2-Methylbutyryl-CoA dehydrogenase deficiency

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2-Methylbutyryl-CoA dehydrogenase deficiency is an organic acid disorder in which the body is unable to break down an amino acid called isoleucine.

Amino acids are the building blocks of protein. Our body uses different enzymes, controlled by genes to break down protein from the food we eat into smaller amino acids so the body can use them as required. Any excess amino acids are broken down further into smaller substances like organic acids and ammonia which are removed from the body via the liver.

This condition is caused by defects in the ACADSB gene (otherwise known as the SBCAD gene). This gene produces an enzyme called 2-methylbutyryl-CoA dehydrogenase which is needed to break down isoleucine into the smaller amino acids. However, the defect in the gene means there is not enough enzyme produced and therefore isoleucine is not broken down. This causes isoleucine and other acids to build up in the body which can become toxic.

Since its first discovery, 30 individuals have been diagnosed with this metabolic condition worldwide. Mostly amongst the Hmong population, an ethnic group of Chinese origin. Both males and females are affected by the metabolic disorder.

In most cases people with this disorder have no symptoms (asymptomatic), however there are others who have delays in reaching developmental milestones or who have neurological symptoms.

Signs and symptoms of the disorder can begin a few days after birth with poor feeding, lack of energy, vomiting, and irritability. If not treated promptly, these symptoms may progress to a metabolic crisis in which the acids build up quickly and the condition can become life-threatening.

Other symptoms may include:

• Low muscle tone (hypotonia)
• Delay in developing motor skills (Motor skills are movements using the muscles – gross motor skills are movements using bigger muscles such as those in the arms and legs and core muscles to perform skills such as sitting, crawling, standing, walking, and climbing. Fine motor skills are movements using smaller muscles which are used to perform skills such as sucking, picking up objects, passing objects between hands, pointing, and writing)
• Poor feeding
• Hypothermia (low body temperature)
• Hypoglycaemia (low blood sugar)
• Lethargy
• Episodes of apnoea (when breathing stops and starts, usually while you sleep)
• Hypoxia (low oxygen levels in the blood)

It is not yet certain why some people develop symptoms and others do not. It has been suggested that in some cases signs and symptoms may be triggered by illness, long periods without food, or foods containing protein.

In some countries, such as the USA this condition can be diagnosed via newborn screening. In other countries, it may be diagnosed using a complete physical examination, a thorough medical history evaluation and a range of specialised blood and urine tests.

There is no cure for this disorder and therefore any treatment is lifelong. Treatment will be directed by a consultant with expertise in inherited metabolic disorders who will tailor any management plan to individual need and symptoms. Due to the variable nature of this condition there is not a one-size-fits-all approach to treatment. Those with this condition may be given an emergency regimen (in the form of a specialised glucose drink) to follow should they feel unwell or are not tolerating food. If illness continues or the regimen is not tolerated then urgent medical care must be sought and the regimen will continue in hospital via a glucose drip (intravenously). Those with this condition may be advised to follow a low-protein diet and be provided with supplements. Dietary management will be supported and monitored by a specialist dietitian. Those affected may also be advised to avoid triggers such as long periods without food, intense physical activity and environmental extremes to prevent crises from occurring.

This condition 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 inherited this condition. 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.

References are available on request. Please contact us by phoning 0845 241 2173 or emailing contact@metabolicsupportuk.org [Resource Library No: MAP027].