, et al: Histopathologic findings of cornea verticillata in woman heterozygous for Fabry’s disease. Cornea 20:233– 236, 2001.
Kleijer WJ, Hussaarts-Odijk LM, Sachs ES, et al: Prenatal diagnosis of Fabry’s disease by direct analysis of chorionic villi. Prenat Diagn 7:283– 287, 1987.
Mastropasqua L, Nubile M, Lanzini M, et al: Corneal and conjunctival manifestations in Fabry disease: in vivo confocal microscopy study. Am J Ophthalmol 14:709–718, 2006.
Miyamura N, Araki E, Matsuda K, et al: A carboxy-terminal truncation of human alpha-galactosidase A in a heterozygous female with Fabry disease and modification of the enzymatic activity by the carboxyterminal domain: Increased, reduced, or absent enzyme activity depending on number of amino acid residues deleted. J Clin Invest 98:1809–1817, 1996.
Ohshima T, Murray GJ, Swaim WD, et al: Alpha-galactosidase A deficient mice: a model of Fabry disease. Proc Natl Acad Sci USA 94:2540–2544, 1997.
Rodriguez FH, Hoffmann EO, Ordinario AT: Fabry’s disease in a heterozygous woman. Arch Pathol Lab Med 109:89–91, 1985.
Sakuraba H, Igarashi T, Shibata T, et al: Effects of vitamin E and ticlopidine on platelet aggregation in Fabry’s disease. Clin Genet 31:349–354, 1987.
Sugimoto Y, Aksentijevich I, Murray GJ, et al: Retroviral coexpression of a multidrug resistance gene (MDR1) and human alpha-galactosidase A for gene therapy of Fabry disease. Hum Gene Ther 6:905–915, 1995.
Tsutsumi A, Uchida Y, Kanai T, et al: Corneal findings in a foetus with Fabry’s disease. Acta Ophthalmol 62:923–931, 1984.
PRECAUTIONS
Genetic counseling and recognition of female carriers are important. The pattern of inheritance is like that of all X-linked recessive disorders: there is no father-to-son transmission, but all daughters of an affected male will be carriers (heterozygotes), and half of the sons of affected daughters will also have Fabry disease. Identification of all female carriers has been difficult because 25% to 40% of suspected heterozygotes may have normal levels of a-galactosidase. Recent studies, however, have shown that carriers can be identified in more than 90% of cases through the use of multiple biochemical tests.
79 HYPERLIPOPROTEINEMIA 272.4
Ahmad M. Mansour, MD
Beirut, Lebanon
Mays El-Dairi, MD
Beirut, Lebanon
ETIOLOGY
Hyperlipoproteinemia is a metabolic disorder characterized by abnormally elevated plasma total cholesterol, low density lipoprotein-cholesterol, triglyceride, or apolipoprotein-B, or
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abnormally low high density lipoprotein (HDL)-cholesterol or apolipoprotein-A1.
DIAGNOSIS
Clinical signs and symptoms
Clinical manifestations are caused by deposition of lipids at various tendons, the vascular system, and the eye.
Ocular
Eye manifestations include corneal arcus, lipemia retinalis and xanthelasma.
●Corneal arcus is accumulation of lipid in peripheral cornea as part of ageing. Juvenile arcus is associated with familial hypercholesterolemia. Presenile corneal arcus is associated with types II-V hyperlipidemia. Unilateral arcus may be a sign of carotid artery disease or ocular hypotony.
Laboratory findings
A standard serum lipid profile consists of total cholesterol, triglycerides, and HDL-cholesterol. Lipoprotein analysis should be performed after 12 hours of fasting to minimize postprandial hyperlipidemia. Lipoprotein electrophoresis is expensive and is unnecessary for the diagnosis of most lipid disorders.
TREATMENT
Systemic
Weight reduction and diet low in saturated fat and cholesterol are advocated. Extreme fat and cholesterol restriction has been achieved with vegetarian diets. Alcohol and estrogen should be avoided in certain types of hyperlipoproteinemias. Aerobic exercise improves insulin sensitivity, HDL-C concentrations and reduces coronary artery disease risk. Lipid lowering drugs include fibric acid derivatives (clofibrate, gemfibrozil, fenofi-
●Xanthomas are localized infiltrates of lipid containing hisbrate), niacin, omega-3 fatty acids, and statins (atorvastatin,
tiocytic foam cells. There are five types. Tendinous xanthoma (xanthoma IA) is associated with xanthelasma and beta-lipoprotein disturbance. Cerebrotendinous xanthomatosis (xanthoma IB) is associated with bilateral juvenile cataracts, xanthelasma, and elevated cholestanol level. Planar xanthoma (xanthoma II) is associated xanthelasma and hyperlipoproteinemia. Tuberous xanthoma (xanthoma III) is associated with broad beta disease. Eruptive xanthoma (xanthoma IV) is associated with lipemia retinalis and hypertriglyceridemia. Disseminated xanthoma (xanthoma V) is associated with corneal and scleral xanthoma with normal lipid profile.
simvastatin, rosuvastatin, cerivastatin, pravastatin, lovastatin, fluvastatin).
Surgical
Ileal bypass or plasmapheresis are performed in selected cases of familial hypercholesterolemia. Liver transplanstation is rarely done in familial hypercholesterolemia.
COMMENTS
Patients with lipid disorder have a higher risk for occlusive
●Lipemia retinalis is caused by elevation of serum triglycervascular disease which is decreased by healthy diet, desirable
ide level above 2500 mg/dL. This occurs in types I and V hyperlipoproteinemia and more often is associated with diabetes mellitus, alcoholism, hypothyroidism, nephrotic syndrome, and biliary obstruction. In mild lipemia retinalis (triglyceride 2500–3500 mg/dL), only peripheral vessels have a creamy tint. In moderate lipemia retinalis (triglyceride 3500–5000 mg/dL), there is posterior extension of the creamy color. In severe lipemia retinalis (triglyceride >5000 mg/dL), there is whitening of all retinal vessels with inability to differentiate arteries from veins. Conjunctival and iris vessels might be creamy providing an easy slit-lamp follow-up for triglyceride level. Complications associated with lipemia retinalis include eruptive xanthoma, hepatosplenomegaly, acute pancreatitis, and atheroma.
weight, and regular exercise.
REFERENCES
Barchiesi BJ, Eckel RH, Ellis PP: The cornea and disorders of lipid metabolism. Surv Ophthalmol 36:1–22, 1991.
Crispin S: Ocular lipid deposition and hyperlipoproteinaemia. Prog Retin Eye Res 21:169–224, 2002.
Mansour AM, Raimer SS: Cerebrotendinous xanthomatosis and other xanthomas. In: Gold D, Weingeist TA, eds: The eye in systemic disease. Philadelphia: Lippincott, 1990:337–340.
Uwaydat S, Mansour AM: Infantile lipemia retinalis et conjunctivalis. J Ped Ophthalmol Strab 7:47–49, 2000.
Hyperlipoproteinemia • 79 CHAPTER
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