Deficiency of methylcysteine synthase is another name for cystathionine beta-synthase (CBS) deficiency, also called classic homocystinuria. In this disease, a body enzyme (CBS) that normally changes the amino acid homocysteine into another substance does not work properly. Because of this, homocysteine and methionine build up in blood and urine and can slowly damage the eyes, bones, brain, and blood vessels.
“Deficiency of methylcysteine synthase” is usually used to mean methionine synthase deficiency (cblG type homocystinuria). In this rare genetic disease, a gene called MTR does not work properly. This gene makes the enzyme methionine synthase, which helps convert the amino acid homocysteine into methionine using vitamin B12 and folate. When the enzyme is weak or missing, homocysteine builds up in blood and urine, and methionine levels become low. This can cause megaloblastic anemia (large red blood cells), developmental delay, seizures, learning problems, movement disorders, and sometimes blood clots or stroke if not treated early.
Because this is a lifelong inborn error of metabolism, treatment focuses on lowering homocysteine, raising methionine, protecting the brain and eyes, and preventing complications. Most care is based on expert experience, small case series, and data from similar “remethylation” disorders. Early diagnosis and continuous follow-up in a metabolic clinic give the best chance for normal growth, learning, and quality of life.
This condition is a genetic, inherited metabolic disorder. It usually follows an autosomal recessive pattern, which means a child gets one changed copy of the CBS gene from each parent. Without early diagnosis and special treatment, people can develop severe eye problems, bone deformities, learning difficulties, and dangerous blood clots.
Other names
Doctors and scientists use several different names for deficiency of methylcysteine synthase. All of the names below refer to the same basic problem: lack of normal CBS enzyme activity and high homocysteine levels.
Cystathionine beta-synthase deficiency (CBS deficiency) – This is the most common medical name and directly describes the missing enzyme.
Classic homocystinuria – “Homocystinuria” means too much homocysteine is passed out in the urine; “classic” usually refers to the CBS-deficiency form.
Homocystinuria due to cystathionine beta-synthase deficiency – A longer, very precise name that links the urine finding (homocystinuria) to the exact enzyme defect.
Homocystinuria caused by CBS deficiency – A shorter form with the same meaning as above, often used in reviews and disease summaries.
Deficiency of methylcysteine synthase – An older synonym; methylcysteine synthase is another historical name for the CBS enzyme.
Deficiency of beta-thionase – Another legacy enzyme name that refers to the same protein encoded by the CBS gene.
Deficiency of serine sulfhydrase – A further older term used for the CBS enzyme, showing how naming changed over time.
Hyperhomocysteinemia, CBS-related – Used in some databases to stress that the main biochemical problem is very high homocysteine due to CBS variants.
CBS-deficient HCU – A short form used in specialist networks, meaning “CBS-deficient homocystinuria.”
Homocystinemia / homocystinemia-homocystinuria – Terms used in some literature to describe high homocysteine in blood and urine due to CBS deficiency.
Types
Doctors can group deficiency of methylcysteine synthase into types based on how the body responds to vitamin B6 (pyridoxine), which is a helper vitamin for the CBS enzyme, and on how early and how severely symptoms start.
Vitamin B6-responsive type – In this type, the faulty CBS enzyme still works a little, and high-dose vitamin B6 can improve its activity. People may have milder symptoms if treatment starts early, because homocysteine levels can be lowered more easily.
Partially vitamin B6-responsive type – Here, high-dose vitamin B6 gives only partial improvement. Homocysteine levels fall but may still stay higher than normal, so other treatments (diet and medicines) are also needed.
Vitamin B6-non-responsive type – In this group, the CBS enzyme is so damaged that even large doses of vitamin B6 cannot help. These people often have more severe disease and need very strict diet and other treatments to control homocysteine.
Early-onset vs late-onset forms – Some children show symptoms in early childhood, while others are not diagnosed until the teen years or adulthood. The same disorder can therefore present at different ages, depending on the exact gene changes and whether newborn screening or family testing is done.
Causes
The main true cause of deficiency of methylcysteine synthase is a change (mutation) in the CBS gene, which stops the enzyme from working normally. The list below explains different genetic and related factors that cause or strongly influence this disease and its severity.
Pathogenic variants in the CBS gene – Harmful changes in the CBS gene sequence reduce or stop production of working cystathionine beta-synthase enzyme, leading to accumulation of homocysteine and methionine.
Autosomal recessive inheritance – A child must receive one faulty CBS gene from each parent to be affected. Parents are usually healthy carriers with one normal and one changed copy, but their child can be born with enzyme deficiency if both pass on the altered copy.
Homozygous CBS mutations – Some people have the same pathogenic change on both copies of the gene (homozygous). This pattern often causes more severe loss of enzyme function and more marked homocysteine elevation.
Compound heterozygous CBS mutations – Others have two different harmful CBS variants, one on each chromosome (compound heterozygous). Together, these changes also reduce CBS activity and cause the disease.
Common missense mutation I278T – A well-known change replaces one amino acid in the enzyme (I278T). This mutation is frequent in some populations and is linked to CBS deficiency, sometimes with vitamin B6 responsiveness.
Common missense mutation G307S – Another important change, G307S, is especially frequent in people of Celtic origin (for example in Ireland) and is often associated with more severe, B6-non-responsive disease.
Other missense variants in CBS – Many other single-letter gene changes alter the shape of the CBS protein. These missense variants can disturb folding or stability of the enzyme and weaken its activity.
Nonsense and frameshift mutations – Some variants introduce a “stop” signal or shift the reading frame, producing a shortened, non-functional enzyme. These severe mutations can result in very low or absent CBS activity.
Splice-site mutations – Changes at splice sites in the CBS gene can cause incorrect cutting and joining of gene messages (mRNA). This leads to abnormal or missing CBS protein and contributes to the deficiency.
Larger deletions or structural variants involving CBS – In some families, part or all of the CBS gene can be deleted or rearranged. These structural variants remove essential coding regions and prevent production of a working enzyme.
Higher carrier frequency in certain populations – CBS mutations are more frequent in some regions, such as Qatar and parts of Europe including Ireland and Norway. In these communities, more couples are carriers, so more babies can be born with the disease.
Consanguinity (closely related parents) – When parents are blood relatives (for example, cousins), they are more likely to share the same CBS mutation. This increases the chance that a child will inherit two faulty copies and develop deficiency.
Lack of newborn screening – In countries without homocystinuria screening, affected babies are not detected early. The genetic cause is the same, but late recognition allows homocysteine levels to remain high for years and makes disease features more severe.
Insufficient vitamin B6 in some individuals – The CBS enzyme needs vitamin B6 as a cofactor. In people with milder CBS variants, low vitamin B6 intake or poor B6 handling can further reduce enzyme activity and increase homocysteine.
Combined deficiency of folate or vitamin B12 – Folate and vitamin B12 help in alternative homocysteine pathways. Low levels of these vitamins do not cause CBS deficiency directly, but they raise homocysteine even more in someone who already has CBS mutations.
High methionine and protein intake in affected individuals – Methionine from dietary protein is the source of homocysteine. In a person with CBS deficiency, large amounts of methionine add extra load to a blocked pathway and worsen the biochemical imbalance.
Poor adherence to special diet or medicines after diagnosis – When an affected person does not follow the recommended dietary and medical plan, homocysteine levels stay high, so the harmful effects of the inherited enzyme deficiency continue.
Intercurrent illness or surgery increasing protein breakdown – Severe infections, trauma, or surgery can increase breakdown of body protein, which releases more homocysteine. In CBS deficiency, this temporary stress can worsen metabolic control.
Coexisting homocysteine pathway disorders – Rarely, a person may have both CBS deficiency and a separate defect in remethylation of homocysteine. Together, these genetic problems cause extremely high homocysteine and more serious symptoms.
General vascular risk factors (for example, smoking, obesity, lack of exercise) – These do not cause CBS deficiency itself, but in a person with high homocysteine, they make blood vessels even more likely to form clots and add to disease complications.
Symptoms
Signs and symptoms can vary widely. Some children are very sick early in life, while others are diagnosed later, sometimes after an eye or blood-clot problem. The list below shows common features; not every person will have all of them.
Severe short-sightedness (myopia) – Many children develop strong myopia at a young age because high homocysteine affects the lens and other eye structures, making vision blurry for distant objects.
Lens dislocation (ectopia lentis) – The eye lens can move from its normal place because supporting fibers are weakened. This can cause very blurred vision, double vision, or glare and is a classic sign of homocystinuria due to CBS deficiency.
Tall, thin body with long limbs (marfanoid habitus) – Many patients are unusually tall with long arms, legs, and fingers, which can look similar to Marfan syndrome. This body build reflects changes in connective tissue caused by long-term high homocysteine.
Chest deformity (pectus excavatum or pectus carinatum) – The breastbone may be sunken in or pushed out. These chest shape changes are also seen in other connective tissue disorders and are part of the skeletal involvement in this disease.
Spine curvature (scoliosis or kyphosis) – The spine can curve sideways or forward over time. Weak bones and altered connective tissue support around the spine make abnormal curvature more likely.
Long, thin fingers (arachnodactyly) – The fingers may appear very long and slender. This is another sign that the connective tissues, including ligaments and bones, are affected by the metabolic disturbance.
Osteoporosis and fragile bones – Reduced bone density can develop even in teenagers or young adults, leading to bone pain or fractures after minor injuries. High homocysteine is thought to harm bone cells and collagen.
Developmental delay in children – Babies and young children may sit, walk, or speak later than expected. This delay can be mild or severe and reflects the effect of the disorder on the developing brain.
Intellectual disability or learning difficulties – Some individuals have problems at school, including poor concentration, slow learning, or lower IQ. Early detection and treatment can prevent or greatly reduce these cognitive problems.
Blood clots in veins or arteries (thromboembolism) – One of the most serious complications is formation of blood clots, which can occur in deep leg veins, lungs, or other vessels, sometimes at a young age. High homocysteine damages vessel walls and increases clotting tendency.
Stroke or transient brain ischemia – Clots can block brain blood vessels and cause stroke or mini-stroke, leading to sudden weakness, speech problems, or other neurological signs even in teenagers or young adults.
Seizures (fits) – Some patients have seizures, which may be related to direct brain involvement or to damage from previous clots. Seizures can occur at any age but are often reported in childhood.
Behavioral and psychiatric problems – Anxiety, shyness, sleep problems, attention difficulties, and sometimes more severe psychiatric symptoms have been described. These issues may improve when homocysteine is well controlled.
Light skin and hair – Some people with CBS deficiency have paler skin and lighter hair compared to their family. Disturbed methionine and homocysteine metabolism can affect pigment pathways, although the exact mechanism is not fully understood.
Malar flush and skin changes – A red flush over the cheeks (malar area) and other subtle skin changes are sometimes observed. These features can give clues to clinicians when combined with eye, bone, and vascular signs.
Diagnostic tests
Diagnosis of deficiency of methylcysteine synthase relies on clinical examination, laboratory tests, genetic testing, and sometimes electrical and imaging studies. The aim is to confirm very high homocysteine, check related amino acids, and look for organ damage.
Physical exam tests
General physical examination and growth check – The doctor looks at height, weight, body proportions, and head size and searches for features such as tall stature, long limbs, chest deformity, or thin build that suggest a metabolic or connective tissue disorder.
Eye examination with light and basic tools – A simple eye exam can detect severe myopia, squint, or signs that the lens is not in the right place. These findings may lead to referral for more detailed ophthalmologic testing.
Skeletal and joint examination – The clinician checks the spine for scoliosis, the chest for deformities, and the hands and feet for long, thin fingers and high-arched feet. These features together can point toward CBS deficiency.
Neurological examination – Reflexes, muscle tone, strength, coordination, and gait are assessed. This helps to detect signs of stroke, pyramidal tract damage, or developmental neurological problems linked to high homocysteine.
Cardiovascular and peripheral vascular examination – The doctor checks heart sounds, blood pressure, limb pulses, and looks for swelling or tenderness in the legs that might suggest a deep vein thrombosis.
Manual / bedside tests
Visual acuity testing (eye chart) – Reading letters or symbols on a standard chart measures how well each eye can see. Marked reduction in distance vision supports the suspicion of eye involvement from this disorder.
Basic developmental screening in young children – Simple checklists or play-based tasks help to see if a child’s motor and language skills match their age. Delays may prompt further metabolic and genetic testing.
Educational and cognitive assessments in school-age children – Structured tests at school or in clinic can show learning difficulties, attention problems, or lower IQ, which are common in untreated CBS deficiency.
Posture and flexibility assessment – The clinician observes standing and walking posture and checks joint range of movement. Abnormal posture, kyphosis, or excessive flexibility can support the diagnosis when combined with other clues.
Laboratory and pathological tests
Plasma total homocysteine level – This is a key test. People with CBS deficiency usually have very high total homocysteine in the blood, far above the normal range. It is one of the main screening and monitoring markers.
Plasma methionine concentration – Methionine is often raised in classic CBS deficiency. Together with high homocysteine, this pattern supports the diagnosis and helps distinguish CBS deficiency from other homocystinurias.
Urinary homocystine measurement – A urine test (screening or quantitative) detects excess homocystine. The finding of homocystinuria gave the disease its name and remains an important clue.
Plasma amino acid profile (chromatography) – Detailed amino acid analysis shows the specific pattern of raised homocysteine-related compounds and methionine, helping to confirm the biochemical diagnosis.
Genetic testing of the CBS gene – DNA analysis identifies the exact CBS variants (for example I278T or G307S). This test confirms the diagnosis, helps with family counselling, and sometimes predicts vitamin B6 responsiveness.
Newborn screening using dried blood spots – In some countries, homocystinuria is included in newborn screening panels. Increased methionine and sometimes elevated homocysteine on these tests prompt early confirmatory evaluations.
Vitamin B6, folate, and vitamin B12 levels – Measuring these vitamins helps rule out simple nutritional causes of high homocysteine and guides treatment for people who also have vitamin deficiencies.
Coagulation profile (clotting tests) – Tests like prothrombin time, activated partial thromboplastin time, and sometimes D-dimer and fibrinogen may be done to evaluate clotting status in people with a history of thrombosis or high homocysteine.
Bone density scan (DEXA) or bone markers – Although often grouped under imaging, bone mineral density measurement can be considered a diagnostic investigation for osteoporosis, which is common in this condition. It helps to document bone loss and plan management.
Electrodiagnostic tests
Electroencephalogram (EEG) – If seizures or concerning neurological symptoms are present, an EEG records brain electrical activity. Abnormal patterns support brain involvement and help guide seizure treatment.
Nerve conduction studies and electromyography (EMG) – These tests are sometimes used when there is weakness, altered reflexes, or signs of peripheral nerve damage. They can show whether nerves and muscles are affected, although they are not required in every patient.
Non-pharmacological treatments (therapies and others)
1. Early newborn and family screening
Early diagnosis is a non-drug treatment because it allows all later therapies to start before damage occurs. Newborn screening (where available) or early homocysteine testing in siblings lets doctors begin vitamin and betaine therapy quickly. This can reduce risk of seizures, delayed milestones, and blood clots. Family screening also helps find mildly affected or carrier relatives, who can then get counseling and regular checks for subtle problems that might otherwise be missed.
2. Individualized low-methionine, balanced-protein diet
Dietitians may advise a controlled methionine intake rather than a completely low-protein diet. The goal is to avoid very high methionine from large amounts of animal protein while still giving enough protein for growth. Special formulas or measured protein servings can be used in children. This diet works together with betaine and vitamins to keep homocysteine down and methionine in a safe range. It must be carefully supervised to prevent malnutrition and poor growth.
3. Folate-rich and B-vitamin-rich food pattern
Although folate and B12 are often given as medicines, a diet naturally rich in leafy greens, legumes, whole grains, eggs, and dairy supports the same metabolic pathway. These foods help the body recycle homocysteine into methionine. Dietitians combine this with methionine control so patients get enough vitamins without excess protein. A nutrient-dense diet also helps overall brain development, immune function, and energy, which are often affected in this condition.
4. Regular physiotherapy and motor training
Children and adults with methionine synthase deficiency can have low muscle tone, unsteady walking, or movement disorders. Regular physiotherapy improves strength, balance, and coordination. Tailored exercises may include stretching, core strengthening, and gait training. This reduces the risk of contractures and falls, helps children reach motor milestones, and supports independence in daily activities. Physical activity must be paced to avoid exhaustion, especially during illness or metabolic stress.
5. Occupational therapy for daily living skills
Occupational therapists help patients learn or adapt fine motor skills and everyday tasks such as writing, dressing, feeding, and using tools or devices. They may suggest adaptive cutlery, writing grips, or modified desks. This therapy builds independence at home and school. It can also reduce caregiver burden and improve self-esteem, which are very important in a chronic rare disease. Sessions are usually combined with physiotherapy and school-based support.
6. Speech and language therapy
High homocysteine and low methionine can affect the developing brain, leading to delayed speech, unclear words, or difficulty understanding language. Speech-language therapy uses play-based exercises, communication boards, or technology to build vocabulary and improve pronunciation. Early intervention is critical, as language skills influence learning, social interactions, and emotional development throughout life. Families are taught home exercises to reinforce progress between sessions.
7. Developmental and educational support plans
Many children need individualized education plans, extra classroom support, or smaller class sizes. Neuropsychological testing can identify specific weaknesses in attention, memory, or processing speed. Teachers can then adapt teaching materials, allow more time for exams, and use visual aids or step-by-step instructions. This non-drug strategy helps children achieve their potential and reduces frustration, anxiety, and early school dropout related to learning difficulties.
8. Psychological counseling and mental-health care
Living with a rare metabolic disease can cause anxiety, depression, or behavior problems for both patients and family members. Counseling offers a space to talk about fears, anger, and treatment fatigue. Cognitive-behavioral therapy can teach coping skills and problem solving. For teenagers, support around independence, body image, and treatment adherence is vital. Mental-health care works best when coordinated with the metabolic team and school.
9. Genetic counseling for patients and relatives
Genetic counseling explains how methionine synthase deficiency is inherited (usually autosomal recessive) and what this means for future pregnancies and siblings. Counselors discuss options such as prenatal diagnosis or preimplantation genetic testing in a sensitive, non-pressured way. This non-pharmacological service helps families make informed choices, plan timing of pregnancies, and prepare emotionally and practically for the possibility of another affected child.
10. Sick-day and emergency action plans
During fever, vomiting, surgery, or fasting, metabolic stress can worsen high homocysteine and low methionine. The metabolic team usually provides a written “sick-day plan” that explains when to increase fluids, when to seek hospital care, and which emergency vitamins or injections may be needed. Keeping this plan with the patient and sharing it with local hospitals helps avoid dangerous delays in treatment during acute illness.
11. Regular monitoring in a metabolic clinic
Non-drug management includes scheduled visits for growth checks, neurological exams, and blood tests for homocysteine, methionine, B12, and folate. These visits allow early detection of complications such as anemia, thrombosis risk, or cognitive decline. If lab results drift, diet and medicines can be adjusted before major problems occur. Consistent follow-up is one of the strongest protective factors in rare metabolic diseases.
12. Eye and vision surveillance
Although lens dislocation is more typical of classic homocystinuria, any long-term hyperhomocysteinemia can affect the eyes. Regular ophthalmology reviews help pick up refractive errors, strabismus, or optic nerve problems. Early glasses or other interventions can prevent amblyopia (lazy eye) and support school performance. Eye doctors also watch for retinal or vascular changes, especially if there is a history of thrombosis or stroke.
13. Lifestyle measures to reduce blood-clot risk
Even in children, high homocysteine can damage blood vessels and increase clot risk. Non-drug measures include avoiding smoking and second-hand smoke, keeping a healthy weight, staying active, moving during long travel, and staying well hydrated. These habits support blood flow and reduce stress on the heart and brain. They are especially important during adolescence and adulthood, when other risk factors like obesity and hormonal contraceptives may appear.
14. Vaccinations and infection prevention
Common infections can trigger metabolic decompensation. Keeping routine vaccines up to date lowers the chance of serious illness. Flu and pneumonia vaccines may be particularly helpful in high-risk patients. Good hand hygiene, prompt treatment of infections, and avoiding unnecessary exposure to sick contacts are simple but powerful non-pharmacological tools that protect patients from hospitalizations and regression.
15. Structured sleep and daily routine
Children with neurological or developmental issues often sleep poorly, which worsens behavior and learning. A regular sleep schedule, calming bedtime routine, and limiting screens before sleep can improve rest. Good sleep supports brain repair, hormone balance, and mood. It also helps caregivers maintain their own health so they can provide consistent support and medication supervision.
16. Social work and financial support services
Social workers help families access disability benefits, educational supports, equipment funding, and respite care. This non-medical support protects family stability and reduces burnout. When parents are less overwhelmed by financial and practical stress, they are better able to attend appointments, follow complex treatment plans, and create a stable home environment for the child.
17. Peer and patient-support groups
Connecting with other families through patient organizations or online communities reduces isolation and fear. Parents can learn practical tips for feeding, giving medicines, and dealing with school problems. Older children and adults can share experiences about work, relationships, and independence. Peer support does not replace medical advice, but it adds emotional strength and realistic hope.
18. Telemedicine and remote follow-up
Because this disease is rare, many families live far from specialist centers. Video clinics and telephone reviews can provide regular contact between major in-person visits. Patients can show lab results, discuss symptoms, and adjust plans without long travel. Telemedicine makes it easier to maintain tight metabolic control and quick response to new problems between scheduled visits.
19. Rehabilitation programs after acute events
If a patient has experienced stroke-like episodes, seizures, or regression, intensive rehabilitation programs can help re-learn lost skills. Programs may combine physiotherapy, speech therapy, occupational therapy, and neuropsychology over several weeks. Early rehab can improve independence, reduce long-term disability, and support return to school or work.
20. Advance care planning in severe cases
In very severe, treatment-resistant cases, families and doctors may discuss advance care plans. These plans describe goals of care, wishes around intensive treatments, and preferred symptom relief approaches. Talking about these topics early and revisiting them over time can reduce anxiety and help everyone make decisions that match the patient’s values and quality-of-life goals.
Drug treatments
Note: Examples of doses below are typical ranges from medical references and FDA labels for related indications, not personal prescriptions. Never start, stop, or change any medicine without a specialist doctor.
1. Betaine anhydrous (Cystadane® and generics)
Betaine anhydrous is the key methyl-donor drug for many forms of homocystinuria. It donates a methyl group so an alternate enzyme can convert homocysteine to methionine, bypassing the defective methionine synthase. FDA labeling for Cystadane indicates betaine to lower homocysteine in homocystinuria, with typical total adult doses around 6 g/day divided twice daily, adjusted by weight and blood levels. Common side effects are body odor, gastrointestinal upset, and rarely serious breathing problems.
2. Hydroxocobalamin injection (parenteral vitamin B12)
Hydroxocobalamin is an active form of vitamin B12 and a cofactor for methionine synthase. High-dose intramuscular or intravenous hydroxocobalamin can boost residual enzyme activity in some cblG patients and improve homocysteine and methionine levels. FDA labels mainly cover cyanide poisoning and B12 deficiency, but metabolic specialists use it off-label in remethylation disorders. Doses are individualized (often mg/kg) and side effects can include red discoloration of skin and urine, high blood pressure, and injection-site reactions.
3. Cyanocobalamin injection or tablets
Cyanocobalamin is another form of vitamin B12, widely used and inexpensive. In some patients, especially where hydroxocobalamin is not available, cyanocobalamin is used to correct B12 deficiency and support methionine synthase. Typical adult replacement doses for B12 deficiency range from daily injections for several days to monthly injections thereafter, with oral doses in microgram ranges. Side effects are usually mild, but rare allergic reactions and optic nerve problems in specific genetic conditions have been reported.
4. Folic acid (pteroylmonoglutamic acid)
Folic acid is a synthetic form of folate, the vitamin that helps regenerate 5-methyltetrahydrofolate, the methyl donor used by methionine synthase. Supplementing folic acid supports the folate cycle, improves folate stores, and can significantly lower homocysteine over months at doses as low as 200–800 µg/day in adults. Higher doses are sometimes used under supervision in inborn errors. Side effects are uncommon but very high doses may mask uncorrected B12 deficiency.
5. Folinic acid (leucovorin)
Folinic acid is a “reduced” folate that bypasses some steps of folate activation and feeds directly into the folate cycle. It is often used with hydroxocobalamin and betaine in remethylation disorders, especially in infants with severe disease. Doses vary widely and are tailored to age and response. Folinic acid may cause gastrointestinal upset or rare allergic reactions but is usually well tolerated. It is especially useful when folate metabolism is impaired or when high-dose folic acid is not effective.
6. L-methylfolate (5-methyltetrahydrofolate)
L-methylfolate is the active folate form that directly donates a methyl group to homocysteine via methionine synthase. It may be more effective and less likely to mask B12 deficiency than folic acid in some patients, though data are limited. Studies suggest that 5-MTHF supplementation can improve homocysteine metabolism in folate-cycle problems. Doses and preparations vary, and side effects are similar to other folate forms, mainly mild digestive symptoms.
7. Vitamin B6 (pyridoxine)
Pyridoxine is not a direct treatment for methionine synthase deficiency, but it supports other enzymes in homocysteine metabolism and is standard in some homocystinuria types. It may be included as part of a broad B-vitamin regimen. Typical supplemental doses for metabolic conditions are higher than usual vitamin needs and must be monitored, as very high long-term doses can cause nerve damage. Side effects include tingling or numbness if overdosed.
8. Vitamin B2 (riboflavin)
Riboflavin is a cofactor for several enzymes including MTHFR, which produces 5-MTHF. Good riboflavin status can therefore indirectly support methionine synthase activity. Supplement doses are usually modest and well tolerated, with the main side effect being bright yellow urine. In some hyperhomocysteinemia patients with certain MTHFR variants, riboflavin supplementation has been shown to reduce homocysteine.
9. Oral methionine supplements
In patients with very low methionine that does not normalize despite other therapy, doctors may prescribe oral L-methionine. The goal is to provide enough methionine for protein synthesis and methylation reactions while continuing betaine and vitamin therapy to keep homocysteine controlled. Doses are individually titrated based on blood levels. If overused, methionine can worsen homocysteine and cause symptoms like lethargy or liver stress, so close monitoring is required.
10. Levocarnitine (L-carnitine)
Levocarnitine helps transport fatty acids into mitochondria for energy production and is used in several metabolic disorders. In remethylation defects, it is sometimes given to support energy metabolism, reduce fatigue, and prevent secondary carnitine depletion, especially when patients are on special diets or multiple medications. Doses depend on weight and lab levels. Side effects may include fishy body odor, diarrhea, or cramps.
11. Low-dose aspirin (antiplatelet therapy)
Because high homocysteine can promote blood clots, some older adolescents and adults may receive low-dose aspirin as antiplatelet therapy, especially if they have other clotting risks or a history of thrombosis. Aspirin reduces platelet stickiness and can lower stroke and heart attack risk in selected patients. It also carries bleeding risk and must be used only when the benefit is clearly greater than the risk, under specialist guidance.
12. Anticoagulants (e.g., warfarin, DOACs where appropriate)
If a patient has already had a deep vein thrombosis, pulmonary embolism, or stroke, doctors may prescribe anticoagulants for weeks, months, or long-term. These drugs thin the blood more strongly than aspirin. Dosing is very individualized and closely monitored with blood tests or clinical reviews. Side effects include bruising and bleeding risk, and interactions with diet and other medicines must be carefully managed.
13. Antiepileptic drugs for seizures
Some patients develop seizures or epilepsy due to brain involvement. In these cases, standard antiepileptic medicines such as levetiracetam, valproate, or others may be used, chosen according to age, seizure type, and other health factors. Doses are titrated slowly to balance seizure control and side effects like drowsiness or mood changes. Optimizing metabolic treatment can sometimes reduce seizure frequency over time.
14. Antispasticity medications (e.g., baclofen)
If patients have significant muscle stiffness or spasticity, drugs like baclofen or similar agents may be added. These medicines act on the nervous system to relax muscles, improve mobility, and reduce discomfort. Doses must be adjusted carefully to avoid too much weakness or sedation. They are usually used along with physiotherapy, not instead of it.
15. Antidepressants and anxiolytics (for mood and anxiety)
Adolescents and adults with chronic illness and neurological symptoms may suffer from depression or anxiety. When counseling alone is not enough, doctors may prescribe antidepressant or anti-anxiety medicines. These improve mood, sleep, and coping, which can also enhance adherence to metabolic treatment. Drug choice and dose are personalized and monitored for side effects like weight changes, sleep disturbance, or activation.
16. Vitamin D and calcium supplements
Restricted diets, limited outdoor activity, and chronic illness can increase risk of low bone mineral density. Vitamin D and calcium supplements are often used to maintain bone health and reduce fracture risk. Doses are based on age, weight, and blood levels. Side effects are rare at correct doses but very high intake can cause high blood calcium, nausea, and kidney problems, so supervision is essential.
17. Omega-3 fatty acid preparations
Purified omega-3 supplements may be used to support cardiovascular health and possibly reduce inflammation in patients with elevated vascular risk. While not specific to methionine synthase deficiency, they may help counter some long-term vessel effects of hyperhomocysteinemia. Typical doses are based on EPA/DHA content. Side effects can include fishy aftertaste and mild bleeding tendency at high doses.
18. Multivitamin and trace-element preparations
Because special diets and chronic illness can lead to multiple micronutrient gaps, many patients receive complete multivitamins with trace elements like zinc and selenium. These support immune function, growth, and antioxidant defenses. Doses usually follow age-appropriate recommendations. Over-supplementation can be harmful, so “more” is not always better.
19. Parenteral or enteral nutrition formulas
In severe cases with feeding difficulties or after major illness, liquid formulas through a feeding tube or intravenous nutrition may be used temporarily. These are carefully designed mixtures of amino acids, carbohydrates, fats, vitamins, and minerals. They are dosed by specialized teams and adjusted as the patient recovers.
20. Experimental or compassionate-use therapies
Some centers may offer experimental drugs or gene-targeted approaches within clinical trials for remethylation disorders. These are highly regulated and only used when potential benefits justify unknown risks. Families considering such options receive detailed counseling and long-term follow-up within research protocols.
Dietary molecular supplements
1. L-methylfolate supplement
L-methylfolate provides the exact folate form used by methionine synthase to recycle homocysteine into methionine. Typical adult supplement doses range from low milligrams daily, but in rare disorders, doctors may use individualized doses guided by blood levels. Functionally, it directly feeds the methylation cycle and can help normalize homocysteine when combined with B12 and betaine. Mechanistically, it crosses the blood–brain barrier better than folic acid, which may support brain function.
2. Methylcobalamin (oral active B12)
Methylcobalamin is an active coenzyme form of vitamin B12. Oral methylcobalamin can complement parenteral B12 injections, especially in stable patients. Doses vary from hundreds to thousands of micrograms per day. It provides B12 directly in the form the body uses for methionine synthase, helping lower homocysteine and support nerve health. Mechanistically, it participates in transferring a methyl group to homocysteine to form methionine.
3. N-acetylcysteine (NAC)
N-acetylcysteine is a precursor of glutathione, the main antioxidant inside cells. Doses for general antioxidant use are usually in the hundreds of milligrams per day, adjusted for age and indication. In theory, NAC may help counter oxidative stress related to high homocysteine and protect blood vessels and brain cells. Its mechanism is to supply cysteine for glutathione synthesis and to act directly as a free-radical scavenger.
4. Omega-3 fatty acids (EPA/DHA)
Concentrated omega-3 capsules provide EPA and DHA, key fatty acids for brain membranes and cardiovascular health. Doses depend on age and indication, often in the range of several hundred milligrams of combined EPA/DHA daily. Omega-3s lower triglycerides, have mild antiplatelet effects, and may reduce inflammation in vessels. In hyperhomocysteinemia, they may help protect the heart and brain when used with standard metabolic therapy.
5. Vitamin D3 (cholecalciferol)
Vitamin D3 supplements support bone mineralization, muscle strength, and immune function. Doses are individualized based on blood 25-OH vitamin D levels and age, often from hundreds to a few thousand IU daily. In chronic rare diseases with limited sun exposure or restricted diets, maintaining optimal vitamin D helps reduce fracture risk and supports overall health. Its mechanism involves regulating calcium and phosphate absorption and influencing many genes.
6. Choline
Choline is a precursor for phosphatidylcholine in cell membranes and also contributes methyl groups through its metabolite betaine. Supplemental choline in modest doses supports liver function, nerve membranes, and methylation pathways. Mechanistically, choline is oxidized to betaine, which then donates a methyl group for homocysteine remethylation via betaine-homocysteine methyltransferase, providing a secondary pathway alongside methionine synthase.
7. S-adenosylmethionine (SAMe)
SAMe is the main universal methyl donor inside cells, made from methionine and ATP. In theory, SAMe supplements could support methylation reactions when methionine is low, but clinical data in this rare disease are limited. Doses must be chosen carefully to avoid side effects such as gastrointestinal upset or mood changes. Mechanistically, SAMe donates methyl groups to many reactions affecting DNA, neurotransmitters, and phospholipids.
8. Taurine
Taurine is a sulfur-containing compound with antioxidant and membrane-stabilizing actions. Supplemental taurine (in gram or sub-gram doses) may support heart and nervous system function and help modulate calcium movement in cells. In theory, it might help buffer some toxic effects of disturbed sulfur amino acid metabolism, but direct evidence in methionine synthase deficiency is limited.
9. Magnesium
Magnesium is a cofactor for many enzymes, including those in energy and DNA metabolism. Supplemental magnesium in standard doses helps prevent deficiency, which can worsen muscle cramps, fatigue, and arrhythmias. Mechanistically, magnesium stabilizes ATP and supports many phosphorylation reactions. Maintaining normal magnesium may support overall cellular health in chronic metabolic diseases.
10. Probiotics
Probiotic supplements supply live beneficial gut bacteria. While not specific to this disorder, they may improve gut barrier function, vitamin synthesis, and immune modulation. Better gut health can improve nutrient absorption of folate and B vitamins, which are crucial for homocysteine metabolism. Doses are usually expressed in colony-forming units and chosen according to strain and age.
Immunity-booster and regenerative / stem-cell related drug approaches
Because this is a very rare disorder, there are no standard “stem cell drugs” approved specifically for methionine synthase deficiency. The following approaches are conceptual or used in broader contexts and always require specialist oversight.
1. Optimized vitamin and micronutrient regimen
A carefully balanced combination of B12, folate, B6, riboflavin, vitamin D, zinc, and other micronutrients indirectly “boosts” immune function by correcting deficiencies that impair white blood cells. Rather than one magic pill, this approach uses multiple vitamins at safe therapeutic doses to normalize the metabolic environment in which immune cells work.
2. Intravenous immunoglobulin (IVIG) in selected cases
IVIG is a pooled antibody product used in some autoimmune or immunodeficiency settings. In rare situations where a patient with methionine synthase deficiency also has significant immune dysfunction, IVIG might be used to prevent or treat severe infections. Dosing is weight-based and administered in hospital. Its mechanism is complex, including pathogen neutralization and modulation of immune responses. This is not routine and is decided case by case.
3. Hematopoietic stem-cell transplantation (HSCT) – theoretical
For some inborn errors of metabolism, bone marrow (hematopoietic stem-cell) transplantation can supply donor cells with normal enzymes. For methionine synthase deficiency, experience is extremely limited and this approach remains experimental or theoretical. It carries major risks (infection, graft-versus-host disease, organ damage) and is considered only in very severe, treatment-resistant cases within research or specialized centers.
4. Gene therapy research
Future treatments may use gene therapy to correct the defective MTR gene in liver or bone marrow cells. Experimental vectors (like viral vectors) could carry a working MTR copy, allowing cells to produce functional methionine synthase. At present, this is still in the research pipeline, with no approved gene therapy for cblG type. Participation in such trials requires strict ethical oversight and detailed counseling about unknown long-term effects.
5. Neuroprotective agents in research contexts
Some clinicians consider general neuroprotective drugs or supplements (such as certain antioxidants) to try to protect brain cells from homocysteine-induced damage. Evidence is weak, and any such use should be within clinical trials or carefully documented practice. The idea is to reduce oxidative stress, excitotoxicity, and vascular damage in the brain, but these approaches are secondary to core metabolic treatment.
6. Anti-inflammatory and vascular-protective strategies
Drugs that lower inflammation and protect blood vessels (for example, statins or ACE inhibitors in adults with high cardiovascular risk) may sometimes be used in conjunction with metabolic therapy. Their role is to stabilize the vascular endothelium and reduce long-term stroke and heart disease risk in patients whose homocysteine has been high for many years. These choices are individualized and based on overall risk, not just the genetic disorder.
Surgeries (procedures and why they are done)
1. Central venous access device placement
Some patients need frequent IV medications, blood sampling, or parenteral nutrition. In these cases, a surgeon may place a central venous catheter or port. This procedure is done under anesthesia and reduces repeated needle sticks. It also allows emergency access during metabolic crises. However, it carries risks such as infection and thrombosis, so it is reserved for patients with clearly defined needs.
2. Orthopedic surgery for contractures or deformities
If severe spasticity, weakness, or bone problems cause joint contractures or spinal deformity, orthopedic surgery may be needed. Procedures can include tendon lengthening, osteotomies, or spinal fusion. The goal is to improve sitting, standing, or walking, reduce pain, and facilitate care (for example, easier hygiene and dressing). Surgery is usually timed after maximizing physiotherapy and medical management.
3. Ophthalmic surgery for lens or other eye problems
While more typical in classic homocystinuria, significant lens dislocation or other structural eye problems may rarely require surgery. Eye surgeons can remove or reposition the lens and place an artificial lens if needed. The purpose is to improve vision, reduce glare, and prevent complications such as glaucoma. Pre-operative metabolic optimization lowers surgical risk.
4. Vascular surgery or interventional procedures for clots
If a large blood clot blocks major vessels (such as in deep vein thrombosis or stroke), vascular surgeons or interventional radiologists may perform clot-removal procedures (thrombectomy) or place stents. These are emergency or urgent interventions. They aim to restore blood flow, save tissue, and prevent permanent disability. Long-term, they are combined with anticoagulants and intensive metabolic control to prevent recurrence.
5. Gastrostomy tube placement for feeding
Children with severe neurological impairment or feeding difficulties may benefit from a gastrostomy tube placed surgically into the stomach. This allows safe delivery of formula, water, and medicines, reduces aspiration risk, and improves growth and hydration. It also allows more precise control of protein intake and vitamin supplements in complex metabolic diets.
Preventions
1. Carrier and prenatal testing in high-risk families
In families with a known MTR mutation, carrier testing and optional prenatal diagnosis can help parents plan pregnancies. Identifying at-risk fetuses early allows immediate postnatal treatment or, in some settings, preimplantation genetic testing could be considered.
2. Routine newborn screening where available
Advocating for inclusion of remethylation disorders in newborn screening programs helps detect affected babies before symptoms start. Early treatment clearly reduces complications in similar conditions like MTHFR deficiency and CBS deficiency.
3. Avoiding folate and B12 deficiency in pregnancy
Women who are carriers or affected must have good folate and B12 status before and during pregnancy. Appropriate supplements, under medical guidance, lower homocysteine and support fetal brain development.
4. Regular metabolic clinic follow-up
Keeping all scheduled clinic visits and lab tests helps prevent sudden metabolic crises, stroke, or developmental regression, because treatment can be adjusted early.
5. Early treatment of infections and other stressors
Quickly managing fever, vomiting, or poor intake with the sick-day plan prevents prolonged catabolism (body breaking down its own proteins), which would raise homocysteine and worsen symptoms.
6. Lifestyle measures for heart and vessel health
Not smoking, staying active, controlling blood pressure and weight, and eating a heart-healthy diet lower long-term vascular risk on top of metabolic treatment.
7. Medication reconciliation at every visit
Checking all medicines, vitamins, and supplements regularly helps avoid harmful interactions or double dosing, and prevents drugs that could worsen homocysteine or interact with anticoagulants from being used accidentally.
8. Vaccinations and infection prevention
Up-to-date immunizations and good hygiene reduce hospitalizations and the metabolic stress of serious infections.
9. Education for families, schools, and local doctors
Clear written summaries and emergency letters help prevent mismanagement during emergencies and ensure that local providers know which drugs, diets, and strategies are needed.
10. Mental-health and adherence support
Supporting mental health and addressing treatment fatigue prevent “silent” non-adherence, which can lead to preventable crises.
When to see doctors
People with methionine synthase deficiency should see their metabolic or neurology team regularly, even if they feel well, to check growth, development, labs, and vision. Urgent medical review is needed if there is new or worsening weakness, seizures, confusion, severe headache, sudden visual loss, chest pain, shortness of breath, limb swelling, or difficulty speaking or walking, because these can signal stroke or blood clots. Persistent vomiting, poor feeding, high fever, or rapid regression in skills also need prompt assessment, as they may indicate metabolic decompensation, infection, or another serious problem. All new medicines or supplements should be discussed with the specialist before starting.
What to eat and what to avoid
1. Eat: measured portions of lean protein (for example, chicken, fish, or egg), according to the diet prescribed by the metabolic dietitian, to provide enough methionine and other amino acids for growth.
2. Eat: plenty of fruits, vegetables, and whole grains to supply natural folate, B vitamins, fiber, and antioxidants that support homocysteine metabolism and heart health.
3. Eat: dairy products or suitable fortified alternatives for calcium, vitamin D, and protein, adjusting amounts as advised in the individualized protein plan.
4. Eat: foods containing natural betaine and choline, such as beets, spinach, and whole grains, where allowed in the diet, as these can support alternate homocysteine-remethylation pathways.
5. Eat: healthy fats such as olive oil, nuts, seeds, and appropriate omega-3-rich foods to protect the heart and brain.
6. Avoid or limit: very high-protein portions (large meat servings, multiple eggs, protein powders) that may raise methionine and homocysteine above the target range. Always follow the dietitian’s protein prescription.
7. Avoid or limit: heavily processed foods high in sugar, trans fats, and salt, which worsen cardiovascular risk.
8. Avoid: unprescribed herbal products or “mega-dose” vitamin mixes that could interact with medicines or push some nutrients to unsafe levels.
9. Avoid: energy drinks and excess caffeine, which may disturb sleep, heart rhythm, and appetite and make adherence to treatment schedules harder.
10. Avoid: alcohol in adolescents and adults, as it can damage the liver, interfere with folate and B12 metabolism, and increase risk of accidents or missed medicines.
Frequently asked questions (FAQs)
1. Is methionine synthase deficiency the same as classic homocystinuria?
No. Classic homocystinuria usually refers to cystathionine β-synthase (CBS) deficiency, while methionine synthase deficiency (cblG type) affects the remethylation pathway. Both cause high homocysteine but differ in genetics, lab patterns (for example, methionine level), and treatment details.
2. Can this condition be cured?
At present, there is no complete cure, because the underlying gene change remains. However, many patients do very well when treated early and consistently with betaine, B12, folate, and careful diet. The goal is to keep homocysteine low, support brain development, and prevent complications, allowing as normal a life as possible.
3. Why is homocysteine dangerous?
Homocysteine in high amounts can damage the inner lining of blood vessels, making them more likely to form clots. It also increases oxidative stress and may be toxic to brain cells. Over many years, this raises risks of stroke, heart disease, and cognitive problems if not controlled.
4. Why do patients need life-long treatment?
Because the enzyme defect is genetic and present from birth, the body cannot “learn” to fix it. Vitamins and betaine act like tools that help bypass or support the pathway, but they must be present every day. Stopping treatment often leads to rising homocysteine and slow or sudden complications.
5. How often are blood tests needed?
In infants and during treatment changes, blood tests may be quite frequent (for example, every few weeks). In stable older children and adults, they might be spaced to every few months. The exact schedule is personalized and aims to keep homocysteine and methionine within target ranges without over-treating.
6. Can children with this condition attend regular school?
Many can, especially if diagnosed early and treated well. Some will need additional learning support, speech therapy, or physical aids. Collaboration between families, teachers, and the metabolic team helps build realistic expectations and the right accommodations.
7. Is pregnancy possible for women with methionine synthase deficiency?
Yes, but pregnancies are high-risk and need close planning with metabolic, obstetric, and hematology teams. Treatment often needs adjustment before conception and during pregnancy, and clot-prevention strategies may be considered. With good management, successful pregnancies are possible in many inherited metabolic disorders.
8. Are brothers and sisters at risk?
Because the condition is usually autosomal recessive, siblings of an affected child have a 25% chance of being affected, 50% chance of being carriers, and 25% chance of being unaffected if both parents are carriers. Genetic counseling and testing help clarify each sibling’s status.
9. What happens if treatment starts late?
Late treatment may not fully reverse brain injury, anemia, or vascular damage that has already occurred, but it can still lower homocysteine and prevent further harm. Some patients show impressive improvements even when treatment begins months after symptoms appear, especially with high-dose B12, folinic acid, and betaine.
10. Are there special risks during surgery or anesthesia?
Yes. Fasting, stress, and some anesthetic drugs can stress metabolism. Surgeries should be planned with the metabolic team, using clear perioperative protocols, adequate glucose, and continued vitamins and betaine wherever possible to avoid decompensation.
11. Can vaccines trigger crises?
Vaccines themselves rarely trigger crises; the main issue is fever or poor intake afterward. Using antipyretics, encouraging fluids, and following the sick-day plan keep things safe. The protection vaccines give against serious infections is generally far more important than the small, short-term risk.
12. Is a completely protein-free diet ever needed?
No. Protein is essential for growth, immune function, and tissue repair. The goal is controlled protein and methionine intake, not complete exclusion. Very low-protein diets without specialist supervision can cause severe malnutrition and must be avoided.
13. Can over-the-counter “homocysteine-lowering” supplements replace medical treatment?
No. Many commercial products contain B vitamins or other ingredients, but doses and quality control vary widely. They cannot replace prescription betaine, properly dosed B12 and folate, or medical monitoring. Using them without guidance may delay effective treatment or cause side effects.
14. How is this condition different from simple vitamin B12 deficiency?
In simple B12 deficiency, giving B12 alone usually corrects anemia and high homocysteine. In methionine synthase deficiency, the enzyme itself is faulty, so high-dose B12 must be combined with other measures like betaine and folate, and treatment is life-long. The pattern of lab results and genetics clearly distinguishes the two.
15. Where can families find trustworthy information and support?
Reputable sources include national metabolic disease organizations, rare disease databases, and genetic counseling services linked to major hospitals. These groups provide educational materials, connect families, and share updates about research and clinical trials, always encouraging families to discuss any new information with their own doctors.
Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.
The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members
Last Updated: January 27, 2025.
