What are the other Names for this Condition? (Also known as/Synonyms)

• Lipoate Biosynthesis Defect

What is Lipoic Acid Biosynthesis Defects? (Definition/Background Information)

• Lipoic Acid Biosynthesis Defects are a group of conditions caused by different enzymatic deficiencies
• Lipoate is a cofactor essential for important reactions in humans involving several genes (LIPT1, LIAS, DLD) which codify different enzymes. Lipoic acid is essential for normal aerobic metabolism
• Mutations in LIAS have been identified that result in a variant form of nonketotic hyperglycinemia with early-onset convulsions combined with a defect in mitochondrial energy metabolism with encephalopathy and cardiomyopathy (increased size of the heart muscle)
• LIPT1 deficiency resulted in early death in one patient and in a less severely affected individual with a Leigh-like syndrome clinical features. In DLD gene deficiency the clinical features are very varied depending on which of the affected enzymes is most rate limiting

(Source: Lipoic Acid Biosynthesis Defects; Genetic and Rare Disease Information Center (GARD) of National Center for Advancing Translational Science (NCATS), USA.)

Who gets Lipoic Acid Biosynthesis Defects? (Age and Sex Distribution)

• Lipoic Acid Biosynthesis Defects is a rare congenital disorder. The presentation of symptoms may occur at birth
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Lipoic Acid Biosynthesis Defects? (Predisposing Factors)

• A positive family history may be an important risk factor, since Lipoic Acid Biosynthesis Defects can be inherited
• Currently, no other risk factors have been clearly identified for the condition

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Lipoic Acid Biosynthesis Defects? (Etiology)

• Lipoic Acid Biosynthesis Defects include a set of conditions that develop due to deficiency in enzymes in the lipoic acid biosynthesis pathway
• At least 3 causative genes have been identified for this disorder, namely LIPT1,  LIAS and DLD genes
  • LIPT1 gene codes for the enzyme lipoyl tranferase 1
  • LIAS gene codes for lipoic acid synthetase enzyme
  • The DLD gene codes for the enzyme dihydrilipoamide dehydrogenase (also known as pyruvate dehydrogenase E3)
• The gene mutation(s) causing Lipoic Acid Biosynthesis Defects are inherited in an autosomal recessive manner

Autosomal recessive inheritance: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Lipoic Acid Biosynthesis Defects?

The signs and symptoms of Lipoic Acid Biosynthesis Defects may be determined by the causative gene mutation, and vary among affected individuals.

Signs and symptoms of Lipoic Acid Biosynthesis Defects due to LIPT1 gene mutation(s) include:

• Vomiting
• Diarrhea 
• Lactate build-up in the body
• Nystagmus
• Swallowing difficulties
• Muscle weakness
• Loss of balance
• Peripheral neuropathy
• Breathing difficulty

Signs and symptoms of Lipoic Acid Biosynthesis Defects due to LIAS gene mutation(s) include:

• Nonketotic hyperglycinemia 
• Early-onset convulsions 
• Defect in mitochondrial energy metabolism 
• Encephalopathy 
• Cardiomyopathy

Signs and symptoms of Lipoic Acid Biosynthesis Defects due to DLD gene mutation(s) include:

• Neonatal lactic acidosis
• Delayed development
• Muscle weakness
• Abdominal pain
• Episodic vomiting
• Liver cell dysfunction
• Encephalopathy

How is Lipoic Acid Biosynthesis Defects Diagnosed?

Lipoic Acid Biosynthesis Defects is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests
• Imaging studies
• Biopsy studies, if necessary
• Molecular genetic testing to check for or confirm causative gene mutation(s)

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Lipoic Acid Biosynthesis Defects?

The complications of Lipoic Acid Biosynthesis Defects may include:

• Delay in reaching developmental milestones
• Problems with movement, due to muscle weakness and problems with balance 
• Respiratory distress
• Risk of heart function abnormalities, which may lead to cardiac arrest

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Lipoic Acid Biosynthesis Defects Treated?

There is no cure for Lipoic Acid Biosynthesis Defects, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complication that develops.

How can Lipoic Acid Biosynthesis Defects be Prevented?

Lipoic Acid Biosynthesis Defects may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy), if available, may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Lipoic Acid Biosynthesis Defects? (Outcomes/Resolutions)

• The prognosis of Lipoic Acid Biosynthesis Defects is dependent upon the severity of the signs and symptoms and associated complications, if any
• Individuals with mild conditions have better prognosis than those with severe symptoms and complications
• A LIPT1 gene mutation affecting the lipoylation of 2-ketoacid dehydrogenase complexes may be fatal
• Typically, the prognosis may be only assessed on a case-by-case basis

Additional and Relevant Useful Information for Lipoic Acid Biosynthesis Defects:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/