Phosphoserine Aminotransferase Deficiency

A number sign (#) is used with this entry because of evidence that phosphoserine aminotransferase deficiency (PSATD) is caused by compound heterozygous mutation in the PSAT1 gene (610936) on chromosome 9q21. One such family has been reported.

Description

Deficiency of phosphoserine aminotransferase (PSAT) is characterized biochemically by low plasma and cerebrospinal fluid (CSF) concentrations of serine and glycine and clinically by intractable seizures, acquired microcephaly, hypertonia, and psychomotor retardation. Outcome is poor once the individual becomes symptomatic, but treatment with serine and glycine supplementation from birth can lead to a normal outcome (Hart et al., 2007).

Clinical Features

Hart et al. (2007) identified PSAT deficiency in a brother and sister, the children of nonconsanguineous British parents, who showed low concentrations of serine and glycine in plasma and CSF. The index patient was healthy at birth, with head circumference and weight in the 9th percentile. At age 2 weeks he was admitted to the hospital with poor feeding and cyanotic episodes. At age 7 weeks he was experiencing jerking movements and posturing. At age 9 weeks he presented with severe, intractable seizures and slight hypertonia. His head circumference was less than the 0.4th percentile, whereas weight was in the 2nd percentile. His seizures could not be controlled despite multiple-anticonvulsant therapy. Extensive biochemical investigations revealed no abnormalities with the exception of low plasma and CSF concentrations of serine and glycine. Cranial imaging showed generalized atrophy, a hypoplastic cerebellar vermis, and poor white matter development. Treatment with serine begun at 11 weeks of age normalized plasma and CSF concentrations, but the clinical effect was limited. Severe seizure episodes continued, hypertonia worsened, and the patient died at age 7 months. In the proband's younger sister plasma and CSF samples in the neonatal period revealed low concentrations of serine and glycine, and supplementation with serine and glycine was begun in the first 24 hours of life. Her growth and development were normal at 3 years of age, with the exception of an apneic episode at age 2 weeks. Analysis of fibroblasts from the proband revealed phosphoserine aminotransferase activity that was low in comparison to that in controls (approximately 50% decreased), but not sufficiently so to conclude the presence of a deficiency disorder. Hart et al. (2007) also noted that plasma serine and glycine concentrations were only marginally below the reference range in the proband, emphasizing the importance of measuring serine and glycine in CSF as well as plasma.

Molecular Genetics

In 2 sibs with PSAT deficiency, Hart et al. (2007) identified compound heterozygosity for mutations in the PSAT1 gene: a frameshift mutation on the paternal allele (G107del; 610936.0001) and a missense mutation on the maternal allele (D100A; 610936.0002). Expression studies of the D100A mutant protein revealed a V(max) of only 15% of that of the wildtype protein.