From EyeWiki

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]


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]


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]


The pathophysiology of homocystinuria is not completely understood. However, 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]


Systemic Manifestations

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]

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.[8][9][10] 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.).[11]

Ocular Manifestations

Ophthalmic complications include high myopia, ectopia lentis, pupillary block glaucoma, and retinal detachments.[2][5] Ectopia lentis is the most common ophthalmic complication of homocystinuria, seen in approximately 90% of patients.[10] 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][8] 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). 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.[8][10]

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.[12] 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] 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.[12] Patients with homocystinuria also have increased risk of retinal detachments, cataracts, strabismus, and amblyopia.[2][8]

Lab Testing

The most important tool for homocystinuria diagnosis is newborn screening, which has high sensitivity to detect many inborn errors of metabolism, including homocystinuria.[13] 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]

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.


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][14] 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.[11] 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 and require either glasses or contacts for refractive correction.[8][10] The zonular instability generally precludes the placement of an intracapsular IOL, so patients are often left aphakic. 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.[15][16]

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.[10]


Early diagnosis and management within the first 6 weeks of life significantly reduces the morbidity and mortality of homocystinuria.[3][17] 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][18]


  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 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.
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  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 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. 8.0 8.1 8.2 8.3 8.4 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
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