Homocystinuria

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Article initiated by:
Michael A. Puente, MD, Catherine Gilbert
All contributors:
Grace Zhou, Alpa S. Patel, M.D., Derek W DelMonte, MD, Bayan Al Othman, MD, Kourtney Houser, MD, S. Grace Prakalapakorn, MD, MPH, Michael A. Puente, MD, Amanda Ely, M.D., Osama Al Deyabat, MBBS
Assigned editor:
Amanda Ely, M.D., Joseph Christenbury, MD
Review:
Assigned status Up to Date
 by Bayan Al Othman, MD on October 1, 2024.


Homocystinuria is an autosomal recessive inborn error of amino acid metabolism that results in inability to break down homocysteine to cystathionine due to deficiency in the enzyme cystathionine beta-synthase. Homocysteine is toxic to cells, so its accumulation can lead to abnormalities in the eye, skeletal system, vascular system, and central nervous system.[1][2] Common clinical manifestations include ectopia lentis, developmental delay, marfanoid habitus, and thromboembolism.[2][3]

Epidemiology

The worldwide prevalence of homocystinuria is estimated to be 0.82:100,000 according to clinical records and 1.09:100,000 by neonatal screening. Minimum worldwide incidence is estimated to be ~0.38:100,000 and the incidence has been shown to be higher in non-Finnish Europeans (~0.72:100,000) and Latin Americans (~0.45:100,000) and lower in Africans (~0.20:100,000) and Asians (~0.02:100,000).[4]

Genetics

Homocystinuria is inherited in an autosomal recessive manner. Barring a new sporadic mutation, each parent must be a carrier and each of their children has 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.[3] Therefore, it is important to test siblings of children who present with homocystinuria.[5]

Cystathionine beta-synthase is a protein coded on chromosome 21 (21q22.3) with 164 pathogenic mutations currently identified, the most common being p.Ile278Thr and p.Gly307Ser, found in exon 8.[3][6] Of these mutations, 67% are missense mutations.[3] Different mutations are associated with variation in the expected phenotype, with some mutations associated with milder, or conversely more severe, disease.[7] Genetic testing can involve confirmation through cystathionine beta-synthase deficiency in cultured fibroblasts[8].

Pathophysiology

The pathophysiology of homocystinuria is not completely understood. Homocysteine is created from methionine and is involved as a key intermediate in various methylation reactions. Homocysteine can be converted into cysteine, a process which requires enzymes along with vitamins B6, B9, and B12, the lack of any of which could lead to hyperhomocysteinemia. The remethylation pathway of homocysteine involves catalyzation by the methionine synthase (MTR) enzyme, which requires vitamin B12 as a cofactor. The methyl group is extracted from 5-Methyl-tetrahydrofolate (5-methyl-THF), which as a result is converted into THF, a derivative of folate. THF is then converted into  5,10-methylene THF by serine hydroxymethyltransferase (SHMT), which is reconverted back to 5-methyl THF by vitamin B2-dependent enzyme methylenetetrahydrofolate reductase (MTHFR). A separate remethylation pathway involves betaine-homocysteine methyltransferase (BHMT). In this process, betaine is demethylated to create dimethylglycine, which can be further metabolized into glycine. Another way homocysteine can be metabolized is via transsulfuration by cystathionine β-synthase (CBS), which is dependent on vitamin B6. Unlike the two former reactions, the transsulfuration pathway involves irreversible degradation into cysteine, an antioxidant and essential compound involved in detoxifying many xenobiotics. The malfunction of any of these steps would lead to elevated homocysteine.

Raised homocysteine concentrations interfere with the cross-linking of sulfonhydryl groups in proteins such as those in elastin.[2] Increased S-adenosylhomocysteine (SAH), a precursor to homocysteine, impairs methylation reactions; and decreased concentrations of cystathionine and cysteine are associated with apoptosis, oxidative stress, and alterations of structural proteins like fibrillin. The alterations to fibrillin and cross-linking modification in elastin may contribute to connective tissue abnormalities and vascular endothelial dysfunction.[1][2] This cross-linking interference is thought to contribute to ectopia lentis and the skeletal abnormalities seen in homocystinuria. The interference between elastin proteins may also cause alterations of the scleral connective tissue. Additionally, the lens zonules of the eye have high cysteine content and are possibly weakened by the reduced level of cysteine.[1]

Risk Factors

The main and most prevalent cause of acquired homocystinuria involves enzyme and cofactor dysfunctions involving defects in remethylation and transsulfuration. Non-genetic hyperhomocysteinemia can be caused by lifestyle factors like cigarette smoking, alcohol consumption, and coffee consumption in addition to medications like methotrexate, nitrous oxide, phenytoin, and carbamazepine[9] [10]. Homocysteine levels naturally increase with age and are higher in males than females[11].

Diagnosis

Systemic Manifestations

High blood homocysteine level is associated with many disease processes, often due to oxidative stress. Individuals with homocystinuria can present with any number of different systemic manifestations. If the skeletal system is affected, they can be described as having “Marfanoid habitus” which includes excessive height, long limbs, scoliosis, and pectus excavatum. The central nervous system is often involved, presenting with developmental delay, intellectual disability, movement disorders, and seizures.[2][3] Elevated homocysteine can damage the endothelial layer of blood vessels, thus it can initiate and worsen atherosclerosis[12] which could potentially lead to amaurosis fugax, which is caused by atherosclerosis of the ipsilateral internal carotid artery[13] . The largest concern is the effects elevated homocysteine has on the vascular system leading to thromboembolic events (stroke, pulmonary embolism, embolus of the iris) that increase the morbidity and mortality of the disease.[14][15][16] Risk of thrombosis is increased during any perioperative period and appropriate precaution should be taken peri-operatively (heparin, aspirin, low-molecular weight dextran, compression stockings, etc.)[17].

Hyperhomocysteinemia is also positively associated with congestive heart failure, serving as a prognostic marker for long-term cardiac events[18], but there still lacks a clear disease mechanism. High blood homocysteine level can also provoke Alzheimer’s disease and acts as a modifiable risk factor for cognitive dysfunction[19].  Moreover, mutations leading to hyperhomocysteinemia, like MTHFR, is implicated in cancers like those of the breast[20], bladder[21], and lung. Birth complications and defects like preeclampsia, spontaneous abortion, neural tube defects, Down’s syndrome, and premature delivery are among the multitude of risk factors in pregnant women[22].

While hyperhomocysteinemia has historically been linked to the pathogenesis of CVD[23], some interventional trials have proven this otherwise, which led to a controversy on homocysteine role in cardiovascular diseases[24]. One explanation to this paradox could be that hyperhomocysteinemia becomes an important risk factor only when its plasma levels are elevated to extremely high levels. Decreasing its levels via supplementation of B vitamins subsequently markedly reduces adverse cardiovascular events[25]. Meanwhile, the protective effects of lowering relatively mild hyperhomocysteinemia has not yet been proven to have significant clinical benefits[26]. Another explanation is that the benefits of reduced homocysteine levels are offset by its damage: the positive influence on the redox state of cells may be offset by concurrent inflammatory effects from unmetabolized folic acid that accumulates when supplemented[27]. Given the unproven benefits and the potential harm that uncontrolled vitamin and mineral supplementation could cause for populations like elderly women, the American Heart Association does not recommend using routine vitamin B supplementation to reduce CVD risk[28].

Ocular Manifestations

Ophthalmic complications include...

  • Ectopia lentis[2][5] Ectopia lentis is the most common ophthalmic complication of homocystinuria, seen in approximately 90% of patients.[16] The prevalence in patients <7 years old is around 70%, rising to 95% in the fifth decade.[1] Classically, lens dislocation is bilateral and inferonasal, but can happen in any direction.[1][2][5][14] Additionally, lens dislocation and subluxation can be seen in several other heritable disorders. Therefore, direction of lens dislocation should not be considered pathognomonic for homocystinuria.[1] Ectopia lentis may be the first and only sign of disease and should be investigated thoroughly as restoration of biochemical control can halt progression of complications.[2] Increased lens mobility and zonular disruption are often age related, thus individuals with complete anterior lens dislocation are often older (10.2 years old).
  • High myopia[2][5]Severe myopia is the second-most common ocular manifestation of homocystinuria.[1][2] The etiology of this myopia may be both axial and lenticular, as patients with homocystinuria often have increased axial length in additional to anterior dislocation of the lens.[29] The severity of myopia varies depending on age of diagnosis and level of control. Patients who are diagnosed at birth, begin treatment before 6 weeks of age, and maintain good control often will be emmetropic or have mild to moderate hyperopia or myopia. Those who are diagnosed within the first 6 weeks of life but do not maintain good homocysteine control are usually highly myopic (> -5D) with progressively worsening myopia. Patients diagnosed later in life usually first present to the ophthalmologist due to lens subluxation or dislocation. These individuals may have severe myopia that can average to approximately -10D.[1][5]
  • Pupillary block glaucoma[2][5]Anterior dislocation can cause an acute pupillary block glaucoma attack and may also traumatize the corneal endothelium, leading to corneal edema, stromal opacification, or bullous keratopathy.[14][16]
  • Open angle glaucoma[30] It is proposed that homocysteine can increase arterial pressure and can contribute to increased ocular perfusion pressure and intraocular pressure, contributing to the development of open-angle glaucoma[30].
  • Retinal detachments.[2][5] [31]
  • NAION[32] Non-arteritic anterior ischemic optic neuropathy (NAION), a result of the optic nerve head’s posterior ciliary artery circulation obstruction, could also be accelerated by the local atherogenesis caused by hyperhomocysteinemia[32].
  • Cataracts[2][14] Elevated exposure to homocysteine increases prevalence of posterior subcapsular cataracts[33].
  • Strabismus[2]
  • Amblyopia[2] Interestingly, in a study by Mulvihill et al., patients who were diagnosed and treated before the age of 6 weeks, even if later poorly controlled, were all able to achieve a visual acuity of 20/40 or better. Whereas <30% of patients with late diagnosis were able to achieve a visual acuity of 20/40 or better.[29]
  • AMD. Another weak association is age-related macular degeneration (AMD)[34]. Several hypotheses, however, include apoptosis of retinal ganglion cells, extracellular matrix alterations, decreased lysyl oxidase activity and oxidative stress[35].
  • Other: Elevated exposure to homocysteine increases prevalence of retinal artery occlusive disease[36], papillophlebitis[37], and cerebral venous sinus thrombosis[38]. Longer diabetic duration and microvascular complications associated with diabetic retinopathy may also be associated with elevated homocysteine[31]. It is still unknown whether the elevated A1C levels, renal dysfunction, and elevated blood pressure associated with diabetes mellitus act independently of homocysteine.


The precise mechanisms for hyperhomocysteinemia related eye disease remain ill defined. Thus, homocysteine may serve as an important biomarker for an assortment of ocular disease processes.

Lab Testing

Homocysteine levels of greater than 15 μmol/L are typically considered elevated[39]. Levels are commonly measured via plasma test, usually during the fasting state or after an oral methionine dose, which is a form of provocative testing[40]. However, the role of methionine loading, with the excess cost, time, and variation among individuals, is still controversial. To prevent false elevated reading of homocysteine from release from red blood cells, an anticoagulant like EDTA should be added into the blood sample and then centrifuged within 30 minutes of collection [41].

The most important tool for homocystinuria diagnosis is newborn screening, which has high sensitivity to detect many inborn errors of metabolism, including homocystinuria.[42] However, patients with a less severe form of the disease that is responsive to pyridoxine may have false-negative newborn screening test results and may present to the ophthalmologist, or other specialist, with ocular or other systemic manifestations.[5] Biochemical features that can be tested for are significantly increased total plasma or urine concentrations of homocysteine and methionine. Additionally, genetic testing can be done and diagnosis confirmed with biallelic pathogenic variants in CBS.[3]

One important scenario during which homocysteine levels should be checked is in bilateral nutritional optic neuropathy[43]. While bilateral nutritional optic neuropathy may have different etiologies involving deficiencies in vitamin B9, B12, B1, B6, or copper, causes may be narrowed down to deficiency in either vitamin B9 or B12 when homocysteine levels are elevated. A distinction between the two can be made when methylmalonic acid levels are elevated, which would indicate a vitamin B12 deficiency.

Differential diagnosis

Several other diseases may present with ectopia lentis but will vary with other clinical features.

  • Ectopia Lentis et pupillae will have also have an ectopic pupil, a flat-appearing iris, and often presents with cataracts.
  • Marfan syndrome will also have marfanoid habitus, but can also present with signficant cardiac concerns. In contrast, individuals with Marfan syndrome will not have intellectual disability or seizures.
  • Weill-Marchesani syndrome will additionally present with microspherophakia, brachydactyly, and joint stiffness.
  • Mutations in methylnetetrahydrofolate reductase (MTHFR), cystathionine beta-synthase (CBS), or methionine synthase (MS).
  • Nutritional deficiencies in vitamins B6, B9, or B12.

Management

Systemic treatment

The primary goal of systemic management is to maintain appropriate levels of homocysteine and to prevent thrombosis. Homocysteine concentrations should be kept below 120 μmol/L. However, given concentration fluctuations and poor compliance, homocysteine levels should aim to be kept below 100 μmol/L.[2] One primary treatment to maintain homocysteine levels is vitamin B6 (pyridoxine) supplementation. Pyridoxine is a cofactor of CBS and is known to stimulate any residual activity of CBS and play a critical role in regulating its activity. Unfortunately, not all patients respond to vitamin B6 treatment and therefore, the treatment is confined to vitamin B6 responsive individuals.[6][44] For those who are not responsive to Pyridoxine, a methionine-restricted diet and folate and vitamin B12 supplementation are used.[3] Betaine, a methyl donor that facilitates the conversion of homocysteine back to methionine, is usually added and can be the major form of treatment.[3][6] Individuals should be monitored regularly for homocysteine levels and complications. Due to increased coagulability and risk for thromboembolism, surgery should be avoided if possible, and females should avoid oral contraceptives.[3] If surgery cannot be avoided, nitrous oxide should be avoided due to its inactivation of methionine synthase causing possible functional disorder of the nervous system.[17] Additionally, physicians should monitor glycemic levels as anesthesia causes alteration in insulin release associated with high levels of methionine leading to hypoglycemia.

Ophthalmologic treatment

Lensectomy is the most common surgical procedure in patients with homocystinuria, often requiring combined vitrectomy due to zonular instability and associated vitreous prolapse. Patients are typically aphakic after surgery, due to zonular instability, and require either glasses or contacts for refractive correction.[14][16] However, the intellectual disability and developmental delay that often accompanies homocystinuria can decrease compliance with aphakic contacts or spectacles, leading to the consideration of implantable intraocular lenses. Options include iris-fixated, scleral fixated, or anterior chamber IOL’s.[45][46]

Acute pupillary block glaucoma due to anterior lens dislocation can initially be treated medically with cycloplegic and IOP-reducing agents and manual relocation. If relapse occurs, surgical interventions should then be considered. A study by Harrison et al., demonstrated that all patients with an anterior lens dislocation ultimately required surgery despite an initial trail of medical treatment. Additionally, laser iridectomy was unsuccessful in preventing lens dislocation into the anterior chamber.[16]

Prognosis

Early diagnosis and management within the first 6 weeks of life significantly reduces the morbidity and mortality of homocystinuria.[3][47] If left untreated, 82% of patients will have ectopia lentis by 10 years of age and 27% will have a clinically detectable thromboembolic event by 15 years old.[5] Half of individuals with untreated homocystinuria will have an event before the age of 30 and one predicted event per 25 years at the time of maximal risk. Vascular events remain the major cause of morbidity and mortality in untreated patients. However, appropriate long-term treatment is effective in reducing the potentially life-threatening thromboembolic events and any other complication, ocular, skeletal, or nervous.[2][48]

Summary

Clinicians should be aware of the clinical ophthalmic manifestations of hyperhomocysteinemia and homocystinuria (see Table 1). Testing for serum homocysteine levels may be indicated for ophthalmic vascular ischemic events but the role of folate and B12 supplementation in reducing risk remains controversial. Although genetic mutations in MTHFR can also lead to elevated homocysteine levels, the current recommendations do not support genetic testing in these patients. The evaluation of homocystinuria, however, in children includes testing and treatment because of the severity of the disorder. The precise mechanism for homocysteine in various ophthalmic disorders remains ill defined and deserves continued study.

Homocysteinemia Homocystinuria
NAION, central retinal artery occlusion, central retinal vein, papilledema, temporal optic disc pallor, optic nerve diseases, normal fundus with field defects, age-related macular degeneration, diabetic retinopathy[49][50] Ectopia lentis et pupillae, iridodonesis, high myopia, nearsightedness, dislocated eye lenses, retinal degeneration and detachment, secondary glaucoma, stromal opacification, bullous keratopathy, aniridia, congenital glaucoma, lens subluxation, absent zonules, pupillary block[51] [52]

Table 1: Ophthalmic manifestations for homocysteinemia and homocystinuria.

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Gus PI, Donis KC, Marinho D, Martins TF, Moura de Souza CF, Carloto RB, et al. Ocular manifestations in classic homocystinuria. Ophthalmic Genet. 2020; 42(1): 71-74, DOI: 10.1080/13816810.2020.1821384
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 Morris A, Kozich V, Santra S, Andria G, Ben-Omran TI, Chakrapani A, et al. Guidelines for the diagnosis and management of cystathionine beta‐synthase deficiency. J Inherit Metab Dis. 2017; 40:49–74.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 Sacharow SJ, Picker JD, Levy HL. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. 2004 Jan 15 [Updated 2017 May 18]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. https://www.ncbi.nlm.nih.gov/books/NBK1524/pdf/Bookshelf_NBK1524.pdf
  4. ↑ Hoss GRW, Sperb-Ludwig F, Schwartz I, Blom HJ. Classical homocystinuria : A common inborn error of metabolism? An epidemiological study based on genetic databases. Mol Genet Genomic Med. 2020; 8(6): e1214. doi: 10.1002/mgg3.1214
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 Mulvihill A, Yap SM, O’Keefe M, Howard P, Naughten ER. Ocular Findings Among Patients with Late-Diagnosed or Poorly Controlled Homocystinuria Compared with a Screened, Well-Controlled Population. J AAPOS. 2001;5(5):311–5.
  6. ↑ 6.0 6.1 6.2 Taylor RH, Burke J, O’Keefe M, Beighi B, Naughten ER. Ophthalmic abnormalities in homocystinuria: the value of screening. Eye. 1998;12:427–30.
  7. ↑ Sadiq, MA, Vanderveen, D. Genetics of Ectopia Lentis. Seminars in Ophthalmology. 2013; 28:5-6:313-320, DOI: 10.3109/08820538.2013.825276
  8. ↑ Kraus, J. P. et al. Cystathionine beta-synthase mutations in homocystinuria. Hum. Mutat. 13, 362–375 (1999).
  9. ↑ Panagiotakos, D. B. et al. Effect of exposure to secondhand smoke on markers of inflammation: the ATTICA study. Am. J. Med. 116, 145–150 (2004).Panagiotakos, D. B. et al. Effect of exposure to secondhand smoke on markers of inflammation: the ATTICA study. Am. J. Med. 116, 145–150 (2004).
  10. ↑ Nygård, O., Refsum, H., Ueland, P. M. & Vollset, S. E. Major lifestyle determinants of plasma total homocysteine distribution: the Hordaland Homocysteine Study. Am. J. Clin. Nutr. 67, 263–270 (1998).
  11. ↑ Amorim De Farias Leal, A. et al. Homocysteine: cardiovascular risk factor in children and adolescents? Rev. Assoc. Médica Bras. 59, 622–628 (2013).
  12. ↑ Sreckovic, B. et al. Homocysteine is a marker for metabolic syndrome and atherosclerosis. Diabetes Metab. Syndr. Clin. Res. Rev. 11, 179–182 (2017).
  13. ↑ Inan, S., Yavas, G. & Inan, U. U. Homocysteinemia as a cause for amaurosis fugax in  a patient without an apparent embolic source. Romanian J. Ophthalmol. 63, 188–192 (2019).
  14. ↑ 14.0 14.1 14.2 14.3 14.4 Miraftabi A, Zand A, Aghdam KA. Unilateral and Spontaneous Complete Anterior Dislocation of the Crystalline Lens in a Patient With Homocystinuria Case Presentation. Cureus. 2021;13(4):1–6
  15. ↑ Saxena KN, Kapoor S, Chopra N, Dua C. Anaesthetic management of a case of homocystinuria. Indian J Anaesth. 2006, 50:476-8
  16. ↑ 16.0 16.1 16.2 16.3 16.4 Harrison DM, Mullaney P, Mesfer S, Awad AM, Dhindsa HM. Management of Ophthalmic Complications of Homocystinuria. Ophthalmology. 1998;105:1886–90.
  17. ↑ 17.0 17.1 Yamada T, Hamada H, Mochizuki S, Sutoh M, Tsuji M, Kawamoto M, et al. General anesthesia for patient with type III homocystinuria (tetrahydrofolate reductase deficiency). J Clin Anesth. 2005;17(7):565–7.
  18. ↑ Iqbal, N. S., Wu, Y., Hazen, S. & Tang, W. H. W. Elevated Plasma Homocysteine Identifies Patients With Chronic Heart Failure at Increased Cardiovascular Risk. J. Card. Fail. 18, S87 (2012).
  19. ↑ Beydoun, M. A. et al. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health 14, 643 (2014).
  20. ↑ Castiglia, P. et al. Methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms in breast cancer: a Sardinian preliminary case-control study. Int. J. Med. Sci. 16, 1089–1095 (2019).
  21. ↑ Kouidhi, S. et al. MTHFR gene polymorphisms and bladder cancer susceptibility: a meta-analysis including race, smoking status and tumour stage. Asian Pac. J. Cancer Prev. APJCP 12, 2227–2232 (2011).
  22. ↑ Miller, J. W. Homocysteine. in Encyclopedia of Human Nutrition (Third Edition) (ed. Caballero, B.) 424–430 (Academic Press, Waltham, 2013). doi:10.1016/B978-0-12-375083-9.00144-6.
  23. ↑ Rabelo, N. N. et al. Homocysteine is associated with higher risks of ischemic stroke: A systematic review and meta-analysis. PLOS ONE 17, e0276087 (2022).
  24. ↑ Smulders, Y. M. & Blom, H. J. The homocysteine controversy. J. Inherit. Metab. Dis. 34, 93–99 (2011).
  25. ↑ Yap, S. et al. Vascular outcome in patients with homocystinuria due to cystathionine beta-synthase deficiency treated chronically: a multicenter observational study. Arterioscler. Thromb. Vasc. Biol. 21, 2080–2085 (2001).
  26. ↑ Rodionov, R. N. & Lentz, S. R. The Homocysteine Paradox. Arterioscler. Thromb. Vasc. Biol. 28, 1031–1033 (2008).
  27. ↑ Herrmann, W. & Herrmann, M. The Controversial Role of HCY and Vitamin B Deficiency in Cardiovascular Diseases. Nutrients 14, 1412 (2022).
  28. ↑ Diet and Lifestyle Recommendations Revision 2006 | Circulation. https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.106.176158.
  29. ↑ 29.0 29.1 Mulvihill A, O’Keeffe M, Yap S, Naughten E, Howard P, Lanigan B. Ocular axial length in homocystinuria patients with and without ocular changes: Effects of early treatment and biochemical control. J AAPOS. 2004;8(3):254–8.
  30. ↑ 30.0 30.1 Washington, J., Ritch, R. & Liu, Y. Homocysteine and Glaucoma. Int. J. Mol. Sci. 24, 10790 (2023).
  31. ↑ 31.0 31.1 Huang, E.-J. et al. Homocysteine and other biochemical parameters in Type 2 diabetes mellitus with different diabetic duration or diabetic retinopathy. Clin. Chim. Acta 366, 293–298 (2006).
  32. ↑ 32.0 32.1 Biousse, V., Kerrison, J. B. & Newman, N. J. Is non-arteritic anterior ischaemic optic neuropathy related to homocysteine? Br. J. Ophthalmol. 84, 554–554 (2000).
  33. ↑ Tan, A. G. et al. Serum Homocysteine, Vitamin B12, and Folate, and the Prevalence and Incidence of Posterior Subcapsular Cataract. Invest. Ophthalmol. Vis. Sci. 56, 216–220 (2015).
  34. ↑ Ghosh, S., Saha, M. & Das, D. A study on plasma homocysteine level in age-related macular degeneration. Nepal. J. Ophthalmol. 5, 195–200 (2013).
  35. ↑ Ajith, T. A. & Ranimenon,  null. Homocysteine in ocular diseases. Clin. Chim. Acta Int. J. Clin. Chem. 450, 316–321 (2015).
  36. ↑ Fallico, M. et al. Risk of acute stroke in patients with retinal artery occlusion: a systematic review and meta-analysis. Eye 34, 683–689 (2020).
  37. ↑ Güzel, H. et al. Bilateral Papillophlebitis in a Patient with Mutation of Metilenetetrahydrofolate Reductase Enzyme. Türk Oftalmol. Derg. 46, 182–185 (2016).
  38. ↑ Gowda, V. K., Nanjundappa, R. C., Pendharkar, H. & Benakappa, N. Homocystinuria with Cerebral Venous Sinus Thrombosis: Excellent Recovery with Intravenous Recombinant Tissue Plasminogen Activator. Iran. J. Child Neurol. 11, 48–52 (2017).
  39. ↑ Son, P. & Lewis, L. Hyperhomocysteinemia. https://www.ncbi.nlm.nih.gov/books/NBK554408/#:~:text=Hyperhomocysteinemia%20refers%20to%20the%20condition,for%20more%20serious%20medical%20conditions. (2022).
  40. ↑ Diaz-Arrastia, R. Homocysteine and Neurologic Disease. Arch. Neurol. 57, (2000).
  41. ↑ Stein, J. H. & McBride, P. E. Hyperhomocysteinemia and Atherosclerotic Vascular Disease: Pathophysiology, Screening, and Treatment. Arch. Intern. Med. 158, 1301 (1998).
  42. ↑ Rose N, Dolan S. Newborn Screening and the Obstetrician. Obstet Gynecology. 2012;120(4):908–17
  43. ↑ Roda, M., di Geronimo, N., Pellegrini, M. & Schiavi, C. Nutritional Optic Neuropathies: State of the Art and Emerging Evidences. Nutrients 12, 2653 (2020).
  44. ↑ Kumar T, Sharma GS, Singh LR. Homocystinuria: Therapeutic approach. Clin Chim Acta. 2016;458:55–62. http://dx.doi.org/10.1016/j.cca.2016.04.002
  45. ↑ Mittelviefhaus H, Mittelviefhaus K, Gerling J. Transscleral suture fixation of posterior chamber intraocular lenses in children under 3 years. Graefe’s Arch Clin Exp Ophthalmol. 2000;238(2):143–8.
  46. ↑ Sen P, S. VK, Bhende P, Rishi P, Rishi E, Rao C, et al. Surgical outcomes and complications of sutured scleral fixated intraocular lenses in pediatric eyes. Can J Ophthalmol. 2018;53(1):49–55.
  47. ↑ Burke JP, O’Keefe M, Bowell R, Naughten ER, Burke JP, Keefe MO, et al. Ocular complications in homocystinuria--early and late treated. Br J Ophthalmol. 1989;73:427–31.
  48. ↑ Yap S. Classical homocystinuria: vascular risk and its prevention. J Inherit Metab Dis. 2003;26:259–65. PubMed PMID: 12889665.
  49. ↑ Miskin, A. et al. To Study the Role of Serum Homocysteine Levels and Ocular Involvement in Retinal Vasculitis. Indian J. Clin. Biochem. 37, 212–217 (2022).
  50. ↑ Sowbhagya, H. N., Kothari, M., Kumar, L. K. & Nikhil, N. Ocular Manifestations of Hyperhomocysteinemia and their Response to Therapeutic Modalities. 3, (2015).
  51. ↑ Homocystinuria. American Academy of Ophthalmology https://www.aao.org/education/disease-review/homocystinuria-3 (2015).
  52. ↑ Cross, H. E. & Jensen, A. D. Ocular manifestations in the Marfan syndrome and homocystinuria. Am. J. Ophthalmol. 75, 405–420 (1973).
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