Dicarboxylic Aminoaciduria

A number sign (#) is used with this entry because of evidence that dicarboxylic aminoaciduria (DBCXA) is caused by homozygous mutation in the SLC1A1 gene (133550) on chromosome 9p24.

Clinical Features

Teijema et al. (1974) described a female child with a defect in renal and probably intestinal transport of 2 acidic amino acids, glutamic and aspartic acids. The child was mentally retarded and also showed moderate hyperprolinemia and hypoglycemia.

Melancon et al. (1977) reported a 38-month-old male infant with large amounts of the dicarboxylic amino acids, aspartic and glutamic, in the urine without generalized aminoaciduria and without neurologic and developmental abnormalities. The patient was found soon after birth by routine screening. Intestinal transport and in vitro oxidation of dicarboxylic amino acids suggested that the basic defect was selective, one of renal conservation. Transport defects have been observed in 4 other groups of amino acids: beta-amino acids, dibasic amino acids, amino acids and glycine, and neutral amino acids. The authors found a report of dicarboxylic aminoaciduria and associated fasting hypoglycemia and mental retardation. In a later study in which 500 mentally retarded children were screened for amino acid disorders, Swarna et al. (1989) found 1 case of dicarboxylic aminoaciduria in a girl.

Bailey et al. (2011) reported a 44-year-old Australian man of Italian ancestry who presented with kidney stones at the age of 20. His brother also reported kidney stones at the same age. The proband was diagnosed with dicarboxylic aminoaciduria by urinary analysis, which showed elevations in urinary glutamate level (1,377 micromol/mmol creatinine) and aspartate level (46 micromol/mmol creatinine). All other urinary amino acids were normal. He had life-long evidence of obsessive-compulsive disorder (OCD; 164230) but declined formal psychologic assessment. The brother of the proband was diagnosed with dicarboxylic aminoaciduria at age 40 after similar screenings showed elevated levels of glutamate and aspartate (1,052 and 51 micromol/mmol creatinine, respectively). Bailey et al. (2011) also reported a second proband, a 4-year-old girl of French Canadian descent, who had been diagnosed with dicarboxylic aminoaciduria at birth by newborn screening. Urinary analysis at age 4 confirmed the diagnosis. No other members of her family were affected.

Molecular Genetics

In 2 brothers with dicarboxylic aminoaciduria, Bailey et al. (2011) detected homozygosity for a missense mutation in the SLC1A1 gene (R445W; 133550.0002). Unaffected family members were heterozygous for the mutation. In a second pedigree, Bailey et al. (2011) found that an affected child carried a homozygous 3-bp deletion in exon 10 of the SLC1A1 gene (133550.0003), resulting in deletion of the isoleucine at position 395. The parents were heterozygous for the mutation.

Animal Model

Peghini et al. (1997) found that Slc1a1 (133550)-null mice developed dicarboxylic aminoaciduria with increased excretion of glutamate and aspartate. However, these mice showed no major neurologic or cognitive abnormalities up to over 12 months of age, although homozygous mice showed a decrease in spontaneous locomotion activity. Peghini et al. (1997) concluded that dicarboxylic aminoaciduria associated with mental retardation in humans (Teijema et al., 1974) probably represents a more complex hereditary or multifactorial defect.