Phenotypic heterogeneity and adverse effects of serine treatment in 3-phosphoglycerate dehydrogenase deficiency: Report on two siblings

Clinical experience with the treatment of 3-phosphoglycerate dehydrogenase deficiency, a rare inherited disorder of serine synthesis, is scarce. We re port on two sisters with phenotypic heterogeneity and a favourable response to combined serine and glycine supplementation. The elder sibling was foun d to be normocephalic at birth and showed moderate delay of white matter my elinisation, while her seizures arrested spontaneously even without treatme nt. In the younger sister with the classical phenotype, feeding difficultie s with recurrent gastro-oesophageal reflux prompted us to treat her tempora rily with high-dose serine (1400 mg/kg/day). An arrest of head growth then occurred but could be reversed by reducing the serine supply. In both child ren serine therapy was associated with decreased concentrations of methioni ne, isoleucine, and ornithine in the cerebrospinal fluid, attributed to com petitive inhibition of neutral amino acid transport across the blood-brain barrier. In contrast to reports in the literature, these findings demonstra te that congenital microcephaly, intractable seizures, and dysmyelinisation are not invariably present in patients with 3-phosphoglycerate dehydrogena se deficiency. An adverse effect of high-dose serine therapy on head growth and on the transport of neutral amino acids across the blood-brain barrier should be considered and requires adjustment of treatment.