Congenital Lactic Acidosis

 Congenital Lactic Acidosis 

DISEASE OVERVIEW

Lactate is a chemical compound normally produced by all cells and plays important roles in several chemical processes in the body. Lactic acidosis occurs when lactate and other molecules, called protons, accumulate in bodily tissues and fluids faster than the body can remove them. Consequently, tissues and fluids may become acidic and impair the normal functioning of cells. Lactic acidosis can have many different causes and is often present in severely ill patients hospitalized in intensive care units.

Congenital lactic acidosis is a rare form of lactic acidosis. The word “congenital” means that the underlying condition that increases risk of developing lactic acidosis is present at birth. In most cases, the cause of congenital lactic acidosis is due to a defect in an enzyme responsible for helping the body convert carbohydrates and fats into energy. Most of these enzymes are located in specialized structures within the cell called mitochondria. Therefore, most causes of congenital lactic acidosis are due to genetic mitochondrial enzyme deficiencies. These are either inherited from one or both parents or arise spontaneously in the developing embryo.

SIGNS & SYMPTOMS

The enzyme deficiencies that give rise to congenital lactic acidosis can potentially affect many different organ systems of the body and, therefore, lead to a wide variety of symptoms and signs. Whereas some individuals may have persistently elevated levels of lactic acid in blood, cerebrospinal fluid and urine, other people may have only occasional increases in lactic acid that are brought on by another illness, such as an infection, a seizure or an asthmatic attack.

In some children (especially those with a severe enzyme defect), clinical manifestations of congenital lactic acidosis appear within the first hours or days of life and may include loss of muscle tone (hypotonia), lethargy, vomiting and abnormally rapid breathing (tachypnea). Eventually, the condition may progress to cause developmental delay, intellectual disability, motor abnormalities, behavioral issues, abnormalities of the face and head and, ultimately, multi-organ failure. In some individuals in whom the disease is due to a mutation in mitochondrial DNA, the complications of congenital lactic acidosis may not appear until adolescence or adulthood.

CAUSES

Most cases of congenital lactic acidosis are caused by one or more inherited mutations of genes in DNA located in the nucleus (nDNA) or in genes in the mitochondria (mtDNA) of cells. Genes carry the genetic instructions for cells. A mutation (also called a pathogenic variant) is a change in a gene located in nuclear or mitochondrial DNA that may cause disease. Mutations in nDNA, which occur in cellular chromosomes, can be inherited in different patterns, including autosomal recessive, autosomal dominant or X-linked recessive inheritance.

Mutations affecting the genes for mitochondria (mtDNA) are inherited from the mother. The mtDNA in sperm cells is typically lost during fertilization and as a result, all human mtDNA comes from the mother. An affected mother will pass on the mutation to all her children, but only her daughters will pass on the mutation to their children. Mitochondria, which are found by the hundreds or thousands in the cells of the body, particularly in muscle and nerve tissue, carry the blueprints for regulating energy production.

As cells divide, the number of normal mtDNA and mutated mtDNA are distributed in an unpredictable pattern in different tissues. Consequently, mutated mtDNA accumulates at different rates in different tissues in the same individual. Therefore, family members who have the identical mutation in mtDNA may exhibit a variety of different symptoms and signs at different times and to varying degrees of severity.

Pyruvate dehydrogenase complex (PDC) deficiency is a genetic mitochondrial disease of carbohydrate metabolism that is due to a mutation in nDNA. It is generally considered to be the most common cause of biochemically proven cases of congenital lactic acidosis. PDC deficiency can be inherited in an autosomal recessive or X-linked recessive pattern.

Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the mutated gene and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

Dominant genetic disorders occur when only a single copy of a mutated gene is necessary to cause the disease. The mutated gene can be inherited from either parent or can be the result of a changed gene in the affected individual. The risk of passing the mutated gene from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

X-linked genetic disorders are conditions caused by a mutated gene on the X chromosome and mostly affect males. Females who have a mutated gene on one of their X chromosomes are carriers for that disorder. Carrier females usually do not have symptoms because females have two X chromosomes and only one carries the mutated gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a mutated gene, he will develop the disease.

Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son.

If a male with an X-linked disorder is able to reproduce, he will pass the mutated gene to all his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male children.

X-linked dominant disorders are caused by a mutated gene on the X chromosome and mostly affect females. Females are affected when they have an X chromosome with the mutated gene for the disease. Males with a mutated gene for an X-linked dominant disorder are more severely affected than females and often do not survive.

Although genetic mitochondrial diseases are the most common causes of congenital lactic acidosis, additional conditions that are present at birth can result in the disorder. These include biotin deficiency, bacterial infection in the bloodstream or body tissues (sepsis), certain types of glycogen storage disease, Reye syndrome, short-bowel syndrome, liver failure, a defect in the heart or blood vessels that leads to a deficiency in the amount of oxygen reaching the body’s tissues (hypoxia) and bacterial meningitis (which causes elevated lactic acid in cerebrospinal fluid).

DIAGNOSIS

A diagnosis of congenital lactic acidosis is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Blood and cerebrospinal fluid tests can reveal certain findings associated with congenital lactic acidosis such as elevated levels of lactate. An enzyme deficiency may be diagnosed by tests conducted on white blood cells or on skin or muscle cells obtained by biopsy. Genetic testing can be used to determine the molecular cause (pathogenic variants or mutations) of congenital lactic acidosis in many patients.

Treatment

There is no proven treatment for congenital lactic acidosis that is due to a genetic mitochondrial disease. Therefore, treatment is directed toward the specific symptoms and signs that are present in each individual. Vitamins and certain co-factors (for example, carnitine and coenzyme Q) are frequently administered to patients with congenital lactic acidosis, but there is no proof that such agents are effective, except in extremely rare cases of PDC deficiency that respond to high doses of thiamine or in biochemically proven cases of coenzyme Q deficiency.

For many years so-called “ketogenic” diets that are very high in fat and very low in carbohydrate have been used in patients with PDC deficiency, with beneficial effects reported in the scientific literature. However, the long-term safety and effectiveness of ketogenic diets have not been studied in a rigorous fashion.

Additional therapies for individuals with congenital lactic acidosis are directed at specific complications, such as anti-seizure medications (anti-convulsants) for seizures.

Genetic counseling is recommended for affected individuals and their families.

TYPE OF DOCTOR AND DEPARTMENT: gluconeogenesis SPECIALIST CAN DIAGNOSE THIS DISEASE.