Beta-Ureidopropionase Deficiency

A number sign (#) is used with this entry because beta-ureidopropionase deficiency (UPB1D) is caused by homozygous or compound heterozygous mutation in the UPB1 gene (606673) on chromosome 22q11.

Description

Beta-ureidopropionase deficiency is a rare autosomal recessive inborn error of metabolism due to a defect in pyrimidine degradation. Less than 10 patients have been reported, and the phenotype can range from severe neurologic involvement with mental retardation and seizures to normal neurologic development (Yaplito-Lee et al., 2008).

Clinical Features

Assmann et al. (1998) reported a 17-month-old girl who presented with muscular hypotonia, dystonic movements, scoliosis, microcephaly, and severe developmental delay. Biochemical studies showed increased N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid in plasma, urine, and cerebrospinal fluid (CSF). Van Kuilenburg et al. (2000) reported the analysis of all 3 enzymes of the pyrimidine degradation pathway in liver biopsy of this patient and provided unambiguous evidence for complete deficiency of the activity of the third enzyme, beta-ureidopropionase.

Van Kuilenburg et al. (2004) reported 3 additional unrelated patients with genetically confirmed beta-ureidopropionase deficiency. A girl, born of consanguineous Turkish parents, developed afebrile seizures at age 8 months and showed motor retardation. Brain MRI showed delayed myelinization and an EEG showed hypsarrhythmia. At age 3 years, she had psychomotor retardation, severe mental retardation, and a speech disorder, although visual contact appeared to be normal. Another child was found to be cyanotic at age 4 months, developed status epilepticus, and had increased serum and CSF lactate. Other clinical details were limited. The last patient had hypertonia associated with an infection at age 1 month. The patient had normal psychomotor and neurologic development at 12 months. She started to walk independently at the age of 10 months and started to talk at 12 months. Two brothers had died at birth and at age 9 months. All had biochemical abnormalities consistent with the disorder.

Yaplito-Lee et al. (2008) reported an Australian boy with multiple congenital genitourinary and colorectal anomalies, including bladder exstrophy, anal atresia, duplicated appendix and distal colon, and bifid phallus and scrotum. Renal imaging showed moderate pelvicalyceal and ureteric dilatation and echogenic areas. At age 12 months, he showed normal growth, development, and neurologic examination. The authors noted that such structural abnormalities had not previously been reported in this disorder, and it could not be determined if the enzyme deficiency was responsible for these defects.

Molecular Genetics

Van Kuilenburg et al. (2004) reported 3 mutant alleles in the UPB1 gene among 4 patients with beta-ureidopropionase deficiency, including the original patient described by Assmann et al. (1998) (606673.0001-606673.0003). The authors speculated that an altered homeostasis of beta-aminoisobutyric acid and/or increased oxidative stress might contribute to some of the clinical abnormalities encountered in these patients.

In an Australian patient with beta-ureidopropionase deficiency and normal neurologic development, Yaplito-Lee et al. (2008) identified compound heterozygosity for 2 mutations in the UPB1 gene (606673.0001 and 606673.0004).