Amino Acid Synthesis Deficiencies

In recent years the list of disorders affecting amino acid synthesis has grown rapidly. Not only the number of defects has increased, but also the associated clinical phenotypes have expanded spectacular, the latter mainly due to the advances of next-generation sequencing diagnostics. An important reason for the contribution of NGS in the diagnosis of amino acid synthesis disorders is the fact that the biochemical diagnosis of some of these synthesis disorders can be quite challenging, synthesis defects may present with low values of amino acids, or their concentrations can even be completely normal. Defects in the synthesis pathways of serine metabolism, glutamine, glutamate, proline, and asparagine have been reported, and all pose specific challenges to a biochemical diagnosis. An exception to this are the disorders of pyrroline-5-carboxylate (P5C) synthesis where ornithine or proline is strongly elevated and easily detected by plasma amino acid analysis. Finally, Snyder-Robinson, a defect in the synthesis of the polyamine spermine, is discussed here as well, and molecular testing is advised for this disorder as well. Although the amino acid synthesis defects in this chapter are not all in related metabolic pathways, they do share some clinical features. In children the central nervous system is primarily affected, giving rise to (congenital) microcephaly, early-onset seizures, and mental retardation to a variable degree. The brain abnormalities can be accompanied by skin disorders such as cutis laxa in proline defects, collodion-like skin and ichthyosis in serine deficiency, necrolytic erythema in glutamine deficiency, and difficult to classify skin abnormalities in glutaminase hyperactivity. In adults with serine or proline disorders, several forms of polyneuropathy with or without intellectual disability appear to be the major presenting symptom. An exception to this is ornithine aminotransferase deficiency which primarily affects the choroid and retina and Snyder-Robinson syndrome in which mental retardation is accompanied by seizures, dysmorphic features, and severe osteoporosis.