Case Report: A Previously Healthy Young Woman With Lethal, Unremitting Metabolic Acidosis: Could a Novel Variant in...

Heme synthesis is critical for several biological processes, including mitochondrial energy production and oxygen delivery via hemoglobin. The initial and rate-limiting step in heme synthesis is the conjugation of glycine with succinyl-CoA to form 5-aminolevulinic acid (ALA), which is catalyzed by two closely related enzymes that are coded by highly homologous genes, known as ALAS1 and ALAS2. Loss-of-function variants in ALAS2 result in sideroblastic anemia, whereas gain-of-function variants result in porphyria. We present a case of a woman who died with severe metabolic acidosis and was found to have a rare variant in ALAS2. We propose the hypothesis that the ALAS2 variant, in conjunction with other factors, was responsible for her demise.

A previously healthy 34-year-old woman presented to the emergency department of her local hospital complaining of severe fatigue. Her arterial pH was 6.95. No cause for her acidosis could be identified, and she expired from unremitting acidosis. The autopsy was notable for an enlarged liver. Whole exome sequencing identified a rare, paternally inherited variant in ALAS2. This prompted a re-evaluation of the autopsy and the development of a novel hypothesis to explain her acidosis. We propose that the ALAS2 variant identified in this family, NM_000032.5(ALAS2)c.1273C>T(p.Pro425Ser), is a conditional allele that can contribute to mitochondrial dysfunction under unusual conditions.

We hypothesize that the P425S variant identified in ALAS2 leads to dysfunction of the homeostatic down-regulation of ALAS2 in times of cofactor deficiency. This case illustrates that DNA sequencing as a part of the autopsy procedure will, as it becomes more routine, lead to the identification of sequence variants that may or may not be clinically relevant. The pursuit of hypotheses, prompted by genetic data, has the potential to identify novel pathogenic mechanisms.