Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 2 - M-Z - I

Opitz syndrome

TABLE 1

Frequencies of common conditions associated with Opitz syndrome

Hypospadias	93%	LTE cleft/fistula	38%
Hypertelorism	91%	Cleft lip and palate	32%
Swallowing problems	81%	Strabismus	28%
Ear abnormalities	72%	Heart defects	27%
Developmental delay	43%	Imperforate anus	21%
Kidney anomalies	42%	Undescended testes	20%

Diagnosis

Diagnostic testing

The diagnosis and cause of Opitz syndrome is often difficult to establish. In most cases, Opitz syndrome is diagnosed through a clinical evaluation and not through a blood test. This means a genetic specialist (geneticist) has examined the patient and found enough symptoms of Opitz syndrome to make a diagnosis. Since not all patients have obvious symptoms or even any symptoms at all, this can be a difficult task. It can also be difficult to establish whether an individual has an X-linked form or an autosomal dominant form, and whether it has been inherited or occurred spontaneously. In many cases, the geneticist has to rely on physical examinations or pictures of multiple family members and a description of the family’s medical history to establish the cause of Opitz syndrome. In some cases the cause cannot be established.

Sometimes a clinical diagnosis is confirmed through fluorescence in situ hybridization (FISH). FISH testing can detect whether a person has a deletion of the region of chromosome 22 that is associated with Opitz syndrome. Fluorescent (glowing) pieces of DNA containing the region that is deleted in Opitz syndrome are mixed with a sample of cells obtained from a blood sample. If there is a deletion in one of the chromosomes, the DNA will only stick to one chromosome and not the other and only one glowing section of a chromosome will be visible instead of two. Most patients with the autosomal dominant form of Opitz syndrome cannot be diagnosed through FISH testing since they possess a tiny change in the gene that cannot be detected with this procedure. As of 2001, researchers are still trying to discover the specific gene and gene changes that cause autosomal dominant Opitz syndrome.

FISH testing is unable to detect individuals with the X-linked form of Opitz syndrome. As of 2001, DNA testing for the X-linked form of Opitz disease is not available through clinical laboratories. Some research laboratories are looking for changes in the MID1 gene and the MID2 gene as part of their research and may occasionally confirm a clinical diagnosis of X-linked Opitz syndrome.

Prenatal testing

It is difficult to diagnose Opitz syndrome in a baby prior to its birth. Sometimes doctors and technicians (ultrasonographers) who specialize in performing ultrasound evaluations are able to see physical features of Opitz syndrome in the fetus. Some of the features they may look for in the ultrasound evaluation are heart defects, wide spacing between the eyes, clefts in the lip, hypospadias, and agenesis of the corpus callosum. It is very difficult, however, even for experts to diagnose or rule-out Opitz syndrome through an ultrasound evaluation.

Opitz syndrome can be definitively diagnosed in a baby prior to its birth if a MID gene change is detected in the mother or if a deletion in chromosome 22 is detected in the mother or father. Cells from the baby are obtained through an amniocentesis or chorionic villus sampling. These cells are analyzed for the particular MID gene change or chromosome 22 deletion found in one of the parents.

Treatment and management

As of 2001 there is no cure for Opitz syndrome and no treatment for the underlying condition. Management of the condition involves diagnosing and managing the symptoms. Clefts, heart defects, and genital abnormalities can often be repaired by surgery. Feeding difficulties can sometimes be managed using feeding tubes through the nose, stomach, or small intestine. Early recognition and intervention with special education may help individuals with mental retardation.

Prognosis

For most patients, the prognosis and quality of life of Opitz syndrome is good, with individuals typically living a normal lifespan. The prognosis, however, is very dependent on the type of organ abnormalities and the quality of medical care. Patients with severe heart defects and major abnormalities in the trachea and esophagus may have a poorer prognosis.

Resources

PERIODICALS

Buchner, G., et al. “MID2, a homologue of the Opitz syndrome gene MID1: Similarities in subcellular localization and differences in expression during development.” Human Molecular Genetics 8 (August 1998): 1397-407.

Jacobson, Z., et al. “Further delineation of the Opitz G/BBB syndrome: Report of an infant with congenital heart disease and bladder extrophy, and review of the literature.” American Journal of Medical Genetics (July 7, 1998): 294-299.

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Macdonald, M. R., A. H. Olney, and P. Kolodziej. “Opitz syndrome (G/BBB Syndrome).” Ear Nose & Throat Journal 77, no. 7 (July 1998): 528-529.

Schweiger, S., et al. “The Opitz syndrome gene product, MID1, associates with microtubules.” Proceedings of the National Academy of Sciences of the United States of America 96, no. 6 (March 16, 1999): 2794-2799.

ORGANIZATIONS

Canadian Opitz Family Network. Box 892, Errington, BC V0R 1V0. Canada [phone]. Fax: [phone]. [e-mail]. http://www.apollos.net/arena/opitz/ start.html .

March of Dimes Birth Defects Foundation. 1275 Mamaroneck Ave., White Plains, NY 10605. [phone]. [e-mail]. http://www.modimes

.org .

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. [phone] or [phone]. Fax: [phone]. http://www

.rarediseases.org .

Opitz G/BBB Family Network. PO Box 515, Grand Lake, CO 80447. [e-mail]. http://www.gle.egsd.k12.co

.us/opitz/index.html .

Smith-Lemli-Opitz Advocacy and Exchange (RSH/SLO). 2650 Valley Forge Dr., Boothwyn, PA 19061. [phone].http://members.aol.com/slo97/index.html .

WEBSITES

McKusick, Victor A. “Hypertelorism with Esophageal Abnormality and Hypospadias.” OMIM—Online Mendelian Inheritance in Man. http://www3.ncbi.nlm.nih.gov/ htbin-post/Omim/dispmim?145410 . (March 28, 2000)

McKusick, Victor A. “Opitz syndrome.” OMIM—Online Mendelian Inheritance in Man. http://www3.ncbi.nlm.nih

.gov/htbin-post/Omim/dispmim?300000 . (February 6, 2001).

Lisa Maria Andres, MS, CGC

Opitz-Frias syndrome see Opitz syndrome

Opitz-Kaveggia syndrome see FG syndrome

I Oral-facial-digital syndrome

Definition

Oral-facial-digital (OFD) syndrome is a generic name for a variety of different genetic disorders that result in malformations of the mouth, teeth, jaw, facial bones, hands, and feet.

Description

Oral-facial-digital syndrome includes several different but possibly related genetic disorders. OFD syndromes are also referred to as digito-orofacial syndromes. As of 2001, there are nine different OFD syndromes, identified as OFD syndrome type I, type II, and so on. OFD syndromes are so named because they all cause changes in the oral structures, including the tongue, teeth, and jaw; the facial structures, including the head, eyes, and nose; and the digits (fingers and toes). OFD syndromes are also frequently associated with developmental delay.

The different OFD syndromes are distinguished from each other based on the specific physical symptoms and the mode of inheritance. There are many alternate names for OFD syndromes. A partial list of these is:

•OFD syndrome type I: Gorlin syndrome I, GorlinPsaume syndrome, Papillon-Leage syndrome;

•OFD syndrome type II: Mohr syndrome, MohrClaussen syndrome;

•OFD syndrome type III: Sugarman syndrome;

•OFD syndrome type IV: Baraitser-Burn syndrome;

•OFD syndrome type V: Thurston syndrome;

•OFD syndrome type VI: Juberg-Hayward syndrome, Varadi syndrome, Varadi-Papp syndrome;

•OFD syndrome type VII: Whelan syndrome.

Genetic profile

The mode of inheritance of OFD syndrome depends on the type of the syndrome. Type I is inherited as an X- linked dominant trait and is only found in females because it is fatal in males. X-linked means that the syndrome is carried on the female sex chromosome, while dominant means that only one parent has to pass on the gene mutation in order for the child to be affected with the syndrome.

OFD syndrome type VII is inherited either as an X- linked or autosomal dominant pattern of inheritance. Autosomal means that the syndrome is not carried on a sex chromosome.

OFD syndrome types II, III, IV, V, and VI are passed on through an autosomal recessive pattern of inheritance. Recessive means that both parents must carry the gene mutation in order for their child to have the disorder.

OFD syndrome types VIII and IX are characterized by either an autosomal or X-linked recessive pattern of inheritance.

The gene location for OFD syndrome type I has been assigned to Xp22.3-22.2, or, on the 22nd band of the p arm of the X chromosome. As of 2001, the specific gene

syndrome digital-facial-Oral

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K E Y T E R M S

Digit—A finger or toe. Plural–digits.

mutations responsible for the other types of OFD syndrome have not been identified.

Demographics

There does not appear to be any clear-cut ethnic pattern to the incidence of OFD syndrome. Most types of OFD syndrome affect males and females with equal probability, although type I, the most common type, affects only females (since it is lethal in males before birth). The overall incidence of OFD syndrome has not been established due to the wide variation between the different types of the syndrome and the difficulty of definitive diagnosis.

Signs and symptoms

The symptoms observed in people affected by OFD syndrome vary depending on the specific type of the syndrome. In general, the symptoms include the following:

Oral features:

•Cleft lip

•Cleft palate or highly arched palate

•Lobed or split tongue

•Tumors of the tongue

•Missing or extra teeth

•Gum disease

•Misaligned bite

•Smaller than normal jaw

Facial features:

•Small or wide set eyes

•Missing structures of the eye

•Broad base or tip of the nose

•One nostril smaller than the other

•Low-set or angled ears

Digital features:

•Extra fingers or toes

•Abnormally short fingers

•Webbing between fingers or toes

•Clubfoot

•Permanently flexed fingers

One of the many traits found in individuals with OFD syndrome is webbing of the fingers and toes. (Custom Medical Stock Photos, Inc.)

Mental development and central nervous system:

•Mental retardation

•Brain abnormalities

•Seizures

•Spasmodic movements or tics

•Delayed motor and speech development

Other:

•Growth retardation

•Cardiovascular abnormalities

•Sunken chest

•Susceptibility to respiratory infection

Diagnosis

Diagnosis is usually made based on the observation of clinical symptoms. There is currently no medical test that can definitively confirm the diagnosis of OFD syndrome, with the exception of genetic screening for OFD syndrome type I.

Treatment and management

Treatment of OFD syndrome is directed towards the specific symptoms of each case. Surgical correction of the oral and facial malformations associated with OFD syndrome is often required.

Prognosis

Prognosis depends on the specific type of OFD syndrome and the symptoms present in the individual. OFD syndrome type I is lethal in males before birth. However, other types of OFD syndrome are found in both males and females. Due to the wide variety of symptoms seen

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in the nine types of the syndrome, overall survival rates are not available.

Resources

ORGANIZATIONS

Children’s Craniofacial Association. PO Box 280297, Dallas, TX 75243-4522. [phone] or [phone]. [e-mail]. http://www.ccakids.com .

FACES: The National Craniofacial Association. PO Box 11082, Chattanooga, TN 37401. [phone] or (800) 3322373. [e-mail]. http://www.faces-cranio

.org/ .

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. [phone] or [phone]. Fax: [phone]. http://www

.rarediseases.org .

WEBSITES

“Mohr Syndrome.” OMIM—Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov/htbin-post/Omim/ dispmim?252100 (20 April 2001).

“Oral-Facial-Digital Syndrome, Type III.” OMIM—Online

Mendelian Inheritance in Man. http://www.ncbi.nlm.nih

.gov/htbin-post/Omim/dispmim?258850 (20 April 2001).

“Oral-Facial-Digital Syndrome, Type IV.” OMIM—Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih

.gov/htbin-post/Omim/dispmim?258860 (20 April 2001).

“Oral-Facial-Digital Syndrome with Retinal Abnormalities.”

OMIM—Online Mendelian Inheritance in Man.

http://www.ncbi.nlm.nih.gov/htbin-post/Omim/ dispmim?258865 (20 April 2001).

“Orofaciodigital Syndrome I.” OMIM—Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?311200 (20 April 2001).

“Varadi-Papp Syndrome.” OMIM—Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov/htbinpost/Omim/dispmim?277170 (20 April 2001).

Paul A. Johnson

I 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-methylcrotonyl- glycemia, 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 acylCoA dehydrogenase (SCAD) deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, longchain 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 twenty-third or sex chromosome. People with only one abnormal gene are carriers but since the gene is recessive, they do not have the disorder. Their children

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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 97.8ºF or 36.6ºC), 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-methylcro- tonglycemia, 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-methyl- tetrahydrofolate: 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,

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K E Y T E R M S

Acidosis—A condition of decreased alkalinity resulting from abnormally high acid levels (low pH) in the blood and tissues. Usually indicated by sickly sweet breath, headaches, nausea, vomiting, and visual impairments.

Alopecia—Loss of hair or baldness.

Biotin—A growth vitamin of the vitamin B complex found naturally in liver, egg yolks, and yeast.

Branched-chain—An open chain of atoms having one or more side chains.

Dystonia—Painful involuntary muscle cramps or spasms.

Homocysteine—An amino acid that is not used to produce proteins in the human body.

Hyperammonemia—An excess of ammonia in the blood.

Hypotonia—Reduced or diminished muscle tone.

Ketoacidosis—A condition that results when organic compounds (such as propionic acid, ketones, and fatty acids) build up in the blood and urine.

Ketolactic acidosis—The overproduction of ketones and lactic acid.

Ketonuria—The presence of excess ketone bodies

(organic carbohydrate-related compounds) in the urine.

L-carnitine—A substance made in the body that carries wastes from the body’s cells into the urine.

Lysine—A crystalline basic amino acid essential to nutrition.

Metabolic acidosis—High acidity (low pH) in the body due to abnormal metabolism, excessive acid intake, or retention in the kidneys.

Neutropenia—A condition in which the number of leukocytes (a type of white or colorless blood cell) is abnormally low, mainly in neutrophils (a type of blood cell).

Organic aciduria—The condition of having organic acid in the urine.

Pancytopenia—An abnormal reduction in the number of erythrocytes (red blood cells), leukocytes (a type of white or colorless blood cell), and blood platelets (a type of cell that aids in blood clotting) in the blood.

Thrombocytopenia—A persistent decrease in the number of blood platelets usually associated with hemorrhaging.

Tryptophan—A crystalline amino acid widely distributed in proteins and essential to human life.

VLCAD, and LCHAD. General symptoms for all five of these disorders include influenzaor 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.

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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 are 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. [phone]. [e-mail]. http://www.fodsupport.org/welcome

.htm .

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National Newborn Screening and Genetics Resource Center. 1912 W. Anderson Lane, Suite 210, Austin, TX 78757. Fax: [phone]. http://www.genes-r-us.uthscsa.edu .

Organic Acidemia Association. 13210 35th Ave. North, Plymouth, MN 55441. [phone]. Fax: [phone]. http://www.oaanews.org .

Ken R. Wells

I Ornithine transcarbamylase deficiency

Definition

Ornithine transcarbamylase deficiency is a disorder in which there is a failure of the body to properly process ammonia, which can lead to coma and death if left untreated.

Description

Persons with ornithine transcarbamylase deficiency (OTC deficiency) have a problem with nitrogen metabolism. Too much nitrogen in the blood in the form of ammonia can cause brain damage, coma, and death. Ammonia is made up of nitrogen and hydrogen. Ammonia found in humans mostly comes from the breakdown of protein, either protein broken down from muscles, organs, and tissues already in the body, or excess protein that is eaten in the diet. Since excess ammonia is harmful, it is immediately excreted in normal humans after passing through the urea cycle and becoming urea. Ornithine transcarbamylase is a gene involved in the urea cycle–the process of making ammonia into urea, which occurs in the liver.

It is important to make urea, because, unlike ammonia, urea an be excreted by the kidney into the urine. Ammonia, on the other hand, cannot be effectively excreted by the kidney. So, if the ornithine transcarbamylase (OTC) function is reduced or impaired, ammonia builds up in the bloodstream. This buildup of ammonia in the bloodstream can lead to consequences as severe as coma and death. The amount of ammonia found in the bloodstream, and the severity of the disorder, depend on how well the OTC gene functions. If it functions reasonably well, the person should have a minor form of the disorder or no disorder. If the gene functions extremely poorly, or not at all, the disorder will be severe.

Synonyms for ornithine transcarbamylase deficiency include Hyperammonemia Type II, Ornithine carbamyl

transferase deficiency, OTC deficiency, UCE, Urea cycle disorder, OTC Type, and Hyperammonemia due to ornithine transcarbamylase deficiency.

Genetic profile

OTC deficiency is an X-linked recessive disorder. This means that it is found on the X chromosome (specifically, it is located on the short arm at Xp21.1) Recessive disorders require that only abnormal genes, and no normal genes, be present. For non-sex chromosomes, this means that both copies of a gene (one received from each parent) must be abnormal in order for that person to have the disorder.

In X-linked recessive disorders, however, only one abnormal copy of a gene must be present to cause the disorder in males. Males possess only one X chromosome, from thier mother, and one Y chromosome, which they receive from their father. If the mother is a carrier for the disorder (she has one normal gene and one abnormal gene), a male child would have a 50% chance of receiving an abnormal gene from her. If he receives the abnormal gene, he will have the disorder. So male children of a female carrier have a 50% chance of having the disorder.

A female child of a female carrier is much less likely to have the disorder. Unless the father has OTC deficiency, a female child will have one normal and one abnormal gene. Since recessive disorders require that both genes be mutated, the female child cannot have the disorder. Females with only one mutant OTC gene may have a mild form of the disorder because it is not purely recessive. Usually, the normal copy of the gene can sufficiently compensate for the poor functioning of the second, abnormal gene.

Some females do have the full-blown disorder, probably because of a phenomenon called X-inactivation. Although females have two X chromosomes in each cell, only one is active. Therefore, it is possible a female could have the disorder because only the abnormal gene was active in each cell of the liver, which is where OTC function takes place. Not enough is known about X-inactiva- tion to speculate on the likelihood of this occuring. Overall, many more men than women have the disease. This means that OTC disease due to X-inactivation is not very common.

If the father has the gene for the disorder, he cannot pass it on to his male child (he does not give the male child an X chromosome, only a Y). He can give his female child one copy of the gene, which might result in a mild form of the disorder or the full-blown disorder due to X-inactivation.

deficiency transcarbamylase Ornithine

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Ornithine transcarbamylase deficiency

Demographics

OTC affects infants at the rate of approximately one birth in every 70,000. As expected with an X-linked disorder, the disorder is more common in males.

Signs and symptoms

Before birth there are no symptoms of OTC deficiency because the exchange of nutrients and fluids between the mother and fetus allows the excess ammonia to leave the infant’s blood and go into the mother’s blood. The mother is then able to get rid of the ammonia as urea because she either lacks the disorder or her ammonia levels are medically well-controlled.

The most severe cases of OTC deficiency usually present in infants before they are a week old, typically in males. It may take several days for symptoms to appear, since it takes that long for protein, and therefore ammonia levels, to build up in the infant. Affected infants generally show periods of inactivity, a failure to feed, and vomiting. Unfortunately, many other disorders may also present with these same general symptoms, and new parents may not recognize these as abnormal in an infant. These symptoms are always accompanied in OTC deficiency by hyperammonemia, or high levels of ammonia in the blood.

Hyperammonemia is the most important symptom for identification and treatment of ornithine transcarbamylase deficiency. It is the cause of all other symptoms seen in OTC deficiency. Additionally, hepatomegaly (an enlarged liver), and seizures may also be present. If the disorder, or at least the hyperammonemia, is not recognized and treated, the symptoms may progress into coma and eventually, death. A failure to quickly resolve the hyperammonemia once an infant lapses into a coma may also lead to severe mental retardation or death.

Patients with milder forms of the disorder may show symptoms later in life such as failure to grow at a normal rate or they may experience developmental delay. Developmental delay is an inability to reach recognized milestones like speaking or grasping objects at an appropriate age. These milder symptoms would be accompanied by hyperammonemia, but the levels of ammonia would be much lower than in an episodic attack of hyperammonemia or in the severely ill infant. Other persons with mild forms of the disorder may have no symptoms, or may only experience nausea after a meal with a large protein content.

Persons with a mild form of the disorder and no other symptoms may also learn they have the disorder from an episode of acute hyperammonemia. Acute conditions are brief and immediate, whereas chronic conditions are long-lasting.

An episodic attack of acute hypperammonemia, then, is a an episode where levels of ammonia climb above what may be already high levels of ammonia. A person with an episode of acute hyperammonemia can have symptoms including some, or all, of the following: vomiting, lack of apetite, drowsiness, hepatomegaly, seizures, coma, and death. These episodes can be lifethreatening and may require hospitalization depending on their severity and response to medication.

These episodic attacks are probably related to a large increase in the amount of protein being broken down in the body, which results in too much ammonia being produced. This ammonia cannot be immediately excreted, which results in hyperammonemia. The most common reasons for a change in the amount of protein broken down are probably starvation, illness, and surgery. Even persons with no previous symptoms can experience a fatal episode of acute hyperammonemia brought on by an increase in protein breakdown. Since an episodic attack of hyperammonemia can be fatal without any previous symptoms, persons who have at least one family member with OTC deficiency should consider testing to determine whether they have the gene for the disorder. If the disorder is known to be present, an episode of hyperammonemia might be anticipated and its effect lessened.

Diagnosis

A definitive diagnosis of OTC deficiency is made by laboratory tests, since physical synptoms are very general and common to a large number of disorders. A high level of ammonia in the blood is the hallmark of this disorder and other disorders that affect the urea cycle. In the short term, the levels of two amino acids in the urine, orotate and citrulline, should distinguish between OTC deficiency and other urea cycle deficiencies. In OTC deficiency, citrulline levels are normal or low, and orotate levels are usually high. In the long term, however, the most definitive diagnosis can be made through DNA analysis, or through a test of OTC activity in a small piece of liver tissue (a biopsy) taken from the patient.

Prenatal diagnosis of the disorder is difficult and not indicated unless there is an affected family member with the disorder. In that case, if the mutation is known, DNA analysis would reveal the same mutation as in the family member with OTC deficiency. If the mutation is not known, a method called linkage analysis may be used. In linkage analysis, the OTC gene itself is not analyzed, but the DNA near the gene is analyzed. The “near DNA” can then be compared to the “near DNA” of the affected family member. If the DNAs are different, then the fetus should not have the disorder. If they are the same, then the fetus probably has the disorder.

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Treatment and management

Long-term management

The severity of the disorder is the most important factor in determining long-term treatment of OTC deficiency. The most severely affected individuals, usually infant males, should have liver transplants. As previously mentioned, the urea cycle and OTCs function occur in the liver. The transplantation immediately corrects OTC deficiency. Episodes of life-threatening ammonemia are prevented, although monitoring of tissue levels of ammonia is suggested. Another important benefit is that the transplant allows the child to develop and grow in a normal manner, without the threat of developmental delay or mental retardation. Transplants are now recommended even for children less than one year of age with a severe form of the disorder.

Two problems with liver transplants exist, however. First, it is difficult to obtain a liver from among the limited supply of donors, especially if the child is not currently hospitalized. The second problem arises from the way in which organs are assigned. Persons who are critically ill receive priority in organ donor lists. This means children whose disease is manageable may not be able to receive a transplant.

Second, children with transplants must have their immune system suppressed. The immune system fights off, and lets one recover from infections like colds, flus, and chicken pox. However, it also fights the introduction of an organ from someone else’s body, even a relative— except identical twins. Thus, as long as a person has a transplant, that person must have their immune system suppressed so that the transplanted organ is not killed by the body it is in. The problem with immune suppression is that a person is much more likely to become sick. This disadvantage is far outweighed by the advantages of normal mental development and the prevention of death in patients with severe OTC deficiency.

Patients in rural areas, or areas where there is no immediate access to a hospital equipped to care for a patient with an acute attack of hyperammonemia, should also be strongly considered for a liver transplant if the patient is predisposed to attacks of life-threatening hyperammonemia.

For less severely affected children, or children unable to obtain a liver transplant, long-term therapy consists of a combination of drugs, usually oral, sodium phenylbutyrate, and diet. This bypasses the normal process of the breakdown of protein into urea in the liver, which is the usual way that ammonia leaves the body. Children with OTC deficiency are placed on a low protein diet so their protein breakdown system does not become overwhelmed and lead to hyperammonemia. Children with OTC deficiency are also given arginine, an

K E Y T E R M S

Developmental delay—When children do not reach certain milestones at appropriate ages. For example, a child should be able to speak by the time he or she is five years old.

Hyperammonemia—An excess of ammonia in the blood.

Urea—A nitrogen-containing compound that can be excreted through the kidney.

Urea cycle—A series of complex biochemical reactions that remove nitrogen from the blood so ammonia does not accumulate.

amino acid, which, for reasons that are unclear, causes more nitrogen, which is part of ammonia, to be excreted in the urine, and lowers blood ammonia. Dietary regimens vary from patient to patient based on their age, size, and the severity of the disorder. A nutrition expert must be consulted when developing an appropriate diet. The most strict diet consists of vitamin supplements and no protein other than essential amino acids. Essential amino acids are those that cannot be made by the body and must be obtained through food. Since proteins are made up of amino acids, and only amino acids, that means this diet is extremely restrictive. It also means that very little ammonia is left in the bloodstream since most of the otherwise free ammonia is tied up in the synthesis of the non-essen- tial amino acids, amino acids made by the body itself.

Any chronic disease is stressful for a family. Parents and patients should consider support and information groups like the National Urea Cycle Disorders Foundation.

Short-term management

Short-term management of attacks of crisis hyperammonemia (severe acute hyperammonemia) consists of dialysis and drug therapy. Dialysis and large doses of the drugs sodium benzoate and sodium phenylacetate and doses of arginine are used to decrease the levels of ammonia in the blood. These methods are used together due to their synergistic effect.

Dialysis is a process where a toxic substance is removed from the blood. This can best be understood by pouring a small amount of cola into a glass. Now pour a large amount of water into it. In this way, the cola is “watered down” or diluted. Ammonia is diluted in a similar way using dialysis. Blood is removed from a patient and run through a hose. At one point, this hose runs through a tank made up of liquid that contains all

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