Dihydropyrimidine Dehydrogenase Deficiency

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This disorder is caused by a problem with the DLD gene. This gene provides instructions for the dihydrolipoamide dehydrogenase (DLD) enzyme which represents one component of three different groups of enzymes (BCKD, PDH, αKGDH) that work together. BCKD is involved in breaking down three amino acids (leucine, isoleucine, valine) that are commonly found in protein-rich foods and therefore, producing molecules that are used for energy. PDH and αKGDH transform the energy from food into energy a cell can use.

If you have a problem with the DLD gene, the BCKD, PDH and αKGDH will not work properly. Therefore, some molecules will not be broken down and their byproducts will not build up in the body. This will damage tissues, lead to lactic acidosis, chemical imbalances, and diminution of cellular energy.

We do not know how many people have this disorder. It is rare with only a small amount of cases that are known. However, it is estimated 1 in 35,000 to 48,000 individuals of Ashkenazi Jewish descent is affected by the disorder. This population typically has a liver disease as the primary symptom.

Signs and symptoms of this condition usually appear shortly after birth, and they can vary widely among affected individuals.

A common feature lactic acidosis can cause:

• Nausea
• Vomiting
• Severe breathing problems
• Abnormal heartbeat

Another common feature includes neurological problems:

• Decreased muscle tone (hypotonia)
• Extreme tiredness (lethargy)
• Difficulty feeding
• Decreased alertness

Liver problems that range from an enlarged liver (hepatomegaly) to life-threatening liver failure may also occur and in some patients may be the primary symptom. They can occur any time between infancy and childhood and are usually followed by vomiting and abdominal pain.

Other symptoms are:

• Weakness of the muscles used for movement (skeletal muscles)
• Droopy eyelids
• Weakened heart muscle (cardiomyopathy)
• Excess ammonia in the blood (hyperammonemia)
• Buildup of molecules called ketones in the body (ketoacidosis)
• Low blood sugar levels (hypoglycemia)
• Vision impairment / optic atrophy

This deficiency typically occurs in episodes that are triggered by fever, injury, or other stresses on the body. Many infants do not survive the first years of life. Those who survive past childhood usually have delayed growth and neurological problems:

• Intellectual disability
• Muscle stiffness (spasticity)
• Difficulty coordinating movements (ataxia)
• Seizures

You will be diagnosed after a clinical examination and specialised blood and urine tests by your specialist or doctor. This deficiency may also be detected through routine newborn screening. The UK does not offer newborn screening for Dihydrolipoamide dehydrogenase deficiency. A genetic test may be needed to confirm the diagnosis. 

This is a progressive disorder and unfortunately, there is no cure. Therefore, treatment is focused on managing individual symptoms and providing comfort and relief in the form of supporting the individual and any family members. A multi-disciplinary team of specialists and support networks will be involved in the management of the condition and to offer practical and emotional support. 

 The assistance of a specialist dietitian is advised to follow bespoke diet and supplement requirements. Feeding therapy and consideration of a gastrostomy tube for persistent feeding issues are recommended. Specialists shall be consulted to manage developmental delay / intellectual disability, cardiac dysfunction, and vision impairment / optic atrophy. Liver problems may require the removal or treatment of precipitating factors and dialysis.   

Dihydrolipoamide dehydrogenase deficiency 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 Dihydrolipoamide dehydrogenase deficiency. 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 Helen Morris by phoning 0845 241 2173 or emailing contact@metabolicsupportuk.org [Resource Library No: AAP002].