Are You Confident of the Diagnosis?

Homocystinuria is a metabolic disorder of the aminoacid methionine. The first case of homocystinuria was reported from Northern Ireland in 1960. Classical homocystinuria is an autosomal recessive disease and is characterized by accumulation of homocysteine in the serum and excretion of homocystine in urine.

Newborn infants with homocystinuria appear healthy. Initial symptoms may appear as mild delay in development or failure to thrive. Increasing visual problems may lead to the diagnosis of this disorder. Occasionally seizures and muscular dystonia can be the initial manifestations.

What you should be alert for in the history

Classic homocystinuria is accompanied by a variety of clinical features involving four organ systems: the eye, skeletal, central nervous and the vascular systems. Other organs including the liver, hair and skin have also been reported to be involved. Clinical presentation may be variable, ranging from patients presenting with many complications to some presenting with only a few. The patient with cystathionine beta-synthase deficiency is normal at birth and if left untreated progressively develops the full-blown picture.

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At birth the symptoms and signs are vague. The neonate can present with brittle hair and seizures. Children can present with a stroke in early childhood with symptoms and signs of seizures and hemiparesis. They can also present with failure to thrive, visual problems, Facial flush, psychotic symptoms and mental retardation. Adolescents and adults can present with seizures, chest pain, visual symptoms, psychosis, mental retardation, symptoms and signs of cerebrovasculoar accident and thromboembolism.

Characteristic findings on physical examination

Cutaneous: facial flush, thin brittle hypopigmented hair, livedo reticularis on the extremities and rarely on the trunk (Figure 1, Figure 2, Figure 3).

Ocular: Ectopia lentis and high myopia are the major ocular manifestations. Ectopia lentis is the most frequent and consistent feature in classical homocystinuria and many cases have been diagnosed because of it. It occurs in 85% of cases of classical homocystinuria. Seventy percent of the patients develop ectopia lentis by 10 years of age. High myopia is seen in more than 50% of the patients. Other ocular manifestations include iridodenesis, glaucoma, retinal detatchment, central retinal artery occlusion.

Central nervous system: Mental retardation is the most frequent abnormality and often the first sign of classical homocystinuria. It may present as developmental delay. There is a wide variation in IQ reported (ranges from 10 to 138). Seizures occur in 21% of untreated patients. Many patients have psychiatric problems, including anxiety, depression, personality disorder, obsessive compulsive disorder, and psychotic episodes.

Skeletal: Skeletal changes are not evident at birth. The appearance of genu valugum and pes cavus are usually the first signs. By puberty, chest wall deformities occur. Affected individuals are tall and slender with asthenic habitus. Fifty percent of the individuals show osteoporosis by their teens. Osteoporosis is an important feature that differentiates this condition from Marfan’s syndrome. Other findings include scoliosis, kyphosis, high arched palate, pectus carinatum or pectus excavatum, and genu valgum.

Vascular: The cardinal feature in classical homocystinuria is thromboembolism affecting both large and small arteries and veins. Vascular occlusion can occur at any age. Fifty percent of the patients develop vascular complications by 30 years of age. Preganancy increases the risk of thromboembolism.

Other manifestations include colicky abdominal pain, pancreatitis, and pancreatic pseudocysts.

Expected results of diagnostic studies

Early diagnosis of homocystinuria is vital to prevent mental retardation, delayed development, ocular complications and, in the long run, prevention of thromboembolic phenomenon.

The best possible option is an extended newborn screening program. The Guthrie test is done as a newborn screening test to detect inborn errors of aminoacid metabolism. It is gradually being replaced by tandem mass spectometry, which can detect a wider variety of congenital diseases.

Early diagnosis of homocystinuria can be made and the child can be put on a protein- and methionine-restricted diet to prevent the accumulation of toxic intermediaries and correct the biochemical abnormality. This will prevent most of the complications and help in near normal development of the child. When the diagnosis is made during adolescence and adulthood specific dietary restrictions and medications can lessen the development of long term complications.

The diagnosis is based on clinical features and results of laboratory analysis.


Urine examination

–Cyanide-nitroprusside test (Brand test): It is a qualitative screening test for the presence of homocystine in urine. It is not a totally sensitive or specific test. The test is also positive in patients with high creatinine levels, acetonuria, cystinuria and in those taking penicillamine.

–Silver nitroprusside test: This test is more specific as it excludes cystinuria.

Blood examination: It is essential for the diagnosis of classical homocystinuria to be confirmed by determination of amino acids in fasting blood (Table I).

Table I.
Analyte Specimen Expected findings in affected neonate Expected findings in untreated individual control
homocystine plasma 10-100 micromol/litre >100 micromol/litre <1 micromol/litre
Total homocysteine Plasma 50-100 micromol/litre >100 micromol/litre <15 micromol/litre
Methionine Plasma 200-1500 micromol/litre >50 micromol/litre 10-40 micromol/litre 
Homocystine Urine Detectable Detectable Undetectable

Direct enzyme assays: Estimating the cystathionine beta synthase enzyme in liver biopsy specimens or cultured skin fibroblasts or cultured lymphocytes.

Molecular diagnosis: Screening for cystathionine beta synthase mutations can be done on cultured fibroblasts.

Antenatal diagnosis: Prenatal diagnosis of cystathionine beta synthase deficiency has been feasible. Extracts of cells from cultured amniotic fluid activity contains readily detectable activity of cystathionine beta synthase.

Diagnosis confirmation

The main differential diagnosis includes Marfan’s syndrome (Table II). The features common to both include tall and slender habitus, myopia, ectopia lentis, and chest deformities.

Table II.
Inheritance       Autosomal recessive  Autosomal dominant
Mental retardation Common Uncommon
Thrombosis Common Uncommon
Osteoporosis Frequent at a young age Absent
Genu valgum and scoliosis Uncommon Common
Hair changes Present Absent
Ectopia lentis Downwards & in Upwards&out
Who is at Risk for Developing this Disease?

Homocystinuria is worldwide in distribution. Incidence is approximately 1:335,000 but varies from 1:65,000 (Ireland) to 1:900,000 (Japan).

What is the Cause of the Disease?

Homocystinuria is a disorder of methionine metabolism. Classical homoycystinuria occurs due to deficiency of the enzyme cystathionine beta-synthase. It is an autosomal recessive disorder due to mutations in cystathionine beta-synthase gene. Less common causes of homocystinuria are :

  • Defects in 5, 10- methylene tetrahydrofolate reductase activity which result in vitamin B12 deficiency

  • Transcobalamin deficiency which causes defective cellular uptake of vitamin B12.

  • Defect in remethylation of homocysteine to methionine resulting in insufficient vitamin B12 synthesis and subsequently homocystinuria. Methylmalonic aciduria is present.

  • Deficiency of methylene tetrahydrofolate reductase


Homocysteine is metabolised by means of two pathways: remethylation and transsulfuration The remethylation pathway comprises two intersecting pathways and results in the transfer of a methyl group (CH3) to homocysteine from methylcobalamin, which receives its methyl group from S-adenosyl cobalamin (universal methyl donor) which participates in many metabolic pathways, including methylation of DNA and myelin.

The transsulfuration pathway of homocysteine/methionine degradation produces the aminoacids cysteine and taurine. This pathway is dependent on the adequate intake of vitamin B6 and the conversion of vitamin B6 into its active form, pyridoxal-5’ phosphate (P5P). The aminoacid serine, a metabolite generated from betaine via remethylation pathway is another necessary step.

Cystathionine beta-synthase is an enzyme that converts homocysteine to cystathionine in the transulfuration pathway. It requires P5P as a cofactor. Folate and vitamin B12 are required for the methylation of homocysteine to methionine.

In classical homocystinuria, the characterstic aminoacid profile includes homocystinuria and hyperhomocysteinaemia, hypermethionaemia and low plasma cystine and cystathionine.

Systemic Implications and Complications

Patients with homocystinuria in the long run can develop atherosclerotic heart, cerebrovascular disease and pancreatitis. The patients need to be monitored for these diseases.

Treatment Options

There is no cure for homocystinuria and the treatment should be given lifelong. The aim of treatment is to prevent complications by early diagnosis and treatment. If the disease is diagnosed in the newborn infant, as ideally it should be, the aim must be to prevent the development of ocular, skeletal, intravascular thromboembolic complications and to ensure the development of normal intelligence.

If the diagnosis is made late when some recognized complications have already occured, then the goal must be to prevent life-threatening thromboembolic events and to prevent further escalation of the complications already suffered.

Optimal Therapeutic Approach for this Disease

The currently available modalities of treatment include:

  • Vitamin B6 (Pyridoxine) therapy

  • Methionine restricted, cysteine supplemented diet

  • Betaine, a methyl donor

  • Folate and vitamin B12 supplementation

The best option is to diagnose the disease in the newborn by extended newborn screening before the newborn leaves the hospital.

Treatment depends upon pyridoxine (vitamin B6) responsiveness.

Pyridoxine trial to ascertain responsive status

All newly diagnosed patients must be given a pyridoxine trial while remaining on normal diet. Pyridoxine 50mg three times a day in the neonate and 100-200mg three times a day in older children is given to asses vitamin responsiveness.

Biochemically, vitamin B6 responsiveness is indicated by falling homocysteine and methionine levels while remaining on pyridoxine, in the presence of adequate vitamin B12 and folate. While on pyridoxine, the patient is deemed vitamin responsive when the free homocystine is <5 mmol/L. If the free homocystine and methionine levels remain persistently elevated or rise while on pyridoxine then the patients is biochemically pyridoxine nonrespnsive.

The status of pyridoxine responsiveness in a neonate may be difficult to determine based on biochemistry alone. While on trial of pyridoxine, a fall in homocysteine and methionine levels due to coincidental growth spurt may be mistakenly attributed to pyridoxine responsiveness.

Pyridoxine responsive patients have a less severe disease compared to pyridoxine non responders. The nonresponders are treated with Betaine and put on methionine restricted diet.


Approximately 50% of classical homocystinuria patients respond to pharmacological doses of pyridoxine (30-600mg orally once a day can be increased to 1000-1200mg per day if necessary).

There are no reported side effects from the usage of high dose of pyridoxine (up to 500mg/day) in classical homocystinuria. Misuse of mega doses of pyridoxine (2-6gm/day) can result in ataxia and sensory neuropathy which are improved on withdrawl of the drug.

Methionine restricted, cysteine rich diet

An early diet consisting of methionine restriction and cysteine supplementation is of paramount importance. Currently, proprietary formulas based on a methionine-free synthetic mixture supplemented with cysteine are virtually in exclusive use.

Diet for homocystinuria patient

Forbidden foods:

(a) Meat, chicken, fish, eggs

(b) Milk, cheese, curd, ice cream, chocolates, Horlicks, Ovaltine

(c) Wheat flour, bajra, maize, barley, jowar, oatmeal, bread, cakes, biscuits, pastries

(d) Rice and pulses

(e) Maggi and other soup cubes

(f) Peas

Foods to be consumed in moderate amounts:

(a) Beans, beet root, cauliflower, cabbage, carrot, onion, potatoes, radish, sweet potato, brinjal, ladies finger, pumpkin, tomatoes

(b) Banana, grapes, mango, guava, papaya, apple

Unrestricted foods:

(a) Arrowroot, cornflour sago, custard powder

(b) Sugars, honey, jam, jellies

(c) Butter, cooking fat, oil

(d) Tea, coffee, squash

(e) Salt, pepper, vinegar, spices, curry powder


Betaine is useful in pyridoxine nonresponders who cannot tolerate a methionine-restricted diet or as an adjunct to such a diet. Treatment with betaine provides an alternate remethylation pathway to convert excess homocysteine to methionine and may help to prevent complications, especially thrombosis. In converting homocysteine to methionine, betaine lowers the plasma homocysteine levels but raises plasma methionine levels.


Adults: 4-6gm/day orally in two divided doses

In children < 3 years: 100mg/kg/day orally

Side effects are few: (1) detectable body odor in some individuals (2) the increase in methionine is usually harmless but can cause cerebral edema when the values are very high (>1000 micromoles/litre). Cerebral edema can be resolved by stopping the drug.

Folate and vitamin B12 supplementation

Folate and vitamin B12 optimize the conversion of homocysteine to methionine by methionine synthase, thus helping to decrease plasma homocystine concentration. When the red blood cell folate and vitamin B12 concentrations are reduced, supplementation is given. Folic acid is given in dose of 1 to 5 milligram orally once a day. Vitamin B12 given as cyanocobalamin 25-250 micrograms per day or hydroxycobalamin 1 milligram intramuscular per month.

Management of complications

Ocular: management of myopia, glaucoma, surgical removal of lens in case of ectopia lentis.

Skeletal: surgial correction of deformities and management of osteoporosis

Vascular: prevention and management of thromoemboic events.

Patient Management

Patients should be periodically tested for plasma homocysteine and methionine. The patient and family members should be educated about the chronic nature of the disease and the need for strict compliance with regard to diet and treatment.

Parents of a child should be counseled by a genetics professional concerning discuss future pregnancies.

Unusual Clinical Scenarios to Consider in Patient Management

Patients with homocystinuria are prone to develop thromboembolic complications, especially during pregnancy and following surgery. Because women are prone to thromboembolism, especially in the postpartum period, prophylactic anticoagulation during during the third trimester of pregnancy and postpartum is recommended

The usual regimen is injection of low molecular weight heparin during the last two weeks of pregnancy and first six weeks postpartum. Aspirin in low doses has also been given throughout pregnancy.

What is the Evidence?

Yap, S. “Homocystinuria due to cystathionine ß-synthase deficiency”. Orphanet encyclopedia. February 2005. (The aims of treatment in classical homocystinuria vary according to the age of diagnosis. If CbS deficiency is diagnosed in the newborn infant, as ideally it should be, the aim then must be to prevent the development of ocular, skeletal, intravascular and thromboemobolic complications and to ensure the development of normal intelligence. On the other hand, if diagnosed late when some recognized complications have already occurred, then the clinician’s goal must be to prevent life-endangering thromboembolic events and to prevent further escalation of complications already suffered.)

Lawson-Yuen, A, Levy, HL. “The use of betaine in the treatment of elevated homocysteine”. Mol Genet Metab. vol. 88. 2006. pp. 201-7. (Discussion of the disease and therapeutic options. Betaine is useful in pyridoxine nonresponders who cannot tolerate a methionine restricted diet. Treatment with betaine provides an alternative remethylation pathway to convert excess homocysteine to methionine and may help to prevent complications especially thrombosis.)

Mudd, SH, Skovby, F, Levy, HL, Pettigrew, KD. “The natural history of homocystinuria due to cystathionine beta-synthase deficiency”. Am J Hum Genet. vol. 37. 1985. pp. 1-31. (Excellent overall review of the disease. Discusses the natural history of the disease.)

Mudd, SH, Levy, HL, Kraus, JP, Scriver, CR, Beaudet, AL, Sly, WS, Valle, D. “Disorders of transulfuration”. The metabolic and molecular basis of inherited disease.. 2001b. pp. 2016-40. (The transulfuration pathway of homocysteine/methionine degradation produces the aminoacids cysteine and taurine. This pathway is dependent on the adequate intake of vitamin B6 and the conversion of vitamin B6 to its active form. pyridoxal5’-pyrophosphate.)

Yaghmai, R, Kashani, AH, Geraghty, MT, Okoh, J. “Progressive cerebral edema associated with high methionine levels and betaine therapy in a patient with cystathionine beta-synthase(CBS) deficiency”. Am J Med Genet. vol. 108. 2002. pp. 57-63. (Complications of the disease and of some therapies is discussed.)

Yap, S, Rushe, H, Howard, PM, Naughten, ER. “The intellectual abilities of early-treated individuals with pyridoxine-nonresponsive homocystinuria due to cystathionine beta-synthase deficiency”. J Inherit Metab Dis. vol. 24. 2001b. pp. 437-47. (Discusses early therapeutic intervention on the outcome of those afflicted with homocystinuria.)

Yap, S. “Classical homocystinuria: vascular risk and its prevention”. J Inherit Metab Dis. vol. 26. 2003. pp. 259-65. (Review of homocystinuria, with emphasis on the risk of thromobosis.)