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 report on two sisters with phenotypic heterogeneity and a favourable response to combined serine and glycine supplementation. The elder sibling was found to be normocephalic at birth and showed moderate delay of white matter myelinisation, while her seizures arrested spontaneously even without treatment. In the younger sister with the classical phenotype, feeding difficulties with recurrent gastro-oesophageal reflux prompted us to treat her temporarily 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 children serine therapy was associated with decreased concentrations of methionine, isoleucine, and ornithine in the cerebrospinal fluid, attributed to competitive inhibition of neutral amino acid transport across the blood-brain barrier. In contrast to reports in the literature, these findings demonstrate that congenital microcephaly, intractable seizures, and dysmyelinisation are not invariably present in patients with 3-phosphoglycerate dehydrogenase 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.

Key words

3-Phosphoglycerate dehydrogenase deficiency - West syndrome - Microcephaly - Serine, therapeutic use - Amino acids, therapeutic use, adverse effects - Metabolism, inborn errors, therapy

References

• 1 de Koning T J, Duran M, Dorland L, Gooskens R, Van Schaftingen E, Jaeken J. et al . Beneficial effects of L-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency.  Ann Neurol. 1998;  44 261-265
• 2 de Koning T J, Poll-The B T, Jaeken J. Continuing education in neurometabolic disorders - serine deficiency disorders.  Neuropediatrics. 1999;  30 1-4
• 3 de Koning T J, Duran M, Dorland L, Jakobs C, Wevers R A, Berger R. et al . Neurotransmitters in 3-phosphoglycerate dehydrogenase deficiency.  Eur J Pediatr. 2000;  159 939-940
• 4 Jaeken J, Detheux M, van Maldergem L, Foulon M, Carchon H, Van Schaftingen E. 3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis.  Arch Dis Child. 1996;  74 542-545
• 5 Klomp L W, de Koning T J, Malingre H E, van Beurden E A, Brink M, Opdam F L. et al . Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency - a neurometabolic disorder associated with reduced L-serine biosynthesis.  Am J Hum Genet. 2000;  67 1389-1399
• 6 Pineda M, Vilaseca M A, Artuch R, Santos S, González M MG, Sau I. et al . 3-Phosphoglycerate dehydrogenase deficiency in a patient with West syndrome.  Dev Med Child Neurol. 2000;  42 629-633
• 7 Segawa H, Fukasawa Y, Miyamoto K, Takeda E, Endou H, Kanai Y. Identification and functional characterization of a Na⁺-independent neutral amino acid transporter with broad substrate selectivity.  J Biol Chem. 1999;  274 19745-19751
• 8 Smith Q R, Momma S, Aoyagi M, Rapoport S I. Kinetics of neutral amino acid transport across the blood-brain barrier.  J Neurochem. 1987;  49 1651-1658
• 9 Swoboda K J, Korson M S, Darras B T, Natowicz M R. Amino acid loading studies and L-serine supplementation in 3-phosphoglycerate dehydrogenase deficiency.  Ann Neurol. 1999;  46 547
• 10 van Den Berg I E, de Koning T J, Malingre H E, van Beurden E A, Brink M, Opdam F L. et al .Missense mutations in the 3-phosphoglycerate dehydrogenase gene are associated with a serine biosynthesis defect and neurological impairment. 49th Annual Meeting of the American Society of Human Genetics, California, San Francisco; 1999.