Organic acidemias

Definition

Organic acidemias are a collection of amino and fatty acid oxidation disorders that cause non-amino organic acids to accumulate and be excreted in the urine.

Description

Organic acidemias are divided into two categories: disorders of amino acid metabolism and disorders involving fatty acid oxidation. There are several dozen different organic acidemia disorders. They are caused by inherited deficiencies in specific enzymes involved in the breakdown of branched-chain amino acids, lysine, and tryptophan, or fatty acids. Some have more than one cause.

Amino acids are chemical compounds from which proteins are made. There are about 40 amino acids in the human body. Proteins in the body are formed through various combinations of roughly half of these amino acids. The other 20 play different roles in metabolism. Organic acidemias involving amino acid metabolism disorders include isovaleric acidemia, 3-methylcrotonylglycemia, combined carboxylase deficiency, hydroxymethylglutaric acidemia, propionic acidemia , methylmalonic acidemia , beta-ketothiolase deficiency, and glutaric acidemia type I.

Fatty acids, part of a larger group of organic acids, are caused by the breakdown of fats and oils in the body. Organic acidemias caused by fatty acid oxidation disorders include glutaric acidemia type II, short-chain acyl-CoA dehydrogenase (SCAD) deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, long-chain acyl-CoA dehrdrogenase (LCAD) deficiency, very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency.

Most organic acidemias are considered rare, occurring in less than one in 50,000 persons. However, MCAD occurs in about one in 23,000 births. Most of these disorders produce life-threatening illnesses that can occur in newborns, infants, children, and adults. In nearly all cases, though, the symptoms appear during the first few years of life, usually in children age two or younger. If left undiagnosed and untreated in young children, they can also delay physical development.

Genetic profile

Genes are the blueprint for the human body, directing the development of cells and tissue. Mutations in some genes can cause genetic disorders such as the organic acidemias. Every cell in the body has 23 pairs of chromosomes, 22 pairs of which contain two copies of individual genes. The twenty-third pair of chromosomes is called the sex chromosome because it determines a person's gender. Men have an X and a Y chromosome while women have two X chromosomes.

Organic acidemias are generally believed to be autosomal recessive disorders that affect males and females. Autosomal means that the gene does not reside on the sex chromosome. People with only one abnormal gene are carriers but since the gene is recessive, they do not have the disorder. Their children will be carriers of the disorder 50% of the time but not show symptoms of the disease. Both parents must have one of the abnormal genes for a child to have symptoms of an organic acidemia. When both parents have the abnormal gene, there is a 25% chance each child will inherit both abnormal genes and have the disease. There is a 50% chance each child will inherit one abnormal gene and become a carrier of the disorder but not have the disease itself. There is a 25% chance each child will inherit neither abnormal gene and not have the disease nor be a carrier.

Demographics

Organic acidemias affect males and females roughly equally. The disorders primarily occur in Caucasian children of northern European ancestry, such as English, Irish, German, French, and Swedish. In a 1994 study by Duke University Medical Center, 120 subjects with MCAD were studied. Of these, 118 were Caucasian, one was black, and one was Native American; 65 were female and 55 were male; and 112 were from the United States while the other eight were from Great Britain, Canada, Australia, and Ireland.

Signs and symptoms

Symptoms of organic acidemias vary with type and sometimes even within a specific disorder. Isovaleric acidemia (IA) can present itself in two ways: acute severe or chronic intermittent. Roughly half of IA patients have the acute sever disorder and half the chronic intermittent type. In acute severe cases, patients are healthy at birth but show symptoms between one to 14 days later. These symptoms include vomiting, refusal to eat, dehydration, listlessness, and lethargy. Other symptoms can include shaking, twitching, convulsions, and low body temperature (under 97.8°F or 36.6°C), and a foul "sweaty feet" odor. If left untreated, the infant can lapse into a coma and die from severe ketoacidosis, hemorrhage, or infections. In the chronic intermittent type, symptoms usually occur within a year after birth and is usually preceded by upper respiratory infections or an increased consumption of protein-rich foods, such as meat and dairy products. Symptoms include vomiting, lethargy, "sweaty feet" odor, acidosis, and ketonuria. Additional symptoms may include diarrhea, thrombocytopenia, neutropenia, or pancytopenia.

There is a wide range of symptoms for 3-methylcrotonglycemia, which can occur in newborns, infants, and young children. These include irritability, drowsiness, unwillingness to eat, vomiting, and rapid breathing. Other symptoms can include hypoglycemia, alopecia, and involuntary body movements.

Approximately 30% of patients with hydroxymethylglutaric acidemia show symptoms within five days after birth and 60% between three and 24 months. Symptoms vary and can include vomiting, deficient muscle tone, lethargy, seizures, metabolic acidosis, hypoglycemia, and hyperammonemia.

Symptoms of methylmalonic acidemia (MA) due to methylmalonyl-CoA mutase (MCoAM) deficiency include lethargy, failure to thrive, vomiting, dehydration, trouble breathing, deficient muscle tone, and usually present themselves during infancy. MA due to N-methyltetrahydrofolate: homocysteine methyltransferase deficiency and high homocysteine levels usually occurs during the first two months after birth but has been reported in children as old as 14 years. General symptoms are the same as for MA due to MCoAM but can also include fatigue, delirium, dementia , spasms, and disorders of the spinal cord or bone marrow.

Symptoms of glutaric acidemia type I usually appear within two years after birth and generally become apparent when a minor infection is followed by deficient muscle tone, seizures, loss of head control, grimacing, and dystonia of the face, tongue, neck, back, arms, and hands. Glutaric acidemia type II symptoms fall into three categories:

• Infants with congenital anomalies present symptoms within the first 24 hours after birth, with symptoms of deficient muscle tone, severe hypoglycemia, hepatomegaly (enlarged liver), metabolic acidosis, and sometimes a "sweaty feet" odor. In some patients, signs include a high forehead, low-set ears, enlarged kidneys, excessive width between the eyes, a mid-face below normal size, and genital anomalies.
• Infants without congenital anomalies have signs of deficient muscle tone, tachypnea (increased breathing rate), metabolic acidosis, hepatomegaly, and a "sweaty feet" odor.
• Mild or later onset symptoms in children that include vomiting, hypoglycemia, hepatomegaly, and myopathy (a disorder of muscle or muscle tissue).

There are two types of propionic acidemia, one caused by propionyl-CoA carboxylase (PCoAC) deficiency and the other caused by multiple carboxylase (MC) deficiency. Symptoms of both disorders are generally the same and include vomiting, refusal to eat, lethargy, hypotonia, dehydration, and seizures. Other symptoms may include skin rash, ketoacidosis, irritability, metabolic acidosis, and a strong smelling urine commonly described as "tom cats"' urine.

There are five types of organic acidemias of fatty acid oxidation that involve deficiencies of acyl-CoA dehydrogenase enzymes: SCAD, MCAD, LCAD, VLCAD, and LCHAD. General symptoms for all five of these disorders include influenza-or cold-like symptoms, hyperammonemia, metabolic acidosis, hyperglycemia, vomiting, a "sweaty feet" odor, and delay in physical development. In young children, other symptoms can include loss of hair, involuntary or uncoordinated muscle movements (ataxia), and a scaly rash (seborrhea rash.) Symptoms generally appear between two months and two years of age, but can appear as early as two days after birth up to six years of age.

There are two combined carboxylase deficiency organic acidemias: holocarboxylase synthetase deficiency and biotindase deficiency. Symptoms of holocarboxylase deficiency include sleep and breathing difficulties, hypotonia, seizures, alopecia, developmental delay, skin rash, metabolic acidosis, ketolactic acidosis, organic aciduria, and hyperammonemia. Symptoms of biotindase deficiency include seizures, involuntary muscular movements, hypotonia, rapid breathing, developmental delay, hearing loss, and visual problems. Skin rash, alopecia, metabolic acidosis, organic acidemia, and hyper ammonemia can also occur.

Symptoms of beta-ketothiolase deficiency vary. In infants, the most common symptoms include severe metabolic acidosis, ketosis, vomiting, diarrhea (often bloody), and upper respiratory or gastrointestinal infections. Adults with the disorder are usually asymptomatic (showing no outward signs of the disease).

Diagnosis

In all types of organic acidemia, diagnosis cannot be made by simply recognizing the outward appearance of symptoms. Instead, diagnosis is usually made by detecting abnormal levels of organic acid cells in the urine through a urinalysis. The specific test used is called combined gas chromatography-mass spectrometry. In gas chromatography, a sample is vaporized and its components separated and identified. Mass spectrometry electronically weighs molecules. Every molecule has a unique weight (or mass). In newborn screening, mass spectrometry analyzes blood to identify what amino acids and fatty acids are present and the amount present. The results can identify if the person tested has a specific organic acidemia. Many organic acidemias also can be diagnosed in the uterus by using an enzyme assay of cultured cells, or by demonstrating abnormal organic acids in the fluid surrounding the fetus. In some laboratories, analysis is done on blood, skin, liver, or muscle tissue. Molecular DNA testing is also available for common mutations of MCAD and LCHAD.

Since most organic acidemias are rare, routine screening of fetuses or newborns is not usually done and is not widely available. In MCAD, a more common organic acidemia, abnormal organic acids are excreted in the urine intermittently so a diagnosis is made by detecting the compound phenylpropionylglycine in the urine.

Treatment and management

There are few medications available to treat organic acidemias. The primary treatments are dietary restrictions tailored to each disorder, primarily restrictions on the intake of certain amino acids. For example, patients with some acidemias, such as isovaleric and beta-ketothiolase deficiency, must restrict their intake of leucine by cutting back on foods high in protein. Patients with propionic or methylmalonic acidemias must restrict their intake of threonine, valine, methionine, and isoleucine. The intake of the restricted amino acids is based on the percentage of lean body mass rather than body weight. Some patients also benefit from growth hormones. Patients with combined carboxylase deficiency are sometimes treated with large doses of biotin. Some patients with methylmalonic acidemia are treated with large doses of vitamin B₁₂.

Glucose infusion (to provide calories and reduce the destructive metabolism of proteins) and bicarbonate infusion (to control acidosis) are often used to treat acute episodes of some acidemias, including isovaleric, 3-methylcrotonylglycemia, and hydroxymethylglutaric.

The primary treatment for MCAD is to not go without food for more than 10 or 12 hours. Children should eat foods high in carbohydrates, such as pasta, rice, cereal, and non-diet drinks, when they are ill. A low fat diet is also recommended. The drug L-carnitine is sometimes used by physicians to prevent low blood sugar when patients have infections or are not eating regularly.

The treatment of LCHAD is similar to that of MCAD, except that L-carnitine is usually not prescribed. Children with LCHAD are often treated with medium chain triglycerides oil.

Holocarboxylase synthetase deficiency is generally treated by administering 10 milligrams (mg) of biotin daily. Eating large amounts of yeast, liver, and egg yolks, which naturally contain biotin, did not improve the condition. Biotinidase deficiency is usually treated successfully with pharmacological doses of between five and 20 mg of biotin daily. However, hearing and vision problems appear to be less reversible.

Prognosis

The prognosis of patients with organic acidemias varies with each disorder and usually depends on how quickly and accurately the condition is diagnosed and treated. Some patients with organic acidemias are incorrectly diagnosed with other conditions, such as sudden infant death syndrome (SIDS) or Reye syndrome. Without a quick and accurate diagnosis, the survival rate decreases with each episode of the disorder. Death occurs within the first few years of life, often within the first few months. With a quick diagnosis and aggressive monitoring and treatment, patients can often live relatively normal lives. For example, children with either biotinidase deficiency or holocarboxylase synthetase deficiency, when detected early and treated with biotin, have generally shown resolution of the clinical symptoms and biochemical abnormalities.

Resources

BOOKS

Eaton, Simon. Current Views of Fatty Acid Oxidation and Ketogenesis. Kluwer Academic Publishers, Dordrecht, the Netherlands, 2000.

Narins, Robert G. Maxwell and Kleeman's Clinical Disorders of Fluid and Electrolyte Metabolism, Fifth Edition. McGraw-Hill Publishing, Inc., New York, 1994.

Scriver, Charles R., et al. The Metabolic Basis of Inherited Disease, Eighth Edition. McGraw-Hill Publishing, Inc., New York, 2000.

PERIODICALS

Brink, Susan. "Little-Used Newborn Test can Prevent Real Heartache." U.S. News & World Report (January 17, 2000): 59.

McCarthy, Michael. "Report Calls for Reform of U.S. Newborn Baby Screening Programmes." The Lancet (August 12, 2000): 571.

Mitka, Mike. "Neonatal Screening Varies by State of Birth." JAMA, The Journal of the American Medical Association (October 25, 2000): 2044.

Thomas, Janet A., et al. "Apparent Decreased Energy Requirements in Children with Organic Acidemias: Preliminary Observations." Journal of the American Dietetic Association (September 2000): 1074.

Wang, S. S., et al. "Medium Chain Acyl-CoA-Dehydrogenace Deficiency: Human Genome Epidemiology Review." Genetic Medicine (January 1999): 332-339.

ORGANIZATIONS

Fatty Oxidation Disorders (FOD) Family Support Group. 805 Montrose Dr., Greensboro, NC 27410. (336) 547-8682. [email protected]. <http://www.fodsupport.org/welcome.htm>.

National Newborn Screening and Genetics Resource Center. 1912 W. Anderson Lane, Suite 210, Austin, TX 78757. Fax: (512) 454-6419. <http://www.genes-rus.uthscsa.edu>.

Organic Acidemia Association. 13210 35th Ave. North, Plymouth, MN 55441. (763) 559-1797. Fax: (863) 694-0017. <http://www.oaanews.org>.

Ken R. Wells