Information on the following diseases can be found in the Related Disorders section of this report:

• Glutaricaciduria IIA (GA IIA)
• Glutaricaciduria IIB (GA IIB)

Babies with glutaricaciduria I usually appear normal at birth. At almost any time during the first year of life, usually as a result of an acute illness, there may occur a crisis involving decreased muscle tone (hypotonia), vomiting, and high levels of organic acids in the blood, and central nervous system degeneration. Such babies often assume strange positions due to disordered muscle tone (dystonia), and involuntary and ceaseless slow, sinuous, writhing (athetotic) or jerky (choreic) movements of the trunk and limbs may also occur. Mental retardation may accompany these symptoms.

Elevated concentrations of glutaric acid, beta-hydroxy-glutaric acid and occasionally glutaconic acid appear in the urine of children with this disorder. Excretion of glutaric acid in the urine may exceed 1 gram per day, an excessive amount. Glutaric acid concentrations are also elevated in blood serum, cerebrospinal fluid, and body tissues. Some of these patients may have unusual facial features (dysmorphia). A type of spasm in which the head and the heels are bent backward while the trunk is bowed forward (opisthotonus) may also occur.

Glutaricaciduria is an autosomal recessive hereditary disorder caused by a deficiency of the enzyme glutaryl-CoA dehydrogenase. Accumulation of 5- carbon dicarboxylic acids may impair synthesis of gamma-aminobutyric acid (GABA), which functions as a neurotransmitter in the brain, inhibiting nerve excitation. The gene associated with glutaricaciduria I has been mapped to chromosome 19 (19p13.2).

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 19p13.2" refers to band 13 on the short arm of chromosome 19. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one 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 defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry a few abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Glutaricaciduria is a very rare inborn error of metabolism that affects males as often as females. It has been estimated that there are about 140 cases of this type of organic aciduria in the United States.

There are many rare disorders caused by enzyme deficiencies. To locate these disorders in the Rare Disease Database choose "Enzyme Deficiency" as your search term.

There are two forms of glutaricaciduria II which occur during different stages of life. They are both forms of organic acidemias which are a group of metabolic disorders characterized by excess acid in the blood and urine.

1) Glutaricaciduria IIA (GA IIA), neonatal form of glutaricaciduria II. This neonatal form of glutaricaciduria II is a very rare, sex-linked hereditary disorder characterized by large amounts of glutaric and other acids in blood and urine. Some researchers believe the disorder is caused by a defect in the breakdown of acyl-CoA compounds.

2) Glutaricaciduria IIB (GA IIB; Ethylmalonic Adipicaciduria), adult form of glutaricaciduria II. This milder form of the disorder is inherited as an autosomal recessive trait. Acidity of the body tissues (metabolic acidosis), and a low blood sugar level (hypoglycemia) without an elevated level of ketones in body tissues (ketosis), occur during adulthood. Large amounts of glutaric acid in the blood and urine are caused by a deficiency of the enzyme "multiple acyl-CoA dehydrogenase". (For more information on this disorder, choose "Glutaricaciduria II" as your search term in the Rare Disease Database.)

Diagnosis
Glutaricaciduria is suspected upon a finding of excessive urinary glutaric acid and confirmed by measuring the presence and concentration of the deficient enzyme in white blood cells (leukocytes). Detection of the disorder in a fetus may be possible by testing for the enzyme glutaryl CoA dehydrogenase. It is important to test for this disorder as soon after birth as possible.

Treatment
Acute episodes of acidity in blood and body tissues (acidosis) and dehydration are treated with fluids and bicarbonate. Peritoneal dialysis hemodialysis may be necessary. The usefulness of restricting the amino acids lysine, hydroxylysine, and tryptophan (which generate glutaric acid when they are metabolized), is not established at the present time. Many of the adverse effects of organic acidemias are due to secondary carnitine depletion. Such patients should have plasma carnitine measured and, if deficient, begin a supplement of 100-300 mg/kg/day of oral l-carnitine.

Genetic counseling is recommended for families of children with glutaricaciduria.

Glutaricaciduria has been treated on an experimental basis with a low protein diet, riboflavin and Lioresal, a gamma-aminobutyric acid (GABA)-analog. Diet and riboflavin have had a slight-to-moderate effect on the clinical symptoms. The excretion of glutaric acid and 2-amino-adipic acid in the urine decreased considerably during this treatment. Some neurological symptoms regressed during treatment with Lioresal. Although this treatment is experimental, some researchers suggest that patients with glutaricaciduria should be treated as early as possible with this method. However, long-term effects are unknown.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Glutaric Acidemia I. Entry Number; 231670: Last Edit Date; 1/22/2003.

TEXTBOOKS
Goodman SI, Frerman FE. Organic acidemias due to defects in lysine oxidation: 2-ketoadipic acidemia and glutaric acidemia. In: Scriver CR, Beaudet AL, Sly WS, et al. Eds. The Metabolic Molecular Basis of Inherited Disease. 7th ed. McGraw-Hill Companies. New York, NY; 1995:1451-60.

JOURNAL ARTICLES
Bahr O, Mader I, Zschocke J, et al. Adult onset glutaric aciduria type I presenting with leukoencephalopathy. Neurology. 2002;59:1802-04.

Zafeiriou DI, Zschocke J, Augustidou-Savvopoulou P, et al. Atypical and variable clinical presentation of glutaric aciduria type I. Neuropediatrics. 2000;31:303-06.

Kolker S, Ramaekers VT, Zschocke J, et al. Acute encephalopathy despite early therapy in a patient with homozygosity for E365K in the glutaryl-coenzyme A dehydrogenase gene. J Pediatr 2001;138:277-79.

Kafil-Hussain NA, Monavari A, Bowell R, et al. Ocular findings in glutaric aciduria type I. J Pediatr Ophthalmol Strabismus. 2000;37:289-93.

Busquets C, Coll MJ, Merinero B, et al. Prenatal molecular diagnosis of glutaric aciduria type I by direct mutation analysis. Prenat Diagn. 2000;20:761-64.

Baric I, Wagner L, Feyh P, et al. Sensitivity and specificity of free and total glutaric acid and 3-hydroxyglutaric acid measurements by stable isotope-dilution assays for the diagnosis of glutaric aciduria type I. J Inherit Metab Dis. 1999;22:867-81.

Naylor EW, Chace DH. Automated tandem mass spectrometry for mass newborn screening for disorders in fatty acid, organic acid, and amino acid metabolism. J Child Neurol. 199;14 Suppl 1:S4-8.

Hoffmann GF, Szchocke J. Glutaric aciduria type I: from clinical, biochemical and molecular diversity successful therapy. J Inherit Metab Dis. 1999;22:381-91.

FROM THE INTERNET
Cincinnati Children’s Hospital Medical Center. Professional’s Toolkit. Clinical, Radiological, Pathological and Ocular findings in Glutaric Aciduria Type 1. nd. 13pp.
www.cincinnatichildrens.org/svc/prog/child-abuse/tools/shakenbaby.htm

Save Babies Through Screening. Glutaric acidemia Type I (GA-I). Last updated on 4/18/03. 2pp.
www.savebabies.org/diseasedescriptions/ga1.htm

Glutaric Aciduria. nd. 2pp.
www.peroxisome.org/Scientist/Biochemistry/disorders/gltaricaciduriatext.html