Homocystinuria is a disease caused by a congenital deficiency of cystathionine beta-synthase (CBS) in the methionine metabolic pathway, leading to accumulation of homocystine in the blood and its massive excretion in the urine. It follows an autosomal recessive inheritance pattern.
The CBS gene is located on chromosome 21 (21q22.3). Currently, 164 pathogenic mutations have been identified, the most common being p.Ile278Thr and p.Gly307Ser. 67% of mutations are missense mutations.
The global prevalence is estimated at 0.82 per 100,000 based on medical records and 1.09 per 100,000 based on newborn screening. In Japan, the incidence is reported as 1 per 1,000,000 births. In Ireland, a high frequency of 1 per 64,900 births has been reported 2). It is a target disease for newborn mass screening, detected by elevated blood methionine levels.
The four major features are lens dislocation, intellectual disability, skeletal abnormalities (Marfanoid habitus), and thromboembolism 1).
QHow is it different from Marfan syndrome?
A
Both conditions share skeletal abnormalities and lens dislocation, but there are several distinguishing points. In homocystinuria, the lens is often displaced downward, while in Marfan syndrome it is often upward and superotemporal. Marfan syndrome does not involve intellectual disability and usually does not present with osteoporosis. The inheritance pattern is also different: Marfan syndrome is autosomal dominant.
Decreased visual acuity: As lens dislocation progresses, myopia and astigmatism increase. Monocular diplopia may also occur.
High myopia: The second most common ocular symptom. It can be caused by both axial and lenticular factors. Patients diagnosed at birth and well-controlled may have emmetropia to mild refractive errors, but poorly controlled cases can develop progressive high myopia of -5D or more.
Acute eye pain and vision loss: Can occur due to pupillary blockglaucoma caused by anterior lens dislocation.
Systemic subjective symptoms are as follows.
Skeletal abnormalities: Marfanoid habitus including tall stature, long limbs, scoliosis, and pectus excavatum.
Developmental delay and epilepsy: Psychiatric symptoms may occur as central nervous system disorders.
Thromboembolism: Without treatment, coronary artery thrombosis, pulmonary embolism, and cerebral thrombosis/embolism may develop after puberty.
Clinical Findings (Findings Confirmed by Physician Examination)
Lens dislocation: The most characteristic ocular finding. It occurs in about 90% of patients, and two-thirds are displaced inferonasally. It is bilateral and symmetrical. Without treatment, it is usually observed by around 8 years of age. While Marfan syndrome shows superotemporal dislocation, the inferonasal dislocation in homocystinuria is an important clue for differential diagnosis.
Iridodonesis and phacodonesis: The lens trembles during eye movements due to weakening of the zonules of Zinn.
The essence of homocystinuria is a deficiency of the CBS enzyme. CBS is an enzyme in the transsulfuration pathway that converts homocysteine to cystathionine and requires vitamin B6 as a coenzyme. CBS deficiency leads to accumulation of homocysteine in the blood, causing damage to multiple organs.
The main pathologies due to homocysteine accumulation are as follows:
Inhibition of elastin cross-linking: Weakening of connective tissue. Causes skeletal abnormalities and lens dislocation.
Alteration of fibrillin: Contributes to vascular endothelial dysfunction.
Decreased cysteine: The zonular fibers of the lens have high cysteine content, and a decrease weakens them.
Increased oxidative stress: Promotes vascular endothelial damage and atherosclerosis.
The inheritance pattern is autosomal recessive; if both parents are carriers, 25% of children will be affected and 50% will be asymptomatic carriers. Testing of siblings of affected children is recommended.
Acquired hyperhomocysteinemia can also occur due to deficiency of vitamins B6, B9 (folate), and B12, as well as smoking, alcohol consumption, and medications such as methotrexate, nitrous oxide, phenytoin, and carbamazepine.
QWhat is the inheritance pattern? Should siblings be tested?
A
It is autosomal recessive. If both parents are carriers, 25% of children will be affected and 50% will be carriers. Testing is recommended for siblings of an affected child even if asymptomatic.
Newborn mass screening is the most important diagnostic tool. It detects elevated blood methionine levels. However, mild pyridoxine-responsive forms may be false-negative, and patients may later present with eye or systemic symptoms.
Since methionine can also be elevated in liver disease and other metabolic disorders, confirmation requires evidence of massive urinary homocystine excretion.
The main goal of treatment is to maintain homocysteine levels within an appropriate range and prevent thrombosis. Maintaining homocysteine concentrations below 100 μmol/L in adults and below 50 μmol/L in children is expected to halt the progression of lens subluxation and resume normal bone growth.
For pyridoxine-nonresponsive patients, a methionine-restricted diet is the mainstay of treatment. In infants, methionine-free, cystine-added special formula and natural protein are used, with intake adjusted to achieve a fasting blood methionine level of 1 mg/dL or less. Folic acid and vitamin B12 supplementation are also given. Dietary therapy must be continued lifelong; poor control can lead to thrombosis.
The E-HOD (European Homocystinuria Network) guidelines recommend target plasma total homocysteine levels below 50 μmol/L for pyridoxine-responsive patients and below 100 μmol/L for nonresponsive patients 1).
A methyl donor that promotes remethylation of homocysteine back to methionine. It is used as adjunctive therapy when target levels cannot be achieved by other means 1).
Refractive correction: If lens displacement is mild and corrected visual acuity is good, manage with glasses for refractive correction and observation.
Lens extraction: Indicated when displacement progresses or visual impairment occurs. Due to zonular instability, vitrectomy is often combined. Postoperatively, the eye becomes aphakic, requiring correction with glasses or contact lenses. If contact lens wear is difficult, consider intraocular lenses (iris-fixated, scleral-fixated, or anterior chamber lenses).
Pupillary blockglaucoma: Use cycloplegics for mydriasis and intraocular pressure-lowering medications. Miotics are contraindicated because they contract the ciliary muscle, relax the zonules, and promote forward movement of the lens. Recurrent cases require surgical intervention.
Spherophakia: May require intracapsular lens extraction.
QWhat should I be careful about when undergoing surgery?
A
Because of the high risk of thromboembolism, optimize biochemical control before surgery and take preventive measures such as elastic stockings and low-molecular-weight heparin. Nitrous oxide (laughing gas) is contraindicated in anesthesia 1). Early mobilization and adequate hydration are important after surgery.
Homocysteine is a metabolic intermediate of methionine. Three pathways are involved in its metabolism.
Transsulfuration pathway: Homocysteine is irreversibly converted to cystathionine by CBS (coenzyme: vitamin B6) and eventually to cysteine. This pathway is impaired in this disease.
Remethylation pathway (MTR): Methionine synthase (coenzyme: vitamin B12) transfers a methyl group from 5-methylTHF to homocysteine, converting it back to methionine.
Remethylation pathway (BHMT): Betaine-homocysteine methyltransferase transfers a methyl group from betaine to homocysteine.
Accumulation of homocysteine due to CBS deficiency causes multi-organ damage through the following mechanisms:
Inhibition of cross-linking of sulfhydryl groups in elastin: This causes structural abnormalities in connective tissue, leading to skeletal deformities and lens dislocation.
Accumulation of S-adenosylhomocysteine (SAH): Inhibits methylation reactions.
Decreased cysteine and cystathionine levels: Leads to reduced antioxidant capacity and promotion of apoptosis. Since the lens zonules have a particularly high cysteine content, decreased cysteine weakens them, leading to lens dislocation.
Alteration of fibrillin: Contributes to vascular endothelial dysfunction and promotion of thrombus formation.
Regarding skeletal deformities, disproportionate bone growth results in the pubis-to-heel length exceeding the crown-to-pubis length 1). It is reported that 70% of untreated patients develop spinal osteoporosis by age 16 1), which can lead to vertebral collapse and scoliosis. Since osteoporosis becomes apparent after puberty, regular bone density assessment by DEXA scan from puberty onward is recommended 1).
7. Latest Research and Future Perspectives (Research-stage Reports)
Homocystinuria is a prothrombotic state, and risk management during pregnancy is a challenge.
Hart et al. (2021) reported the experience of 2 women with pyridoxine-nonresponsive homocystinuria in Ireland, involving 5 pregnancies 2). The E-HOD guidelines recommend low molecular weight heparin (LMWH) administration from the third trimester, but this facility started LMWH from the time of pregnancy confirmation. In late pregnancy, an increase in methionine tolerance and a tendency for homocysteine levels to decrease were observed. However, in one case, pulmonary embolism occurred immediately after discontinuation of LMWH at 6 weeks postpartum, highlighting the importance of strict metabolic monitoring during the postpartum period and individualization of the LMWH administration period.
Ramakrishnan E, Muthu S, Balasubramaniam P, Chellamuthu G, Priyadharshini K. Holistic approach in the management of skeletal deformity in a case of homocystinuria. J Orthop Case Rep. 2021;11(4):1-5.
Hart C, McNulty J, Cotter M, Al Jasmi F, Crushell E, Monavari AA. The challenges of pregnancy management in pyridoxine nonresponsive homocystinuria: the Irish experience. JIMD Rep. 2021;61(1):34-41.
