Methylmalonic Acidaemia and Homocystinuria Combined

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MMA & HCU is a rare metabolic disorder that prevents the body from breaking down fats and certain amino acids which are found in protein (leucine, valine, methionine, and threonine) . This causes a build up of harmful substances in the body.

MMA & HCU is caused by problems in several genes. There are different forms of this condition and this is determined by which gene has the problem. A problem in the MMACHC gene will cause the Cobalamin C (CblC) type, which is the most common form of MMA & HCU. The remaining types are much rarer and are caused by the following genes:

• Cobalamin D (CblD) – MMADHC gene
• Cobalamin F (CblF) – LMBRD1 gene
• Cobalamin J (CblJ) – ABCD4 gene
• Cobalamin X (CblX) – HCFC1 gene

These genes are needed to convert cobalamin (also known as vitamin B12) into a form that the body can use. It is broken down into one of two molecules. These are called Adenosylcobalamin (AdoCbl) and Methylcobalamin (MeCbl).

AdoCbl is needed to break down some amino acids, lipids and cholesterol. MeCbl is needed for another chemical reaction in the body which converts an amino acid called homocysteine into another one called methionine.

A problem in the genes means your body will not make enough of these two molecules. As a result, your body will not break down amino acids and lipids properly causing toxic substances to accumulate. The amino acid homocysteine will also build up in the blood and urine as it cannot be converted, this also means you will have low levels of methionine too.

The Cobalamin C (CblC) form affects approximately 1 in every 200,000 newborns worldwide. It may have a higher incidence in California, USA. Other forms of MMA&HCU are significantly rarer.

This condition affects individuals differently and although it most often presents in infancy, the condition can occur at any age. During infancy symptoms may include:

• Failure to grow or gain weight at the expected rate
• Lack of interest in food/feeding
• Lethargy
• Weak muscle tone
• Seizures
• Pale skin
• Small head size (microcephaly)
• Fluid on the brain (hydrocephaly)
• Delays in reaching developmental milestones
• Learning difficulties

Less frequently, these symptoms may occur:

• Sight problems
• Skin rash
• Heart problems
• Kidney problems
• Anaemia

A sudden onset or progression of severe symptoms called a metabolic crisis can be triggered by a number of factors including a high amount of protein in the diet, a long period without food, illness or infection, and stress. If left untreated these crises can cause seizures, breathing problems, coma and can be fatal.

Symptoms can in some cases present for the first time anytime between childhood and into adulthood. In these cases, symptoms predominantly cause cognitive and behavioural problems. Symptoms include:

• A sudden decline or loss of skills related to thinking, reasoning and remembering (cognitive skills)
• Confusion
• Behavioural problems
• Episodes of psychosis, hallucinations, or delirium
• Lethargy
• Uncontrollable shaking or trembling (tremor)
• Subacute degeneration of the spinal cord (a condition causing numbness or weakness in the limbs, walking difficulties, unsteadiness, and frequent falls)
• Speech difficulties
• Blood clots
• Anaemia
• Sight problems
• Kidney problems

This condition can be diagnosed through specialised blood and urine tests. Diagnosis is confirmed through genetic testing. In some countries, this condition can be detected at birth via newborn screening programmes. This is not currently available in the UK.

There is no cure for this condition. Treatment is lifelong and will be overseen by a specialist in inherited metabolic disorders, and a specialist dietitian. Treatment involves:

• Avoidance of triggers (i.e. long periods without food, high levels of stress etc.)
• A low protein diet, as instructed by the specialist dietitian. This may include protein substitutes and formulas to ensure adequate nutrition.
• Medications such as vitamin B12 (hydroxocobalamin) or betaine

You will be given an emergency regimen to follow should you become unwell or if symptoms suddenly worsen. This will be fully explained to you by your consultant.

Other treatment is symptomatic and supportive.

Humans have chromosomes composed of DNA. Genes are pieces of DNA that carry the genetic instruction. Each chromosome may have several thousand genes. We inherit particular chromosomes from the egg of the mother and sperm of the father. The genes on those chromosomes carry the instructions that determine a person’s characteristics, which are a combination of the parents.

This is an inherited condition. There is nothing that could have been done to prevent it.

Everyone has a pair of genes that are needed to convert cobalamin. If you have this condition, neither of these genes works correctly. You will inherit one non-working gene from each parent.

Parents of children with this condition are known as carriers. Carriers do not have the disorder because the other gene of this pair is working correctly.

When both parents are carriers, in each pregnancy the risk to the baby is as follows:

• 25% chance (1 in 4) of developing the condition
• 50% chance (1 in 2) for the baby to be a carrier
• 25% chance (1 in 4) for the baby to have two working genes and neither have the condition, nor be a carrier

References are available on request. Please contact us on 0800 652 3181 or by emailing contact@metabolicsupport.org.

Please note calls to 0800 numbers are free from UK landlines and mobiles. Calls from business lines may be charged – please check with your provider.

This information about metabolic diseases is provided by Metabolic Support UK and is intended for educational purposes only. It should not be used for diagnostic or treatment purposes.

Should you require more detailed information please contact Metabolic Support UK by email (contact@metabolicsupport.org) or by telephone ( 0800 652 3181). For specific medical information regarding a disorder or individual please contact your GP or Paediatrician. Metabolic Support UK accepts no responsibility for any errors or omissions nor does Metabolic Support UK assume any liability of any kind for the content of any information contained within this summary or any use that you may make of it.