Methionine Synthase Deficiency – cblG

What else is it called?

  • Functional methionine synthase deficiency type cblG 
  • Homocystinuria without methylmalonic aciduria 
  • Functional methionine synthase deficiency 
  • Methylcobalamin deficiency, cblG type 
  • Homocystinuria-megaloblastic anemia, cblG complementation type; hmag 
  • Homocystinuria-megaloblastic anemia due to defect in cobalamin metabolism, cblG complementation type 
  • Methionine synthase deficiency 

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What causes it?

Methionine Synthase Deficiency- cblG is caused by a problem in the MTR gene. This gene provides instructions for making an enzyme called methionine synthase. Methionine synthase is essential for the synthesis of methionine, which is important for protein synthesis and other critical functions in the body. 

The problem in the MRT gene leads to its limited activity or complete absence of its activity in the body. As a result, the body is unable to process certain amino acids (building blocks of protein) properly.  

How common is it?

Methionine Synthase Deficiency cblG is an extremely rare condition, and its exact prevalence is unknown. Up to now, 38 cases of this disorder have been reported in the scientific literature.  

What are the signs and symptoms?

Most often, this condition presents within the first 2 years of life. However, the onset of symptoms can vary from feeding difficulties being apparent in the neonatal period to more rarely, psychiatric symptoms or acute changes in brain function occurring in adolescence or adulthood. 

Signs and symptoms of this condition can vary significantly and can include:  

  • seizures 
  • a disturbance of brain function (encephalopathy) 
  • a blood disorder caused by your bone marrow producing red blood cells which are larger than average (macrocytic anaemia) 
  • weak muscle tone (hypotonia) 
  • pain, weakness, or a partial inability to move the legs or hips 
  • delays in reaching developmental milestones 
  • small head size (microcephaly) 
  • instability when walking 
  • tremors 
  • failure to grow or gain weight (failure to thrive) 
  • learning difficulties 
  • repetitive involuntary eye movements (nystagmus) 
  • yellowing of the skin and whites of the eyes (jaundice) 
  • diarrhoea  

How is it diagnosed?

Because of the variation in symptoms this disorder is often misdiagnosed as other conditions including multiple sclerosis. It can therefore take a while to reach a confirmed diagnosis. The discovery of a build-up of homocysteine levels in the blood and urine and a decreased amount of methionine may raise suspicion and warrant more tests to rule out related inherited metabolic disorders. This disorder can be confirmed by genetic testing. 

Can it be treated?

There is no cure for this disorder at the moment. The treatment is based on intramuscular injections of hydroxycobalamin. In some cases, doctors may recommend additional treatment with folates and betaine. 

With the treatment, the prognosis is generally good as clinical symptoms disappear or improve quicky after the initiation of the treatment.  

Do my family need to be tested?

Methionine Synthase Deficiency – cblG can only be passed on to a child if both parents have a copy of the faulty gene. This is called autosomal recessive inheritance. A person who has a copy of the faulty gene is known as a carrier. 

If both parents are carriers, their child has a one in four (25%) chance of inheriting the disorder, and a one in two chance (50%) of being a carrier. This is the same for each child the parents have. 

If the child only inherits one copy of the faulty gene, they will be a carrier but will not have the disorder. In some rare cases, carriers have had mild symptoms of the disorder for which they carry the faulty gene.  

Once you are diagnosed, you can speak to a genetic counsellor. They can explain how you may have Methionine Synthase Deficiency – cblG. They can also tell you about genetic testing for the rest of your family. They can provide advice and support if you go on to have children of your own or plan future children. 

Relevant Organisations


References are available on request. Please contact Metabolic Support UK by phoning 0800 652 3181 or emailing [Resource Library No: MAP063]. 

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