Rare Gastroenterology News

Disease Profile

Dihydrolipoamide dehydrogenase deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.
<1 / 1 000 000

< 331

US Estimated

< 514

Europe Estimated

Age of onset

Childhood

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ICD-10

E74.4

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

Pyruvate dehydrogenase E3 deficiency; DLD deficiency; E3-deficient maple syrup urine disease;

Categories

Congenital and Genetic Diseases; Metabolic disorders; Nervous System Diseases

Summary

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]

Symptoms

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]

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.

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

Cause

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]

Treatment

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.

Learn more

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.

References

  1. Shane C Quinonez and Jess G Thoene. Dihydrolipoamide Dehydrogenase Deficiency. GeneReviews. July 17, 2014; https://www.ncbi.nlm.nih.gov/books/NBK220444/.
  2. Dihydrolipoamide dehydrogenase deficiency. Genetics Home Reference. September, 2014; https://ghr.nlm.nih.gov/condition/dihydrolipoamide-dehydrogenase-deficiency.
  3. Brown G. Pyruvate dehydrogenase E3 deficiency. Orphanet. April, 2012; https://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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