METHYLENETETRAHYDROFOLATE REDUCTASE GENE MUTATION IN A 16-YEAR-OLD GIRL WITH COMBINED CENTRAL RETINAL VEIN OCCLUSION/ CILIORETINAL ARTERY OCCLUSION Tina A. Scheufele, MD, Cristiana G. Pieroni, MD, Caroline R. Baumal, MD
Purpose: This case report describes combined central retinal veincilioretinal artery occlusion in a 16-year-old healthy girl. To our knowledge, our patient is the youngest described so for in the MEDLINE literature. Methods: The patient underwent a full history, physical examination, and extensive laboratory studies to determine the potential risk factors leading to her vascular occlusion. Results: Her family history was significant for multiple miscarriages and early cerebrovascular events. Laboratory testing revealed a compound heterozygous mutation (C677T and A1298C) in the methylenetetrahydrofolate reductase (MTHFR) gene and an elevated factor VIII level. As a result of her ocular occlusive event, abnormal hypercoagulable findings, and family history, the hematologist treated her with folate and warfarin. She has had no further ocular or systemic thrombotic events to date. Conclusion: The combination of the compound heterozygous C677TA1298C MTHFR mutation and an elevated factor VIII level may lead to an increased thrombotic tendency and may have resulted in combined central retinal veincilioretinal artery occlusion in an otherwise healthy 16-year-old girl. RETINAL CASES & BRIEF REPORTS 1:134 –137, 2007
From the Department of Ophthalmology, New England Eye Center, Tufts University School of Medicine, Boston, Massachusetts.
Risk factors for combined CRVO/cilioretinal artery occlusion include hypertension, atherosclerosis, diabetes, glaucoma, and hormone replacement therapy.2 In patients younger than 50 years of age, additional associations may include migraine headache, oral contraceptive use, and smoking.1,2 Young patients or those with a family history of thrombosis or spontaneous abortion should undergo a thorough medical evaluation, including blood pressure measurement and laboratory studies for hypercoagulability.3 The most common hematologic abnormalities described in young individuals with CRVO are hyperhomocysteinemia and antiphospholipid antibodies.4 However, most of the time, no medical or laboratory abnormalities are found.2 Some investigators have proposed an inflammatory-mediated process and have treated these patients with systemic steroids, but this has not been proven to be effective.1
A
cilioretinal artery supplies the macula in up to one third of the population. Possible etiologies for combined central retinal vein occlusion (CRVO)/ cilioretinal artery occlusion include hypercoagulable states, atherosclerotic disease, and inflammatory-mediated processes. CRVO may result in reduced anterograde flow through the low-pressure cilioretinal artery. Alternatively, generalized atherosclerosis of the retinal arteries, including the small cilioretinal artery, may compress the adjacent central retinal vein.1 The authors have no proprietary interests relating to this report. Reprint requests: Caroline R. Baumal, MD, New England Eye Center/Tufts University School of Medicine, 750 Washington Street, Box 450, Boston, MA 02111; e-mail: [email protected]
134
135
MTHFR MUTATION, VASCULAR OCCLUSION
We describe combined CRVO/cilioretinal artery occlusion in a healthy 16-year-old girl (who to our knowledge is the youngest described person to date). Extensive risk factor evaluation of this individual revealed two mutations of the methylenetetrahydrofolate reductase (MTHFR) gene, as well as a mildly elevated factor VIII level. The hypothetical association of these laboratory abnormalities with her vascular occlusion and the widespread implications of these findings are discussed. Case Report A 16-year-old Caucasian girl was referred for evaluation of a relative paracentral scotoma in the left eye that was noted upon awaking 1 week before presentation. Her medical history included remote oral contraceptive and isotretinoin use for a 6-month period over 2 years before presentation. At presentation, she was taking no medications and denied tobacco use. She had undergone bilateral strabismus surgery at 18 months of age. Her family history was significant for multiple miscarriages on her mother’s side and three generations of maternal grandparents who had cerebrovascular accidents in their 50s. Both her father and her brother have thalassemia minor, but her hemoglobin level determined by protein electrophoresis was normal. Visual acuity was 20/20 in each eye without correction. Intraocular pressure was 19 mmHg bilaterally. There was no relative afferent pupillary defect. Amsler grid testing revealed a blurred area superior to fixation in the left eye. Findings of slit-lamp examination were normal. Results of dilated funduscopic examination of the right eye were normal (Fig. 1A). The left eye had an area of retinal whitening in the inferior macula, as well as mildly dilated, tortuous veins, and mild disk edema with superficial disk hemorrhages (Fig. 1B). The clinical appearance was suggestive of combined CRVO/cilioretinal artery occlusion. Fluorescein angiography confirmed the inferior macular location of a cilioretinal artery, which filled during the choroidal flush (Fig. 2A). The arteriovenous transit time was prolonged at 26 seconds. There was mildly delayed venous filling and emptying (Fig. 2B). The optic disk stained late without leakage. Extensive hematologic testing revealed that she carried the compound heterozygous mutation (C677T and A1298C) for the MTHFR gene. Her mother was subsequently found to carry the same gene mutation. The fasting homocysteine level was 8.8 mol/L, which was in the upper range of normal (⬍10.4 mol/L). She also had a persistently elevated factor VIII level measured on three occasions over a 4-month period (164%, 183%, and 174%; reference range, 50 –150%). Results of the remainder of the laboratory studies were normal, including complete blood cell count, prothrombin time, partial thromboplastin time, basic blood chemistry, erythrocyte sedimentation rate, liver function tests, proteins C and S, antinuclear and anticardiolipin antibodies, lupuslike anticoagulant, thyroid function tests, serum protein electrophoresis, angiotensin-converting enzyme, antineutrophil cytoplasmic antibodies, antithrombin III, activated protein C resistance, Russell viper venom time, fibrinogen, von Willebrand factor, and prothrombin G20210A gene mutation. Blood pressure, electrocardiography, echocardiography, computed tomography, magnetic resonance imaging, and magnetic resonance angiography findings were normal. Results of B-hCG pregnancy testing were negative. At the recommendation of the hematology service, she was
Fig. 1. Red-free photographs of the right eye (A) and the left eye (B). In the left eye, there is an area of retinal whitening in the inferior macula, dilated and tortuous veins, and mild disk edema with nerve fiber layer hemorrhages.
treated with subcutaneous enoxaparin sodium (Lovenox威) at presentation. This treatment was changed to oral warfarin indefinitely based on her potential thrombotic risk, and she did not had any further thrombotic episodes in 12 months of follow-up. When her MTHFR mutation was identified, she was also prescribed a multivitamin and folate. The homocysteine level declined to 7.5 mol/L. The retinal signs of combined CRVO/cilioretinal artery occlusion resolved over subsequent weeks, but the paracentral scotoma persisted unchanged.
Discussion Combined CRVO/cilioretinal artery occlusion occurs rarely in adolescents and young adults. Cardiovascular disease and atherosclerosis, the most common risk factors in an older population, are less likely in younger patients, who more often have an associated hypercoagulable state. Lahey et al4 found that 27% of CRVO patients younger than 56 years of age had one or more inherited or acquired conditions
136
RETINAL CASES & BRIEF REPORTSℜ
Fig. 2. A, The inferior macula is supplied by a large cilioretinal artery (arrow), which fills early, during the choroidal flush. Occlusion of this cilioretinal artery, which has now become reperfused, resulted in retinal ischemia of the inferior macula. B, Middle-phase fluorescein angiogram shows mildly delayed venous filling.
associated with hypercoagulability. The retinal circulation may be more sensitive to thrombotic events than the systemic circulation because it is a low-flow system and the capillary beds connecting arterioles to venules are not interconnected. This anatomy leads to watershed zones and a lack of collateral circulation. The enzyme MTHFR is one of the main regulators of homocysteine metabolism. It catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which transfers its methyl group to homocysteine to form methionine.5 The most commonly recognized MTHFR gene mutation, the C677T mutation, leads to decreased enzyme activity, resulting in buildup of homocysteine, especially when serum folate levels are low.6 Homozygosity for C677T has recently been recognized as a risk factor for systemic thrombosis associated with cerebrovascular dis-
●
2007
●
VOLUME 1
●
NUMBER 3
ease, coronary artery disease, deep venous thrombosis, and spontaneous abortion.7 Ocular associations include CRVO, central retinal artery occlusion, and nonarteritic ischemic optic neuropathy.6 Most published reports attribute the hypercoagulability associated with MTHFR mutations to the coexisting hyperhomocysteinemia. However, a recent analysis of patients with coronary artery disease showed that increased plasma homocysteine levels were only significant when found in association with the C677T mutation8; in patients who were not homozygous for C677T, the homocysteine levels did not correlate with coronary artery disease. This finding suggests that C667T may be an independent risk factor for coronary artery disease.8 The A1298C MTHFR mutation, in the homozygous or heterozygous state, affects the regulatory properties of the enzyme, resulting in decreased enzyme activity in vitro.9 Often, homocysteine levels are normal.9 A recent case-controlled study documented the association between A1298C mutations and early-onset coronary artery disease in patients with normal homocysteine, folic acid, and vitamin B12 levels.9 Thus, A1298C mutations may also represent an independent risk factor for thrombosis. Other known risk factors for venous thrombosis include factor V Leiden mutation, prothrombin G20210A mutation, and elevated factor VIII levels. Factor VIII levels of ⬎150% (150 U/dL) have been associated with an increased risk of venous thromboembolism, which may necessitate chronic warfarin therapy.7 To our knowledge, elevated factor VIII levels have not been previously described in patients with ocular thrombotic events. When two or more genetic abnormalities leading to hypercoagulability are present in the same individual, the risk of thrombosis may be greater than if only one is present. For example, when the C677T MTHFR mutation and the factor V Leiden mutation occur together, the risk of venous thrombosis is higher than when they occur alone.10 We propose that the combination of the compound heterozygous C677T/A1298C MTHFR mutation and elevated factor VIII levels led to an increased thrombotic tendency resulting in the combined CRVO/cilioretinal artery occlusion in this young individual. Because homocysteine levels may be normal in the presence of the C677T/A1298C MTHFR mutation, testing for the genetic polymorphisms of the MTHFR gene may be more sensitive than relying on the plasma homocysteine level alone as a marker of hypercoagulability. Our knowledge of genetic factors that predispose patients to thrombosis continues to expand. In this case, testing for polymorphisms of the MTHFR gene
137
MTHFR MUTATION, VASCULAR OCCLUSION
and for factor VIII levels identified a genetic predisposition in a 16-year-old girl with combined CRVO/ cilioretinal artery occlusion. Patients with compound heterozygous MTHFR mutations may benefit from folate therapy, and any patient with a significant thrombotic tendency may require long-term anticoagulation. Key words: A1298C, C677T, cilioretinal artery occlusion, central retinal vein occlusion, factor VIII, homocysteine, hypercoagulability, methylenetetrahydrofolate reductase gene mutation, methylenetetrahydrofolate reductase.
5.
6.
7. 8.
References 1.
2. 3. 4.
Keyser BJ, Duker JS, Brown GC, et al. Combined central retinal vein occlusion and cilioretinal artery occlusion associated with prolonged retinal arterial filling. Am J Ophthalmol 1994;117:308–313. McLeod D, Ring CP. Cilio-retinal infarction after retinal vein occlusion. Br J Ophthalmol 1976;60:419–426. Fong ACO, Schatz H. Central retinal vein occlusion in young adults. Surv Ophthalmol 1993;37:393–417. Lahey JM, Tunc M, Kearney J. Laboratory evaluation of
9.
10.
hypercoagulable states in patients with central retinal vein occlusion who are less than 56 years of age. Ophthalmology 2002;109:126–131. Hanson NQ, Aras O, Yang F, Tsai MY. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: incidence and effect of combined genotypes on plasma fasting and post-methionine load homocysteine in vascular disease. Clin Chem 2001;47:661–666. Kifley CB, Wong TY, Mitchell P. Homocysteine and retinal vein occlusion: a population-based study. Am J Ophthalmol 2005;139:181–182. Thomas RH. Hypercoagulability syndromes. Arch Intern Med 2001;161:2433–2439. Mager A, Koren-Morag N, Shohat M, et al. Family history, plasma homocysteine, and age at onset of symptoms of myocardial ischemia in patients with different methylenetetrahydrofolate reductase genotypes. Am J Cardiol 2005;95: 1420–1424. Szczeklik A, Sanak M, Jankowski M, et al. Mutation A1298C of methylenetetrahydrofolate reductase: risk for early coronary disease not associated with hyperhomocysteinemia. Am J Med Genet 2001;101:36–39. Keijzer MD, den Heijer M, Blom HJ, et al. Interaction between hyperhomocysteinemia, mutated methylenetetrahydrofolate reductase (MTHFR) and inherited thrombophilic factors in recurrent venous thrombosis. Thromb Haemost 2002;88:723–728.
Purpose: This case report describes combined central retinal veincilioretinal artery occlusion in a 16-year-old healthy girl. To our knowledge, our patient is the youngest described so for in the MEDLINE literature. Methods: The patient underwent a full history, physical examination, and extensive laboratory studies to determine the potential risk factors leading to her vascular occlusion. Results: Her family history was significant for multiple miscarriages and early cerebrovascular events. Laboratory testing revealed a compound heterozygous mutation (C677T and A1298C) in the methylenetetrahydrofolate reductase (MTHFR) gene and an elevated factor VIII level. As a result of her ocular occlusive event, abnormal hypercoagulable findings, and family history, the hematologist treated her with folate and warfarin. She has had no further ocular or systemic thrombotic events to date. Conclusion: The combination of the compound heterozygous C677TA1298C MTHFR mutation and an elevated factor VIII level may lead to an increased thrombotic tendency and may have resulted in combined central retinal veincilioretinal artery occlusion in an otherwise healthy 16-year-old girl. RETINAL CASES & BRIEF REPORTS 1:134 –137, 2007
From the Department of Ophthalmology, New England Eye Center, Tufts University School of Medicine, Boston, Massachusetts.
Risk factors for combined CRVO/cilioretinal artery occlusion include hypertension, atherosclerosis, diabetes, glaucoma, and hormone replacement therapy.2 In patients younger than 50 years of age, additional associations may include migraine headache, oral contraceptive use, and smoking.1,2 Young patients or those with a family history of thrombosis or spontaneous abortion should undergo a thorough medical evaluation, including blood pressure measurement and laboratory studies for hypercoagulability.3 The most common hematologic abnormalities described in young individuals with CRVO are hyperhomocysteinemia and antiphospholipid antibodies.4 However, most of the time, no medical or laboratory abnormalities are found.2 Some investigators have proposed an inflammatory-mediated process and have treated these patients with systemic steroids, but this has not been proven to be effective.1
A
cilioretinal artery supplies the macula in up to one third of the population. Possible etiologies for combined central retinal vein occlusion (CRVO)/ cilioretinal artery occlusion include hypercoagulable states, atherosclerotic disease, and inflammatory-mediated processes. CRVO may result in reduced anterograde flow through the low-pressure cilioretinal artery. Alternatively, generalized atherosclerosis of the retinal arteries, including the small cilioretinal artery, may compress the adjacent central retinal vein.1 The authors have no proprietary interests relating to this report. Reprint requests: Caroline R. Baumal, MD, New England Eye Center/Tufts University School of Medicine, 750 Washington Street, Box 450, Boston, MA 02111; e-mail: [email protected]
134
135
MTHFR MUTATION, VASCULAR OCCLUSION
We describe combined CRVO/cilioretinal artery occlusion in a healthy 16-year-old girl (who to our knowledge is the youngest described person to date). Extensive risk factor evaluation of this individual revealed two mutations of the methylenetetrahydrofolate reductase (MTHFR) gene, as well as a mildly elevated factor VIII level. The hypothetical association of these laboratory abnormalities with her vascular occlusion and the widespread implications of these findings are discussed. Case Report A 16-year-old Caucasian girl was referred for evaluation of a relative paracentral scotoma in the left eye that was noted upon awaking 1 week before presentation. Her medical history included remote oral contraceptive and isotretinoin use for a 6-month period over 2 years before presentation. At presentation, she was taking no medications and denied tobacco use. She had undergone bilateral strabismus surgery at 18 months of age. Her family history was significant for multiple miscarriages on her mother’s side and three generations of maternal grandparents who had cerebrovascular accidents in their 50s. Both her father and her brother have thalassemia minor, but her hemoglobin level determined by protein electrophoresis was normal. Visual acuity was 20/20 in each eye without correction. Intraocular pressure was 19 mmHg bilaterally. There was no relative afferent pupillary defect. Amsler grid testing revealed a blurred area superior to fixation in the left eye. Findings of slit-lamp examination were normal. Results of dilated funduscopic examination of the right eye were normal (Fig. 1A). The left eye had an area of retinal whitening in the inferior macula, as well as mildly dilated, tortuous veins, and mild disk edema with superficial disk hemorrhages (Fig. 1B). The clinical appearance was suggestive of combined CRVO/cilioretinal artery occlusion. Fluorescein angiography confirmed the inferior macular location of a cilioretinal artery, which filled during the choroidal flush (Fig. 2A). The arteriovenous transit time was prolonged at 26 seconds. There was mildly delayed venous filling and emptying (Fig. 2B). The optic disk stained late without leakage. Extensive hematologic testing revealed that she carried the compound heterozygous mutation (C677T and A1298C) for the MTHFR gene. Her mother was subsequently found to carry the same gene mutation. The fasting homocysteine level was 8.8 mol/L, which was in the upper range of normal (⬍10.4 mol/L). She also had a persistently elevated factor VIII level measured on three occasions over a 4-month period (164%, 183%, and 174%; reference range, 50 –150%). Results of the remainder of the laboratory studies were normal, including complete blood cell count, prothrombin time, partial thromboplastin time, basic blood chemistry, erythrocyte sedimentation rate, liver function tests, proteins C and S, antinuclear and anticardiolipin antibodies, lupuslike anticoagulant, thyroid function tests, serum protein electrophoresis, angiotensin-converting enzyme, antineutrophil cytoplasmic antibodies, antithrombin III, activated protein C resistance, Russell viper venom time, fibrinogen, von Willebrand factor, and prothrombin G20210A gene mutation. Blood pressure, electrocardiography, echocardiography, computed tomography, magnetic resonance imaging, and magnetic resonance angiography findings were normal. Results of B-hCG pregnancy testing were negative. At the recommendation of the hematology service, she was
Fig. 1. Red-free photographs of the right eye (A) and the left eye (B). In the left eye, there is an area of retinal whitening in the inferior macula, dilated and tortuous veins, and mild disk edema with nerve fiber layer hemorrhages.
treated with subcutaneous enoxaparin sodium (Lovenox威) at presentation. This treatment was changed to oral warfarin indefinitely based on her potential thrombotic risk, and she did not had any further thrombotic episodes in 12 months of follow-up. When her MTHFR mutation was identified, she was also prescribed a multivitamin and folate. The homocysteine level declined to 7.5 mol/L. The retinal signs of combined CRVO/cilioretinal artery occlusion resolved over subsequent weeks, but the paracentral scotoma persisted unchanged.
Discussion Combined CRVO/cilioretinal artery occlusion occurs rarely in adolescents and young adults. Cardiovascular disease and atherosclerosis, the most common risk factors in an older population, are less likely in younger patients, who more often have an associated hypercoagulable state. Lahey et al4 found that 27% of CRVO patients younger than 56 years of age had one or more inherited or acquired conditions
136
RETINAL CASES & BRIEF REPORTSℜ
Fig. 2. A, The inferior macula is supplied by a large cilioretinal artery (arrow), which fills early, during the choroidal flush. Occlusion of this cilioretinal artery, which has now become reperfused, resulted in retinal ischemia of the inferior macula. B, Middle-phase fluorescein angiogram shows mildly delayed venous filling.
associated with hypercoagulability. The retinal circulation may be more sensitive to thrombotic events than the systemic circulation because it is a low-flow system and the capillary beds connecting arterioles to venules are not interconnected. This anatomy leads to watershed zones and a lack of collateral circulation. The enzyme MTHFR is one of the main regulators of homocysteine metabolism. It catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which transfers its methyl group to homocysteine to form methionine.5 The most commonly recognized MTHFR gene mutation, the C677T mutation, leads to decreased enzyme activity, resulting in buildup of homocysteine, especially when serum folate levels are low.6 Homozygosity for C677T has recently been recognized as a risk factor for systemic thrombosis associated with cerebrovascular dis-
●
2007
●
VOLUME 1
●
NUMBER 3
ease, coronary artery disease, deep venous thrombosis, and spontaneous abortion.7 Ocular associations include CRVO, central retinal artery occlusion, and nonarteritic ischemic optic neuropathy.6 Most published reports attribute the hypercoagulability associated with MTHFR mutations to the coexisting hyperhomocysteinemia. However, a recent analysis of patients with coronary artery disease showed that increased plasma homocysteine levels were only significant when found in association with the C677T mutation8; in patients who were not homozygous for C677T, the homocysteine levels did not correlate with coronary artery disease. This finding suggests that C667T may be an independent risk factor for coronary artery disease.8 The A1298C MTHFR mutation, in the homozygous or heterozygous state, affects the regulatory properties of the enzyme, resulting in decreased enzyme activity in vitro.9 Often, homocysteine levels are normal.9 A recent case-controlled study documented the association between A1298C mutations and early-onset coronary artery disease in patients with normal homocysteine, folic acid, and vitamin B12 levels.9 Thus, A1298C mutations may also represent an independent risk factor for thrombosis. Other known risk factors for venous thrombosis include factor V Leiden mutation, prothrombin G20210A mutation, and elevated factor VIII levels. Factor VIII levels of ⬎150% (150 U/dL) have been associated with an increased risk of venous thromboembolism, which may necessitate chronic warfarin therapy.7 To our knowledge, elevated factor VIII levels have not been previously described in patients with ocular thrombotic events. When two or more genetic abnormalities leading to hypercoagulability are present in the same individual, the risk of thrombosis may be greater than if only one is present. For example, when the C677T MTHFR mutation and the factor V Leiden mutation occur together, the risk of venous thrombosis is higher than when they occur alone.10 We propose that the combination of the compound heterozygous C677T/A1298C MTHFR mutation and elevated factor VIII levels led to an increased thrombotic tendency resulting in the combined CRVO/cilioretinal artery occlusion in this young individual. Because homocysteine levels may be normal in the presence of the C677T/A1298C MTHFR mutation, testing for the genetic polymorphisms of the MTHFR gene may be more sensitive than relying on the plasma homocysteine level alone as a marker of hypercoagulability. Our knowledge of genetic factors that predispose patients to thrombosis continues to expand. In this case, testing for polymorphisms of the MTHFR gene
137
MTHFR MUTATION, VASCULAR OCCLUSION
and for factor VIII levels identified a genetic predisposition in a 16-year-old girl with combined CRVO/ cilioretinal artery occlusion. Patients with compound heterozygous MTHFR mutations may benefit from folate therapy, and any patient with a significant thrombotic tendency may require long-term anticoagulation. Key words: A1298C, C677T, cilioretinal artery occlusion, central retinal vein occlusion, factor VIII, homocysteine, hypercoagulability, methylenetetrahydrofolate reductase gene mutation, methylenetetrahydrofolate reductase.
5.
6.
7. 8.
References 1.
2. 3. 4.
Keyser BJ, Duker JS, Brown GC, et al. Combined central retinal vein occlusion and cilioretinal artery occlusion associated with prolonged retinal arterial filling. Am J Ophthalmol 1994;117:308–313. McLeod D, Ring CP. Cilio-retinal infarction after retinal vein occlusion. Br J Ophthalmol 1976;60:419–426. Fong ACO, Schatz H. Central retinal vein occlusion in young adults. Surv Ophthalmol 1993;37:393–417. Lahey JM, Tunc M, Kearney J. Laboratory evaluation of
9.
10.
hypercoagulable states in patients with central retinal vein occlusion who are less than 56 years of age. Ophthalmology 2002;109:126–131. Hanson NQ, Aras O, Yang F, Tsai MY. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: incidence and effect of combined genotypes on plasma fasting and post-methionine load homocysteine in vascular disease. Clin Chem 2001;47:661–666. Kifley CB, Wong TY, Mitchell P. Homocysteine and retinal vein occlusion: a population-based study. Am J Ophthalmol 2005;139:181–182. Thomas RH. Hypercoagulability syndromes. Arch Intern Med 2001;161:2433–2439. Mager A, Koren-Morag N, Shohat M, et al. Family history, plasma homocysteine, and age at onset of symptoms of myocardial ischemia in patients with different methylenetetrahydrofolate reductase genotypes. Am J Cardiol 2005;95: 1420–1424. Szczeklik A, Sanak M, Jankowski M, et al. Mutation A1298C of methylenetetrahydrofolate reductase: risk for early coronary disease not associated with hyperhomocysteinemia. Am J Med Genet 2001;101:36–39. Keijzer MD, den Heijer M, Blom HJ, et al. Interaction between hyperhomocysteinemia, mutated methylenetetrahydrofolate reductase (MTHFR) and inherited thrombophilic factors in recurrent venous thrombosis. Thromb Haemost 2002;88:723–728.
![[Cilioretinal artery occlusion in hemochromatosis].](/assets/img/hold.png)
