Homocystinuria - all you need to know

What is in this report:


We’ve taken the latest medical information used by doctors from clinical databases and broken down all the medical terms into easy pieces to give you everything you need to navigate this condition throughout life.


If you had any trouble understanding something in this report, please feel free to reach us at founders@lamarhealth.com. We’ll get back to you immediately.  


This report has 5 main sections:

1.    Summary

2.    Symptoms

3.    Treatment/Management

4.    Agents/Circumstances to Avoid

5.    Resources


A brief summary of Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency

Homocystinuria caused by Cystathionine Beta-Synthase Deficiency is a condition caused by problems breaking down an amino acid called methionine found in protein in food. (Cystathionine Beta-Synthase Deficiency).

Babies with homocystinuria look healthy and normal at birth. Over time, if the condition is not treated, it can cause growth and learning delays. It can also affect the eyes, bones, heart, and blood vessels.

This disorder impacts different body systems thus causing various signs and symptoms in affected individuals. The seriousness of the symptoms varies from person to person ranging from mild to severe.

Homocystinuria is also called:

  • Homocystinemia
  • Cystathionine beta-synthase deficiency
  • CBS deficiency

Homocystinuria caused by cystathionine β-synthase (CBS) deficiency is characterized by affecting different body systems, for instance, the eye: dislocation of the lens and/or short-sightedness (ectopia lentis and/or severe myopia); skeletal system: excessive height, long limbs, spine twist and curve to the side (scoliosis) and sunken/funnel chest deformity (pectus excavatum), vascular system: a circulating blood clot that gets stuck and causes an obstruction of the blood vessel (thromboembolism), and central nervous system: delay in reaching language, thinking, social, or motor skills milestones  (developmental delay/intellectual disability). All four ‒ or only one ‒ of the systems can be involved; the degree of all of the expression of the clinical signs is variable. It is not unusual for a previously asymptomatic individual to present in adult years with only a thromboembolic event- which occurs when a blood clot breaks off and blocks another blood vessel that is often located in the brain.

Torn-off blood clot which occludes a blood vessel in different body parts, for instance in the brain, (thromboembolism) is the major cause of early death and morbidity. IQ in individuals with untreated homocystinuria ranges widely, from 10 to 138. In B6-responsive individuals, the mean IQ is 79 versus 57 for those who are B6-non-responsive. Other features that may occur include seizures, psychiatric problems, inability to sit still, involuntary muscle contraction, tremors, stiff muscles, involuntary facial movements (extrapyramidal signs (e.g., dystonia)), loss of the colour (hypopigmentation) of the skin and hair, a rash on the nose and cheeks (malar flush), netlike pattern of reddish-blue skin discolouration (livedo reticularis), and inflammation of the pancreas (pancreatitis).




From a number of research studies by scientists and doctors on CBS, below are lists of symptoms that have been seen in CBS patients. Different people will have very different symptoms so you may not necessarily have some or any of the below.


It’s sometimes helpful to know what other people have seen just so there’s less uncertainty about what to expect.


Homocystinuria is characterized by the involvement of the eye, skeletal system, vascular system, and central nervous system. All four or only one of the systems can be involved.


It is not unusual for a previously asymptomatic individual to present in adult years with only a  blood clot causing an obstruction (thromboembolic event) that is often located in the brain blood vessel (cerebrovascular).


There are two types of homocystinuria. The milder type can be treated with vitamin B6 supplements. The other type does not respond to vitamin B6. Symptoms of both types vary widely from person to person. B6-responsive homocystinuria is typically (but not always) milder than the non-responsive variant. Vitamin B6 responsiveness is determined by a pyridoxine challenge test.

Eyes. Short-sightedness (myopia) followed by lens dislocation (ectopia lentis) typically occurs after the age of one year. In the majority of untreated individuals, lens dislocation occurs by the age of eight years. This usually happens earlier in affected individuals who are B6 non-responsive than in those who are B6 responsive. Rarely, lens dislocation occurs in infancy.

High short-sightedness may be present in the absence of lens dislocation.


Skeletal system

Affected individuals are often tall and slender including long limbs, an arm span that is at least 1.03 of the height of the individual, and a tooth crowding, sometimes with a high arch in the palate, long, slender, and curved fingers (arachnodactyly), and hypermobility of the joints. This body appearance is described as marfanoid habitus.


Individuals with homocystinuria are prone to decreased bone density (osteoporosis), especially of the small bones forming a backbone( vertebrae) and long bones (bones in the upper and lower limbs); 50% of individuals show signs of bone density decrease (osteoporosis) by their teens. Osteoporosis may be detected radiographically by a side view of the lower (lumbar) spine or bone density studies. DXA bone density analysis usually shows reduced density in the lower (lumbar) spine and hip [Weber et al 2016].


Spine side curvature (scoliosis), high-arched palate, long, slender and curved fingers (arachnodactyly), elevated foot arch (pes cavus), a funnel chest and pigeon chest – breastbone deformities (pectus excavatum or pectus carinatum), and knock-knee deformity (genu valgum) are also frequently seen.


Vascular system. 

Blood vessel occlusion due to the ripped-off blood clot (thromboembolism) is the major cause of morbidity and early death . It can affect any vessel. Blood clots accidents in the brain have been described in infants, although problems typically appear in young adults.


Among B6-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature of homocystinuria. Cerebral venous sinus thrombosis occurs when a blood clot forms in the brain’s venous sinuses which prevents blood from draining out of the brain and it has been a presenting sign in childhood.


Pregnancy increases the risk for thromboembolism, especially in the period after delivery  (postpartum); most pregnancies, however, are uncomplicated.


CNS (central nervous system). 

Delay in reaching language, thinking, social, or motor skills milestones (developmental delay) is often the first abnormal sign in individuals with homocystinuria. IQ in individuals with homocystinuria ranges from 10 to 138. B6-responsive individuals are more likely than individuals with B6-non-responsive homocystinuria to be cognitively intact or only mildly affected; the mean IQ of untreated individuals with B6 responsiveness is 79 versus 57 for those who are B6 non-responsive. B6-non-responsive individuals who were identified on newborn screening received early treatment and had good compliance (maintenance of plasma-free homocysteine <11 μmol/L) and had a mean IQ of 105.


Seizures occur in 21% of untreated individuals.


Many individuals have psychiatric problems including personality disorder, anxiety, depression, obsessive-compulsive behaviour, and delusions or hallucinations (psychotic) episodes. Psychosis may be a presenting sign in adolescence.


Nervous system impairments signs such as movement disorder that causes the muscles to contract involuntarily (dystonia) may occur.


Other features 

include loss of colour (hypopigmentation) of the skin and hair, a rash on the nose and cheeks (malar flush), netlike pattern of reddish-blue skin discolouration (livedo reticularis), and inflammation of the pancreas (pancreatitis).




Treatment of symptoms: Treatment aims to correct biochemical abnormalities, especially to control plasma homocysteine concentrations and prevent the formation of blood clots (thrombosis). Complications of homocystinuria should be managed appropriately; e.g., by surgery for dislocated eye lens (ectopia lentis).


Prevention of primary manifestations: Individuals are treated to maintain normal or near-normal plasma total homocysteine concentrations using vitamin B6 (pyridoxine) therapy (if shown to be B6 responsive), a methionine-restricted diet, and folate and vitamin B12 supplementation. Betaine therapy is usually added to the therapeutic regimen; in adolescents and adults, betaine may be the major form of treatment, but it is preferable to remain on a life-long metabolic diet.


Surveillance: Affected individuals should be monitored at regular intervals to detect any clinical complications that may develop, for dietary compliance and measurement of plasma total homocysteine and amino acids.


Agents/circumstances to avoid: Hormone-containing medications that are taken by mouth to prevent pregnancy (oral contraceptives) in affected females. Surgery if possible. If surgery is required, appropriate fluid intake is important (intravenous fluid with 5% dextrose in 0.5 normal salines at 1.5 times maintenance should be given and continued until oral fluids are taken ad lib), with close monitoring to avoid fluid overload.


Evaluation of relatives at risk: Measurement of total homocysteine and amino acids in at-risk sibs immediately after birth ensures reduction of disease incidence (morbidity) and death rate (mortality) by early diagnosis and treatment. If the cystathionine beta-synthase (CBS) pathogenic gene variants in the family are known, molecular genetic testing can be used to clarify the genetic status of sibs


Pregnancy management: For women with classic homocystinuria: dietary treatment and betaine, and vitamin B6 for those B6 responsive, with careful biochemical monitoring throughout pregnancy. Prophylactic anticoagulation to prevent blood clot formation with blood thinner low molecular-weight heparin is recommended during the third trimester and after baby delivery (postpartum) to reduce the risk of a blood clot-caused vessel occlusion complication (thromboembolism).


Agents/Circumstances to Avoid


Hormone-containing medications that are taken by mouth to prevent pregnancy (oral contraceptives), which may tend to increase blood clot formation (coagulability) and represent a risk for blood clot-related blood vessel occlusion (thromboembolism), should be avoided in females with homocystinuria.


Surgery should also be avoided if possible because the increase in plasma homocysteine concentrations during surgery and especially post-surgery elevates the risk for a thromboembolic event. If surgery is required, appropriate intravenous fluid administration is required before, during, and after surgery until fluids can be taken orally. If fluids this maintenance represent a risk in people with a known heart condition as a result of fluid overload, basic fluid maintenance may be administered with careful clinical observation. 



Eesha Sharma

Written By: Eesha Sharma

Genetics Ph.D., Stanford Alumni

Sister of Rare Disease Patient

CEO, Founder

Lamar Health