Both mothers described in the paper had glutaric acidemia, type 1. Although plasma and urinary metabolite levels do not describe the potential severity of the genetic defect or the vulnerability of the person carrying them, the analyte levels are high enough, in urine, to suggest that the mutations are consequential and cause a severe disruption in the glutaryl-CoA catabolic pathway. On the other hand the normal results of the plasma glutarylcarnitine measurements underscores what is known from newborn screening, that affected individuals may not be ascertained by this method8
. Whether the majority of older patients gradually evolve normal plasma levels of glutarylcarnitine is unknown to us at this time.
The mutations involved are consistent with the biochemical inference that these are severe mutations. In family 1, one allele is null as a consequence of a one base pair deletion in exon 1 (c11delG) and the second allele has cysteine substituted by phenylalanine at position 228 due to a T>G mutation in exon 7 (C228F:c682T>G). Although not previously reported, this substitution caused a significant change in amino acid properties and was likely, as reflected in the analytes, to cause a severe diminution in enzyme activity.
In family 2 the mother carried a single A>G mutation in exon 6 in apparent homozygousity (or hemizygosity), causing a glutamine at position 181 to be changed to a glycine (E181G:c542 A>G). Although not reported previously, this change from a larger charged amino acid to a smaller uncharged one and was likely to disrupt the protein structure greatly. Other known mutations causing changes in this amino acid residue have been associated with severe disease and positive enzymatic and biochemical analyses2
The fact that both women who were untreated were apparently unaffected by their condition is not surprising, given our knowledge of patients homozygous for these mutations who have not been treated2
. A biochemically more mild condition is a plausible, but unlikely explanation. Neither is it surprising that the very low carnitine levels were either asymptomatic or minimally so. Although the plasma levels were as low or lower than patients affected with carnitine transporter deficiency, the presence of a normal transporter system likely resulted in a more favorable intramuscular carnitine level. Although this low carnitine level is presumably due to years of excretion of excessive glutarate as glutarylcarnitine, this was not pursued aggressively as it didn’t impinge on the main purpose or conclusion of the paper.
It was the hyperphenylalaninemias that first establish the precedent of detecting maternal biochemical perturbations during newborn screening7
. We have since added maternal methylcrotonyl-CoA carboxylase to this list9
and we added at least two more, systemic carnitine deficiency earlier this year6
and now glutaric acidemia, type 1. This latter conclusion is supported by a similar observation made in 2 affected probands from Portugal and now published online prior to appearing in print10
. Surely the list is not complete.