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Dihydrolipoamide dehydrogenase deficiency


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Other Names:
Pyruvate dehydrogenase E3 deficiency; DLD deficiency; E3-deficient maple syrup urine disease; Pyruvate dehydrogenase E3 deficiency; DLD deficiency; E3-deficient maple syrup urine disease; E3 deficiency; Maple syrup urine disease, type III See More
Categories:
Congenital and Genetic Diseases; Metabolic disorders; Nervous System Diseases
This disease is grouped under:
Lipoic acid biosynthesis defects; Pyruvate dehydrogenase complex deficiency

Summary Summary


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Dihydrolipoamide dehydrogenase (DLD) deficiency is a very rare condition that can vary in age of onset, symptoms and severity. The condition may be characterized by early-onset lactic acidosis and delayed development (most commonly); later-onset neurological dysfunction; or adult-onset isolated liver disease. Signs and symptoms may include lactic acidosis shortly after birth; hypotonia and lethargy in infancy; feeding difficulties; seizures; and various other health issues. Liver problems can range from hepatomegaly to life-threatening liver failure. Symptoms often occur in episodes that may be triggered by illness or other stresses on the body. Many affected infants do not survive the first few years of life; those who survive through early childhood often have growth delay and intellectual disability. Some with onset later in childhood may have neurological dysfunction with normal cognitive development. DLD deficiency is caused by mutations in the DLD gene and is inherited in an autosomal recessive manner.[1][2][3]
Last updated: 8/26/2015

Symptoms Symptoms


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The signs and symptoms of dihydrolipoamide dehydrogenase (DLD) deficiency can vary widely among affected people. Early-onset DLD deficiency typically appears in early infancy with decreased muscle tone (hypotonia), lethargy, and lactic acidosis. Lactic acidosis can cause nausea, vomiting, severe breathing problems, and an abnormal heartbeat. Symptoms typically occur in episodes that may be triggered by illness, injury, or other stresses on the body. Affected infants often do not survive their initial episode or may die within the first few years of life during a recurrent episode. Children who live beyond the first two to three years often have growth delays and neurological problems such as intellectual disability, spasticity, ataxia, and seizures. However, normal intellect has been reported in a few people with the early-onset form of DLD deficiency.[1][2][3]

Isolated liver involvement, which can range from hepatomegaly (enlarged liver) to life-threatening liver failure, can also occur in the newborn period, or as late as the 3rd decade of life. A few people with DLD deficiency have become affected later in childhood with ataxia and dystonia, with normal cognitive development. Rarely, affected people have muscle weakness (particularly during exercise) or a weakened heart muscle (cardiomyopathy).[1][2][3]
Last updated: 8/26/2015

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Showing of 36 |
Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Generalized hypotonia
Decreased muscle tone
Low muscle tone
[ more ]
0001290
Global developmental delay 0001263
Increased serum lactate 0002151
Lactic acidosis
Increased lactate in body
0003128
Neurodevelopmental delay 0012758
Vomiting
Throwing up
0002013
30%-79% of people have these symptoms
Elevated hepatic transaminase
High liver enzymes
0002910
Elevated plasma branched chain amino acids 0008344
Feeding difficulties
Feeding problems
Poor feeding
[ more ]
0011968
Hepatic encephalopathy 0002480
Hepatomegaly
Enlarged liver
0002240
Hypercoagulability 0100724
Hypoglycemia
Low blood sugar
0001943
Increased urine alpha-ketoglutarate concentration 0012402
Lethargy 0001254
Seizure 0001250
Spasticity
Involuntary muscle stiffness, contraction, or spasm
0001257
5%-29% of people have these symptoms
Abnormal cardiac ventricular function 0030872
Ataxia 0001251
Behavioral abnormality
Behavioral changes
Behavioral disorders
Behavioral disturbances
Behavioral problems
Behavioral/psychiatric abnormalities
Behavioural/Psychiatric abnormality
Psychiatric disorders
Psychiatric disturbances
[ more ]
0000708
Cardiomyopathy
Disease of the heart muscle
0001638
Decreased liver function
Liver dysfunction
0001410
Decreased plasma carnitine 0003234
Failure to thrive
Faltering weight
Weight faltering
[ more ]
0001508
Hepatic failure
Liver failure
0001399
Hyperammonemia
High blood ammonia levels
0001987
Hyperisoleucinemia
High blood isoleucine concentration
0010913
Microcephaly
Abnormally small skull
Decreased circumference of cranium
Decreased size of skull
Reduced head circumference
Small head circumference
[ more ]
0000252
Muscle spasm 0003394
Reduced visual acuity
Decreased clarity of vision
0007663
Percent of people who have these symptoms is not available through HPO
Autosomal recessive inheritance 0000007
Dystonia 0001332
Encephalopathy 0001298
Hypertrophic cardiomyopathy
Enlarged and thickened heart muscle
0001639
Metabolic acidosis 0001942
Variable expressivity 0003828
Showing of 36 |
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Last updated: 2/1/2021
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Cause Cause


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Dihydrolipoamide dehydrogenase (DLD) deficiency is caused by changes (mutations) in the DLD gene. This gene gives the body instructions to make an enzyme called dihydrolipoamide dehydrogenase (DLD). DLD is one part of 3 different groups of enzymes that work together (enzyme complexes). These enzyme complexes are involved in breaking down amino acids commonly found in protein-rich foods, and in other reactions that help to convert energy from food into a form that our cells can use.[2]

Mutations in the DLD gene impair the function of DLD, preventing the 3 enzyme complexes from functioning properly. This causes a build-up of molecules that are normally broken down, which in turn leads to tissue damage, lactic acidosis and other chemical imbalances. The brain is especially sensitive to the buildup of molecules and lack of cellular energy, which is why there are neurological problems associated with DLD deficiency.[2]
Last updated: 8/26/2015

Inheritance Inheritance


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Dihydrolipoamide dehydrogenase (DLD) deficiency is inherited in an autosomal recessive manner.[2] This means that a person must have a mutation in both copies of the responsible gene in each cell to be affected. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not have any signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to be affected, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% to be unaffected and not be a carrier.
Last updated: 8/27/2015

Treatment Treatment


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There are currently no consensus recommendations for the management of dihydrolipoamide dehydrogenase (DLD) deficiency. Management can be hard because various metabolic pathways are affected and 3 enzyme complexes are involved. Deficiencies in enzyme pathways vary depending on the specific mutation(s) each affected person has.

Unfortunately, the treatments that have been attempted in children with the early-onset neurologic form do not appear to significantly alter the course of the disease. Even with treatment, children often do not survive infancy or have varying degrees of chronic neurologic impairment if they survive the initial episode. Depending on individual enzyme complex deficiencies, treatment may involve certain dietary restrictions or certain diets; use of medical foods; and/or supplementation of specific amino acids or other substances.

There is limited data for the chronic management of people with the primarily hepatic (liver-related) form of the disease. Management typically involves supportive therapy during times of acute liver injury or failure, and may include nutritional support; IV glucose for hypoglycemia; correction of metabolic acidosis; correction of coagulopathy; and avoidance of liver-toxic medications.[1]

More detailed information about the management of DLD deficiency can be viewed on the GeneReviews Web site. GeneReviews is intended for use by genetics professionals. Those not familiar with the principles discussed on the GeneReviews Web site are encouraged to speak with a genetics professional or other healthcare provider regarding information of interest.
Last updated: 8/27/2015

Prognosis Prognosis


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The long-term outlook (prognosis) for people with dihydrolipoamide dehydrogenase (DLD) deficiency depends on the specific symptoms and severity in each person. Children diagnosed in the newborn period often do not survive their first episode or die within the first few years of life.[2] However, multiple people have been reported surviving into their second and third decade of life.[4] Those who survive past early childhood often have delayed growth and various neurological problems including intellectual disability, spasticity, ataxia, and seizures.[2]

Those who become symptomatic after the neonatal period typically have milder signs and symptoms, with a significantly lower mortality rate. However, given the limited amount of information available in the medical literature, the degree of morbidity that surviving people experience is difficult to determine.[4] The frequency of acute episodes reportedly decreases with age in most people with DLD deficiency.[1]
Last updated: 8/27/2015

Find a Specialist Find a Specialist


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If you need medical advice, you can look for doctors or other healthcare professionals who have experience with this disease. You may find these specialists through advocacy organizations, clinical trials, or articles published in medical journals. You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.

If you can’t find a specialist in your local area, try contacting national or international specialists. They may be able to refer you to someone they know through conferences or research efforts. Some specialists may be willing to consult with you or your local doctors over the phone or by email if you can't travel to them for care.

You can find more tips in our guide, How to Find a Disease Specialist. We also encourage you to explore the rest of this page to find resources that can help you find specialists.

Healthcare Resources

  • To find a medical professional who specializes in genetics, you can ask your doctor for a referral or you can search for one yourself. Online directories are provided by the American College of Medical Genetics and the National Society of Genetic Counselors. If you need additional help, contact a GARD Information Specialist. You can also learn more about genetic consultations from MedlinePlus Genetics.

Learn More Learn More


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These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on Dihydrolipoamide dehydrogenase deficiency. This website is maintained by the National Library of Medicine.

In-Depth Information

  • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Dihydrolipoamide dehydrogenase deficiency. Click on the link to view a sample search on this topic.

News & Events News & Events


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News

  • Rare Disease Day at NIH 2021
    March 1, 2021

GARD Answers GARD Answers


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Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know.

Have a question? Contact a GARD Information Specialist.

References References


  1. Shane C Quinonez and Jess G Thoene. Dihydrolipoamide Dehydrogenase Deficiency. GeneReviews. July 17, 2014; http://www.ncbi.nlm.nih.gov/books/NBK220444/.
  2. Dihydrolipoamide dehydrogenase deficiency. Genetics Home Reference. September, 2014; http://ghr.nlm.nih.gov/condition/dihydrolipoamide-dehydrogenase-deficiency.
  3. Brown G. Pyruvate dehydrogenase E3 deficiency. Orphanet. April, 2012; http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=2394.
  4. Shane C. Quinonez, Steven M. Leber, Donna M. Martin, Jess G. Thoene, and Jirair K. Bedoyan. Leigh syndrome in a girl with a novel DLD mutation causing E3 deficiency. Pediatr Neurol. January, 2013; 48(1):67-72.
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