The mechanistic basis for these symptoms is not fully understood, but the observations that cells from ASNSD children rely on extracellular Asn for proliferation [14,15], variant ASNS proteins have reduced Asn synthesis activity [7,16,17] or cannot be expressed due to instability [10,17], and that variant ASNS proteins cannot rescue growth of an ASNS null cell line [16,17] all indicate a direct link between the variants and ASNS enzymatic deficiency. This evidence concerns the gene ASNS and congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome.